Publications by authors named "Jun Goto"

140 Publications

Qualitative Research on the Primary Effect of Fish Pet Ownership Using the Bottleium, a Bottle-Type Aquarium, on Community-Dwelling Older Adults in Japan: A Potential Preventive Measure Towards Social Isolation.

Geriatrics (Basel) 2021 Feb 10;6(1). Epub 2021 Feb 10.

The Institute of Gerontology, University of Tokyo, Tokyo 113-8656, Japan.

Aging increases the risk of social isolation, which could lead to conditions such as depressive mood. Pet ownership is known to reduce social isolation. However, previous studies have mainly focused on mammals as pets, which could be difficult at old age. A small ornamental fish is relatively easy to culture and might be a suitable alternative. In this research, we aimed to elucidate the possible effects of fish ownership on the psychological state of community-dwelling older adults in Japan. A Bottleium, a bottle-type aquarium, was selected to lower the burden of fish ownership. A workshop was hosted in 2019 and participants brought home their own Bottleium, with fish and water snail inside. Nineteen participants gave consent to the follow-up interview a month later. Five themes, "observation of fish and water snail," "interaction between the fish and the owner," "taking care of the fish as pet owner," "facilitation of interpersonal interaction," and "development of support system," emerged from thematic analysis. The promotion of animal-to-human, and human-to-human interaction and development of responsibility could relate to a sense of social inclusion and , a purpose of life. Fish ownership, when using equipment that suits the physical capability of older adults, could act as a positive stimulus.
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http://dx.doi.org/10.3390/geriatrics6010017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985762PMC
February 2021

Enhancement of elastin expression by transdermal administration of sialidase isozyme Neu2.

Sci Rep 2021 Feb 8;11(1):3302. Epub 2021 Feb 8.

Department of Biochemistry, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, 422-8526, Japan.

Reduction of elastin in the skin causes various skin diseases as well as wrinkles and sagging with aging. Sialidase is a hydrolase that cleaves a sialic acid residue from sialoglycoconjugate. Cleavage of sialic acid from microfibrils by the sialidase isozyme Neu1 facilitates elastic fiber assembly. In the present study, we showed that a lower layer of the dermis and muscle showed relatively intense sialidase activity. The sialidase activity in the skin decreased with aging. Choline and geranate (CAGE), one of the ionic liquids, can deliver the sialidase subcutaneously while maintaining the enzymatic activity. The elastin level in the dermis was increased by applying sialidase from Arthrobacter ureafaciens (AUSA) with CAGE on the skin for 5 days in rats and senescence-accelerated mice prone 1 and 8. Sialidase activity in the dermis was considered to be mainly due to Neu2 based on the expression level of sialidase isozyme mRNA. Transdermal administration of Neu2 with CAGE also increased the level of elastin in the dermis. Therefore, not only Neu1 but also Neu2 would be involved in elastic fiber assembly. Transdermal administration of sialidase is expected to be useful for improvement of wrinkles and skin disorders due to the loss of elastic fibers.
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http://dx.doi.org/10.1038/s41598-021-82820-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7870814PMC
February 2021

Cerebellar Ataxia as a Common Clinical Presentation Associated with DNMT1 p.Y511H and a Review of the Literature.

J Mol Neurosci 2021 Jan 12. Epub 2021 Jan 12.

Department of Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, 113-8655, Japan.

The phenotypes of patients with disease-associated variants in DNMT1 have been classified into two syndromes: hereditary sensory and autonomic neuropathy type 1E (HSAN1E, MIM614116, https://www.omim.org/ ) and autosomal dominant cerebellar ataxia, deafness, and narcolepsy (ADCA-DN, MIM604121). The amino acid codon 511 is a hotspot, and p.Y511C is the most frequently observed disease-associated variant among those in HSAN1E patients, whereas there have been only a few reports on patients with p.Y511H. In this study, we report on the cases of a kindred carrying the DNMT1 variant NM_001130823.2:c.1531 T > C (p.Y511H) presenting with the ADCA-DN phenotype. The review of the literature further revealed that later ages at onset and the presence of cerebellar ataxia are the main characteristics of patients carrying the DNMT1 p.Y511H as compared with those carrying DNMT1 p.Y511C. Although HSAN1E and ADCA-DN are proposed to be called DNMT1-complex disorders owing to their overlapping symptoms, this finding suggests a distinct genotype-phenotype correlation regarding the DNMT1 p.Y511H and p.Y511C variants.
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http://dx.doi.org/10.1007/s12031-020-01784-5DOI Listing
January 2021

Unmet needs for emergency care and prevention of prehospital death in acute myocardial infarction.

J Cardiol 2021 Jun 30;77(6):605-612. Epub 2020 Nov 30.

Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.

Introduction: Percutaneous coronary intervention (PCI) has successfully reduced the mortality of patients with acute myocardial infarction (AMI). However, patients with out-of-hospital cardiac arrest have high mortality, which is difficult to control by hospital staff. In this study, we investigated the prevalence of prehospital death (PHD) in patients with AMI. Furthermore, we investigated the risk factors associated with 30-day mortality in patients with AMI who survived PHD.

Methods: We investigated the prevalence of PHD using data from the Yamagata AMI registry and from death certification of the entire Yamagata Prefecture in Japan between 2010 and 2015. Furthermore, we investigated the risk factors for 30-day mortality in patients who survived PHD, using data from the Yamagata AMI registry from 1993 to 2015. AMI was identified by the International Classification of Diseases, 10th revision code I21.

Results: Out of the 6984 patients with AMI, 3771 patients had PHD. Patients with PHD were older and more likely to be women than those without PHD. More PHD occurred in winter and spring than in summer or autumn. Multivariate regression analysis showed that age, female sex, and winter onset were independently associated with PHD. We also investigated the risk factors associated with 30-day mortality in 9675 patients who survived PHD. The rate of PCI was remarkably lower in patients with acute death than in those without acute death. Multivariate regression analysis showed that age, anterior infarction, estimated glomerular filtration rate, Killip class, and PCI were independently associated with 30-day mortality after adjusting for confounding factors.

Conclusion: Approximately half of the patients with AMI died before they could reach the destination hospital. Although emergency PCI is the most important factor in reducing 30-day mortality in patients with AMI, attempts to reduce patient delay and system delay are possibly needed to further reduce PHD.
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http://dx.doi.org/10.1016/j.jjcc.2020.11.013DOI Listing
June 2021

HECT (Homologous to the E6-AP Carboxyl Terminus)-Type Ubiquitin E3 Ligase ITCH Attenuates Cardiac Hypertrophy by Suppressing the Wnt/β-Catenin Signaling Pathway.

Hypertension 2020 12 2;76(6):1868-1878. Epub 2020 Nov 2.

From the Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Japan.

The HECT (homologous to the E6-AP carboxyl terminus)-type ubiquitin E3 ligase ITCH is an enzyme that plays an important role in ubiquitin-proteasomal protein degradation. Disheveled proteins (Dvl1 [disheveled protein 1], Dvl2, and Dvl3) are the main components of the Wnt/β-catenin signaling pathway, which is involved in cardiac hypertrophy. The aim of this study was to examine the role of ITCH during development of cardiac hypertrophy. Thoracic transverse aortic constriction (TAC) was performed in transgenic mice with cardiac-specific overexpression of ITCH (ITCH-Tg) and wild-type mice. Cardiac hypertrophy after TAC was attenuated in ITCH-Tg mice, and the survival rate was higher for ITCH-Tg mice than for wild-type mice. Protein interaction between ITCH and Dvls was confirmed with immunoprecipitation in vivo and in vitro. Expression of key molecules of the Wnt/β-catenin signaling pathway (Dvl1, Dvl2, GSK3β [glycogen synthase kinase 3β], and β-catenin) was inhibited in ITCH-Tg mice compared with wild-type mice. Notably, the ubiquitination level of Dvl proteins increased in ITCH-Tg mice. Protein and mRNA expression levels of ITCH increased in response to Wnt3a stimulation in neonatal rat cardiomyocytes. Knockdown of ITCH using small-interfering RNA increased cardiomyocyte size and augmented protein expression levels of Dvl proteins, phospho-GSK3β, and β-catenin after Wnt3a stimulation in cardiomyocytes. Conversely, overexpression of ITCH attenuated cardiomyocyte hypertrophy and decreased protein expression levels of Dvl proteins, phospho-GSK3β and β-catenin. In conclusion, ITCH targets Dvl proteins for ubiquitin-proteasome degradation in cardiomyocytes and attenuates cardiac hypertrophy by suppressing the Wnt/β-catenin signaling pathway.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.15487DOI Listing
December 2020

A Case of Anti-LGI1 Encephalitis Developing Immunoglobulin Responsive Orthostatic Hypotension after Remission.

Intern Med 2020 Oct 14. Epub 2020 Oct 14.

Department of Neurology, International University of Health and Welfare Mita Hospital, Japan.

Anti-leucine-rich glioma-inactivated 1 (LGI1) antibody is associated with limbic encephalitis. We herein report a patient with anti-LGI1 encephalitis who developed severe orthostatic hypotension (OH) responsive to immunoglobulin therapy five years after developing symptoms of encephalitis. A 71-year-old man presented with amnesia caused by limbic encephalitis. The symptoms of encephalitis improved partially without any immunotherapy. Five years later, he developed severe OH, and anti-LGI1 antibody was positive. The catecholamine dynamics indicated that the central autonomic nervous system was the lesion of his OH. Intravenous immunoglobulin therapy improved the OH. This case suggests that anti-LGI1 antibody can be associated with severe OH.
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http://dx.doi.org/10.2169/internalmedicine.5359-20DOI Listing
October 2020

Clinical efficacy of haematopoietic stem cell transplantation for adult adrenoleukodystrophy.

Brain Commun 2020 14;2(1):fcz048. Epub 2020 Jan 14.

Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Accumulated experience supports the efficacy of allogenic haematopoietic stem cell transplantation in arresting the progression of childhood-onset cerebral form of adrenoleukodystrophy in early stages. For adulthood-onset cerebral form of adrenoleukodystrophy, however, there have been only a few reports on haematopoietic stem cell transplantation and the clinical efficacy and safety of that for adulthood-onset cerebral form of adrenoleukodystrophy remain to be established. To evaluate the clinical efficacy and safety of haematopoietic stem cell transplantation, we conducted haematopoietic stem cell transplantation on 12 patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy in a single-institution-based prospective study. Through careful prospective follow-up of 45 male adrenoleukodystrophy patients, we aimed to enrol patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy at early stages. Indications for haematopoietic stem cell transplantation included cerebral form of adrenoleukodystrophy or cerebello-brainstem form of adrenoleukodystrophy with Loes scores up to 13, the presence of progressively enlarging white matter lesions and/or lesions with gadolinium enhancement on brain MRI. Clinical outcomes of haematopoietic stem cell transplantation were evaluated by the survival rate as well as by serial evaluation of clinical rating scale scores and neurological and MRI findings. Clinical courses of eight patients who did not undergo haematopoietic stem cell transplantation were also evaluated for comparison of the survival rate. All the patients who underwent haematopoietic stem cell transplantation survived to date with a median follow-up period of 28.6 months (4.2-125.3 months) without fatality. Neurological findings attributable to cerebral/cerebellar/brainstem lesions became stable or partially improved in all the patients. Gadolinium-enhanced brain lesions disappeared or became obscure within 3.5 months and the white matter lesions of MRI became stable or small. The median Loes scores before haematopoietic stem cell transplantation and at the last follow-up visit were 6.0 and 5.25, respectively. Of the eight patients who did not undergo haematopoietic stem cell transplantation, six patients died 69.1 months (median period; range 16.0-104.1 months) after the onset of the cerebral/cerebellar/brainstem lesions, confirming that the survival probability was significantly higher in patients with haematopoietic stem cell transplantation compared with that in patients without haematopoietic stem cell transplantation ( = 0.0089). The present study showed that haematopoietic stem cell transplantation was conducted safely and arrested the inflammatory demyelination in all the patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy when haematopoietic stem cell transplantation was conducted in the early stages. Further studies are warranted to optimize the procedures of haematopoietic stem cell transplantation for adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy.
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http://dx.doi.org/10.1093/braincomms/fcz048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425345PMC
January 2020

Loss-of-function variants in NEK1 are associated with an increased risk of sporadic ALS in the Japanese population.

J Hum Genet 2021 Mar 12;66(3):237-241. Epub 2020 Sep 12.

Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Loss-of-function (LoF) variants in NEK1 have recently been reported to be associated with amyotrophic lateral sclerosis (ALS). In this study, we investigated the association of NEK1 LoF variants with an increased risk of sporadic ALS (SALS) and the clinical characteristics of patients with SALS carrying LoF variants in a Japanese case series. Whole-exome sequencing analysis was performed for a series of 446 SALS patients in whom pathogenic variants in familial ALS-causative genes have not been identified and 1163 healthy control subjects in our Japanese series. We evaluated LoF variants, defined as nonsense, splice-site disrupting single-nucleotide variants (SNVs), or short insertion/deletion (indel) variants predicted to cause frameshifts in NEK1. We identified seven NEK1 LoF variants in patients with SALS (1.57%), whereas only one was identified in control subjects (0.086%) (P = 0.00073, Fisher's exact test). This finding is consistent with those in recent reports from other regions in the world. In conclusion, we demonstrated that NEK1 LoF variants are also associated with an increased risk of SALS in the Japanese population.
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http://dx.doi.org/10.1038/s10038-020-00830-9DOI Listing
March 2021

Splice-site mutations in KIF5A in the Japanese case series of amyotrophic lateral sclerosis.

Neurogenetics 2021 03 19;22(1):11-17. Epub 2020 Aug 19.

Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-8655, Japan.

Our objective was to investigate the frequency of KIF5A variants in amyotrophic lateral sclerosis (ALS) and the clinical characteristics of familial ALS (FALS) associated with variants in KIF5A. Whole-exome sequence analysis was performed for a Japanese series of 43 families with FALS and 444 patients with sporadic ALS (SALS), in whom causative variants had not been identified. We compared the frequencies of rare variants (MAF < 0.01) in KIF5A, including missense and loss of function (LoF) variants, between ALS and control subjects (n = 1163). Clinical characteristics of patients with FALS carrying pathogenic variants in KIF5A were also described. LoF variants were identified only in the probands of two families with FALS, both of which were 3' splice-site variants leading to exon skipping and an altered C-terminal domain, located in the mutational hotspot causing FALS, and were considered to be pathogenic for FALS. Rare missense variants in KIF5A were identified in five patients with SALS (1.13%) and 11 control subjects (0.95%, carrier frequency), which were not significantly different. Consequently, the pathogenic LoF variants in KIF5A accounted for 2.1% of all FALS families in this study. These patients suffered from ALS characteristically associated with the predominant involvement of upper motor neuron. In conclusion, we identified two pathogenic splice-site variants in KIF5A in the probands in two Japanese families with FALS, which altered the C-terminal region of KIF5A. Our findings broaden the phenotype spectrum of ALS associated with variants in KIF5A in the Japanese series.
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http://dx.doi.org/10.1007/s10048-020-00626-1DOI Listing
March 2021

The association between microRNA-21 and hypertension-induced cardiac remodeling.

PLoS One 2020 10;15(2):e0226053. Epub 2020 Feb 10.

Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, Yamagata, Japan.

Hypertension is a major public health problem among the aging population worldwide. It causes cardiac remodeling, including hypertrophy and interstitial fibrosis, which leads to development of hypertensive heart disease (HHD). Although microRNA-21 (miR-21) is associated with fibrogenesis in multiple organs, its contribution to cardiac remodeling in hypertension is poorly understood. Circulating miR-21 level was higher in patients with HHD than that in the control subjects. It also positively correlated with serum myocardial fibrotic markers. MiR-21 expression levels were significantly upregulated in the mice hearts after angiotensin II (Ang II) infusion or transverse aortic constriction (TAC) compared with control mice. Expression level of programmed cell death 4 (PDCD4), a main target of miR-21, was significantly decreased in Ang II infused mice and TAC mice compared with control mice. Expression levels of transcriptional activator protein 1 (AP-1) and transforming growth factor-β1 (TGF-β1), which were downstream targets of PDCD4, were increased in Ang II infused mice and TAC mice compared with control mice. In vitro, mirVana-miR-21-specific inhibitor attenuated Ang II-induced PDCD4 downregulation and contributed to subsequent deactivation of AP-1/TGF-β1 signaling pathway in neonatal rat cardiomyocytes. Thus, suppression of miR-21 prevents hypertrophic stimulation-induced cardiac remodeling by regulating PDCD4, AP-1, and TGF-β1 signaling pathway.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0226053PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010249PMC
May 2020

Novel variant in a Japanese patient with idiopathic basal ganglia calcification-1 (IBGC1) associated with dopa-responsive parkinsonism.

Hum Genome Var 2019 4;6:44. Epub 2019 Sep 4.

1Department of Neurology, Kyorin University School of Medicine, Tokyo, Japan.

Idiopathic basal ganglia calcification-1 (IBGC1) is an autosomal dominant disorder characterized by calcification in the basal ganglia, which can manifest a range of neuropsychiatric symptoms, including parkinsonism. We herein describe a 64-year-old Japanese IBGC1 patient with bilateral basal ganglia calcification carrying a novel variant (p.Val322Glufs*92). The patient also presented with dopa-responsive parkinsonism with decreased dopamine transporter (DAT) density in the bilateral striatum and decreased cardiac I-meta-iodobenzylguanidine uptake.
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http://dx.doi.org/10.1038/s41439-019-0073-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6804589PMC
September 2019

Therapeutic inhibition of microRNA-34a ameliorates aortic valve calcification via modulation of Notch1-Runx2 signalling.

Cardiovasc Res 2020 04;116(5):983-994

Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine, 2-2-2 Iida-Nishi, Yamagata 990-9585, Japan.

Aims: Calcific aortic valve stenosis (CAVS) is the most common valvular heart disease and is increased with elderly population. However, effective drug therapy has not been established yet. This study aimed to investigate the role of microRNAs (miRs) in the development of CAVS.

Methods And Results: We measured the expression of 10 miRs, which were reportedly involved in calcification by using human aortic valve tissue from patients who underwent aortic valve replacement with CAVS or aortic regurgitation (AR) and porcine aortic valve interstitial cells (AVICs) after treatment with osteogenic induction medium. We investigated whether a specific miR-inhibitor can suppress aortic valve calcification in wire injury CAVS mice model. Expression of miR-23a, miR-34a, miR-34c, miR-133a, miR-146a, and miR-155 was increased, and expression of miR-27a and miR-204 was decreased in valve tissues from CAVS compared with those from AR. Expression of Notch1 was decreased, and expression of Runt-related transcription factor 2 (Runx2) was increased in patients with CAVS compared with those with AR. We selected miR-34a among increased miRs in porcine AVICs after osteogenic treatment, which was consistent with results from patients with CAVS. MiR-34a increased calcium deposition in AVICs compared with miR-control. Notch1 expression was decreased, and Runx2 expression was increased in miR-34a transfected AVICs compared with that in miR-control. Conversely, inhibition of miR-34a significantly attenuated these calcification signals in AVICs compared with miR-control. RNA pull-down assay revealed that miR-34a directly targeted Notch1 expression by binding to Notch1 mRNA 3' untranslated region. In wire injury CAVS mice, locked nucleic acid miR-34a inhibitor suppressed aortic velocity, calcium deposition of aortic valves, and cardiac hypertrophy, which were involved in decreased Runx2 and increased Notch1 expressions.

Conclusion: miR-34a plays an important role in the development of CAVS via Notch1-Runx2 signalling pathway. Inhibition of miR-34a may be the therapeutic target for CAVS.
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http://dx.doi.org/10.1093/cvr/cvz210DOI Listing
April 2020

Noncoding CGG repeat expansions in neuronal intranuclear inclusion disease, oculopharyngodistal myopathy and an overlapping disease.

Nat Genet 2019 08 22;51(8):1222-1232. Epub 2019 Jul 22.

Department of Neurology, The University of Tokyo Hospital, Tokyo, Japan.

Noncoding repeat expansions cause various neuromuscular diseases, including myotonic dystrophies, fragile X tremor/ataxia syndrome, some spinocerebellar ataxias, amyotrophic lateral sclerosis and benign adult familial myoclonic epilepsies. Inspired by the striking similarities in the clinical and neuroimaging findings between neuronal intranuclear inclusion disease (NIID) and fragile X tremor/ataxia syndrome caused by noncoding CGG repeat expansions in FMR1, we directly searched for repeat expansion mutations and identified noncoding CGG repeat expansions in NBPF19 (NOTCH2NLC) as the causative mutations for NIID. Further prompted by the similarities in the clinical and neuroimaging findings with NIID, we identified similar noncoding CGG repeat expansions in two other diseases: oculopharyngeal myopathy with leukoencephalopathy and oculopharyngodistal myopathy, in LOC642361/NUTM2B-AS1 and LRP12, respectively. These findings expand our knowledge of the clinical spectra of diseases caused by expansions of the same repeat motif, and further highlight how directly searching for expanded repeats can help identify mutations underlying diseases.
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http://dx.doi.org/10.1038/s41588-019-0458-zDOI Listing
August 2019

Prominent Spasticity and Hyperreflexia of the Legs in a Nepalese Patient with Friedreich Ataxia.

Intern Med 2019 Oct 7;58(19):2865-2869. Epub 2019 Jun 7.

Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Japan.

Friedreich ataxia (FRDA) is an autosomal recessive spinocerebellar ataxia caused by mutations of FXN. Hypotonus and hyporeflexia of the lower extremities are observed in most FRDA patients. Patients with hyperreflexia, called Friedreich ataxia with retained reflexes (FARR), have also been identified. We herein report the case of a 16-year-old Nepalese boy presenting with early-onset ataxia with prominent spasticity and hyperreflexia of the legs. Mutational analyses established the diagnosis of FRDA presenting as FARR. A haplotype analysis revealed that expanded alleles of the patient shared a common haplotype with Indian and European FRDA patients, suggesting that the mutation descended from a common founder.
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http://dx.doi.org/10.2169/internalmedicine.2953-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6815894PMC
October 2019

Association of ATXN2 intermediate-length CAG repeats with amyotrophic lateral sclerosis correlates with the distributions of normal CAG repeat alleles among individual ethnic populations.

Neurogenetics 2019 05 7;20(2):65-71. Epub 2019 Mar 7.

Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-8655, Japan.

Intermediate-length CAG repeats in ATXN2 have been widely shown to be a risk factor for sporadic amyotrophic lateral sclerosis (SALS). To evaluate the association of ATXN2 intermediate-length CAG repeat alleles with an increased risk of SALS, we investigated distributions of CAG repeat alleles in 394 patients with SALS and 490 control individuals in the Japanese population. In the intermediate-length repeat units of 29 or more, we identified one SALS patient with 31 repeat units and two control individuals with 30 repeat units. Thus, no significant differences in the carrier frequency of intermediate-length CAG repeat alleles were detected between patients with SALS and control individuals. When we investigated the distribution of "large normal alleles" defined as ATXN2 CAG repeats ranging from 24 up to 33 in the Japanese population compared with those in other populations in previous studies, the frequency of large normal alleles was significantly higher in the European and North American series than in the Japanese series. Moreover, these frequencies in the Turkish, Chinese, Korean, and Brazilian (Latin American) series were also higher than that in the Japanese series. These results raise the possibility that the frequencies of large normal alleles in individual populations underlie the frequencies of ALS risk alleles in the corresponding populations.
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http://dx.doi.org/10.1007/s10048-019-00570-9DOI Listing
May 2019

Establishing extracorporeal membrane oxygenation team increased number of patients and improved data recording.

J Intensive Care 2019 7;7:11. Epub 2019 Feb 7.

1Department of Emergency and Critical Care Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.

Background: For patients treated with extracorporeal membrane oxygenation (ECMO), employing a well-coordinated, multidisciplinary team specializing in ECMO has reportedly been effective in delivering better clinical outcomes. This study aims to assess the impact of establishing such a specialized team for patients treated with ECMO.

Method: This retrospective cohort study was performed at a tertiary-care hospital in Japan. We reviewed medical records of all consecutive patients treated with ECMO during October 2010-September 2016. The results obtained in pre-ECMO team cases (PRE group; October 2011-September 2012) and post-ECMO team cases (POST group; October 2014-September 2015) were compared.

Results: The results obtained in pre-ECMO team cases (PRE group; October 2011-September 2012) and post-ECMO team cases (POST group; October 2014-September 2015) were compared. During the study period, 177 patients were treated with ECMO. Before the introduction of ECMO team, an average of 22.7 patients underwent ECMO treatment per year; after establishing ECMO team, this number increased to 36.3 patients per year. ECMO was applied mainly to cardiac arrest patients 52/69 (75%). The PRE ( = 27) and POST ( = 42) groups did not differ with regard to the survival rate to hospital discharge, ECMO duration, ventilator days, and length of hospital stay. However, PaO and positive end-expiratory pressure were significantly higher in the POST group at 6 h after ECMO initiation than those in the PRE group [367 (186-490) vs. 239 (113-430) mmHg,  = 0.047 and 8 (5-10) vs. 7 (5-8) cmHO,  = 0.01, respectively]. In addition, data recording the detailed time points of ECMO initiation was conducted in significantly more cases in the POST group (28/126 (22%) than in the PRE group (6/81 (7%);  = 0.01).

Conclusions: Following the establishment of an ECMO team, the survival rate of patients treated with ECMO, ECMO duration, and length of hospital stay were not improved. However, the number of ECMO cases increased and the recording of clinical data was improved.
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http://dx.doi.org/10.1186/s40560-019-0366-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6367753PMC
February 2019

Associations among behavioral and psychological symptoms of dementia, care burden, and family-to-work conflict of employed family caregivers.

Geriatr Gerontol Int 2019 Jan 16;19(1):51-55. Epub 2018 Dec 16.

Department of Family Nursing, Division of Health Sciences & Nursing, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Aim: The present study aimed to examine the associations among behavioral and psychological symptoms of dementia (BPSD) of persons with dementia (PWD), care burden and family-to-work conflict (FWC) of employed family caregivers.

Method: A cross-sectional study was carried out with employed adult daughter or son (or in-law) caregivers for PWD from two rural cities in Japan. FWC, care burden and the degree of BPSD were evaluated by the Survey Work-Home Interaction-NijmeGen, Zarit Burden Scale-Short Version and Dementia Behavior Disturbance Scale, respectively. Of the 200 questionnaires distributed, 130 were returned. A total of 53 respondents were not employed, and seven questionnaires had missing data for demographic variables, Survey Work-Home Interaction-NijmeGen, Zarit Burden Scale-Short Version or Dementia Behavior Disturbance Scale. Thus, complete data from 70 respondents were analyzed through structural equation modeling.

Results: The mean age of employed family caregivers was 56 years, and 34 (48.5%) were men. The mean age of PWD was 84 years, and there were 68 (68.6%) men. The path model with a good fit was shown (root mean square error of approximation 0.136, comparative fit index 0.960 and goodness of fit index 0.965). The path model showed that BPSD affected FWC, and that the association was partially mediated by care burden.

Conclusions: The results show that a decrease in not only care burden, but also BPSD, of PWD is important for employed family caregivers to reduce their FWC and maintain their work-life balance. Geriatr Gerontol Int 2019; 19: 51-55.
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http://dx.doi.org/10.1111/ggi.13556DOI Listing
January 2019

Neuroimaging, genetic, and enzymatic study in a Japanese family with a GBA gross deletion.

Parkinsonism Relat Disord 2019 04 2;61:57-63. Epub 2018 Dec 2.

Department of Neurology, Graduate School of Medical Sciences, University of Yamanashi, Yamanashi, Japan. Electronic address:

Introduction: Glucocerebrosidase gene (GBA) variants are associated with Parkinson's disease (PD) and dementia with Lewy bodies (DLB). The molecular mechanisms underlying these diseases with GBA variants, however, are not well understood. In order to determine the effect of a deletion mutation in GBA, we performed a neuroimaging, genetic, and enzymatic study in a Japanese family with a gross deletion of exons 3 to 11 in GBA.

Methods: We performed [I] FP-CIT SPECT and [I] N-isopropyl-p-iodoamphetamine SPECT (IMP-SPECT), and determined GBA expression and glucocerebrosidase (GCase) activity in leukocytes in two GBA-associated PD patients and nine unaffected individuals (including four mutation carriers) in a Japanese family with a heterozygous gross deletion mutation in the GBA gene.

Results: The two PD patients and two of the four clinically unaffected carriers showed decreased [I] FP-CIT uptake. IMP-SPECT showed a pattern like that in DLB in one patient. When we compared PD patients with GBA mutations with clinically unaffected carriers, there was a poor correlation between the development of PD and the expression level of GBA or GCase activity.

Conclusion: We confirmed the gross deletion mutation in the GBA gene, which appeared to be associated with the PD or reduced [I] FP-CIT in this family. However, since we cannot conclude whether a reduction of GCase activity is directly correlated with the pathogenesis of PD or not, longitudinal follow-up of this family is needed.
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http://dx.doi.org/10.1016/j.parkreldis.2018.11.028DOI Listing
April 2019

Burden of rare variants in causative genes for amyotrophic lateral sclerosis (ALS) accelerates age at onset of ALS.

J Neurol Neurosurg Psychiatry 2019 05 24;90(5):537-542. Epub 2018 Oct 24.

Department of Molecular Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Objectives: To evaluate the burden of rare variants in the causative genes for amyotrophic lateral sclerosis (ALS) on the age at onset of ALS in a Japanese case series.

Methods: We conducted whole-exome sequencing analysis of 89 families with familial ALS (FALS) and 410 patients with sporadic ALS (SALS) to identify known pathogenic mutations or rare functionally predicted deleterious variants in the causative genes for ALS. Rare variants (minor allele frequency <1%) with scaled Combined Annotation-Dependent Depletion score >20 were defined as rare functionally predicted deleterious variants. The patients with ALS were classified on the basis of the number of pathogenic and/or rare functionally predicted deleterious variants, and the age at onset was compared among the classified groups.

Results: Whole-exome sequencing analysis revealed known pathogenic mutations or rare functionally predicted deleterious variants in causative genes for ALS in 56 families with FALS (62.9%) and 87 patients with SALS (21.2%). Such variants in multiple genes were identified in seven probands with FALS and eight patients with SALS. The ages at onset in the patients with ALS with multiple variants were significantly earlier than those in other patients with ALS. Even when the patients with known pathogenic mutations were excluded, a significantly earlier onset of the disease was still observed in patients with multiple rare functionally predicted deleterious variants.

Conclusions: A substantial number of patients carried rare variants in multiple genes, and the burden of rare variants in the known causative genes for ALS affects the age at onset in the Japanese ALS series.
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http://dx.doi.org/10.1136/jnnp-2018-318568DOI Listing
May 2019

Decreased Psoas Muscle Computed Tomography Value Predicts Poor Outcome in Peripheral Artery Disease.

Circ J 2018 11 29;82(12):3069-3075. Epub 2018 Sep 29.

Department of Cardiology, Pulmonology, and Nephrology, Yamagata University School of Medicine.

Background: The prognosis of peripheral artery disease (PAD) and comorbid sarcopenia is poor. Some reports indicate that the computed tomography (CT) value of skeletal muscle, which reflects intramuscular fat deposition as well as skeletal muscle mass, is considered a marker of sarcopenia. However, it remains unclear if skeletal muscle area and CT value are associated with poor outcomes in patients with PAD. Methods and Results: Psoas muscle area and CT value were measured by manual trace at the level of the third lumbar vertebral body in 327 consecutive patients with PAD undergoing endovascular therapy (EVT). The endpoint was major adverse cardiovascular and limb events (MACLE). There were 60 MACLE during the follow-up period. Patients with MACLE had lower mean psoas muscle CT value than those without. However, there was no significant difference in total psoas muscle area between patients with and without MACLE. Kaplan-Meier analysis demonstrated that the lowest tertile of psoas muscle CT value was associated with the highest risk of MACLE. Multivariate Cox hazard analysis revealed that psoas muscle CT value was associated with MACLE after adjustment for Fontaine class, previous ischemic heart disease, prevalence of diabetes mellitus, brain natriuretic peptide, and serum albumin.

Conclusions: Psoas muscle CT value is a feasible predictor of MACLE in patients with PAD.
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http://dx.doi.org/10.1253/circj.CJ-18-0726DOI Listing
November 2018

Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy.

Nat Genet 2018 04 5;50(4):581-590. Epub 2018 Mar 5.

Department of Epilepsy, Nishi-Niigata Chuo National Hospital, Niigata, Japan.

Epilepsy is a common neurological disorder, and mutations in genes encoding ion channels or neurotransmitter receptors are frequent causes of monogenic forms of epilepsy. Here we show that abnormal expansions of TTTCA and TTTTA repeats in intron 4 of SAMD12 cause benign adult familial myoclonic epilepsy (BAFME). Single-molecule, real-time sequencing of BAC clones and nanopore sequencing of genomic DNA identified two repeat configurations in SAMD12. Intriguingly, in two families with a clinical diagnosis of BAFME in which no repeat expansions in SAMD12 were observed, we identified similar expansions of TTTCA and TTTTA repeats in introns of TNRC6A and RAPGEF2, indicating that expansions of the same repeat motifs are involved in the pathogenesis of BAFME regardless of the genes in which the expanded repeats are located. This discovery that expansions of noncoding repeats lead to neuronal dysfunction responsible for myoclonic tremor and epilepsy extends the understanding of diseases with such repeat expansion.
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http://dx.doi.org/10.1038/s41588-018-0067-2DOI Listing
April 2018

Frequency and characteristics of the TBK1 gene variants in Japanese patients with sporadic amyotrophic lateral sclerosis.

Neurobiol Aging 2018 04 11;64:158.e15-158.e19. Epub 2017 Dec 11.

Department of Computational Biology, Graduate School of Frontier Sciences, University of Tokyo, Chiba, Japan.

Amyotrophic lateral sclerosis (ALS) is a devastating neurological disease, and the etiology of sporadic ALS is generally unknown. The TANK-binding kinase 1 (TBK1) gene was identified as an ALS gene contributing to a predisposition toward ALS. To reveal the frequency and characteristics of variants of the TBK1 gene in sporadic ALS patients in Japan, we analyzed the TBK1 gene by exome sequencing in a large Japanese cohort of 713 sporadic ALS patients and 800 controls. We identified known or potentially toxic rare variants of TBK1 gene in 9 patients (1.26%) with sporadic ALS, including 4 novel missense variants (p.V23I, p.H322R, p.R358C, and p.T478I) and 3 loss-of-function variants (p.R357X, p.P378_I379del, and p.T419_G420del). The odds ratio between sporadic ALS patients and controls was 10.2 (p = 0.008, 95% confidence interval = 1.67-62.47). These findings support the contribution of TBK1 to the etiology of sporadic ALS in Japanese patients.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.12.005DOI Listing
April 2018

Molecular epidemiological study of familial amyotrophic lateral sclerosis in Japanese population by whole-exome sequencing and identification of novel HNRNPA1 mutation.

Neurobiol Aging 2018 01 6;61:255.e9-255.e16. Epub 2017 Sep 6.

Department of Neurology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. Electronic address:

To elucidate the genetic epidemiology of familial amyotrophic lateral sclerosis (FALS) in the Japanese population, we conducted whole-exome sequencing analysis of 30 FALS families in whom causative mutations have not been identified in previous studies. Consequently, whole-exome sequencing analysis revealed novel mutations in HNRNPA1, TBK1, and VCP. Taken together with our previous results of mutational analyses by direct nucleotide sequencing analysis, a microarray-based resequencing method, or repeat-primed PCR analysis, causative mutations were identified in 41 of the 68 families (60.3%) with SOD1 being the most frequent cause of FALS (39.7%). Of the mutations identified in this study, a novel c.862/1018C>G (p.P288A/340A) mutation in HNRNPA1 located in the nuclear localization signal domain of hnRNPA1, enhances the recruitment of mutant hnRNPA1 into stress granules, indicating that an altered nuclear localization signal activity plays an essential role in amyotrophic lateral sclerosis pathogenesis.
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http://dx.doi.org/10.1016/j.neurobiolaging.2017.08.030DOI Listing
January 2018

Clinicopathologic features of myositis patients with CD8-MHC-1 complex pathology.

Neurology 2017 Sep 9;89(10):1060-1068. Epub 2017 Aug 9.

From the Department of Neurology (C.I., A.K., K.T., N.U., M.H.M., Y.N., H.I., S.T., J.S.), Graduate School of Medicine, the University of Tokyo; Division of Neurology (M.K., K.K.), Department of Internal Medicine, National Defense Medical College, Saitama; Department of Neurology (A.H.), National Center for Global Health and Medicine; Department of Neurology (M.H.M.), Federation of National Public Service Personnel Mutual Aid Associations Toranomon Hospital; Okinaka Memorial Institute For Medical Research (M.H.M.); and Department of Neurology (J.G.), International University of Health and Welfare, Mita Hospital, Tokyo, Japan.

Objective: To determine the clinical features of myositis patients with the histopathologic finding of CD8-positive T cells invading non-necrotic muscle fibers expressing major histocompatibility complex class 1 (CD8-MHC-1 complex), which is shared by polymyositis (PM) and inclusion body myositis (IBM), in relation to the p62 immunostaining pattern of muscle fibers.

Methods: All 93 myositis patients with CD8-MHC-1 complex who were referred to our hospital from 1993 to 2015 were classified on the basis of the European Neuromuscular Center (ENMC) diagnostic criteria for IBM (Rose, 2013) or PM (Hoogendijk, 2004) and analyzed.

Results: The 93 patients included were 17 patients with PM, 70 patients with IBM, and 6 patients who neither met the criteria for PM nor IBM in terms of muscle weakness distribution (unclassifiable group). For these PM, IBM, and unclassifiable patients, their mean ages at diagnosis were 63, 70, and 64 years; autoimmune disease was present in 7 (41%), 13 (19%), and 4 (67%); hepatitis C virus infection was detected in 0%, 13 (20%), and 2 (33%); and p62 was immunopositive in 0%, 66 (94%), and 2 (33%), respectively. Of the treated patients, 11 of 16 PM patients and 4 of 6 p62-immunonegative patients in the unclassifiable group showed responses to immunotherapy, whereas all 44 patients with IBM and 2 p62-immunopositive patients in the unclassifiable group were unresponsive to immunotherapy.

Conclusions: CD8-MHC-1 complex is present in patients with PM, IBM, or unclassifiable group. The data may serve as an argument for a trial of immunosuppressive treatment in p62-immunonegative patients with unclassifiable myositis.
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http://dx.doi.org/10.1212/WNL.0000000000004333DOI Listing
September 2017

Partial duplication of causes minifascicular neuropathy: A novel mutation detection of .

Ann Clin Transl Neurol 2017 06 22;4(6):415-421. Epub 2017 May 22.

Department of Neurology Tokyo Teishin Hospital Tokyo Japan.

Minifascicular neuropathy (MN) is an extremely rare developmental malformation in which peripheral nerves are composed of many small fascicles. Only one patient with MN with 46XY gonadal dysgenesis (GD) was found to carry a mutation affecting the start codon in (). We identified an identical novel rearrangement mutation of in two consanguineous families with MN, confirming mutations in cause MN with 46XY GD. The patients with the 46XY karyotype developed GD, whereas a patient with the 46XX karyotype did not. These findings further support that has important roles in perineural formation and male gonadal differentiation.
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http://dx.doi.org/10.1002/acn3.417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5454394PMC
June 2017

[An Autopsied Case of Familial Spinocerebellar Degeneration Presenting with Late-Onset Autonomic Dysfunction].

Brain Nerve 2017 Mar;69(3):277-286

Department of Neurology, The Jikei University Kashiwa Hospital.

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http://dx.doi.org/10.11477/mf.1416200739DOI Listing
March 2017

Three-Year Follow-Up of High-Dose Ubiquinol Supplementation in a Case of Familial Multiple System Atrophy with Compound Heterozygous COQ2 Mutations.

Cerebellum 2017 06;16(3):664-672

Department of Neurology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo, Tokyo, 113-8655, Japan.

We report a 3-year follow-up of high-dose ubiquinol supplementation in a case of familial multiple system atrophy (MSA) with compound heterozygous nonsense (R387X) and missense (V393A) mutations in COQ2. A high-dose ubiquinol supplementation substantially increased total coenzyme Q levels in cerebrospinal fluid as well as in plasma. The patient was at the advanced stage of MSA, and the various scores of clinical rating scales remained stable without changes during the 3 years. The cerebral metabolic ratio of oxygen measured by O PET, however, increased by approximately 30% after administration of ubiquinol, suggesting that ubiquinol can improve mitochondrial oxidative metabolism in the brain. It also suggests the therapeutic potential of ubiquinol for patients with MSA with COQ2 mutations. Further clinical trials of administration of high-dose ubiquinol to MSA patients are warranted.
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http://dx.doi.org/10.1007/s12311-017-0846-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5427137PMC
June 2017

Slowly progressive d-bifunctional protein deficiency with survival to adulthood diagnosed by whole-exome sequencing.

J Neurol Sci 2017 Jan 9;372:6-10. Epub 2016 Nov 9.

Department of Neurology, Graduate School of Medicine, The University of Tokyo, Japan; Department of Neurology, International University of Health and Welfare Mita Hospital, Japan. Electronic address:

d-Bifunctional protein (DBP) deficiency is an autosomal recessive disorder of peroxisomal fatty acid oxidation caused by mutations in HSD17B4. It is typically fatal by the age of two years with symptom onset during the neonatal period, and survival until late childhood is rare. We herein report the case of a patient with DBP deficiency surviving until adulthood, who showed severe sensorineural deafness, disturbances in language acquisition, slowly progressive cerebellar ataxia, and peripheral neuropathy. This patient, in whom findings of prior investigations were nondiagnostic, had been followed up as having an early-onset spinocerebellar degeneration of unknown etiology. Whole-exome sequencing analysis at the age of 36 showed two heterozygous variants in the gene HSD17B4, which encodes DBP in this patient. A panel of peroxisomal investigations showed normal levels of very long chain fatty acids (VLCFAs) in plasma and elevated serum phytanic acid levels. Recently, an increasing number of patients with DBP deficiency surviving until adolescence/adulthood have been reported, in whom abnormalities in the levels of VLCFAs and other peroxisomal metabolites are marginal or nonexistent. Genetic analysis of HSD17B4 should be considered in adult patients with cerebellar ataxia, peripheral neuropathy, and pyramidal signs in addition to sensorineural auditory disturbance since childhood.
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http://dx.doi.org/10.1016/j.jns.2016.11.009DOI Listing
January 2017

CCNF mutations in amyotrophic lateral sclerosis and frontotemporal dementia.

Nat Commun 2016 Apr 15;7:11253. Epub 2016 Apr 15.

Montreal Neurological Institute and Hospital, Department of Neurology and Neurosurgery, McGill University, Montreal, Québec, Canada H3A 2B4.

Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCF(Cyclin F)). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCF(Cyclin F) substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.
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http://dx.doi.org/10.1038/ncomms11253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4835537PMC
April 2016