Publications by authors named "Kengo Maeda"

109 Publications

Neuropathology of the spinal nerve roots, spinal cord, and brain in the first autopsied case of Charcot-Marie-Tooth disease 4F with a D651N mutation in the periaxin gene.

Neuropathology 2021 Aug 17;41(4):281-287. Epub 2021 May 17.

Department of Clinical Laboratory Medicine and Diagnostic Pathology, Shiga University of Medical Science, Ohtsu, Japan.

Charcot-Marie-Tooth disease (CMT) 4F is an autosomal recessive, hereditary peripheral neuropathy, mostly caused by mutations in the periaxin gene (PRX). This article reports neuropathological findings of the spinal nerve roots, spinal cord, and brain of a patient with CMT4F and a D651N missense mutation in PRX. The patient was a 74-year-old woman who had a history of peripheral neuropathy with onset at the age of 30 years. She also had a history of infantile paralysis at the age of 18 months. The most pronounced autopsy finding was diffuse enlargement of anterior and posterior nerve roots, accentuated at the lumbo-sacral levels. On microscopy, the swollen nerve roots showed a loss of large-diameter myelinated fibers and formation of numerous onion bulbs. Most of the onion bulbs lacked the central, regenerating thin myelin sheaths, and in large-diameter nerve fibers whose axons had been lost, collagen fibers occupied the center of the onion bulbs. Some nerve roots formed glial bundles at the proximal end. The spinal cord showed degeneration of the gracile fascicles, and the lumbar segment anterior horn showed an asymmetric neuronal loss with rarefaction of the neuropil. The brain did not show any notable changes except for multiple foci of a radial microcolumnar arrangement of neurons in the cerebral cortex. Degeneration of the lumbar segment anterior horn is most likely secondary to the anterior radiculopathy, but a localized circulatory disturbance is another possibility.
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http://dx.doi.org/10.1111/neup.12731DOI Listing
August 2021

Dystypia Associated with Diaschisis of the Middle Frontal Gyri after Left Angular Infarction.

J Stroke Cerebrovasc Dis 2021 Jul 20;30(7):105803. Epub 2021 Apr 20.

Department of Neurology, National Hospital Organization Higashi-ohmi General Medical Center, 255 Gochi, Higashi-ohmi, Shiga 527-8505, Japan. Electronic address:

Dystypia without aphasia, agraphia, or apraxia is a rare symptom and has been suggested to result from a lesion in the left middle frontal cortex. We herein describe a man with dystypia with agraphia due to infarction of the left angular gyrus. His dystypia seemed to result from the convergence failure of the kana into the alphabetical spellings. During dystypia, hypoperfusion of the bilateral middle frontal cortices was discovered. However, after his symptoms improved, blood flow in the middle frontal cortices returned to normal. This case suggests that the middle frontal cortex is downstream of the angular gyrus in the dictating pathway and a lesion in the left middle frontal cortex could cause pure dystypia.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.105803DOI Listing
July 2021

T2 Star-weighted MRI of Beta-propeller Protein-associated Neurodegeneration.

Intern Med 2021 Feb 19;60(4):655. Epub 2020 Sep 19.

Department of Internal Medicine, Vories Memorial Hospital, Japan.

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http://dx.doi.org/10.2169/internalmedicine.5871-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946514PMC
February 2021

Presence of colocalised phosphorylated TDP-43 and TFG proteins in the frontotemporal lobes of HMSN-P.

J Neurol Neurosurg Psychiatry 2020 11 27;91(11):1231-1232. Epub 2020 Aug 27.

Department of Pathology, Shiga University of Medical Science, Otsu, Shiga, Japan.

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http://dx.doi.org/10.1136/jnnp-2020-323506DOI Listing
November 2020

Long-read sequencing identifies GGC repeat expansions in NOTCH2NLC associated with neuronal intranuclear inclusion disease.

Nat Genet 2019 08 22;51(8):1215-1221. Epub 2019 Jul 22.

Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, Japan.

Neuronal intranuclear inclusion disease (NIID) is a progressive neurodegenerative disease that is characterized by eosinophilic hyaline intranuclear inclusions in neuronal and somatic cells. The wide range of clinical manifestations in NIID makes ante-mortem diagnosis difficult, but skin biopsy enables its ante-mortem diagnosis. The average onset age is 59.7 years among approximately 140 NIID cases consisting of mostly sporadic and several familial cases. By linkage mapping of a large NIID family with several affected members (Family 1), we identified a 58.1 Mb linked region at 1p22.1-q21.3 with a maximum logarithm of the odds score of 4.21. By long-read sequencing, we identified a GGC repeat expansion in the 5' region of NOTCH2NLC (Notch 2 N-terminal like C) in all affected family members. Furthermore, we found similar expansions in 8 unrelated families with NIID and 40 sporadic NIID cases. We observed abnormal anti-sense transcripts in fibroblasts specifically from patients but not unaffected individuals. This work shows that repeat expansion in human-specific NOTCH2NLC, a gene that evolved by segmental duplication, causes a human disease.
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http://dx.doi.org/10.1038/s41588-019-0459-yDOI Listing
August 2019

Gatekeeping in an inpatient rehabilitation facility to reduce morbidity and mortality due to cardiac disease: screening program using of BNP and ECG Auto-diagnosis.

Nagoya J Med Sci 2019 May;81(2):303-312

Kobayashi Memorial Hospital, Hekinan, Japan.

The Kaifukuki-Rehabilitation Ward (KRW) is a type of inpatient rehabilitation facility in Japan. In the KRW of our institute, mortality and frequency of emergency referrals in 2013 were rather high, 2.6% and 4.3%, respectively. We aimed to investigate the usefulness of an original gatekeeping system to reduce mortality and morbidity from cardiac complications, and to improve the quality of medical care in the KRW. A total of 370 consecutive patients admitted to the KRW of Kobayashi Memorial Hospital between 1 May 2015 and 31 March 2016 were enrolled in this prospective observational study. All patients underwent a screening evaluation in which we defined patients as being screen positive (SC-positive) if they had at least one of 20 diagnostic ECG codes and/or BNP level over 140 pg/dL at admission. A cardiologist provided weekly interventions to those among SC-positive patients who needed cardiac disease treatment during hospitalization. In all, 129 patients were classified as SC-positive (mean age 80 years, 124 [32%] male), and weekly intervention was needed in 28 patients, including start of cardiac medication in 17 cases. Mortality and frequency of emergency transfer due to cardiac disease during hospital stay were 0.3% and 0.3%, respectively. Our gatekeeping system involving a screening evaluation at admission and weekly intervention in selected patients by a cardiologist may be useful in reducing mortality and rate of transfer due to cardiac disease and may improve quality of medical care in KRWs.
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http://dx.doi.org/10.18999/nagjms.81.2.303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6556463PMC
May 2019

Akinetopsia on Driving.

Authors:
Kengo Maeda

J Stroke Cerebrovasc Dis 2019 Jul 26;28(7):e102-e103. Epub 2019 Apr 26.

Department of Neurology, National Hospital Organization Higashi-ohmi General Medical Center, Higashi-ohmi, Shiga, Japan. Electronic address:

Akinetopsia is a quite rare symptom. Two types of akinetopsia have been reported: one is cinematographic vision, and the other is invisibility of moving objects. These symptoms are thought to occur due to dysfunction of the MT/V5 area at the occipitoparietal region. I herein describe a 54-year-old man who collided with a car parked on the left side of the road while driving. He complained that the parked car looked to be moving forwards and he could not stop his car when he noticed that it was parked. Magnetic resonance imaging disclosed the fresh infarction on the right temporoparietal region involving the MT/V5 area. His symptom during driving was considered cinematographic vision and it was the cause of the traffic accident. Akinetopsia resulted in illusory kinetopsia on driving and the traffic accident.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2019.02.036DOI Listing
July 2019

Akinetopsia with achromatopsia due to focal epilepsy.

Seizure 2019 Apr 6;67:27-29. Epub 2019 Mar 6.

Department of Neurology, National Hospital Organization Higashi-ohmi General Medical Center, Shiga, Japan.

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http://dx.doi.org/10.1016/j.seizure.2019.03.004DOI Listing
April 2019

[A case of stiff-limb syndrome with anti-glycine receptor antibody].

Rinsho Shinkeigaku 2019 Feb 31;59(2):98-101. Epub 2019 Jan 31.

Department of Neurology, Kitasato University School of Medicine.

A 48-year-old woman with a 3-month history of spontaneously resolving stiff leg symptom at the age of 43 years presented with progressive onset of leg rigidity, walking difficulty, and myoclonic jerks. On admission she had marked stiffness in her foot joints with symmetric sustained dorsiflexion of the ankles and toes, with spontaneous and reflex myoclonic jerks easily provoked by knee tendon tap. She appeared to have a spastic gait due to stiffness in her legs. Needle electromyogram (EMG) examination revealed continuous motor unit activity in the tibialis anterior muscle at rest even when voluntary contraction of the gastrocnemius muscle was instructed, but no myokimic discharge or acute denervation sign was seen. The laboratory tests were unremarkable, including glutamic acid decarboxylase antibody. Cerebrospinal fluid (CSF) examination was also normal, without oligoclonal bands or elevated IgG index. She was diagnosed with stiff-limb syndrome based on neurologic examination and needle EMG findings, and she was treated with intravenous high-dose methylprednisolone (500 mg/day, 3 days), resulting in marked improvement in her symptoms. Anti-glycine receptor antibodies were subsequently identified in her archived serum and CSF obtained before immunotherapy. She was then started on oral prednisolone (30 mg/day) and had been free of symptoms.
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http://dx.doi.org/10.5692/clinicalneurol.cn-001239DOI Listing
February 2019

Symmetric Ventral Brainstem Lesion in Leptomeningeal Carcinomatosis.

Intern Med 2019 Mar 19;58(5):759-760. Epub 2018 Nov 19.

Department of Radiology, National Hospital Organization Higashi-ohmi General Medical Center, Japan.

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http://dx.doi.org/10.2169/internalmedicine.1469-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443546PMC
March 2019

Cortical Hyperintensity on Diffusion-weighted Images as the Presymptomatic Marker of Sporadic Creutzfeldt-Jakob Disease.

Intern Med 2019 Mar 17;58(5):727-729. Epub 2018 Oct 17.

Department of Molecular Microbiology and Immunology, Graduate School of Biomedical Sciences, Nagasaki University, Japan.

We herein report a sporadic Creutzfeldt-Jakob disease (sCJD) patient followed from the presymptomatic phase to death. A 67-year-old woman had abnormal hyperintense cortical lesions on diffusion-weighted magnetic resonance imaging (MRI) one year before the onset. The levels of 14-3-3 protein and total tau protein, and findings from a real-time quaking-induced conversion test were normal at first but became abnormal after disease onset. Although there are four reports of presymptomatic sCJD identified by MRI, this is the first case report in which all three biomarkers had been assessed before and after the disease onset. MRI might be the most sensitive modality for detecting presymptomatic sCJD patients.
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http://dx.doi.org/10.2169/internalmedicine.1155-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443561PMC
March 2019

Lipid Droplets in the Basal Cistern and Ventricles.

Intern Med 2018 Oct 18;57(19):2913-2914. Epub 2018 May 18.

Department of Neurology, National Hospital Organization Higashi-ohmi General Medical Center, Japan.

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http://dx.doi.org/10.2169/internalmedicine.0851-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207815PMC
October 2018

Revival of Historical Kana Orthography in a Patient with Allographic Agraphia.

Intern Med 2018 1;57(5):745-750. Epub 2018 Mar 1.

Departments of Rehabilitation, National Hospital Organization Higashi-ohmi General Medical Center, Japan.

Japanese people born before World War II learned Japanese kana (Japanese syllabograms) writing in a style that is not currently used. These individuals had to learn the current style of kana orthography after the war. An 85-year-old man was taken to our hospital by his family who were surprised by his diary. It was written with kanji (Japanese ideograms) and katakana using the prewar style. A neuropsychological examination revealed impaired recall of hiragana. Neuroimaging studies revealed atrophy of the left fronto-parietal lobe and hypoperfusion of the left frontal lobe. His allographic agraphia might have resulted from the disturbance of the current style of kana orthography.
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http://dx.doi.org/10.2169/internalmedicine.8834-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874353PMC
July 2018

Clinical and genetic features of Charcot-Marie-Tooth disease 2F and hereditary motor neuropathy 2B in Japan.

J Peripher Nerv Syst 2018 03 14;23(1):40-48. Epub 2018 Feb 14.

Department of Neurology and Geriatrics, Kagoshima University, Graduate School of Medical and Dental Sciences, Kagoshima, Japan.

Mutations in small heat shock protein beta-1 (HspB1) have been linked to Charcot-Marie-Tooth (CMT) disease type 2F and distal hereditary motor neuropathy type 2B. Only four cases with HSPB1 mutations have been reported to date in Japan. In this study between April 2007 and October 2014, we conducted gene panel sequencing in a case series of 1,030 patients with inherited peripheral neuropathies (IPNs) using DNA microarray, targeted resequencing, and whole-exome sequencing. We identified HSPB1 variants in 1.3% (13 of 1,030) of the patients with IPNs, who exhibited a male predominance. Based on neurological and electrophysiological findings, seven patients were diagnosed with CMT disease type 2F, whereas the remaining six patients were diagnosed with distal hereditary motor neuropathy type 2B. P39L, R127W, S135C, R140G, K141Q, T151I, and P182A mutations identified in 12 patients were described previously, whereas a novel K123* variant with unknown significance was found in 1 patient. Diabetes and impaired glucose tolerance were detected in 6 of the 13 patients. Our findings suggest that HSPB1 mutations result in two phenotypes of inherited neuropathies and extend the phenotypic spectrum of HSPB1-related disorders.
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http://dx.doi.org/10.1111/jns.12252DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873406PMC
March 2018

Cerebral Blood Flow in a Patient with Hemiballism.

Intern Med 2018 01 1;57(2):289-290. Epub 2017 Nov 1.

Department of Neurology, National Hospital Organization Higashi-ohmi General Medical Center, Japan.

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http://dx.doi.org/10.2169/internalmedicine.8836-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5820056PMC
January 2018

Dynamics of angiogenesis in ischemic areas of the infarcted heart.

Sci Rep 2017 08 2;7(1):7156. Epub 2017 Aug 2.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, 466-8560, Japan.

Cardiomyocytes are susceptible to apoptosis caused by hypoxia during the acute and subacute phases of myocardial infarction (MI). Angiogenesis can reduce MI-induced damage by mitigating hypoxia. It has been speculated that the ischemic border zone is a unique area rescued by angiogenic therapy. However, the mechanism and timing for new vessel formation in the mammalian heart following hypoxia are unclear. Identifying targets that benefit from angiogenesis treatment is indispensable for the development of revolutionary therapies. Here, we describe a novel circulatory system wherein new vessels develop from the endocardium of the left ventricle to perfuse the hypoxic area and salvage damaged cardiomyocytes at 3-14 days after MI by activating vascular endothelial growth factor signaling. Moreover, enhanced angiogenesis increased cardiomyocyte survival along the endocardium in the ischemic zone and suppressed ventricular remodeling in infarcted hearts. In contrast, cardiomyocytes in the border zone's hypoxic area underwent apoptosis within 12 h of MI, and the border area that was amenable to treatment disappeared. These data indicate that the non-perfused area along the endocardium is a site of active angiogenesis and a promising target for MI treatment.
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http://dx.doi.org/10.1038/s41598-017-07524-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5540926PMC
August 2017

Serum uric acid as a predictor of future hypertension: Stratified analysis based on body mass index and age.

Prev Med 2016 09 9;90:201-6. Epub 2016 Jul 9.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Serum uric acid level is a predictor of future hypertension. However, its dependence on body mass index or age is unclear.

Methods: We examined 26,442 Japanese males aged 18-60years free from hypertension or diagnosed cardiovascular disease at baseline followed up between 2000 and 2010. Participants were categorized into three groups according to the tertile of serum uric acid levels [mg/dL; 1st (reference): 0.1-5.3; 2nd: 5.4-6.2; 3rd: 6.3-11.6]. Incident hypertension was defined as newly detected blood pressure≥140/90mmHg and/or antihypertensive drugs initiation. Body mass index (<25kg/m(2) vs. ≥25kg/m(2)) and age (<40years vs. ≥40years) were stratified into two groups.

Results: During a mean follow-up of 7.2years, there were 11,361 (43%) hypertension cases. Mean serum uric acid levels (mg/dL) at baseline in each group were 1st tertile, 4.6; 2nd tertile, 5.8; and 3rd tertile, 7.0. The cumulative incident hypertension rate was significantly higher in the 3rd tertile (50.8%) than in the 1st (37.4%). Multiple-adjusted hazard ratios (95% confidence interval) for incident hypertension compared with 1st tertile were 1.01 (0.96-1.05) and 1.15 (1.10-1.21) in the 2nd and 3rd tertile, respectively. There was a significant interaction between age and serum uric acid level (p for interaction=0.035). In subjects aged ≥40years, the 3rd serum uric acid group showed higher hazard ratios [1.48 (1.38-1.59)].

Conclusion: High serum uric acid level was associated with future hypertension in young and middle-aged Japanese males. This association was stronger among subjects ≥40years old.
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http://dx.doi.org/10.1016/j.ypmed.2016.07.007DOI Listing
September 2016

Clinical Phenotype and Segregation of Mitochondrial 3243A>G Mutation in 2 Pairs of Monozygotic Twins.

JAMA Neurol 2016 Aug;73(8):990-3

Departments of Oncology and Space Environmental Medicine, Kagoshima University Graduate School of Medical and Dental Science, Kagoshima, Kagoshima, Japan.

Importance: The regulatory factors explaining the wide spectrum of clinical phenotypes for mitochondrial 3243A>G mutation are not known. Crosstalk between nuclear genes and mitochondrial DNA might be one factor.

Observations: In this case series, we compared 2 pairs of male twins with the mitochondrial 3243 A>G mutation and mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes syndrome with a female control patient. One pair of monozygotic twins presented with diabetes and deafness in their 30s, stroke-like episodes in their 40s, and cardiac events and death in their 50s. Another pair of twins presented with deafness and stroke-like episodes in their 20s. The degree of heteroplasmy of 3243A>G mutation in the various tissues and organs was similar in the first pair of twins compared with the control patient.

Conclusions And Relevance: The clinical phenotype and segregation of mitochondrial 3243A>G mutation was similar in monozygotic twins. The onset age and distribution of the symptoms might be regulated by nuclear genes. Our findings might help to predict the clinical course of the surviving twins and afford an opportunity for therapy before the onset of mitochondrial disease, especially for monozygotic twins caused by nuclear transfer with a small amount of nuclear-donor mitochondrial DNA.
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http://dx.doi.org/10.1001/jamaneurol.2016.0886DOI Listing
August 2016

Wnt11 Gene Therapy with Adeno-associated Virus 9 Improves Recovery from Myocardial Infarction by Modulating the Inflammatory Response.

Sci Rep 2016 Feb 17;6:21705. Epub 2016 Feb 17.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466-8560, Japan.

Acute myocardial infarction induces activation of the acute phase response and infiltration of leukocytes to the infarcted area. Moreover, myocardium that is remote from ischemic area also becomes inflamed. Inflammatory reaction clears dead cells and matrix debris, while prolongation or expansion of the inflammatory response results in dysfunction following myocardial infarction. Wnt glycolipoproteins are best characterized as regulators of embryonic development. Recently several reports suggest that they also contribute to the inflammatory response in adult animals. However, the effects of Wnt proteins on myocardial infarction have not been explored. Here we show that Wnt11 expression leads to significant improvements of survival and cardiac function by suppressing infiltration of multiple kinds of inflammatory cells in infarcted heart. Wnt11 protein suppresses gene expression of inflammatory cytokines through the modulation of NF-κB in vitro. These results reveal a novel function of Wnt11 in the regulation of inflammatory response and provide a rationale for the use of Wnt11 to manipulate human diseases that are mediated by inflammation.
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http://dx.doi.org/10.1038/srep21705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4756373PMC
February 2016

Agraphia in Mobile Text Messages in a Case of Amyotrophic Lateral Sclerosis with Frontotemporal Dementia.

Intern Med 2015 1;54(23):3065-8. Epub 2015 Dec 1.

Department of Neurology, National Hospital Organization Higashi-ohmi General Medical Center, Japan.

We herein describe the case of a woman with amyotrophic lateral sclerosis (ALS) showing errors in her choice of Japanese kana characters in her mobile text messages and agraphia of the kana in her handwriting in spite of the absence of weakness, ataxia, or apraxia of her hands. Magnetic resonance imaging showed the atrophy of the frontal lobes. Single-photon emission computed tomography revealed hypoperfusion of the frontal lobes including Exner's area. Although patients with bulbar-onset ALS have been reported to show agraphia of handwriting, in this case the basis of her agraphia might have been the disturbance of the pathway converting phones to graphemes in series, by which errors of spelling or writing would appear in any modality of output.
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http://dx.doi.org/10.2169/internalmedicine.54.4982DOI Listing
August 2016

Akt-dependent Girdin phosphorylation regulates repair processes after acute myocardial infarction.

J Mol Cell Cardiol 2015 Nov 21;88:55-63. Epub 2015 Sep 21.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Myocardial infarction is a leading cause of death, and cardiac rupture following myocardial infarction leads to extremely poor prognostic feature. A large body of evidence suggests that Akt is involved in several cardiac diseases. We previously reported that Akt-mediated Girdin phosphorylation is essential for angiogenesis and neointima formation. The role of Girdin expression and phosphorylation in myocardial infarction, however, is not understood. Therefore, we employed Girdin-deficient mice and Girdin S1416A knock-in (Girdin(SA/SA)) mice, replacing the Akt phosphorylation site with alanine, to address this question. We found that Girdin was expressed and phosphorylated in cardiac fibroblasts in vitro and that its phosphorylation was crucial for the proliferation and migration of cardiac fibroblasts. In vivo, Girdin was localized in non-cardiomyocyte interstitial cells and phosphorylated in α-smooth muscle actin-positive cells, which are likely to be cardiac myofibroblasts. In an acute myocardial infarction model, Girdin(SA/SA) suppressed the accumulation and proliferation of cardiac myofibroblasts in the infarcted area. Furthermore, lower collagen deposition in Girdin(SA/SA) mice impaired cardiac repair and resulted in increased mortality attributed to cardiac rupture. These findings suggest an important role of Girdin phosphorylation at serine 1416 in cardiac repair after acute myocardial infarction and provide insights into the complex mechanism of cardiac rupture through the Akt/Girdin-mediated regulation of cardiac myofibroblasts.
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http://dx.doi.org/10.1016/j.yjmcc.2015.09.012DOI Listing
November 2015

Impact of the statin escape phenomenon on long-term clinical outcomes in patients with acute myocardial infarction: Subgroup analysis of the Nagoya Acute Myocardial Infarction Study (NAMIS).

Atherosclerosis 2015 Sep 9;242(1):155-60. Epub 2015 Jul 9.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Background: Statins are reportedly effective in the primary and secondary prevention of cardiovascular disease, mainly due to their ability to aggressively reduce low-density lipoprotein cholesterol (LDL-C) levels. However, patients sometimes exhibit the so-called "statin escape" phenomenon. The purpose of our study was to investigate the impact of the statin escape phenomenon on long-term clinical outcomes in patients with acute myocardial infarction (AMI).

Method: This was a subgroup analysis of 1144 patients from the Nagoya Acute Myocardial Infarction Study (NAMIS) treated between January 2004 and December 2012. We analyzed 660 patients who initiated statin treatment after AMI. Statin escape phenomenon was defined as an increase in the LDL-C levels during the 9-month treatment period by >10% of the initial values after 4 weeks of initiating statin treatment. Patients were divided into two groups depending on whether they exhibited the statin escape phenomenon, with 474 patients in the non-escape group and 186 patients in the escape group.

Result: Compared to the non-escape group, the escape group showed significantly lower LDL-C levels at 4 weeks after treatment initiation (81.3 ± 20.1 mg/dL vs. 101.1 ± 25.4 mg/dL, P < 0.01). By contrast, the escape group showed significantly higher LDL-C levels at 9 months after treatment initiation (105.8 ± 28.3 mg/dL vs. 90.3 ± 22.6 mg/dL, P < 0.01). Major adverse cardiac and cerebrovascular events (MACCE; a composite of all-cause death, MI, and stroke) were more frequent in the escape group than in the non-escape group (10.8% vs. 6.1%, P = 0.03). Multivariate analysis showed that statin escape phenomenon was an independent predictor of MACCE (hazard ratio: 2.02, 95% confidence interval: 1.11-3.66, P = 0.02).

Conclusion: Statin escape phenomenon may be an independent predictor of long-term clinical outcomes in AMI patients.
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http://dx.doi.org/10.1016/j.atherosclerosis.2015.07.012DOI Listing
September 2015

[Pure word deafness due to epilepsy].

Authors:
Kengo Maeda

Rinsho Shinkeigaku 2015 15;55(7):505. Epub 2015 May 15.

Department of Neurology, National Hospital Organization Higashi-ohmi General Medical Center.

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http://dx.doi.org/10.5692/clinicalneurol.cn-000661DOI Listing
August 2016

[Acute disseminated encephalomyelitis following influenza vaccination].

Authors:
Kengo Maeda

Rinsho Shinkeigaku 2015 ;55(4):269

Department of Neurology, National Hospital Organization Higashi-ohmi General Medical Center.

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http://dx.doi.org/10.5692/clinicalneurol.55.269DOI Listing
September 2016

Wnt11 gene therapy with adeno-associated virus 9 improves the survival of mice with myocarditis induced by coxsackievirus B3 through the suppression of the inflammatory reaction.

J Mol Cell Cardiol 2015 Jul 14;84:45-51. Epub 2015 Apr 14.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya 466, Japan.

The wnt signaling pathway plays important roles in development and in many diseases. Recently several reports suggest that non-canonical Wnt proteins contribute to the inflammatory response in adult animals. However, the effects of Wnt proteins on virus-induced myocarditis have not been explored. Here, we investigated the effect of Wnt11 protein in a model of myocarditis induced by coxsackievirus B3 (CVB3) using recombinant adeno-associated virus 9 (rAAV9). The effect of Wnt11 gene therapy on a CVB3-induced myocarditis model was examined using male BALB/c mice. Mice received a single intravenous injection of either rAAV9-Wnt11 or rAAV9-LacZ 2 weeks before intraperitoneal administration of CVB3. Intravenous injection of the rAAV9 vector resulted in efficient, durable, and relatively cardiac-specific transgene expression. Survival was significantly greater among rAAV9-Wnt11 treated mice than among mice treated with rAAV9-LacZ (87.5% vs. 54.1%, P < 0.05). Wnt11 expression also reduced the infiltration of inflammatory cells, necrosis of the myocardium, and suppressed the mRNA expression of inflammatory cytokines. This is the first report to show that Wnt11 expression improves the survival of mice with CVB3-induced myocarditis. AAV9-mediated Wnt11 gene therapy produces beneficial effects on cardiac function and increases the survival of mice with CVB3-induced myocarditis through the suppression of both infiltration of inflammatory cells and gene expression of inflammatory cytokines.
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http://dx.doi.org/10.1016/j.yjmcc.2015.04.009DOI Listing
July 2015

Girdin/GIV regulates transendothelial permeability by controlling VE-cadherin trafficking through the small GTPase, R-Ras.

Biochem Biophys Res Commun 2015 May 11;461(2):260-7. Epub 2015 Apr 11.

Department of Cardiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan.

Vascular permeability is regulated by intercellular junction organization of endothelial cells, the dysfunction of which is implicated in numerous pathological conditions. Molecular mechanisms of how endothelial cells regulate intercellular junction in response to extracellular signals, however, have so far remained elusive. This study identified that Girdin (also termed GIV), an Akt substrate functioning in post natal angiogenesis, was expressed in a mature endothelial monolayer, where it regulated VE-cadherin trafficking to maintain vascular integrity. Girdin depletion abrogated VEGF-induced VE-cadherin endocytosis and the disassembly of adherens junctions in a monolayer of endothelial cells, thus leading to a significant decrease in the permeability. We also showed that activated R-Ras, a member of the Ras family GTPase, known to be a master regulator of transendothelial permeability, interacts with Girdin, and facilitates the complex formation between Girdin and VE-cadherin in endothelial cells. However, the increased permeability mediated by the loss of R-Ras was rescued by Girdin depletion, thus suggesting that the interaction of Girdin with R-Ras functions in VE-cadherin trafficking pathways distinct from endocytosis. The recycling of VE-cadherin was promoted by the exogenous expression of the active mutant of R-Ras, which was attenuated in the Girdin-depleted endothelial cells. These results show that Girdin regulates transendothelial permeability in synergy with R-Ras and VE-cadherin in an endothelial monolayer.
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http://dx.doi.org/10.1016/j.bbrc.2015.04.012DOI Listing
May 2015

New endoplasmic reticulum stress regulator, Gipie, regulates the survival of vascular smooth muscle cells and the neointima formation after vascular injury.

Arterioscler Thromb Vasc Biol 2015 May 19;35(5):1246-53. Epub 2015 Mar 19.

From the Departments of Cardiology (T.N., K.M., S.H., T.M.) and Pathology (N.A., A.E., M.T.), Nagoya University Graduate School of Medicine, Nagoya, Japan.

Objective: The accumulation of unfolded protein in the endoplasmic reticulum (ER) initiates an adaptive stress response, termed the unfolded protein response. Previous studies suggested that ER stress might be involved in the formation of neointima after vascular injury. We recently discovered a novel regulator of ER stress, 78-kDa glucose-regulated protein-interacting protein induced by ER stress (Gipie). The objective of this study was to elucidate the role of Gipie using models of vascular disease.

Approach And Results: We investigated the functions of Gipie in cultured vascular smooth muscle cells (VSMCs) and in a vascular injury model of a rat carotid artery. The expression of Gipie was predominantly detected in synthetic VSMCs and to a much lesser extent in contractile VSMCs, which was augmented by treatment with thapsigargin. Gipie knockdown increased the phosphorylation levels of c-Jun N-terminal kinase and the number of apoptotic cells under ER stress. Moreover, Gipie knockdown decreased the mature form of collagen I in synthetic VSMCs. The expression of Gipie was rarely detected in the medial VSMCs of the intact carotid artery, whereas it was detected in most of the neointimal cells and some of the medial VSMCs after balloon injury. Depletion of Gipie in the rat carotid artery attenuated the neointimal thickening, which was accompanied by increased cell death in the neointima. Conversely, overexpression of Gipie augmented the neointimal thickening.

Conclusions: Gipie participates in the ER stress response in VSMCs and plays an important role in neointima formation after vascular injury.
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http://dx.doi.org/10.1161/ATVBAHA.114.304923DOI Listing
May 2015

Akt-Girdin signaling in cancer-associated fibroblasts contributes to tumor progression.

Cancer Res 2015 Mar;75(5):813-23

Department of Pathology, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya, Japan.

PI3K-Akt signaling is critical for the development, progression, and metastasis of malignant tumors, but its role in the tumor microenvironment has been relatively little studied. Here, we report that the Akt substrate Girdin, an actin-binding protein that regulates cell migration, is expressed and activated by Akt phosphorylation in cancer-associated fibroblasts (CAF) and blood vessels within the tumor microenvironment. Lewis lung tumors grafted into mice defective in Akt-mediated Girdin phosphorylation (SA transgenic mice) exhibited a decrease in both CAF infiltration and tumor growth, compared with wild-type (WT) host control animals. Contrasting with the findings of other studies, we found that Akt-dependent phosphorylation of Girdin was not a rate-limiting step in the growth of endothelial cells. In addition, Lewis lung tumors displayed limited outgrowth when cotransplanted with CAF derived from tumor-bearing SA transgenic mice, compared with CAF derived from tumor-bearing WT mice. Collectively, our results revealed a role for Akt-mediated Girdin phosphorylation in CAF during tumor progression, highlighting the need to inhibit Akt function in both tumor cells and cells that comprise the tumor microenvironment.
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http://dx.doi.org/10.1158/0008-5472.CAN-14-1317DOI Listing
March 2015

Relation between paradoxical decrease in high-density lipoprotein cholesterol levels after statin therapy and adverse cardiovascular events in patients with acute myocardial infarction.

Am J Cardiol 2015 Feb 17;115(4):411-6. Epub 2014 Dec 17.

Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Statin therapy moderately increases high-density lipoprotein cholesterol (HDL-C) levels. Contrary to this expectation, a paradoxical decrease in HDL-C levels after statin therapy is seen in some patients. We evaluated 724 patients who newly started treatment with statins after acute myocardial infarction (AMI). These patients were divided into 2 groups according to change in HDL-C levels between baseline and 6 to 9 months after initial AMI (ΔHDL). In total, 620 patients had increased HDL-C levels and 104 patients had decreased HDL-C levels. Both groups achieved follow-up low-density lipoprotein cholesterol levels <100 mg/dl. Adverse cardiovascular events (a composite of all-cause death, myocardial infarction, and stroke) have more frequently occurred in the decreased HDL group compared with the increased HDL group (15.4% vs 7.1%, p = 0.01). Multivariate analysis showed that decreased HDL, onset to balloon time, and multivessel disease were the independent predictors of adverse cardiovascular events (hazard ratio [HR] 1.95, 95% confidence interval [CI] 1.08 to 3.52; HR 1.05, 95% CI 1.01 to 1.09; and HR 2.08, 95% CI 1.22 to 3.56, respectively). In conclusion, a paradoxical decrease in serum HDL-C levels after statin therapy might be an independent predictor of long-term adverse cardiovascular events in patients with AMI.
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http://dx.doi.org/10.1016/j.amjcard.2014.11.043DOI Listing
February 2015

A family with distal hereditary motor neuropathy and a K141Q mutation of small heat shock protein HSPB1.

Intern Med 2014 1;53(15):1655-8. Epub 2014 Aug 1.

Department of Neurology, National Hospital Organization Higashi-ohmi General Medical Center, Japan.

We herein describe a Japanese family with distal hereditary motor neuropathy carrying a K141Q mutation of small heat shock protein HSPB1. Two patients among them had late onset disease (older than 50 years). The muscles of the distal legs were weak and atrophic. Sensory and autonomic dysfunction were not seen. Even eight years after onset, one patient could still walk without support. A nerve conduction study revealed axonal degeneration of the motor nerves of the legs. A heterozygous K141Q mutation was detected in the affected patients. The late onset and mild clinical phenotype might reflect the mild biochemical alteration of HSP27 induced by the K141Q mutation.
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http://dx.doi.org/10.2169/internalmedicine.53.2843DOI Listing
June 2015
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