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The number of dementia patients is increasing worldwide, especially in Japan, which has the world's highest ageing population. The increase in the number of older people with dementia is a medical and socioeconomic problem that needs to be prevented, but the actual situation is still not fully understood.Four cross-sectional studies on dementia were conducted in 1997, 2004, 2012, and 2016 for complete enumeration of all residents aged 65 years and older. We examined the secular trends in the prevalence of all-cause dementia, Alzheimer's disease (AD), vascular dementia (VaD), and other/unclassified dementia.The age-standardised prevalence of all-cause dementia significantly increased (4.5% in 1997, 5.7% in 2004, 5.3% in 2012, 9.5% in 2016; P for trend0.05). Similar trends were observed for AD (1.7%, 3.0%, 2.5% and 4.9%, respectively; P for trend0.05) and other/unclassified dementia (0.8%, 1.0%, 1.0% and 2.2%, respectively; P for trend0.05), whereas no significant change in VaD was seen (2.1%, 1.8%, 1.8%, 2.4%, respectively; P for trend = 0.77). The crude prevalence of all-cause dementia and AD increased from 1997 to 2016 among participants aged 75-79 years and ≥85 years (all P for trend0.05). Similar trends were observed for other/unclassified dementia among participants aged ≥80 years (all P for trend0.05), but not in VaD.The prevalence of dementia has increased beyond the ageing of the population, suggesting that factors in addition to ageing are involved in the increase in the number of older people with dementia. To control the increase in the number of older people with dementia, elucidation of secular trends in the incidence, mortality, and prognosis of dementia as well as the factors that promote and protect against dementia, and development of preventive strategies are necessary.

Background: Late-onset Alzheimer’s disease (LOAD) is a complex disease in which neuroinflammation plays an important pathophysiological role, and exposure to neurotoxic substrates such as aldehydes may contribute. Blood mRNA expression levels of neuroinflammation-related genes appear to be potential biological markers of LOAD. A relationship between ALDH2 and LOAD has been suggested. Objective: Our objective was to examine blood ALDH2 expression in Japanese LOAD patients, conduct a genetic association study, and add new studies to an extended meta-analysis of the Asian population. Methods: A blood expression study (45 AD subjects, 54 controls) in which total RNA was isolated from whole peripheral blood samples and ALDH2 expression measured was conducted. In addition, a genetic association study (271 AD subjects, 492 controls) using genomic DNA from whole peripheral blood samples was conducted. Finally, a meta-analysis examined the relationship between ALDH2*2 frequency and the risk of LOAD. Results: ALDH2 mRNA expression was significantly higher in LOAD than in controls, and also higher in men with LOAD than in women with LOAD (p = 0.043). The genotypes in the two classified groups and the allele frequency were significantly different between AD and control subjects. The meta-analysis showed a significant difference in the ALDH2*2 allele, with an increased AD risk (OR = 1.38; 95% CI = 1.02–1.85; p = 0.0348, I2 = 81.1%). Conclusion: There was a significant increase in blood ALDH2 expression, and a genetic association with ALDH2*2 in LOAD. ALDH2 may have significant roles in the pathogenesis of LOAD in the Asian population.

Bivalve molluscan shellfish like clams and oysters, etc., are capable to bioaccumulate surrounding contaminants from waters into their digestive systems and posing serious threats of food poisoning. Detection of rotaviruses (RVs) in shellfish is of particular importance because RVs are prone to genome reassortment resulting in the emergence of new RV variants that may compromise vaccine safety. Herein, we have detected the wild-type RVs and Rotarix/RotaTeq vaccine strains in freshwater clams collected on the riverside, Kawasaki city, from July 2019 to January 2020 and correlated the detected genotypes with that of gastroenteritis cases of nearby clinics to understand the transmission of RVs in the environment. The wild-type RVs were detected in 62 (64.6%) out of 96 freshwater clams in every study month: July, September, November, and January that are considered as off-season for RV infections. The most frequent genotypes were G2 (42.9%), G8 (28.6%), G3 (14.3%), G1 (7.1%), and G10 (7.1%), which remained comparable with genotypic distribution found in the clinical samples over the last few years indicating that these RVs may accumulate in clams since a long time. However, G10 genotype was detected in clam but not in clinical samples suggesting the presence of asymptomatic infection or RVs could be carried out from a long distance. Importantly, vaccine strains, RotaTeq (1%) but not Rotarix (0%), were also detected in a clam. Attention must be paid to monitoring the potential transmission of wild-type and vaccine RV strains in the environment to prevent the emergence of new variants generated from genome reassortment with vaccine strains.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder caused by FMR1 premutation expansion of CGG repeats. FXTAS can be misdiagnosed with many neurodegenerative disorders manifesting with cerebellar ataxias owing to their overlapping clinical and radiological features. The frequency of the FMR1 premutation allele in Japan has not been fully determined. Herein, we aimed to determine the frequency of FMR1 premutation alleles in Japanese patients with undiagnosed cerebellar ataxia and multiple system atrophy, using repeat-primed PCR in 186 patients with adult onset of undiagnosed cerebellar ataxia and 668 patients with multiple system atrophy, to identify expanded CGG repeats as well as to detect AGG interruptions within the expanded alleles. The size of expansions was estimated using fragment length analysis of PCR products obtained by conventional PCR employing a pair of unique primers flanking the repeat sequence. We identified FMR1 premutation alleles in three male patients. One patient revealed 84 repeat units with one AGG interruption and another patient showed 103 repeat units. Both had presented with sporadic cerebellar ataxia, giving an estimated frequency of 3.7% among Japanese male patients with sporadic cerebellar ataxia with age at onset above 50 years. One patient with the clinical diagnosis of multiple system atrophy harbored 60 repeat units with four AGG interruptions. FMR1 intermediate alleles were observed in two males and one female among the multiple system atrophy patients. We found that genetic tests for FMR1 premutation should be considered in Japanese male patients with cerebellar ataxia with the age at onset above 50 years.

Individuals with prodromal symptoms of Lewy body disease (LBD), such as rapid eye movement sleep behavior disorder (RBD), often showed imaging defects similar to patients. We examined dopamine transporter (DaT) single-photon-emission computed tomography (SPECT) and metaiodobenzylguanidine (MIBG) scintigraphy in 69 high-risk subjects with ≥ 2 prodromal symptoms (dysautonomia, hyposmia, and RBD) and 32 low-risk subjects without prodromal symptoms, whom were identified through a questionnaire survey of health checkup examinees. The high-risk subjects had significantly worse scores on Stroop test, line orientation test, and the Odor Stick Identification Test for Japanese than the low-risk subjects. The prevalence of abnormalities on DaT-SPECT was higher in the high-risk group than in the low-risk group (24.6% vs. 6.3%, p = 0.030). A decreased uptake on DaT-SPECT was associated with motor impairment, and MIBG scintigraphy defects were associated with hyposmia. The simultaneous evaluation of DaT-SPECT and MIBG scintigraphy may capture a wide range of individuals with prodromal LBD.

Background Enlarged perivascular spaces (EPVS) of the brain may be involved in dementia, such as Alzheimer’s disease and cerebral small vessel disease (CSVD). Hypertension has been reported to be a risk factor for dementia and CSVD, but the association between blood pressure (BP) and perivascular spaces is still unclear. The aim of this study was to determine the association between BP and EPVS volumes and to examine the interactions of relevant factors. Methods A total of 9,296 community-dwelling subjects aged ≥ 65 years participated in a brain magnetic resonance imaging and health status screening examination. Perivascular volume was measured using a software package based on deep learning that was developed in-house. The associations between BP and the EPVS volumes were examined by analysis of covariance and multiple regression analysis. Results The mean EPVS volumes increased significantly with rising systolic and diastolic BP levels (p for trend = 0.003, p for trend

Background: Cyclin-dependent kinase inhibitor 2A (CDKN2A) is an important gene in cellular senescence and aging. Objective: This study assessed the utility of blood CDKN2A mRNA expression levels and methylation status as a potential biomarker for aging and the pathogenesis of Alzheimer’s disease (AD). Methods: The correlation between CDKN2A mRNA expression levels and age was examined in 45 healthy subjects, after which mRNA expression levels were compared among 46 AD patients, 20 mild cognitive impairment due to AD patients, 21 Parkinson’s disease patients, 21 dementia with Lewy bodies patients, and 55 older healthy controls. The methylation rates of the second exon of the CDKN2A gene, known to influence its expression levels, was also examined. Results: A significant correlation between CDKN2A mRNA expression levels and age was found (Spearman’s rank correlation coefficient: r = 0.407, p = 0.005). CDKN2A mRNA expression levels in blood were significantly decreased in AD patients, although those of healthy controls were significantly increased with age. Further, only in AD patients were CDKN2A mRNA expression levels significantly and positively correlated with methylation rates. Conclusion: Although further research with a larger sample size is needed to elucidate the relationships between CDKN2A gene expression in blood and the development of other neurodegenerative diseases, CDKN2A mRNA expression in blood may be a biomarker for differentiating AD from normal aging and other neurodegenerative diseases.

Fabry disease is an X-linked lysosomal storage disorder due to mutations in the alpha-galactosidase A gene, which leads to the accumulation of globotriaosylceramide in various organs. In Fabry disease with end-stage renal disease (ESRD), cerebrovascular events are lethal, even with enzyme replacement therapy (ERT). However, the utility of biomarkers to evaluate the ERT response is unclear. We herein report a case of recurrent cerebrovascular complications under ERT in a Fabry disease patient, progressing to ESRD on peritoneal dialysis. Further studies are warranted, but Fabry disease patients with ESRD receiving ERT might need careful long-term follow-up in cases with cerebrovascular manifestations.

A 72-year-old lady with atrial fibrillation and chronic renal failure was hospitalized due to bradycardic shock with electrocardiographic QRS prolongation. She had experienced limb shaking two days before hospitalization, and additionally developed hallucinations one day before admission. Pilsicainide intoxication was diagnosed from a review of her medications and electrocardiographic findings. Consequently, continuous hemodiafiltration was performed resulting in a resolution of the hallucinations and the QRS prolongation. This is a rare case of psychiatric symptoms caused by pilsicainide intoxication. It is important to know the mode of excretion of a drug and to adjust its dose, so that such drug-related incidents can be avoided.

The number of the patients with coronavirus disease 2019 (COVID-19) is increasing, and shortage of hospital beds for these patients is a cause for serious concern Here, we report the clinical course of 11 patients who were admitted to our hospital with COVID-19 that developed during their quarantine period in a large cruise ship, and discuss the factors associated with the disease severity and length of hospitalization The median age of the 11 patients was 62 years, and 36% were men The disease severity was mild in 7 patients, moderate in 4 patients, and severe in none of the patients The median time from symptom onset to disease remission was 13 days for patients with moderately severe disease, and 7 days for patients with mild disease The median interval from symptom onset to confirmation of the first negative result of PCR was 16 days for patients with moderately severe disease, and 14 days for patients with mild disease The median time from symptom onset to discharge was 22 5 days for patients with moderately severe disease cases, and 16 days for patients with mild disease Some patients needed prolonged hospitalization because of persistently positive results of PCR even after remission of symptoms Comparison between the patient groups with moderately severe disease and mild disease showed that the patients with moderately severe disease were older and had higher serum ferritin and serum amyloid protein (SAA) levels than the patients with mild disease Even in patients with mild to moderate COVID-19, two to three weeks were required from symptom onset to confirmation of the first negative result of PCR, and this was one of the major factors for prolonged hospitalization The serum ferritin levels and SAA levels might be predictors of the disease severity

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder caused by FMR1 premutation expansion of CGG repeats. FXTAS can be misdiagnosed with many neurodegenerative disorders manifesting with cerebellar ataxias owing to their overlapping clinical and radiological features. The frequency of the FMR1 premutation allele in Japan has not been fully determined. Herein, we aimed to determine the frequency of FMR1 premutation alleles in Japanese patients with undiagnosed cerebellar ataxia and multiple system atrophy, using repeat-primed PCR in 186 patients with adult onset of undiagnosed cerebellar ataxia and 668 patients with multiple system atrophy, to identify expanded CGG repeats as well as to detect AGG interruptions within the expanded alleles. The size of expansions was estimated using fragment length analysis of PCR products obtained by conventional PCR employing a pair of unique primers flanking the repeat sequence. We identified FMR1 premutation alleles in three male patients. One patient revealed 84 repeat units with one AGG interruption and another patient showed 103 repeat units. Both had presented with sporadic cerebellar ataxia, giving an estimated frequency of 3.7% among Japanese male patients with sporadic cerebellar ataxia with age at onset above 50 years. One patient with the clinical diagnosis of multiple system atrophy harbored 60 repeat units with four AGG interruptions. FMR1 intermediate alleles were observed in two males and one female among the multiple system atrophy patients. We found that genetic tests for FMR1 premutation should be considered in Japanese male patients with cerebellar ataxia with the age at onset above 50 years.

Schizophrenic patients resistant to antipsychotics are diagnosed as having treatment-refractory schizophrenia, and they are treated with clozapine. However, clozapine is sometimes combined with electroconvulsive therapy (ECT) if clozapine monotherapy fails. In this report, a severe treatment-refractory schizophrenic patient who did not respond to clozapine even with ECT, but who recovered with asenapine monotherapy, is presented. Asenapine, considered a serotonin spectrum dopamine modulator, is a new atypical antipsychotic with unique pharmacological features that is used not only for schizophrenia, but also for bipolar disorder. The unique features of asenapine may be effective for some treatment-refractory schizophrenic patients.

The stable isotopic composition of oxygen (δ18O) in wine is often analysed to determine the geographic origin of the wine and the amount of water dilution. However, little is known regarding the effects of two major winemaking techniques (the addition of acid (acidification) and sugar (chaptalization)) on the δ18O value of water in wine. Here we show that acidification and chaptalization have minor direct effects on the δ18O value but indirect effects based on the ethanol yield, which causes isotopic variation of up to 0.6‰. During fermentation, δ18O values increase at low ethanol yields, suggesting that yeast release water with a high δ18O value into wine when consuming sugars. Additionally, the ethanol yield is negatively correlated with the consumption of amino acids by the yeast, indicating that yeast growth decreases the ethanol yield. We therefore identify ethanol yield, which is decreased by the consumption of sugars by yeast for non-alcohol-fermentation processes as a potential factor leading to variations in the δ18O value of water during the winemaking process.

Background Alanine:glyoxylate aminotransferase 2 (AGXT2; EC 2.6.1.44) is the only enzyme that degrades the R-form of 3-aminoisobutyrate, an intermediate metabolite of thymine. AGXT2, as well as diaminoarginine dimethylaminohydrolase 1 (DDAH1; EC 3.5.3.18), works as an enzyme that degrades asymmetric dimethylarginine (ADMA), which competitively inhibits the nitric oxide synthase family. Thus, these two enzyme activities may change vascular vulnerability for a lifetime via the nitric oxide (NO) system. We investigated the association between vascular conditions and diseases such as hypertension and diabetes mellitus and polymorphisms of these two genes in 750 older Japanese subjects (mean age ± standard deviation, 77.0 ± 7.6 years) recruited using the complete enumeration survey method in the Nakayama study. Demographic and biochemical data, such as blood pressure (BP) and casual blood sugar (CBS), were obtained. Four functional single nucleotide polymorphisms (SNPs; rs37370, rs37369, rs180749, and rs16899974) of AGXT2 and one functional insertion/deletion polymorphism in the promotor region with four SNPs (rs307894, rs669173, rs997251, and rs13373844) of DDAH1 were investigated. Plasma ADMA was also analyzed in 163 subjects. Results The results of multiple regression analysis showed that a loss of the functional haplotype of AGXT2, CAAA, was significantly positively correlated with BP (systolic BP, p = 0.034; diastolic BP, p = 0.025) and CBS (p = 0.021). No correlation was observed between DDAH1 and either BP or CBS. ADMA concentrations were significantly elevated in subjects with two CAAA haplotypes compared with subjects without the CAAA haplotype (p = 0.033). Conclusions Missense variants of AGXT2, but not DDAH1, may be related to vulnerability to vascular diseases such as hypertension and DM via the NO system.

We herein report a case of a combined crystalline light chain tubulopathy, podocytopathy, histiocytosis, and cast nephropathy in a patient with monoclonal gammopathy of renal significance (MGRS). A 66-year-old female with impaired renal function was referred to our department. Despite intravenous fluid resuscitation, the kidney function worsened progressively; thus, a kidney biopsy was performed. The kidney biopsy revealed light chain proximal tubulopathy (LCPT) with crystals, light chain crystal podocytopathy (LCCP), crystal-storing histiocytosis (CSH), and light chain cast nephropathy (LCCN). Of note, LCCP and CSH were diagnosed via electron microscopy. Serum and urine immunoelectrophoresis (IEP) revealed the presence of monoclonal Bence–Jones protein and free κ light chains. Bone marrow aspiration showed

The duration of viral shedding of SARS-CoV-2 is usually less than 10 days. We experienced a COVID-19 case with prolonged viral shedding for 2 months. His cell mediated immunity has been depressed (CD4+T cell

Rapid diagnosis of COVID-19 is essential for instituting measures to prevent viral spread. SARS-CoV-2 antigen rapid diagnostic test (Ag-RDT) based on lateral flow immunochromatography assay (LFIA) principle can visually indicate the presence of SARS-CoV-2 antigens as a band. Ag-RDT is clinically promising as a point-of-care testing because it can give results in a short time without the need for special equipment. Although various antigen capture LFIAs are now available for rapid diagnosis for SARS-CoV-2 infection, they face the problems of low sensitivity. We have previously developed highly specific monoclonal antibodies (mAb) against SARS-CoV-2 nucleocapsid protein (NP) and in this study, we have employed these mAbs to develop a new LFIA that can detect SARS-CoV-2 NP in nasopharyngeal swab samples with higher sensitivity by combining them with silver amplification technology. We also compared the performance of our Ag-RDT against the commercially available Ag-RDTs using clinical samples to find that our newly developed LFIA performed best among tested, highlighting the superiority of silver amplification technology.

An 80-year-old man with myelodysplastic syndrome developed acute kidney injury (AKI) and peripheral blood monocyte-dominant leukocytosis. Glomerular disease was suspected from urinalysis, which showed proteinuria and microscopic hematuria with red cell casts. Eventually, he died of respiratory failure, after which a postmortem was performed. In the glomeruli, the extracapillary space was filled with numerous mononuclear cells and erythrocytes. At first interpretation, the glomerular findings appeared to represent cellular crescents. However, immunostaining revealed that the extracapillary mononuclear cells were in fact leukemic cells. Furthermore, tubular injury due to marked accumulation of lysozyme was also recognized together with infiltration of leukemic cells in the interstitium. The diagnosis of kidney infiltration by chronic myelomonocytic leukemia (CMML) and lysozyme-induced tubular injury was eventually made. Our case is the first report showing extracapillary infiltration of leukemic cells by immunostaining. In addition, lysozyme-induced tubular injury is a forgotten cause of kidney injury in patients with CMML. This case teaches us the rare and forgotten causes of AKI with CMML.

The carbon stable isotopic composition, as indicated by the δ13C value, of wine ethanol is inherited from berry sugars, but little is known about the variation in sugar δ13C values of Japanese grapes relative to overseas grapes. This study found a large variation in sugar δ13C values of Chardonnay grapes grown in Japan (−27.2 ± 0.9‰, mean ± standard deviation, n = 33), with sugar δ13C values depending on the δ13C values and content of monosaccharides. After complete fermentation, the carbon isotope discrimination between berry sugars and wine ethanol was 1.5 ± 0.1‰. Ethanol δ13C values and carbon isotope discrimination enabled prediction of sugar δ13C values in the original must. Imported wines had higher sugar δ13C values than those of wines made from Japanese grapes, suggesting drier overseas viticulture conditions. The determination of sugar δ13C values in grape berries provides valuable information for viticulture and wine authentication.

Determining the geographical origin of wines is a major challenge in wine authentication, but little information is available regarding non-parametric statistical approaches for wines. In this study, we collected 33 domestic Chardonnay wines vinified on a small scale from grapes cultivated in Japan, and 42 Chardonnay wines imported from 8 countries, for oxygen stable isotope and multi-element analyses. Non-metric multidimensional scaling (NMDS), kernel principal component analysis (KPCA) and principal component analysis (PCA) were applied to the oxygen stable isotopic compositions (δ18O) and the concentrations of 18 elements in the wines to compare the extractions by parametric and non-parametric methods. The non-parametric methods, NMDS and KPCA, separated domestic from imported Chardonnay wines better than the parametric method, PCA. Of 19 variables, 18 were important for geographical discrimination, with the δ18O value being the most significant in all statistic methods. Non-parametric multivariate analyses will help discriminate domestic from imported Chardonnay wines.