Acute inhibition of AMPA receptors by perampanel reduces amyloid ß-protein levels by suppressing ß-cleavage of APP in Alzheimer's disease models.

Hippocampal hyperexcitability is a promising therapeutic target to prevent Aß deposition in AD since enhanced neuronal activity promotes presynaptic Aß production and release. This article highlights the potential application of perampanel (PER), an AMPA receptor (AMPAR) antagonist approved for partial seizures, as a therapeutic agent for AD. Using transgenic AD mice combined with in vivo brain microdialysis and primary neurons under oligomeric Aß-evoked neuronal hyperexcitability, the acute effects of PER on Aß metabolism were investigated. A single oral administration of PER rapidly decreased ISF Aß40 and Aß42 levels in the hippocampus of J20, APP transgenic mice, without affecting the Aß40 /Aß42 ratio; 5 mg/kg PER resulted in declines of 20% and 31%, respectively. Moreover, PER-treated J20 manifested a marked decrease in hippocampal APP ßCTF levels with increased FL-APP levels. Consistently, acute treatment of PER reduced sAPPß levels, a direct byproduct of ß-cleavage of APP, released to the medium in primary neuronal cultures under oligomeric Aß-induced neuronal hyperexcitability. To further evaluate the effect of PER on ISF Aß clearance, a γ-secretase inhibitor was administered to J20 1 h after PER treatment. PER did not influence the elimination of ISF Aß, indicating that the acute effect of PER is predominantly on Aß production. In conclusion, acute treatment of PER reduces Aß production by suppressing ß-cleavage of amyloid-ß precursor protein effectively, indicating a potential effect of PER against Aß pathology in AD.

Longitudinal changes and body composition assessment using bioelectrical impedance in elderly patients with mild disequilibrium and different care needs.

[Purpose] This study involved performing longitudinal measurements of muscle mass in elderly patients with mild disequilibrium using a body composition meter. The rate of change and characteristics were determined according to the level of care needed. [Participants and Methods] Bioelectrical impedance was used to measure body composition in 20 elderly females in Care Needs Category 1 (n=10) and 2 (n=8); body composition was measured every 3 months for 1 year. [Results] Compared to Category 1, the muscle mass at each body site was lower in Category 2 and the muscle mass of the whole body and thighs in Category 2 decreased throughout the year. [Conclusion] Muscle mass in elderly patients needing assistance depended on the level of care, as suggested by the decrease in muscle mass in the whole body and thighs in Category 2 over time. In addition, effective rehabilitation intervention for the trunk is important.

[Integrated Community Care from the Perspective of Patients Receiving End-of-Life Treatment].

I studied patients who had received end-of-life care at our clinic and investigated integrated community care based on these experiences. Atotal of 543 patients received end-of-life care at our clinic from October of 2007 to December of 2012. The number of those who received such care at home showed a growing trend while the number of patients receiving such care at hospitals tended to decrease. This was believed to be the effect of the aging population rate continuing to increase each year in Akita City. Understanding of home healthcare is still insufficient not only among patients' families but even among healthcare professionals as well. However, now that extensive home care collaboration networks have been formed, provision of end-of-life care at hospitals may be showing a declining trend. The first report by the Headquarters for the Promotion of Social Security System Reform, dated June 15, 2015, which was compiled by cabinet members, estimated the number of beds considered appropriate as of 2025. According to the report, there were over 150,000 excess beds throughout Japan with Akita Prefecture having approximately 3,500 extra beds. Collaboration between hospitals and home-based healthcare becomes important for many reasons, one of which is to make effective use of the limited number of beds. Therefore, there is a need to further improve and strengthen the integrated community care system.

[The Present Conditions of a Provincial City].

The goal of community-based comprehensive care is to improve the quality of life(QOL)of patients by accommodating their individual values and by making full use of inter-professional collaboration. Since the number of individuals over the age of 65 years in provincial cities has already reached its peak, any future increase in the number of individuals over the age of 65 years will be due to a decrease in the working-age population. As there is no time to spare, immediate actions must be taken to promote collaboration among nursing and welfare facilities. To ensure an accurate understanding and awareness of home care, we have launched in-home treatment support services in a general hospital with the aim of enriching home care and facilitating smooth transitions to in-home treatment. Each community should discuss appropriate measures that will foster the growth of home care services and help individual patients live independent, comfortable lives.

[An examination of home care for patients over age 85 after surgery].

To examine home care for patients over age 85 after surgery, we made comparisons across postoperative courses for their effects on disuse syndrome based on the duration of home care and the duration of survival. The duration of home care was long in surgical cases of patients aged under 74 and patients aged 75-84, and it was short in surgical cases of patients aged over 85. Although having trust in surgeons may delay the transition to home care, early transition is desirable. In terms of the duration of survival, surgery was effective for patients aged under 74 and 75-84, but no difference was noted between patients aged over 85 who had undergone surgical intervention and those who had undergone conservative intervention, showing that surgeries have little effect on prolonging the life of patients aged over 85. Some patients aged over 85 may become bedridden as a result of surgery. There are certainly needs for welfare facilities equipped with medical services and other such measures for those who cannot be cared for at home, but undergoing conservative treatment through integrated community care is also considered an option.

A case of Fukuyama-type congenital muscular dystrophy with acute carnitine deficiency triggered by fever, vomiting, and gastrointestinal bleeding.

BACKGROUND: Carnitine is essential for transporting long-chain fatty acids into mitochondria and promotes energy metabolism via ß-oxidation of long-chain fatty acids. Although carnitine is also present in the peripheral blood, 98% of total carnitine is stored in muscle tissue. Neuromuscular diseases accompanied by muscle atrophy are likely to lead to secondary carnitine deficiency, owing to the reduced amount of total carnitine stored in the body. CASE PRESENTATION: An 8-y-old Japanese boy with Fukuyama-type congenital muscular dystrophy accompanied by severe psychomotor retardation had been constantly bedridden, suffered from dysphagia, and had been fed through a gastrostomy tube since the age of 1 y. Regular oral carnitine supplementation (5 mg/kg/d of levocarnitine) was initiated at the age of 7 y, which increased serum carnitine value to within the normal range (serum total carnitine concentration, 58.5-60.9 µmol/L; acylcarnitine concentration, 45.8-55.0 µmol/L; free carnitine concentration, 5.9-12.7 µmol/L). He developed a fever, vomiting, and gastrointestinal bleeding at the age of 8 y. He fell into a coma and visited an emergency room 12 h later. Hypoglycemia and hypocarnitinemia (serum total carnitine concentration, 3.7 µmol/L; acylcarnitine concentration, 2.9 µmol/L; free carnitine concentration, 0.8 µmol/L; acyl-to-free carnitine ratio, 3.6) were observed, and he was found to be negative for urinary ketone bodies. CONCLUSIONS: Neuromuscular diseases accompanied by muscle atrophy may lead to acute carnitine deficiency, even if the serum carnitine concentration is within the normal range before onset. During sick days, it may be necessary to modify a patient's treatment, such as increasing both oral supplementation and intravenous administration of carnitine.

[Medical cooperation for enabling a smooth shift to remote medical treatment].

To raise awareness of remote medical treatment, seminars are held and patients are invited to participate in medical treatment in a short-term care hospital, a hospice, or a long-term care hospital. The first and second halves of the home treatment period in this clinic were individually examined. The results showed that the home treatment period was extended, which was considered to be the effect of cooperation. By improving medical cooperation with a primary or family physician, medical development and the reduction of incidences in short-term care hospitals are expected. In remote medical treatment, multidisciplinary cooperation is important. It is now also required to enable welfare facilities to participate in networks. Furthermore, such cooperation raises remote medical treatment awareness among patients and medical staff. The original home network suitable for Akita must be developed further to respond to an aging society. This response to a super-aged society may serve as a model throughout the world.

[A case of a patient with rheumatoid vasculitis who was successfully transferred to home-care services through regional cooperation].

We investigated a case of a patient with rheumatoid vasculitis who was successfully transferred to home-care services through regional cooperation. The patient was a 63-year-old woman with rheumatoid vasculitis complicated by small bowel necrosis, cerebral infarction, heart failure, scleritis, etc. In the present system, admission of such patients to acute or long-term care hospitals is difficult. It is also difficult to provide care at welfare facilities.Although symptom control and prognosis have improved owing to medical advances, the care system lags behind in terms of improvement. In the future, strengthening the seamless coordination between the medical and care systems is needed.

[Comparison of home-care and welfare facilities].

Postoperative care conditions for elderly patients were examined. The present case is that of an 86-year-old man who underwent rectal amputation and colostomy owing to rectal cancer. Because he developed cerebral infarction and his disuse syndrome also advanced during postoperative hospitalization, he left the hospital with intravenous hyperalimentation. Because there were no beds available in the long-term care hospital and the care organization was not able to prepare his home appropriately, he had to enter welfare facilities. It is not rare for elderly people to become bedridden because of an operation. Recently, home care has declined because of elder-to-elder nursing care, an increasing trend towards the nuclear family, etc. It is therefore necessary to provide the equivalent medical organization in welfare facilities as provided by home care.

Giant magnetoresistance observed in (Fe,Mn)3O4 artificial nanoconstrained structures at room temperature.

We fabricated ferromagnetic oxide (Fe,Mn)(3)O(4) (FMO) nanoconstrained structures using two different steps involving atomic force microscope lithography in combination with a pulsed laser deposition technique. The widths of three FMO nanoconstrained structures were 150, 100, and 50 nm. The I-V characteristic of the 50 nm width FMO nanoconstrained structure changed dramatically from linear to nonlinear after forming the nanoconstrained structure. The magnetoresistance also increased drastically from -0.2% to 150% at room temperature. These results indicate that well-defined complicated artificial transition metal oxide nanostructures allow the creation of huge spin response devices even at room temperature.

GFAP-Negative Subcutaneous Sacrococcygeal Extraspinal Ependymoma.

Ependymomas are slowly growing glial tumors derived from the ependymal cells and usually occur in the central nervous system (CNS). Ependymomas rarely occur outside of the CNS and they are called extraspinal ependymomas. In spite of their metastatic potential, extraspinal ependymomas can be misdiagnosed for other benign mass like pilonidal cysts. The diagnosis is confirmed by histopathology and most of the cases are known to show glial fibrillary acidic protein (GFAP), S-100 protein, and keratin (AE1AE3) immunoreactivity. Herein, we present a case of GFAP-negative ependymoma, which presented as asymptomatic subcutaneous tumor of the left buttock and was clinically misdiagnosed as epidermal cyst. Our case indicates that ependymomas cannot be ruled out by lack of GFAP immunoreactivity and an asymptomatic subcutaneous mass could be a malignant tumor like ependymomas, which requires careful examinations.

Infection control in the respiratory care of coronavirus disease-19 patients with neuromuscular diseases.

Close contact is unavoidable in the care of patients with neuromuscular diseases (NMD). In addition, respiratory physiotherapy and noninvasive ventilation generate massive amounts of aerosols. Caring for a patient suffering from coronavirus disease-19 raises concerns about the risk of infection not only to the caregiver and/or medical staff but also to other individuals in contact with these personnel. We reviewed the points to be noted in infection control when a patient with neuromuscular diseases receiving respiratory care is infected with COVID-19 and summarizes the recommendation. Infected patients must be isolated in a negative-pressure or actively ventilated room. Clear zoning separating clean and infected areas should be performed for pathogen containment. Caregivers should wear appropriate personal protective equipment and thoroughly clean their hands. Leak-prevention measures and the use of proper respiratory circuits and filters with virus-removal performance are crucial to reducing aerosols in noninvasive ventilation. Although respiratory physiotherapy is essential, treatment should be minimized in consideration of the infection state and sputum status, and alternative therapies such as postural drainage should be carefully considered. Infection control is distinctly obligate; however, it impairs the quality of life and activity of daily living significantly. We should implement it with enough ethical consideration, adequate explanation, and patient consent. We hope that this paper will contribute to appropriate COVID-19 infection control in patients with neuromuscular diseases requiring respiratory care.

Neuroendocrine cancer-specific up-regulating mechanism of insulin-like growth factor binding protein-2 in small cell lung cancer.

Small cell lung cancer (SCLC) exhibits insulin-like growth factor-dependent growth. SCLC is the most aggressive among known in vivo lung cancers, whereas in vitro growth of SCLC is paradoxically slow as compared with that of non-SCLC (NSCLC). In this study, we demonstrate that SCLC cells overexpress insulin-like growth factor binding protein (IGFBP)-2 via NeuroD, a neuroendocrine cell-specific transcription factor. Chromatin immunoprecipitation, electrophoretic mobility shift, and IGFBP-2 promoter assays all revealed that NeuroD binds to the E-box in the 5'-untranslated region of IGFBP-2. A NeuroD transgene in both airway epithelial and NSCLC cells up-regulated the transcription of IGFBP-2 and retarded cell growth. Recombinant IGFBP-2 repressed the growth of both airway epithelial and NSCLC cells in a dose-dependent manner. A NeuroD-specific small interfering RNA repressed IGFBP-2 expression in SCLC, and neutralization of IGFBP-2 and an IGFBP-2-specific small interfering RNA increased SCLC cell growth. Pathological samples of SCLC also expressed IGFBP-2 abundantly, as compared with NSCLC, and showed only rare (8%) IGFBP-2 promoter methylation, whereas the IGFBP-2 promoter was methylated in 71% of adenocarcinomas and 29% of squamous cell carcinomas. These findings suggest that 1) SCLC has an IGFBP-2 overexpression mechanism distinct from NSCLC, 2) secreted IGFBP-2 contributes to the slow growth of SCLC in vitro, and 3) the epigenetic alterations in the IGFBP-2 promoter contribute to the striking differences in IGFBP-2 expression between SCLC and NSCLC in vivo.

Controlled fabrication of epitaxial (Fe,Mn)3O4 artificial nanowire structures and their electric and magnetic properties.

Epitaxial (Fe,Mn)(3)O(4) (FMO) ferromagnetic oxide artificial nanowire (NW) structures were deposited across Pt/Cr bilayer electrodes with a high controllability on their shape and positioning by using atomic force microscope (AFM) lithography with molybdenum (Mo) lift-off in combination with a pulsed laser deposition technique. The oxide wire widths were systematically controlled from 5 microm down to 100 nm by controlling AFM lithography current for Mo-mask. The resistivity of FMO-NW structures was increased at below around 400 nm in width. Magnetic force microscope revealed that FMO-NW with 120 nm showed single line of aligned ferromagnetic domains that caused the resistivity increase. Our results offer well-defined epitaxial transition metal oxide nanostructures with a remarkable flexibility toward nanoscale oxide spintronics.

Early manifestations of epileptic encephalopathy, brain atrophy, and elevation of serum neuron specific enolase in a boy with beta-propeller protein-associated neurodegeneration.

Mutations in WDR45 are responsible for beta-propeller protein-associated neurodegeneration (BPAN), which is an X-linked form of neurodegeneration with brain iron accumulation. BPAN mainly affects females and is characterized by seizures and developmental delay or intellectual disability until adolescence or early adulthood, followed by severe dystonia, parkinsonism, and progressive dementia. However, rare male patients have recently been reported with hemizygous germline mutations in WDR45 and severe clinical manifestations, such as epileptic encephalopathies. We report here a 4-year-old boy presenting with profound developmental delay, non-syndromic epileptic encephalopathy, and early brain atrophy. The level of serum neuron specific enolase (NSE) was elevated, but the level of serum phosphorylated neurofilament heavy chain was not detectable. Targeted next-generation sequencing identified a de novo hemizygous splice donor site mutation, c.830+1G > A in WDR45, which resulted in a splicing defect evidenced by reverse transcriptase-PCR. Mutations in WDR45 should be considered as a cause for epileptic encephalopathies in males with profound developmental delay and brain atrophy. Furthermore, elevation of serum NSE may contribute to early diagnosis of BPAN.

Simple Derivation of Spinal Motor Neurons from ESCs/iPSCs Using Sendai Virus Vectors.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal degenerative disorder of motor neurons (MNs). Embryonic stem cells (ESCs)/induced pluripotent stem cells (iPSCs) now help us to understand the pathomechanisms of ALS via disease modeling. Various methods to differentiate ESCs/iPSCs into MNs by the addition of signaling molecules have been reported. However, classical methods require multiple steps, and newer simple methods using the transduction of transcription factors run the risk of genomic integration of the vector genes. Heterogeneity of the expression levels of the transcription factors also remains an issue. Here we describe a novel approach for differentiating human and mouse ESCs/iPSCs into MNs using a single Sendai virus vector encoding three transcription factors, LIM/homeobox protein 3, neurogenin 2, and islet-1, which are integration free. This single-vector method, generating HB9-positive cells on day 2 from human iPSCs, increases the ratio of MNs to neurons compared to the use of three separate Sendai virus vectors. In addition, the MNs derived via this method from iPSCs of ALS patients and model mice display disease phenotypes. This simple approach significantly reduces the efforts required to generate MNs, and it provides a useful tool for disease modeling.