Exploring the contribution of Japan's experience in addressing rapid aging in Asia: Focus on dementia care.

This review article explores the potential contribution of Japan's experience in addressing rapid aging in Asia with a specific focus on dementia care. As Japan is a frontrunner in terms of aging society, we consider valuable insights and lessons from Japanese policy history and reflect on its contribution. The World Health Organization, Regional Office for the Western Pacific Regional Action Plan on Healthy Ageing for the Western Pacific was compared with the Japanese "Outline for Promotion of Dementia Policies". The following five issues were discussed: i) improving awareness of dementia and community engagement in Japan from a mutual aid perspective; ii) social activities for prevention of dementia at the local level; iii) human resources for medical and long-term care; iv) local coordinators for old people care at home to evaluate the needs for care and tailor the care-plan on an individual basis; v) research and development of long-term care products. Given these factors, it is important to address the aging society through a combined cross-sectoral approach, including policy, research, development of care products, community, and education of care workers. Aging population measures in Japan do not provide a definitive answer, which prompts the consideration of better solutions derived from Japan's trial and error. The aging rate of 7%, 14%, and 21% are commonly used in international comparisons as indicators of the speed of the aging process, but before this 7% is reached, policies tailored to each country should be considered.

Anesthetic Management of a Patient With Central Core Disease Undergoing Thoracoscopic Lung Resection: The Importance of Neuromuscular Monitoring at the Masseter Muscle.

Central core disease is a rare muscular disorder in which anesthetic considerations for the prevention of malignant hyperthermia and for avoidance of residual neuromuscular block are required. A 63-year-old woman with central core disease underwent thoracoscopic sublobar lung resection under total IV anesthesia with a prepared anesthetic workstation. The rocuronium-induced neuromuscular block was monitored by using acceleromyography at the left adductor pollicis muscle and the right masseter muscle. The recovery of neuromuscular block at the masseter was slower than that at the adductor pollicis. The patient showed no symptoms of malignant hyperthermia and residual neuromuscular block and had an uneventful postoperative course. In the present case, malignant hyperthermia was successfully prevented with general anesthesia that is free of triggering agents using a prepared anesthetic machine. The authors speculate that the masseter may be an auxiliary site for neuromuscular monitoring to ensure recovery from neuromuscular block in patients with central core disease.

Experiences of nurses in charge of COVID-19 critical care patients during the initial stages of the pandemic in Japan.

The fatality rate of the coronavirus disease (COVID-19) at the beginning of the pandemic was as high as 8.5%, and it was considered to be an intractable infectious disease. Reports regarding early experiences are essential for improving nurses' quality of care, patient safety, and working conditions during future pandemics. Therefore, this study aimed to describe the experiences of nurses who were in charge of critically ill COVID-19 patients during the early stages of the pandemic in Japan. This was a qualitative study. Participants were nurses who were in charge of critically ill COVID-19 patients in an emerging contagious disease ward between February and April 2020. Interviews were conducted in groups of 2-3 persons based on an interview guide using an online conferencing application to prevent infection. Consent to participation was obtained from 19 nurses. Five categories of experiences were generated from the analysis: "Fear of risk to my own life and to those of others around me", "The shock of finding myself amid an infectious disease pandemic", "Anxiety about unknown challenges", "Driven by a sense of purpose", and "Growth as nurses". Working under harsh conditions where nurses' safety is threatened may affect the quality of care and nurses' mental health. Therefore, nurses should receive both short-term and long-term support.

Intravenous immunoglobulin preparations attenuate lysolecithin-induced peripheral demyelination in mice and comprise anti-large myelin protein zero antibody.

Intravenous immunoglobulin (IVIg) has been used to treat inflammatory demyelinating diseases such as chronic inflammatory demyelinating polyneuropathy, Guillain-Barré syndrome, and multifocal motor neuropathy. Despite studies demonstrating the clinical effectiveness of IVIg, the mechanisms underlying its effects remain to be elucidated in detail. Herein, we examined the effects of IVIg on lysolecithin-induced demyelination of the sciatic nerve in a mouse model. Mice -administered with IVIg 1 and 3 days post-injection (dpi) of lysolecithin -exhibited a significantly decreased demyelination area at 7 dpi. Immunoblotting analysis using two different preparations revealed that IVIg reacted with a 36-kDa membrane glycoprotein in the sciatic nerve. Subsequent analyses of peptide absorption identified the protein as a myelin protein in the peripheral nervous system (PNS) known as large myelin protein zero (L-MPZ). Moreover, injected IVIg penetrated the demyelinating lesion, leading to deposition on L-MPZ in the myelin debris. These results indicate that IVIg may modulate PNS demyelination, possibly by binding to L-MPZ on myelin debris.

How Hospitals Overcame Disruptions in the Early Stages of the COVID-19 Pandemic: A Case Study from Tokyo, Japan.

The COVID-19 pandemic has caused serious disruptions to health systems across the world. While the pandemic has not ended, it is important to better understand the resilience of health systems by looking at the response to COVID-19 by hospitals and hospital staff. Part of a multi-country study, this study looks at the first and second waves of the pandemic in Japan and examines disruptions experienced by hospitals because of COVID-19 and the processes through which they overcame those disruptions. A holistic multiple case study design was employed, and two public hospitals were selected for the study. A total of 57 interviews were undertaken with purposively selected participants. A thematic approach was used in the analysis. The study found that in the early stages of the pandemic, faced with a previously unknown infectious disease, to facilitate the delivery of care to COVID-19 patients while also providing limited non-COVID-19 health care services, the case study hospitals undertook absorptive, adaptive, and transformative actions in the areas of hospital governance, human resources, nosocomial infection control, space and infrastructure management, and management of supplies. The process of overcoming the disruptions caused by the pandemic was complex, and the solution to one issue often caused other problems. To inform preparations for future health shocks and promote resilience, it is imperative to further investigate both organizational and broader health system factors that build absorptive, adaptive, and transformative capacity in hospitals.

How should support for hospital staff during health shocks be improved? A discussion from Japan's experience during the COVID-19 pandemic.

Human resources for health are at the center of healthcare service delivery and play an important role in ensuring the resilience of health systems. Utilizing the results from a case study examining hospital resilience during COVID-19, this article draws on the experience of individual hospital staff during the first and second waves of the pandemic, briefly describes government responses to support human resources for health during the early stages of the pandemic, and argues the importance of constructive discussions about strategies to create an enabling work environment for healthcare providers, both clinical and non-clinical, during future health shocks.

Paranodal Axoglial Junctions, an Essential Component in Axonal Homeostasis.

In vertebrates, a high density of voltage-gated Na+ channel at nodes of Ranvier and of voltage-gated K+ channel at juxtaparanodes is necessary for rapid propagation of action potential, that is, for saltatory conduction in myelinated axons. Myelin loops attach to the axonal membrane and form paranodal axoglial junctions (PNJs) at paranodes adjacent to nodes of Ranvier. There is growing evidence that the PNJs contribute to axonal homeostasis in addition to their roles as lateral fences that restrict the location of nodal axolemmal proteins for effective saltatory conduction. Perturbations of PNJs, as in specific PNJ protein knockouts as well as in myelin lipid deficient mice, result in internodal axonal alterations, even if their internodal myelin is preserved. Here we review studies showing that PNJs play crucial roles in the myelinated axonal homeostasis. The present evidence points to two functions in particular: 1) PNJs facilitate axonal transport of membranous organelles as well as cytoskeletal proteins; and 2) they regulate the axonal distribution of type 1 inositol 1,4,5-trisphosphate receptor (IP3R1) in cerebellar Purkinje axons. Myelinated axonal homeostasis depends among others on the state of PNJs, and consequently, a better understanding of this dependency may contribute to the clarification of CNS disease mechanisms and the development of novel therapies.

[Introduction to Myelin Research].

Myelin is a multilamellar membrane structure formed by oligodendrocytes in the central nervous system (CNS) and Schwann cells in the peripheral nervous system (PNS). It has been recognized as an insulator that is essential for the rapid and efficient propagation of action potentials by saltatory conduction. However, recently many studies have shown that myelin and myelin-forming cells interact with axons and regulate the nervous system far more actively than previously thought. For example, myelination changes axons dynamically and divides them into four distinct functional domains: node of Ranvier, paranode, juxtaparanode, and internode. Voltage-gated Na+ channels are clustered at the node, while K+ channels are at the juxtaparanode, and segregation of these channels by paranodal axoglial junction is necessary for proper axonal function. My research experience began at the neurology ward of the Niigata University Medical Hospital, where I saw a patient with peripheral neuropathy of unknown etiology more than 37 years ago. In the patient's serum, we found an autoantibody against a glycolipid enriched in the PNS. Since then, I have been interested in myelin because of its beautiful structure and unique roles in the nervous system. In this review, our recent studies related to CNS and PNS myelin are presented.

Reporting on the implementation to set up a "care and isolation facility" for mild COVID-19 cases in Tokyo.

The increasing number of COVID-19 cases has placed pressure on medical facilities. Against this backdrop, the Tokyo Metropolitan Government established a facility for mild and asymptomatic COVID-19 cases by using existing hotels. These kinds of facilities were established in several countries, and represented a spectrum from hotel-like to hospital-like care. In this article, we focused on implementation and related strategies for establishing such a facility in Tokyo as implementation research, while ensuring patient and staff safety. This facility had three functions: care, isolation, and buffering. For the implementation strategy, we used several strategies from the Expert Recommendations for Implementing Change (ERIC) to implement functions similar to an ordinary hospital, but using fewer inputs. This experience can be applied to other resource-limited settings such as that in less developed countries.

Influence of novel readthrough agents on myelin protein zero translation in the peripheral nervous system.

Translational readthrough-inducing agents have been developed for the treatment of nonsense mutations in hereditary diseases. The clinical effectiveness of readthrough agents has been reported, although newly developed agents are still desired because of their toxicities or limited clinical effectiveness. Recently, novel negamycin-derived readthrough agents without antimicrobial activity have been developed. Our aim was to evaluate the activities of these readthrough agents by monitoring the production of large myelin protein zero (L-MPZ), the programmed translational readthrough isoform of myelin protein zero (P0, MPZ) mRNA, and to clarify the influence of these agents on the sciatic nerve in vivo. First, we examined the readthrough activities of novel negamycin-derived agents using cell-free and cell culture systems using plasmids encoding human MPZ (hP0) cDNA. Three of the negamycin derivatives, TCP-112, TCP-169, and TCP-1109, suppressed the canonical stop codon to induce readthrough. Direct injection of TCP-1109, which showed higher readthrough activity for Mpz in mouse sciatic nerves, exhibited a 1.3-fold increase in the L-MPZ/P0 ratio compared to that with the vehicle control on western blotting. The nerve conduction velocity and beam walk test showed abnormalities in the classical readthrough agent G418-treated group, but not in the TCP-1109-treated group. Immunofluorescence analysis showed that TCP-1109 caused less damage to the sciatic nerve than G418. In the semi-thin sections, a lower g-ratio and more tomacula-like structures were observed in TCP-1109-treated nerves. Thus, the present results indicate that negamycin-derived readthrough agents enhance programmed translational readthrough, and the management of readthrough activities using canonical stop codons may be important.

Microglial ASD-related genes are involved in oligodendrocyte differentiation.

Autism spectrum disorders (ASD) are associated with mutations of chromodomain-helicase DNA-binding protein 8 (Chd8) and tuberous sclerosis complex 2 (Tsc2). Although these ASD-related genes are detected in glial cells such as microglia, the effect of Chd8 or Tsc2 deficiency on microglial functions and microglia-mediated brain development remains unclear. In this study, we investigated the role of microglial Chd8 and Tsc2 in cytokine expression, phagocytosis activity, and neuro/gliogenesis from neural stem cells (NSCs) in vitro. Chd8 or Tsc2 knockdown in microglia reduced insulin-like growth factor-1(Igf1) expression under lipopolysaccharide (LPS) stimulation. In addition, phagocytosis activity was inhibited by Tsc2 deficiency, microglia-mediated oligodendrocyte development was inhibited, in particular, the differentiation of oligodendrocyte precursor cells to oligodendrocytes was prevented by Chd8 or Tsc2 deficiency. These results suggest that ASD-related gene expression in microglia is involved in oligodendrocyte differentiation, which may contribute to the white matter pathology relating to ASD.

Learning from public health and hospital resilience to the SARS-CoV-2 pandemic: protocol for a multiple case study (Brazil, Canada, China, France, Japan, and Mali).

BACKGROUND: All prevention efforts currently being implemented for COVID-19 are aimed at reducing the burden on strained health systems and human resources. There has been little research conducted to understand how SARS-CoV-2 has affected health care systems and professionals in terms of their work. Finding effective ways to share the knowledge and insight between countries, including lessons learned, is paramount to the international containment and management of the COVID-19 pandemic. The aim of this project is to compare the pandemic response to COVID-19 in Brazil, Canada, China, France, Japan, and Mali. This comparison will be used to identify strengths and weaknesses in the response, including challenges for health professionals and health systems. METHODS: We will use a multiple case study approach with multiple levels of nested analysis. We have chosen these countries as they represent different continents and different stages of the pandemic. We will focus on several major hospitals and two public health interventions (contact tracing and testing). It will employ a multidisciplinary research approach that will use qualitative data through observations, document analysis, and interviews, as well as quantitative data based on disease surveillance data and other publicly available data. Given that the methodological approaches of the project will be largely qualitative, the ethical risks are minimal. For the quantitative component, the data being used will be made publicly available. DISCUSSION: We will deliver lessons learned based on a rigorous process and on strong evidence to enable operational-level insight for national and international stakeholders.

Upregulation of large myelin protein zero leads to Charcot-Marie-Tooth disease-like neuropathy in mice.

Charcot-Marie-Tooth (CMT) disease is a hereditary neuropathy mainly caused by gene mutation of peripheral myelin proteins including myelin protein zero (P0, MPZ). Large myelin protein zero (L-MPZ) is an isoform of P0 that contains an extended polypeptide synthesized by translational readthrough at the C-terminus in tetrapods, including humans. The physiological role of L-MPZ and consequences of an altered L-MPZ/P0 ratio in peripheral myelin are not known. To clarify this, we used genome editing to generate a mouse line (L-MPZ mice) that produced L-MPZ instead of P0. Motor tests and electrophysiological, immunohistological, and electron microscopy analyses show that homozygous L-MPZ mice exhibit CMT-like phenotypes including thin and/or loose myelin, increased small-caliber axons, and disorganized axo-glial interactions. Heterozygous mice show a milder phenotype. These results highlight the importance of an appropriate L-MPZ/P0 ratio and show that aberrant readthrough of a myelin protein causes neuropathy.

The Role of Sulfatides in Axon-Glia Interactions.

Myelin is heavily enriched in lipids (comprising approximately 70% of its dry weight), and the amount of cholesterol and glycolipids is higher than in any other cell membrane. Galactocerebroside (GalC) and its sulfated form, sulfatide, comprise the major glycolipid components of myelin. Their functional significance has been extensively studied using membrane models, cell culture, and in vivo experiments in which either GalC/sulfatide or sulfatide is deficient. From these studies, GalC and sulfatide have been distinctly localized within oligodendrocytes and their specific function in myelin has been elucidated. Here, the function of sulfatide in axo-glial interactions in myelin-forming cells as well as within myelin and its potential mechanisms of action are discussed.

Dysregulation of schizophrenia-related aquaporin 3 through disruption of paranode influences neuronal viability.

Myelinated axons segregate the axonal membrane into four defined regions: the node of Ranvier, paranode, juxtaparanode, and internode. The paranodal junction consists of specific component proteins, such as neurofascin155 (NF155) on the glial side, and Caspr and Contactin on the axonal side. Although paranodal junctions are thought to play crucial roles in rapid saltatory conduction and nodal assembly, the role of their interaction with neurons is not fully understood. In a previous study, conditional NF155 knockout in oligodendrocytes led to disorganization of the paranodal junctions. To examine if disruption of paranodal junctions affects neuronal gene expression, we prepared total RNA from the retina of NF155 conditional knockout, and performed expression analysis. We found that the expression level of 433 genes changed in response to paranodal junction ablation. Interestingly, expression of aquaporin 3 (AQP3) was significantly reduced in NF155 conditional knockout mice, but not in cerebroside sulfotransferase knockout (CST-KO) mice, whose paranodes are not originally formed during development. Copy number variations have an important role in the etiology of schizophrenia (SCZ). We observed rare duplications of AQP3 in SCZ patients, suggesting a correlation between abnormal AQP3 expression and SCZ. To determine if AQP3 over-expression in NF155 conditional knockout mice influences neuronal function, we performed adeno-associated virus (AAV)-mediated over-expression of AQP3 in the motor cortex of mice and found a significant increase in caspase 3-dependent neuronal apoptosis in AQP3-transduced cells. This study may provide new insights into therapeutic approaches for SCZ by regulating AQP3 expression, which is associated with paranodal disruption.

Unconventional Myosin ID is Involved in Remyelination After Cuprizone-Induced Demyelination.

Myelin, which is a multilamellar structure that sheathes the axon, is essential for normal neuronal function. In the central nervous system (CNS), myelin is produced by oligodendrocytes (OLs), which wrap their plasma membrane around axons. The dynamic membrane trafficking system, which relies on motor proteins, is required for myelin formation and maintenance. Previously, we reported that myosin ID (Myo1d) is distributed in rat CNS myelin and is especially enriched in the outer and inner cytoplasm-containing loops. Further, small interfering RNA (siRNA) treatment highlighted the involvement of Myo1d in the formation and maintenance of myelin in cultured OLs. Myo1d is one of the unconventional myosins, which may contribute to membrane dynamics, either in the wrapping process or transport of myelin membrane proteins during myelination. However, the function of Myo1d in myelin formation in vivo remains unclear. In the current study, to clarify the function of Myo1d in vivo, we surgically injected siRNA in the corpus callosum of a cuprizone-treated demyelination mouse model via stereotaxy. Knockdown of Myo1d expression in vivo decreased the intensities of myelin basic protein and myelin proteolipid protein immunofluorescence staining. However, neural/glial antigen 2-positive signals and adenomatous polyposis coli (APC/CC1)-positive cell numbers were unchanged by siRNA treatment. Furthermore, Myo1d knockdown treatment increased pro-inflammatory microglia and astrocytes during remyelination. In contrast, anti-inflammatory microglia were decreased. The percentage of caspase 3-positive cells in total CC1-positive OLs were also increased by Myo1d knockdown. These results indicated that Myo1d plays an important role during the regeneration process after demyelination.

Phylogenetically Conserved Sequences Around Myelin P0 Stop Codon are Essential for Translational Readthrough to Produce L-MPZ.

Myelin protein zero (P0, MPZ) is the main cell adhesion molecule in peripheral myelin, the sequence of which is evolutionarily highly conserved. Large myelin protein zero (L-MPZ) is a novel translational readthrough molecule in mammals in a physiological status and is encoded by the P0 mRNA with an extra domain. The sequence similarities in the L-MPZ-specific region are found in humans and frogs but not in fish P0 cDNA. Actual synthesis of L-MPZ has been detected in rat and mouse sciatic nerve but not yet evaluated in frogs and humans. The production mechanism and physiological functions of L-MPZ remain unknown. Additionally, the sequence context around the canonical stop codon is significant for readthrough in viruses and yeast, but the correlation between the sequence around P0 stop codon and L-MPZ synthesis is unclear. Here, we focused on the phylogenetic pathways in L-MPZ synthesis. We have shown that L-MPZ is widely produced from frogs to humans using western blotting against L-MPZ. Mutation analysis of the sequence around the stop codon for L-MPZ synthesis using a mammalian in vitro transcription/translation system revealed that the evolutionarily conserved sequence around P0 stop codon is susceptible to readthrough and is similar to the consensus motif in viruses and yeast UAG stop codon type molecules. Our results demonstrate that the phylogenetically conserved sequence around the canonical P0 stop codon is essential for L-MPZ synthesis, suggesting that phylogenetic emergence of L-MPZ in amphibians may be related to particular distribution and/or function in the PNS myelin.

Expression of Unconventional Myosin VI in Oligodendrocytes.

Myelin is a specialized multilamellar structure involved in various functions of the nervous system. Oligodendrocytes are responsible for myelin formation in the central nervous system. Motor proteins play important roles in differentiation and myelin formation of the oligodendrocyte lineage. Recently, we revealed that one of the unconventional myosins, myosin ID (Myo1d), is expressed in mature oligodendrocytes and is required for myelin-like membrane formation in vitro. Previously, Cahoy et al. (J Neurosci 28:264-278, 2008) reported that another unconventional myosin VI (Myo6) is upregulated in transcriptome data of differentiated oligodendrocytes. However, it is uncertain whether Myo6 protein is present in oligodendrocytes. In this study, to analyze expression of Myo6 in oligodendrocytes, we performed immunofluorescence analysis on brains of adult normal and cuprizone-induced demyelination mice. Myo6 expression was detected in mature oligodendrocytes and oligodendrocyte progenitor cells in the cerebellum and corpus callosum. To compare temporal expression patterns of myosin superfamily members in vitro, double immunostainings using anti-Myo6, myosin Va (Myo5a), or Myo1d with each stage-specific oligodendrocyte marker antibody were performed. In cultured oligodendrocytes, although Myo1d was found only in mature oligodendrocytes, Myo6 and Myo5a signals were detected in all stages of differentiation, from oligodendrocyte progenitor cells to mature oligodendrocytes. Additionally, similar to Myo5a, Myo6-positive signals were confined to the cell body and processes. These results showed that Myo6 is one of the unconventional myosins in oligodendrocyte lineage cells, which could play a role in clathrin-related endocytosis.

GlcNAc6ST-1 regulates sulfation of N-glycans and myelination in the peripheral nervous system.

Highly specialized glial cells wrap axons with a multilayered myelin membrane in vertebrates. Myelin serves essential roles in the functioning of the nervous system. Axonal degeneration is the major cause of permanent neurological disability in primary myelin diseases. Many glycoproteins have been identified in myelin, and a lack of one myelin glycoprotein results in abnormal myelin structures in many cases. However, the roles of glycans on myelin glycoproteins remain poorly understood. Here, we report that sulfated N-glycans are involved in peripheral nervous system (PNS) myelination. PNS myelin glycoproteins contain highly abundant sulfated N-glycans. Major sulfated N-glycans were identified in both porcine and mouse PNS myelin, demonstrating that the 6-O-sulfation of N-acetylglucosamine (GlcNAc-6-O-sulfation) is highly conserved in PNS myelin between these species. P0 protein, the most abundant glycoprotein in PNS myelin and mutations in which at the glycosylation site cause Charcot-Marie-Tooth neuropathy, has abundant GlcNAc-6-O-sulfated N-glycans. Mice deficient in N-acetylglucosamine-6-O-sulfotransferase-1 (GlcNAc6ST-1) failed to synthesize sulfated N-glycans and exhibited abnormal myelination and axonal degeneration in the PNS. Taken together, this study demonstrates that GlcNAc6ST-1 modulates PNS myelination and myelinated axonal survival through the GlcNAc-6-O-sulfation of N-glycans on glycoproteins. These findings may provide novel insights into the pathogenesis of peripheral neuropathy.