Publications by authors named "Jun Shimizu"

177 Publications

Myasthenia gravis with inflammatory myopathy without elevation of creatine kinase.

Neuromuscul Disord 2021 Apr 1. Epub 2021 Apr 1.

Department of Neurology, Teikyo University School of Medicine, Kaga 2-11-1, Itabashi-ku 1738605, Tokyo, Japan. Electronic address:

Cases of myasthenia gravis with inflammatory myopathy usually show elevated creatine kinase (CK) levels. There are few case reports of myasthenia gravis with inflammatory myopathy without elevated CK levels, and clinical features and useful diagnostic methods for these patients are little known. We describe the case of a 79-year-old man with myasthenia gravis that was complicated with inflammatory myopathy without elevated CK levels and successfully treated with immunological treatment. Initially, he was diagnosed with ocular myasthenia gravis and treated with pyridostigmine, but dysphagia and weakness in the neck and bilateral upper limb without fatigability gradually developed. Needle electromyography revealed myopathic changes, and the results of muscle biopsy were consistent with inflammatory myopathy. Blood tests showed normal CK levels throughout the clinical course and elevated myoglobin levels alone. The possibility of developing inflammatory myopathy in patients with myasthenia gravis cannot be excluded, even if CK levels are normal.
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http://dx.doi.org/10.1016/j.nmd.2021.03.010DOI Listing
April 2021

Reduced impact of viral load of HHV-6 in liquor on severity of AESD due to exanthema subitum: A case report and literature review.

Brain Dev 2021 May 7. Epub 2021 May 7.

Department of Neurology, Nagano Children's Hospital, Azumino, Japan. Electronic address:

Background: The most common causative pathogen of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) was reported as HHV-6. Although excitotoxic injury with delayed neuronal death is considered to be a possible pathogenesis of AESD, the detailed pathophysiology remains unclear.

Case Presentation: We present a twelve-month-old girl with AESD due to HHV-6 primary infection. She was successfully treated for AESD including targeted temperature management and the administration of vitamin B1, B6, and L-carnitine. Although the viral load of HHV-6 in her liquor was high (12,000 copies/mL), she fully recovered without antiviral agent use.

Discussion: There has been no study focusing on the HHV-6 viral load in patients with AESD, and only a few case reports have been published. We reviewed the clinical features and viral load in the liquor of our case and four reported infants with AESD due to HHV-6 primary infection who had real-time PCR tests results. Viral loads in the three patients with a poor prognosis were 31.5, negative, and 3,390 copies/mL, respectively. On the other hand, the copy numbers of HHV-6 DNA in the two patients with no sequelae were 12,000 and 106 copies/mL, respectively, and our case had the highest viral load among the five summarized patients.
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http://dx.doi.org/10.1016/j.braindev.2021.04.008DOI Listing
May 2021

Defective Reelin/Dab1 signaling pathways associated with disturbed hippocampus development of homozygous yotari mice.

Mol Cell Neurosci 2021 04 9;112:103614. Epub 2021 Apr 9.

Department of Immunology and Medicine, St. Marianna University School of Medicine, Sugao 2-16-1, Miyamae-ku, Kawasaki 216-8511, Japan. Electronic address:

Homozygous Dab1 yotari mutant mice, Dab1 (yot/yot) mice, have an autosomal recessive mutation of Dab1 and show reeler-like phenotype including histological abnormality of the cerebellum, hippocampus, and cerebral cortex. We here show abnormal hippocampal development of yot/yot mice where granule cells and pyramidal cells fail to form orderly rows but are dispersed diffusely in vague multiplicative layers. Possibly due to the positioning failure of granule cells and pyramidal cells and insufficient synaptogenesis, axons of the granule cells did not extend purposefully to connect with neighboring regions in yot/yot mice. We found that both hippocampal granule cells and pyramidal cells of yot/yot mice expressed proteins reactive with the anti-Dab1 antibody. We found that Y198- phosphorylated Dab1 of yot/yot mice was greatly decreased. Accordingly the downstream molecule, Akt was hardly phosphorylated. Especially, synapse formation was defective and the distribution of neurons was scattered in hippocampus of yot/yot mice. Some of neural cell adhesion molecules and hippocampus associated transcription factors of the neurons were expressed aberrantly, suggesting that the Reelin-Dab1 signaling pathway seemed to be importantly involved in not only neural migration as having been shown previously but also neural maturation and/or synaptogenesis of the mice. It is interesting to clarify whether the defective neural maturation is a direct consequence of the dysfunctional Dab1, or alternatively secondarily due to the Reelin-Dab1 intracellular signaling pathways.
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http://dx.doi.org/10.1016/j.mcn.2021.103614DOI Listing
April 2021

Female dominance of both spatial cognitive dysfunction and neuropsychiatric symptoms in a mouse model of Alzheimer's disease.

Exp Anim 2021 Apr 9. Epub 2021 Apr 9.

Department of Immunology and Medicine, St. Marianna University of School of Medicine.

Alzheimer's disease (AD) is a prevalent neurological disorder affecting memory function in elderly persons. Indeed, AD exhibits abnormality in cognitive behaviors and higher susceptibility to neuropsychiatric symptoms (NPS). Various factors including aging, sex difference and NPS severity, are implicated during in development of AD. In this study, we evaluated behavioral abnormalities of AD model, PDAPP transgenic mice at young age using the Morris Water Maze test, which was established to assess hippocampal-dependent learning and memory. We found that female AD model mice exhibited spatial learning dysfunction and highly susceptible to NPS such as anxiety and depression, whereas spatial reference memory function was comparable in female PDAPP Tg mice to female wild type (WT) mice. Spatial learning function was comparable in male AD model mice to male WT mice. Multiple regression analysis showed that spatial learning dysfunction was associated with NPS severity such as anxiety and depression. Furthermore, the analysis showed that spatial reference memory function was associated with status of depression, but not anxiety. Thus, these results suggest female dominance of spatial learning dysfunction in the AD model mice accompanying increased NPS severity. The understandings of AD model may be useful for the development of therapeutic agents and methods in human AD.
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http://dx.doi.org/10.1538/expanim.21-0009DOI Listing
April 2021

Dementia model mice exhibited improvements of neuropsychiatric symptoms as well as cognitive dysfunction with neural cell transplantation.

Exp Anim 2021 Apr 8. Epub 2021 Apr 8.

Department of Immunology and Medicine, St. Marianna University of School of Medicine.

Elderly patients with dementia suffer from cognitive dysfunctions and neuropsychiatric symptoms (NPS) such as anxiety and depression. Alzheimer's disease (AD) is a form of age-related dementia, and loss of cholinergic neurons is intimately associated with development of AD symptoms. We and others have reported that neural cell transplantation ameliorated cognitive dysfunction in AD model mice. It remains largely unclear whether neural cell transplantation ameliorates the NPS of AD. It would be interesting to determine whether NPS correlates with cognitive dysfunctions before and after neural cell transplantation in AD model mice. Based on the revalidation of our previous data from a Morris water maze test, we found that neural cell transplantation improved anxiety and depression significantly and marginally affected locomotion activity in AD mice. A correlation analysis revealed that the spatial learning function of AD mice was correlated with their NPS scores both before and after cell transplantation in a similar manner. In contrast, in the mice subjected to cell transplantation, spatial reference memory function was not correlated with NPS scores. These results suggested the neural cell transplantation in the AD model mice significantly improved NPS to the same degree as cognitive dysfunctions, possibly via distinct mechanisms, such as the cholinergic and GABAergic systems.
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http://dx.doi.org/10.1538/expanim.21-0008DOI Listing
April 2021

Differences in fractal patterns and characteristic periodicities between word salads and normal sentences: Interference of meaning and sound.

PLoS One 2021 18;16(2):e0247133. Epub 2021 Feb 18.

United Graduate School of Drug Discovery and Medical Information Sciences, Tokai National Higher Education and Research System, Gifu University, Gifu, Japan.

Fractal dimensions and characteristic periodicities were evaluated in normal sentences, computer-generated word salads, and word salads from schizophrenia patients, in both Japanese and English, using the random walk patterns of vowels. In normal sentences, the walking curves were smooth with gentle undulations, whereas computer-generated word salads were rugged with mechanical repetitions, and word salads from patients with schizophrenia were unreasonably winding with meaningless repetitive patterns or even artistic cohesion. These tendencies were similar in both languages. Fractal dimensions between normal sentences and word salads of schizophrenia were significantly different in Japanese [1.19 ± 0.09 (n = 90) and 1.15 ± 0.08 (n = 45), respectively] and English [1.20 ± 0.08 (n = 91), and 1.16 ± 0.08 (n = 42)] (p < 0.05 for both). Differences in long-range (>10) periodicities between normal sentences and word salads from schizophrenia patients were predominantly observed at 25.6 (p < 0.01) in Japanese and 10.7 (p < 0.01) in English. The differences in fractal dimension and characteristic periodicities of relatively long-range (>10) presented here are sensitive to discriminate between schizophrenia and healthy mental state, and could be implemented in social robots to assess the mental state of people in care.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0247133PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7891721PMC
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

Transcatheter aortic valve replacement in patients with extremely severe aortic stenosis.

Int J Cardiol 2021 04 5;329:162-166. Epub 2021 Jan 5.

Sakakibara Heart Institute, Tokyo, Japan.

Background: Although most patients with severe aortic stenosis (AS) have high aortic valve velocities, outcomes of transcatheter aortic valve replacement (TAVR) in patients with extremely high aortic valve velocities remain unclear. We aimed to investigate the clinical outcomes of patients with peak aortic jet velocity (Vmax) values ≥ 6 m/s.

Methods: The study included 913 consecutive patients who underwent TAVR between 2013 and 2020. To better understand the impacts of the higher Vmax on outcomes, patients with Vmax values < 4.0 m/s, ejection fractions < 50%, valve-in-valve procedures, and unstable hemodynamics were excluded. Patients were grouped according to preprocedural Vmax as follows: 4-5 m/s, 5-6 m/s, and ≥ 6 m/s. According to guidelines describing Vmax ≥ 5.0 m/s as "very" severe AS, Vmax ≥ 6.0 m/s was defined as "extremely" severe AS in this study.

Results: New York Heart Association classification-III/IV and severe left ventricular hypertrophy were more frequent in the extremely severe AS group, which concurred with the advanced stage of severe AS, and they had a similar mortality rate to the other groups. Although they showed the greatest Vmax improvements after TAVR, they had higher paravalvular leak (PVL) rates. Even among the patients who received newer-generation transcatheter aortic valves, they had higher PVL rates, despite more frequent balloon dilation than the other groups.

Conclusion: Although patients with extremely severe AS have similar mortality rates to other patients with severe AS after TAVR, the risk of procedural complications caused by more frequent balloon dilation should be considered.
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http://dx.doi.org/10.1016/j.ijcard.2020.12.080DOI Listing
April 2021

Dengue virus susceptibility in novel immortalized myeloid cells.

Heliyon 2020 Nov 3;6(11):e05407. Epub 2020 Nov 3.

Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, 1-1-1 Honjo, Chuo-ku, Kumamoto, 860-8556, Japan.

Human dendritic cells (DCs) are the main target cells of dengue virus (DENV). Because humans injected with even a small volume of DENV from mosquito saliva display a high level of viremia, DCs are expected to be highly susceptible to DENV. In the present study, we assessed the efficiency of DENV infection using the novel immortalized human myeloid cell lines iPS-ML and iPS-DC. To prepare the DC-like myeloid cell line (iPS-DC), iPS-ML cells were cultured in the presence of IL-4 for 72 h. iPS-DC cells were the most susceptible to DENV, followed by iPS-ML, Vero and K562 cells. In contrast, the highest infective yield titer was observed in Vero cells. To investigate further uses of iPS-ML and iPS-DC, these cells were applied to an assay measuring antibody-dependent enhancement (ADE) activity in DENV infection. Serum samples collected from healthy Thai participants and mouse monoclonal antibodies displayed similar ADE activity patterns when examined with iPS-ML, iPS-DC, or K562 cells, the last of which are usually used in conventional ADE assays. Interestingly, iPS-ML cells showed greater susceptibility to ADE activity than iPS-DC and K562 cells. Here, we demonstrated the potential utility of the novel immortalized human myeloid cell lines iPS-ML and iPS-DC in future research on DENV.
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http://dx.doi.org/10.1016/j.heliyon.2020.e05407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7644905PMC
November 2020

A case of granulomatous myositis in a patient with rheumatoid arthritis receiving anti-TNF-α treatment.

Mod Rheumatol Case Rep 2020 01 24;4(1):1-5. Epub 2019 Jun 24.

Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

A 66-year old woman with a 14-year history of rheumatoid arthritis (RA) and uveitis was admitted to our department for evaluation of a mass in the left neck. Fourteen months prior to this admission the patient was started on golimumab. Serum creatine kinase (CK) level was elevated and myositis-specific and -associated antibodies were negative. Manual muscle test showed weakness in the neck flexor, sternocleidomastoid and deltoid muscles. Magnetic resonance imaging (MRI) of the neck, erector muscle of spine, breech, thigh and lower thigh demonstrated high-intensity lesions in the muscles in short-tau inversion recovery images. Electromyography in the right deltoid detected fibrillation potentials. Muscle biopsy from the left neck mass showed granulomatous myositis. Muscle weakness improved and CK levels normalized after discontinuation of golimumab. We report a case of granulomatous myositis under anti-TNF-α treatment for RA.
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http://dx.doi.org/10.1080/24725625.2019.1628427DOI Listing
January 2020

Cerebrospinal fluid drainage to prevent postoperative spinal cord injury in thoracic aortic repair.

J Anesth 2021 02 26;35(1):43-50. Epub 2020 Sep 26.

Department of Anesthesiology, School of Medicine, The Jikei University, Minato Ku, Japan.

Background: Cerebrospinal fluid drainage (CSFD) is recommended as a spinal cord protective strategy in open and endovascular thoracic aortic repair. Although small studies support the use of CSFD, systematic reviews have not suggested definite conclusion and a large-scale study is needed. Therefore, we reviewed medical records of patients who had undergone descending and thoracoabdominal aortic repair (both open and endovascular repair) at multiple institutions to assess the association between CSFD and postoperative motor deficits.

Methods: Patients included in this study underwent descending or thoracoabdominal aortic repair between 2000 and 2013 at 12 hospitals belonging to the Japanese Association of Spinal Cord Protection in Aortic Surgery. We conducted a retrospective study to investigate whether motor-evoked potential monitoring is effective in reducing motor deficits in thoracic aortic aneurysm repair. We use the same dataset to examine whether CSFD reduces motor deficits after propensity score matching.

Results: We reviewed data from 1214 patients [open surgery, 601 (49.5%); endovascular repair, 613 (50.5%)]. CSFD was performed in 417 patients and not performed in the remaining 797 patients. Postoperative motor deficits were observed in 75 (6.2%) patients at discharge. After propensity score matching (n = 700), mixed-effects logistic regression performed revealed that CSFD is associated with postoperative motor deficits at discharge [adjusted odds ratio (OR), 3.87; 95% confidence interval (CI), 2.30-6.51].

Conclusion: CSFD may not be effective for postoperative motor deficits at discharge.
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http://dx.doi.org/10.1007/s00540-020-02857-wDOI Listing
February 2021

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

Pembrolizumab on pre-existing inclusion body myositis: a case report.

BMC Rheumatol 2020 16;4:48. Epub 2020 Sep 16.

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

Background: Cases of exacerbation of pre-existing neuromuscular diseases induced by immune checkpoint inhibitors (ICIs) have rarely been reported because patients with autoimmune diseases have generally been excluded from ICI therapy due to the increased risk of exacerbation. We describe the first case of an elderly patient who experienced exacerbation of a previously undiagnosed sporadic inclusion body myositis (sIBM), the most common myopathy in the geriatric population, which was triggered by anti-programmed cell death-1 therapy.

Case Presentation: A 75-year-old man who was receiving pembrolizumab presented with limb weakness. Three years prior, he had noticed slowly progressive limb weakness, but he received no diagnosis. After the first infusion of pembrolizumab, his creatine kinase (CK) levels had increased. The neurological examination and muscle biopsy findings confirmed the diagnosis of sIBM and suggested exacerbation of sIBM induced by pembrolizumab. After the patient's CK levels decreased, pembrolizumab was restarted. The tumor progressed after its treatment with pembrolizumab. The patient died after 15 months of follow-up.

Conclusions: In patients with slowly progressive limb weakness, sIBM should be explored before ICI therapy. In addition, if patients show high CK levels after ICI introduction, it is necessary to confirm whether they have sIBM in order to avoid unnecessary immunosuppressive therapies and assess whether they can tolerate ICI reintroduction.
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http://dx.doi.org/10.1186/s41927-020-00144-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493364PMC
September 2020

Elucidation of predictors of disease progression in patients with relapsing polychondritis at the onset: potential impact on patient monitoring.

BMC Rheumatol 2020 11;4:41. Epub 2020 Sep 11.

Department of Immunology and Medicine, and Division of Rheumatology and Allergology, Institute of Medical Science, St. Marianna University School of Medicine, Sugao 2-16-1, Miyamae-ku, Kawasaki, 216-8511 Japan.

Background: In patients with relapsing polychondritis (RP), organ involvement developed in those with progressive and/or long disease courses. For their management, elucidation of a subgroup suggesting disease progression is awaited.

Methods: We previously conducted a physician's questionnaire-based retrospective study to elucidate major clinical features of Japanese patients with RP. We here evaluated organ involvement at disease onset and at the last follow-up. We then counted cumulative numbers of involved organs at the last follow-up in 229 RP patients and compared them with involved organ numbers at disease onset, as possible indicators of disease progression. We assigned their prognosis at the last follow-up into "patient prognostic stages" from no medication (stage 1) to death (stage 5). We utilized nonparametric tests for group comparisons.

Results: Involved organ numbers per-patient were 1.13 ± 0.03 at disease onset and 3.25 ± 0.10 at the last follow-up (disease duration was 4.69 ± 0.33 years), and increased along with the patient prognostic stages.At disease onset, 135 and 48 patients had auricular involvement (59% of 229 patients, defined as auricular-onset subgroup; AO) and respiratory involvement (21%, respiratory-onset subgroup; RO), respectively. 46 patients presented with other conditions (20%, miscellaneous-onset subgroup; MO) including CNS, ocular, and inner ear involvement, among others.RO patients showed worse (poorer) prognostic stages than AO patients. MO patients developed respiratory and/or auricular involvement thereafter and then showed significantly higher mortality rate (15%; 7/46) than AO patients (5.9%; 8/135).In RP patients who did not develop respiratory involvement until the last follow-up (throughout the disease course; 117 patients), mortality rate was 19% in 26 MO patients and 3.3% in 91 AO patients. Accordingly, RO patients and MO patients associated with relatively poor prognosis compared with AO patients.

Conclusions: Allocation of patients to RO and MO subgroups was suggested to associate with poorer prognosis of RP than AO subgroups, especially AO subgroups without respiratory involvement throughout. All RP patients deserve careful monitoring but special attention should be paid to MO patients because of their diverse and accelerated disease progression.
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http://dx.doi.org/10.1186/s41927-020-00141-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7488391PMC
September 2020

Modified essential frailty toolset to determine outcomes following transcatheter aortic valve replacement.

J Cardiol 2021 Apr 23;77(4):341-345. Epub 2020 Aug 23.

Department of Cardiology, Sakakibara Heart Institute, Tokyo, Japan.

Background: Several predictors are available to guide patient selection for transcatheter aortic valve replacement (TAVR) to achieve better outcomes, and the essential frailty toolset (EFT) has been reported as one of those predictors. This study investigated whether a modified EFT could independently predict all-cause mortality following TAVR.

Methods: The study population comprised 176 consecutive patients with severe aortic stenosis whose frailty was assessed with a modified EFT prior to TAVR at the Sakakibara Heart Institute between 2013 and 2018. The primary endpoint was all-cause mortality following TAVR. To understand the association between the modified EFT and all-cause mortality, multivariate Cox regression analysis was performed. In addition, to understand its predictive performance, we conducted a receiver operating characteristic (ROC) analysis.

Results: Patients were elderly, relatively frail, and were likely to have significant heart failure symptoms. By the modified EFT definition, 40 patients (22.7%) were considered frail. With a median follow up of 1145 days, all-cause mortality at 1, 2, and 3 years was 6.2%, 10.2%, and 18.3%, respectively. Patients assessed as more frail on the clinical frailty scale had higher modified EFT scores. In ROC analysis, the area under the curve for predicting all-cause mortality at 1, 2, and 3 years was 0.79 [95% confidence interval (CI) 0.68-0.90]; 0.74 (95% CI 0.62-0.84); and 0.67 (95% CI 0.56-0.79), respectively, with the best cut-off modified EFT score of 1/2.

Conclusions: The modified EFT score was independently associated with all-cause mortality and had excellent predictive performance for all-cause mortality at 1 year.
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http://dx.doi.org/10.1016/j.jjcc.2020.07.021DOI Listing
April 2021

Recurrent HyperCKemia with Immunological Involvement of the Endomysial Capillaries in Neuromyelitis Optica.

Intern Med 2020 Dec 4;59(23):3079-3083. Epub 2020 Aug 4.

Department of Neurology, Showa University Fujigaoka Hospital, Japan.

A 55-year-old woman with neuromyelitis optica (NMO) had recurrent myalgias with hyperCKemia. A muscle biopsy suggested nonspecific myopathic changes. Regarding immunohistochemistry, the expression of both major histocompatibility complex class I and myxovirus resistance protein A was observed in the endomysial capillaries, suggesting immunological involvement of these capillaries, whereas both C5b9 (membrane attack complex) and aquaporin 4 immunofluorescence stainings were normal. The present findings led us to conclude that one possible mechanism for hyperCKemia in NMO underlying the immunological involvement of the endomysial capillaries was an as-yet-unidentified factor that triggered damage to the integrity of the sarcolemma and thereby cause CK leakage into the serum.
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http://dx.doi.org/10.2169/internalmedicine.4600-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759704PMC
December 2020

Transcatheter aortic valve implantation-related futility: prevalence, predictors, and clinical risk model.

Heart Vessels 2020 Sep 6;35(9):1281-1289. Epub 2020 Apr 6.

Department of Cardiology, Sakakibara Heart Institute, 3-16-1 Asahi-cho, Fuchu, Tokyo, 183-0003, Japan.

Futility denotes failure to achieve the projected outcome. We investigated the prevalence, predictors, and clinical risk model of transcatheter aortic valve implantation (TAVI)-related futility. We included 464 consecutive patients undergoing TAVI from 2010 to 2017. Futility was defined as death and/or hospitalization for heart failure (HFH) within 1 year after TAVI. Of 464 patients (mean age: 84.4 years), 69% were females (EuroSCOREII: 6.3%; Society of Thoracic Surgeons [STS] score: 6.9%). Forty-six patients (9.9%) experienced TAVI-related futility, and 36 of 46 patients (69.6%) died within 1 year due to cardiac (37.5%) and non-cardiac (62.5%) causes. Previous HFH (hazard ratio [HR], 2.20; 95% confidence interval [CI]: 1.13-4.35, p = 0.020), chronic obstructive pulmonary disease (COPD) (HR, 3.39; 95% CI: 1.12-8.42, p = 0.033), and moderate/severe mitral or tricuspid regurgitation (HR, 2.98; 95% CI: 1.32-6.27, p = 0.010) were independent predictors of futility. With 1 point assigned to each predictor (total 0 point, futility low-risk; total 1 point, futility intermediate-risk; total 2-3 points, futility high-risk), the futility risk model clearly stratified individual futility risk into three groups (the freedom from futility at 1 year: 96.2%, 82.1%, and 67.9% each). Our futility risk model presented better discrimination than EuroSCOREII, and STS score (c-statistic: 0.73 vs. 0.68 vs. 0.67). Medical futility was recognized in 9.9% of patients undergoing TAVI. Previous HFH, COPD, and concomitant atrioventricular regurgitation were associated with futility. The risk model derived from three predictors showed good performance in predicting futility risk.
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http://dx.doi.org/10.1007/s00380-020-01599-9DOI Listing
September 2020

Microencapsulated G3C Hybridoma Cell Graft Delays the Onset of Spontaneous Diabetes in NOD Mice by an Expansion of Gitr Treg Cells.

Diabetes 2020 05 13;69(5):965-980. Epub 2020 Mar 13.

Section of Pharmacology, Department of Medicine, University of Perugia, Perugia, Italy.

As an alternative to lifelong insulin supplementation, potentiation of immune tolerance in patients with type 1 diabetes could prevent the autoimmune destruction of pancreatic islet β-cells. This study was aimed to assess whether the G3c monoclonal antibody (mAb), which triggers the glucocorticoid-induced TNFR-related (Gitr) costimulatory receptor, promotes the expansion of regulatory T cells (Tregs) in SV129 (wild-type) and diabetic-prone NOD mice. The delivery of the G3c mAb via G3C hybridoma cells enveloped in alginate-based microcapsules (G3C/cps) for 3 weeks induced Foxp3 Treg-cell expansion in the spleen of wild-type mice but not in Gitr mice. G3C/cps also induced the expansion of nonconventional Cd4Cd25Foxp3Gitr (GITR single-positive [sp]) Tregs. Both Cd4Cd25GitrFoxp3 and GITRsp Tregs (including also antigen-specific cells) were expanded in the spleen and pancreas of G3C/cps-treated NOD mice, and the number of intact islets was higher in G3C/cps-treated than in empty cps-treated and untreated animals. Consequently, all but two G3C/cps-treated mice did not develop diabetes and all but one survived until the end of the 24-week study. In conclusion, long-term Gitr triggering induces Treg expansion, thereby delaying/preventing diabetes development in NOD mice. This therapeutic approach may have promising clinical potential for the treatment of inflammatory and autoimmune diseases.
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http://dx.doi.org/10.2337/db19-0087DOI Listing
May 2020

Interaction between SDF1 and CXCR4 Promotes Photoreceptor Differentiation via Upregulation of NFκB Pathway Signaling Activity in Pax6 Gene-Transfected Photoreceptor Precursors.

Ophthalmic Res 2020 14;63(4):392-403. Epub 2020 Jan 14.

Departments of Immunology and Medicine, St. Marianna University Graduate School of Medicine, Kawasaki, Japan,

Background: CCL2 (also known as monocyte chemoattractant protein 1) and CX3CR1 (also known as Fractalkine receptor)-deficient mice have damaged photoreceptors.

Objectives: We examined the interaction of SDF1 and CXCR4 on the differentiation of retinal progenitors into rhodopsin-positive photoreceptors.

Methods: Cloned retinal progenitors were obtained by Pax6 gene transfection of mouse iPS cells followed by serial dilution. Clones were selected by expression of nestin, Musashi1, Six3, and Chx10 mRNA. Cell surface protein expression was analyzed by flow cytometry. The levels of mRNA and intracellular protein were examined by real-time PCR and immunochemistry, respectively. Transient transfection experiments of retinal progenitors were conducted using a human rhodopsin promoter luciferase plasmid.

Results: We selected 10 clones that expressed Six3, Chx10, Crx, Rx1, Nrl, CD73, and rhodopsin mRNA, which, except for rhodopsin, are photoreceptor precursor markers. Clones expressed both CD73 and CXCR4 on the cell surface and differentiated into rhodopsin-positive photoreceptors, which was reinforced by the addition of exogenous SDF1. A CXCR4 inhibitor AMD3100 blocked SDF1-mediated differentiation of progenitors into photoreceptors. SDF1 enhanced human rhodopsin promoter transcription activity, possibly via the NFκB pathway. Addition of SDF1 to the cell culture induced nuclear translocation of NFκB on retinal progenitor cell clones. Neonatal and newborn mouse retinas expressed SDF1 and CXCR4. Cells in the outer nuclear layer where photoreceptors are located expressed CXCR4 at P14 and P56. Cells in the inner nuclear layer expressed SDF1.

Conclusions: These findings suggest that retinal progenitor cell differentiation was at least partly regulated by SDF1 and CXCR4 via upregulation of NFκB activity.
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http://dx.doi.org/10.1159/000503929DOI Listing
June 2021

A Novel de novo KIF1A Mutation in a Patient with Autism, Hyperactivity, Epilepsy, Sensory Disturbance, and Spastic Paraplegia.

Intern Med 2020 Mar 6;59(6):839-842. Epub 2019 Dec 6.

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

Heterozygous mutations in KIF1A have been reported to cause syndromic intellectual disability or pure spastic paraplegia. However, their genotype-phenotype correlations have not been fully elucidated. We herein report a man with autism and hyperactivity along with sensory disturbance and spastic paraplegia, carrying a novel de novo mutation in KIF1A [c.37C>T (p.R13C)]. Autism and hyperactivity have only previously been reported in a patient with c.38 G>A (R13H) mutation. This case suggests that alterations in this arginine at codon 13 might lead to a common clinical spectrum and further expand the genetic and clinical spectra associated with KIF1A mutations.
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http://dx.doi.org/10.2169/internalmedicine.3661-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118386PMC
March 2020

First external validation of sensitivity and specificity of the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for idiopathic inflammatory myopathies with a Japanese cohort.

Ann Rheum Dis 2020 03 6;79(3):387-392. Epub 2019 Nov 6.

Department of Rheumatology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan

Objective: To externally validate the performance of the new European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria set for idiopathic inflammatory myopathies (IIM) with a Japanese cohort.

Methods: This study included 420 IIM and 402 non-IIM cases. Probability of having IIM in each patient was calculated using the collected data set. The cut-off probability was set at 55%, as recommended by EULAR/ACR. Patients classified as IIM by the criteria were further subclassified with classification trees.

Results: When the probability cut-off was set at 55%, the sensitivity/specificity of the new criteria to diagnose IIM were 89.3%/91.0% in the total cohort, 88.1%/95.1% without muscle biopsy data and 90.4%/65.5% with biopsy data. The cohort included 12 overlap syndrome patients with biopsy data, who were included as non-IIM cases in accordance with traditional Japanese methods. When they were included in the IIM cases, the specificity in patients with biopsy increased to 74.4%. The sensitivity/specificity of the new criteria to diagnose polymyositis/dermatomyositis (PM/DM) plus juvenile and amyopathic DM in the Japanese cohort was 87.4%/92.4%, which were greater than those of the Tanimoto's criteria revised to enable classification of amyopathic DM (ADM) (71.2%/87.8%) and were comparable with those of Bohan & Peter's criteria to diagnose those diseases except for ADM (88.4%/88.3%).

Conclusions: Our study externally validated high specificity of the new criteria for the first time, although with several limitations, including low percentage of child patients. The new criteria have higher sensitivity and/or specificity in classification of PM/DM than the previously reported criteria, demonstrating its usefulness for interethnic patients.
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http://dx.doi.org/10.1136/annrheumdis-2019-215488DOI Listing
March 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

Collagen-derived dipeptide prolyl hydroxyproline directly binds to Foxg1 to change its conformation and inhibit the interaction with Runx2.

Biosci Biotechnol Biochem 2019 Nov 19;83(11):2027-2033. Epub 2019 Jul 19.

Faculty of Pharmaceutical Sciences, Josai University , Sakado , Japan.

Collagen-derived dipeptide prolyl hydroxyproline (Pro-Hyp) is involved in the proliferation and differentiation of various types of cultured cells. To elucidate the mechanism underlying Pro-Hyp actions during osteoblast differentiation, we hypothesized that proteins binding to Pro-Hyp serve to mediate cellular signaling, affecting Runx2 expression. Recently, we performed the characterization of Foxg1, that it enhances Runx2 expression in the presence of Pro-Hyp. Our findings indicate that Pro-Hyp directly binds to the Foxg1 recombinant protein, which leads to the structural alteration of the Foxg1 protein. In addition, Foxg1 appears to interact with Runx2 in the absence of Pro-Hyp, with Pro-Hyp disrupting the interaction between Foxg1 and Runx2. Collectively, our results indicate that the Pro-Hyp bound Foxg1 alters the structured conformation of Foxg1, resulting in conformational changes that lead to dissociation from Runx2. These novel findings suggest that during osteoblast differentiation, Pro-Hyp mediates Runx2 activity though directly binding to Foxg1 and increases Runx2 expression. CPT: collagen peptide; GST: Glutathione S-transferase; PAGE: Polyacrylamide gel electrophoresis; PCR: Polymerase chain reaction; prolyl hydroxyproline: Pro-Hyp.
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http://dx.doi.org/10.1080/09168451.2019.1642099DOI Listing
November 2019

Roles of Reelin/Disabled1 pathway on functional recovery of hemiplegic mice after neural cell transplantation; Reelin promotes migration toward motor cortex and maturation to motoneurons of neural grafts.

Exp Neurol 2019 10 8;320:112970. Epub 2019 Jun 8.

Department of Immunology and Medicine, St. Marianna University School of Medicine, Department of Regenerative Medicine, St. Marianna Graduate School of Medicine, Sugao 2-16-1, Miyamae-ku, Kawasaki, Kanagawa 216-8511, Japan. Electronic address:

Reelin is a large glycoprotein which regulates central nervous system (CNS) development. Dysfunctions of Reelin were reported on certain neuropsychiatric diseases. We examined involvement of Reelin pathway in functional recovery of hemiplegic mice after neural transplantation. Reelin was expressed 1 day after cryogenic injury of right motor cortex. We transplanted neural stem/progenitor cells (NSPCs) from wild-type mice into ipsilateral striatum of hemiplegic mice. The grafts migrated from the striatum and reached the injured cortex 14 days after transplantation. The transplantation significantly improved their motor functions (P < .05). The NSPCs migrating toward the cortex expressed Reelin receptors, Apoer and Vldlr, and phosphorylated Disabled1 (Dab1), a downstream signaling molecule of Reelin. The grafts expressed Ncadherin and active form of Integrin β1, both of which were known to become active with Reelin stimulation. At day 28, the grafts expressed Ctip2, Crim1, Foxp2, and Fezf2, all of which were forebrain motoneuron associated markers, and Nfm and Synapsin1 on the damaged cortex. We then transplanted NSPCs of yotari mice (yot/yot genotype) having nonfunctional Dab1 by a mutation of its gene. Majority of the grafts from yotari mice (>80%) did not migrate and thus remained at the striatum. The grafts did not express the forebrain motoneuron associated markers nor the cell adhesion molecules including Ncadherin and active Integrin β1. Reelin pathway was involved in graft migration by regulating certain adhesion molecules and in their differentiation to functional motoneurons accompanying synapse formation. We suggested involvement of Reelin pathway for neural regeneration and functional recovery of hemiplegic mice in adulthood after neural transplantation.
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http://dx.doi.org/10.1016/j.expneurol.2019.112970DOI Listing
October 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

Cognitive assessment using the revised Hasegawa's dementia scale to determine the mid-term outcomes following transcatheter aortic valve replacement.

J Cardiol 2019 Sep 20;74(3):206-211. Epub 2019 Apr 20.

Department of Cardiology, Sakakibara Heart Institute, Tokyo, Japan.

Background: Several predictors are available to guide patient selection for transcatheter aortic valve replacement (TAVR) to achieve better outcomes, and cognitive function is one of these predictors. This study investigated whether the revised Hasegawa's dementia scale (HDS-R) could independently predict mid-term outcomes following TAVR.

Methods: The study population comprised 455 patients with severe aortic stenosis who underwent TAVR at the Sakakibara Heart Institute between 2010 and 2018. The primary endpoint was all-cause mortality following TAVR. Patients were dichotomized into two groups according to the receiver operating characteristic analysis (HDS-R ≤23 and >23).

Results: Patients with HDS-R ≤23 were older, were more frail, were more likely to have peripheral artery disease, had lower serum albumin levels, had lower ejection fractions, and had smaller aortic valve areas than those with HDS-R >23. By definition, 81 of the 455 patients (17.8%) were considered to have dementia (HDS-R ≤20) before TAVR. The discriminatory performance for predicting all-cause mortality at 3 years was greater for dichotomization with 23/24 than that with 20/21 [area under the curve (AUC): 0.63, 95% confidence interval (CI): 0.50-0.76, p=0.047 vs. AUC: 0.52, 95% CI: 0.39-0.65, p=0.713]. From the Kaplan-Meier analysis, patients with HDS-R ≤23 had higher mortality rates than those with HDS-R >23 (86.8±3.3% and 75.4±4.7% at 3 years, respectively; log-rank p=0.001). The multivariate Cox regression analysis found that the HDS-R was independently associated with all-cause mortality (hazard ratio 2.11, 95% CI 1.21-3.69, p=0.008).

Conclusions: Patients with HDS-R ≤23 were sicker and more frail and had greater cognitive impairment. Additionally, HDS-R could independently predict mid-term outcomes following TAVR.
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http://dx.doi.org/10.1016/j.jjcc.2019.03.017DOI Listing
September 2019

Tumefactive multiple sclerosis which initially presented with brainstem encephalitis with a long-term follow-up.

Mult Scler Relat Disord 2019 Jul 17;32:23-26. Epub 2019 Apr 17.

Department of Neurology, Tokyo Teishin Hospital, 2-14-23 Fujimi, Chiyoda-ku, Tokyo 102-8798, Japan.

Tumefactive demyelinating lesions (TDLs) are rare in multiple sclerosis (MS). We herein report a case of tumefactive MS which initially presented with brainstem encephalitis with a long-term follow-up. The patient had experienced relapse mostly in the brainstem in the first twenty years, and then in the periventricular white matter afterwards. The patient responded well to steroid treatment recovered without sequalae. However, immunodeficiency due to the long-term use of oral prednisolone made aggressive therapy during the relapse impossible, so recovery after steroid therapy is incomplete. Our case is different from classical MS in clinical course and response to treatment. Our report offers rare information on long-term outcome of tumefactive MS.
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http://dx.doi.org/10.1016/j.msard.2019.04.018DOI Listing
July 2019

Long-term outcomes in Japanese nonagenarians undergoing transcatheter aortic valve implantation: A multi-center analysis.

Clin Cardiol 2019 Jun 23;42(6):605-611. Epub 2019 Apr 23.

Department of Cardiology, Sakakibara Heart Institute, Tokyo, Japan.

Background And Hypothesis: Japan is an aging society, and the number of nonagenarians with severe aortic stenosis undergoing transcatheter aortic valve implantation (TAVI) is increasing, but their outcomes have not been determined fully.

Methods: We prospectively enrolled 767 consecutive patients who underwent TAVI in three Japanese institutions. Clinical characteristics and outcomes of nonagenarians (n = 94) were evaluated and compared with those of patients aged <90 years (n = 673).

Results: Prevalence of New York Heart Association (NYHA) class III/IV was not different between the two groups. Preoperative risk scores were significantly higher in nonagenarians compared with those in non-nonagenarians, whereas the Clinical Frailty Scale was not different. Thirty-day mortality tended to be higher (P = .06) and major vascular complication was significantly higher in nonagenarians than in non-nonagenarians (P < .05), but 3-year mortality was equivalent between the two groups. Even after adjustment for covariates, female sex (hazard ratio, 0.41; 95% confidence interval: 0.25-0.67), body mass index (0.87, 0.80-0.94), and NYHA class III/IV (1.84, 1.06-3.29) were associated with all-cause mortality. Age ≥ 90 years was not associated with all-cause mortality.

Conclusions: TAVI could be undertaken safely and effectively in nonagenarians, who had acceptable long-term results compared with those for younger patients, although careful attention should be paid to major vascular complication.
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http://dx.doi.org/10.1002/clc.23183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553359PMC
June 2019