Proteomic profile of nuclei containing p62-positive inclusions in a patient with neuronal intranuclear inclusion disease.

Neuronal intranuclear inclusion disease (NIID) is a neurodegenerative disease characterized by eosinophilic hyaline intranuclear inclusions in the neurons, glial cells, and other somatic cells. Although CGG repeat expansions in NOTCH2NLC have been identified in most East Asian patients with NIID, the pathophysiology of NIID remains unclear. Ubiquitin- and p62-positive intranuclear inclusions are the pathological hallmark of NIID. Targeted immunostaining studies have identified several other proteins present in these inclusions. However, the global molecular changes within nuclei with these inclusions remained unclear. Herein, we analyzed the proteomic profile of nuclei with p62-positive inclusions in a NIID patient with CGG repeat expansion in NOTCH2NLC to discover candidate proteins involved in the NIID pathophysiology. We used fluorescence-activated cell sorting and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to quantify each protein identified in the nuclei with p62-positive inclusions. The distribution of increased proteins was confirmed via immunofluorescence in autopsy brain samples from three patients with genetically confirmed NIID. Overall, 526 proteins were identified, of which 243 were consistently quantified using MS. A 1.4-fold increase was consistently observed for 20 proteins in nuclei with p62-positive inclusions compared to those without. Fifteen proteins identified with medium or high confidence in the LC-MS/MS analysis were further evaluated. Gene ontology enrichment analysis showed enrichment of several terms, including poly(A) RNA binding, nucleosomal DNA binding, and protein binding. Immunofluorescence studies confirmed that the fluorescent intensities of increased RNA-binding proteins identified by proteomic analysis, namely hnRNP A2/B1, hnRNP A3, and hnRNP C1/C2, were higher in the nuclei with p62-positive inclusions than in those without, which were not confined to the intranuclear inclusions. We identified several increased proteins in nuclei with p62-positive inclusions. Although larger studies are needed to validate our results, these proteomic data may form the basis for understanding the pathophysiology of NIID.

Evaluation of the usefulness of a paper-pencil group cognitive assessment for older adults in the community.

BACKGROUND: As the older population increases, the need for early detection of cognitive decline is also increasing. In this study, we examined whether our paper-pencil type group examination for cognitive assessment (PAPLICA) could detect the effects of years of education and aging. METHODS: PAPLICA was conducted on 829 older people. The inclusion criteria were age 60 years or older and the ability to come to the event site alone. The exclusion criteria were participants with a medical or psychiatric disorder or dementia.One examiner conducted the test on a group of approximately 10-20 people in approximately 25 min. Participants were instructed on tackling the issues projected on the projector, and their answers were recorded in a response booklet. RESULTS: An independent sample t-test was performed for years of education, and ANCOVA was performed for aging. Among the test items included in PAPLICA, the Speed I and Letter fluency tests were unable to detect the effects of aging. Furthermore, the age at which the effect of aging manifests varies depending on the test item. For instance, a decline in scores in the Speed I and Picture ECR Free recall tests was observed in the 70-74 age group; for that of Word DRT, Picture ECR cued recall, and Similarity, in the 75-79 age group; for CFT, in the 80-84 age group, and for CLOX, the decline was observed in the 85 ≤ age group. CONCLUSIONS: PAPLICA, similar to other neuropsychological tests, was able to detect the effects of years of education and aging. Future testing should be conducted on different demographics to identify the differences in patterns of cognitive decline.

Pharmacokinetics and tissue distribution of orally administrated imidazole dipeptides in carnosine synthase gene knockout mice.

Imidazole dipeptides (ID) are abundant in skeletal muscle and the brain and have various functions, such as antioxidant, pH-buffering, metal-ion chelation. However, the physiological significance of ID has not been fully elucidated. In this study, we orally administered ID to conventional carnosine synthase gene-deficient mice (Carns-KO mice) to investigate the pharmacokinetics. Carnosine or anserine was administered at a dose of 500 mg (∼2 mmol) per kilogram of mouse body weight, and ID contents in the tissues were measured. No ID were detected in untreated Carns-KO mice. In the ID treatment groups, the ID concentrations in the tissues increased in a time-dependent manner in the gastrocnemius muscle, soleus muscle, and cerebrum after ID administration. Our findings suggest that the Carns-KO mice are a valuable animal model for directly evaluating the effects of dietary ID and for elucidating the physiological functions of oral ID administration.

[Successful Thoracic Endovascular Aortic Repair in a Patient with Mid-aortic Syndrome:Report of a Case].

We report a case of thoracic endovascular aortic repair (TEVAR) for mid-aortic syndrome, which is characterized by a segmental narrowing of the aorta, in a 71-year-old man who presented with intermittent claudication. Contrast-enhanced computed tomography (CT) showed segmental stenosis of the descending aorta, for which TEVAR was performed. The ankle-branchial index increased after surgery, and the dorsalis pedis arterial pulses became palpable bilaterally. The patient was discharged on postoperative day 14 without any complication. At present, four years after surgery, he is in good condition with improved renal function, requiring no hospitalization for the treatment of heart failure.

Need of care in interpreting Google Trends-based COVID-19 infodemiological study results: potential risk of false-positivity.

BACKGROUND: Google Trends (GT) is being used as an epidemiological tool to study coronavirus disease (COVID-19) by identifying keywords in search trends that are predictive for the COVID-19 epidemiological burden. However, many of the earlier GT-based studies include potential statistical fallacies by measuring the correlation between non-stationary time sequences without adjusting for multiple comparisons or the confounding of media coverage, leading to concerns about the increased risk of obtaining false-positive results. In this study, we aimed to apply statistically more favorable methods to validate the earlier GT-based COVID-19 study results. METHODS: We extracted the relative GT search volume for keywords associated with COVID-19 symptoms, and evaluated their Granger-causality to weekly COVID-19 positivity in eight English-speaking countries and Japan. In addition, the impact of media coverage on keywords with significant Granger-causality was further evaluated using Japanese regional data. RESULTS: Our Granger causality-based approach largely decreased (by up to approximately one-third) the number of keywords identified as having a significant temporal relationship with the COVID-19 trend when compared to those identified by Pearson or Spearman's rank correlation-based approach. "Sense of smell" and "loss of smell" were the most reliable GT keywords across all the evaluated countries; however, when adjusted with their media coverage, these keyword trends did not Granger-cause the COVID-19 positivity trends (in Japan). CONCLUSIONS: Our results suggest that some of the search keywords reported as candidate predictive measures in earlier GT-based COVID-19 studies may potentially be unreliable; therefore, caution is necessary when interpreting published GT-based study results.

Efficacy and Cost-effectiveness of Promotion Methods to Recruit Participants to an Online Screening Registry for Alzheimer Disease Prevention Trials: Observational Study.

BACKGROUND: Web-based screening may be suitable for identifying individuals with presymptomatic latent diseases for recruitment to clinical studies, as such people do not often visit hospitals in the presymptomatic stage. The promotion of such online screening studies is critical to their success, although it remains uncertain how the effectiveness of such promotion can differ, depending on the different promotion methods, domains of interest, or countries of implementation. OBJECTIVE: The Japanese Trial-Ready Cohort (J-TRC) web study is our ongoing online screening registry to identify individuals with presymptomatic Alzheimer disease (AD), aimed at facilitating the clinical trials for AD prevention. Within the first 9 months of its 2019 launch, the J-TRC web study recruited thousands of online participants via multiple methods of promotion, including press releases, newspaper advertisements, web advertisements, or direct email invitations. Here, we aimed to quantitatively evaluate efficacy and cost-effectiveness of each of these multimodal promotion methods. METHODS: We applied the vector-autoregression model to assess the degree of contribution of each type of promotion to the following target metrics: number of daily visitors to the J-TRC website, number of daily registrants to the J-TRC web study, daily rate of registration among visitors, daily rate of eligible participants among registrants, and median age of daily registrants. The average cost-effectiveness for each promotion method was also calculated using the total cost and the coefficients in the vector-autoregression model. RESULTS: During the first 9 months of the reviewed period from October 31, 2019 to June 17, 2020, there were 48,334 website visitors and 4429 registrations (9.16% of 48,334 visitors), of which 3081 (69.56%) were eligible registrations. Initial press release reports and newspaper advertisements had a marked effect on increasing the number of daily visitors and daily registrants. Web advertisements significantly contributed to the increase in daily visitors (P<.001) but not to the daily registrants, and it also lowered the rate of registrations and the median age of daily registrants. Website visitors from the direct email invitation sent to other cognitive registries seem to have registered with the highest reliability. The calculated average cost-effectiveness for the initial press release was US $24.60 per visitor and US $96.10 per registrant, while the calculated average cost-effectiveness for the newspaper advertisements was US $28.60 per visitor and US $227.90 per registrant. CONCLUSIONS: Our multivariate time-series analysis showed that each promotion method had different features in their effect of recruiting participants to the J-TRC web study. Under the advertisement condition settings thus far, newspaper advertisements and initial press releases were the most effective promotion methods, with fair cost-effectiveness that was equivalent to earlier online studies. These results can provide important suggestions for future promotions for the recruitment of presymptomatic participants to AD clinical trials in Japan.

Ramsay-Hunt syndrome and subsequent sensory neuropathy as potential immune-related adverse events of nivolumab: a case report.

BACKGROUND: Nivolumab is an immune checkpoint inhibitor (ICI) and is used for the treatment of advanced non-small cell lung cancer (NSCLC). Several immune-mediated neurological adverse events associated with ICIs have been reported to date, such as Guillain-Barré syndrome. Nivolumab-associated neurological adverse events can vary, and their etiology remains unclear. CASE PRESENTATION: A 72-year-old man with NSCLC was treated with nivolumab as a second-line therapy. After 13 rounds of nivolumab therapy, he presented with Ramsay-Hunt syndrome (RHS) followed by acute ataxic sensory neuropathy. Antiviral therapy for Varicella-Zoster virus and prednisolone resulted in partial improvement of RHS, while almost no recovery was observed in the sensory neuropathy. However, the sensory ataxia significantly improved after intravenous immunoglobulin (IVIg) therapy, and interestingly, the facial palsy associated with RHS also improved. The neurological manifestations, nerve conduction study result, and imaging findings supported that dorsal root ganglia were the primary lesion site of acute ataxic sensory neuropathy. CONCLUSIONS: Our case presented with the comorbidity of RHS and subsequent ataxic sensory neuropathy after nivolumab therapy to whom IVIg was effective. Our case suggested the wide variability of possible neurological symptoms, and the potential usefulness of IVIg to sensory ataxic neuropathy, seen in cancer patients with ICI treatment.

Neurological and related adverse events in immune checkpoint inhibitors: a pharmacovigilance study from the Japanese Adverse Drug Event Report database.

INTRODUCTION: Immune checkpoint inhibitors (ICPI), a breakthrough immunotherapy for cancer, can cause serious neurological adverse events (AEs). We aimed to investigate the characteristics of the neurological and related AEs associated with ICPI treatment, using a large pharmacovigilance database from Japan. METHODS: We conducted disproportionality analysis using the Japanese Adverse Drug Event Report (JADER) database containing 566,698 patient cases recorded between April 2004 and March 2019, to detect neurological and related AE signals associated with ICPI treatment by calculating reporting odds ratio (ROR). RESULTS: Among 7604 cases with ICPI usage, we identified 583 cases (7.67%) with a significantly high reporting of neurological and related AEs (lower 95% of the ROR > 1), including myasthenia gravis (MG), inflammatory myositis, non-infectious encephalitis/myelitis, non-infectious meningitis, hypophysitis/hypopituitarism, and peripheral neuropathy including Guillain-Barre syndrome (GBS). Among the ICPI subtypes, when compared to nivolumab as a reference, number of hypophysitis, hypopituitarism, and meningitis reports from the use of ipilimumab and number of encephalitis/myelitis and meningitis reports from the use of anti-programmed cell death-ligand-1 (PD-L1) agents were significantly higher. Additionally, time to AE onset of symptoms post administration was short in meningitis (median 21 days), MG (median 28 days), myositis (median 28 days), and encephalitis/myelitis (median 32.5 days), while it was longer in peripheral neuropathy (median 42 days), hypophysitis (median 94 days), and hypopituitarism (median 112 days). CONCLUSIONS: Our results showed characteristic features of neurological and related AEs associated with each ICPI subtype, reported in a large number of Japanese patients. This would help in prompt identification and treatment of neurological AEs associated with ICPI treatment.

Fragility Index in Randomized Controlled Trials of Ischemic Stroke.

OBJECTIVE: The fragility index (FI), a minimum number of events in 1 arm of a clinical trial required to revert the statistically significant result to nonsignificant, has recently been developed as an easy-to-understand novel metric to evaluate the robustness of randomized controlled trials (RCTs). Here, we evaluated the FI of RCTs in the field of neurology, particularly in studies of ischemic stroke. METHODS: Previous literature published between June 1, 2012 and May 31, 2018 were reviewed from the MEDLINE database by the authors. The original article reporting the significant RCT result, of which a dichotomous outcome was set as its primary outcome measure, was included to evaluate the robustness of the result by calculating the FI. In addition, recent studies examining FI in other clinical fields were reviewed and summarized. RESULTS: In the 25 eligible RCT studies, the median total number of study participants was 206 (inter quartile range: 144-450) and the median FI was 7 (inter quartile range: 4-15.0). The FI showed a strong negative correlation with the observed P value. There was no significant difference in the FI between RCTs with and without acute settings. Our median FI was higher than the median FI of 2.5 of previous studies examining FI in other clinical fields, as only 20% (5 of 25) of studies included in our study had an FI less than 2.5. CONCLUSION: Our results suggest that many RCTs in the field of ischemic stroke have a fair robustness, when compared to those in other clinical fields.

Old Stroke as an Independent Risk Etiology for Todd's Paralysis.

BACKGROUND: Todd's paralysis (TP) is a well-known postictal paresis in which patients present with transient weakness in their limb(s) after seizures. Although recognized as a stroke mimic in clinical practice, the pathophysiological mechanism and clinical features of TP remain unknown. Furthermore, its diagnosis can be erroneous in neurological emergency practice. We aimed to illustrate the clinical features and identify factors associated with TP. METHODS: This single-center, retrospective observational study included consecutive adult patients who presented with convulsive seizure and were referred to an urban tertiary care emergency department between August 2010 and April 2016. The diagnosis of TP was set as the primary outcome measure. Clinical and laboratory variables were evaluated. RESULTS: Of 1381 eligible convulsive seizures in 1187 patients, TP was observed in 89 seizures (6.4%) in 75 patients. Patients with TP were significantly older, more likely to have convulsive status epilepticus, and had a longer duration of convulsion than patients without TP. TP was found in 19.7% (39 of 198) of convulsive seizures with remote etiologies including those due to old stroke. These etiologies were identified as independent significant risk factors for TP compared with seizures with cryptogenic etiology. The positive likelihood ratio of TP seizures was 11.2 for remote seizure etiologies. CONCLUSIONS: Our results indicated that the diagnosis of TP highly suggests premorbid or comorbid structural lesions in the central nervous system, including old stroke. This consideration in seizure etiology may help in reducing the risk of misdiagnosis of acute stroke in emergency settings and further antiepileptic treatment.

Clinical application of diffusion-weighted imaging for preoperative differentiation between uterine leiomyoma and leiomyosarcoma.

OBJECTIVE: This study investigated the clinical usefulness of diffusion-weighted imaging (DWI) and the apparent diffusion coefficient (ADC) value for preoperative differentiation between uterine leiomyoma and leiomyosarcoma. STUDY DESIGN: This study included 10 lesions from 5 patients with pelvic leiomyosarcoma and 83 leiomyoma nodules from 76 patients, as identified by postoperative pathological examination (1 autopsy). All magnetic resonance examinations were performed with a 1.5-T superconductive magnetic resonance unit. RESULTS: The leiomyosarcoma lesions were readily apparent via DWI, presenting as an intermediate- to high-intensity area in the uterine wall. All low-intensity areas presented as leiomyoma nodules. The mean ADC value for the 10 leiomyosarcoma lesions was 0.791 ± 0.145 (×10(-3) mm(2)/s), significantly lower than that of the leiomyoma nodules that presented with intermediate-intensity areas, 1.472 ± 0.285 (×10(-3) mm(2)/s) (n = 41) (P < .001), and high-intensity areas (1.100 ± 0.343) (n = 9) (P = .03). Additionally, in this study, the highest ADC value for a leiomyosarcoma was 1.095, with an intermediate DWI intensity. Based on these results, we classified the patients into 2 groups: low-risk group (barely any leiomyosarcoma risk) and high-risk group. Analyses comparing the 2 groups yielded the following: sensitivity, 100%; specificity, 94.0%; positive predictive value, 66.7%; negative predictive value, 100%; and accuracy, 94.6%. CONCLUSION: We suggest that this modality using a combination of signal intensity on DWI and ADC value is very effective, simple, and easy to apply clinically for differential diagnosis of leiomyosarcoma and myoma.

Simplifying Alzheimer's Disease Monitoring: A Novel Machine-Learning Approach to Estimate the Clinical Dementia Rating Sum of Box Changes Using the Mini-Mental State Examination and Functional Activities Questionnaire.

Background: Primary outcome measure in the clinical trials of disease modifying therapy (DMT) drugs for Alzheimer's disease (AD) has often been evaluated by Clinical Dementia Rating sum of boxes (CDRSB). However, CDR testing requires specialized training and 30-50 minutes to complete, not being suitable for daily clinical practice. Objective: Herein, we proposed a machine-learning method to estimate CDRSB changes using simpler cognitive/functional batteries (Mini-Mental State Examination [MMSE] and Functional Activities Questionnaire [FAQ]), to replace CDR testing. Methods: Baseline data from 944 ADNI and 171 J-ADNI amyloid-positive participants were used to build machine-learning models predicting annualized CDRSB changes between visits, based on MMSE and FAQ scores. Prediction performance was evaluated with mean absolute error (MAE) and R2 comparing predicted to actual rmDeltaCDRSB/rmDeltayear. We further assessed whether decline in cognitive function surpassing particular thresholds could be identified using the predicted rmDeltaCDRSB/rmDeltayear. RESULTS: The models achieved the minimum required prediction errors (MAE < 1.0) and satisfactory prediction accuracy (R2>0.5) for mild cognitive impairment (MCI) patients for changes in CDRSB over periods of 18 months or longer. Predictions of annualized CDRSB progression>0.5, >1.0, or >1.5 demonstrated a consistent performance (i.e., Matthews correlation coefficient>0.5). These results were largely replicated in the J-ADNI case predictions. CONCLUSIONS: Our method effectively predicted MCI patient deterioration in the CDRSB based solely on MMSE and FAQ scores. It may aid routine practice for disease-modifying therapy drug efficacy evaluation, without necessitating CDR testing at every visit.

Advertisement by medical facilities as an opportunity route of APOE genetic testing in Japan: a website analysis.

The APOE-ε4 allele(s) is a strong risk factor for Alzheimer's disease (AD). A significant point of access for this allele testing is through services provided by medical facilities in Japan, which advertise out-of-insurance APOE testing on their websites. There is a concern that website advertisements for APOE testing may influence the ability for individuals to adequately self-determine whether to undergo APOE testing. We conducted a cross-sectional survey on medical facility websites in Japan advertising APOE genetic testing. We predefined desirable features for advertisement descriptions based on legal regulations and guidelines published by relevant professional societies and evaluated each website according to these features. We identified 220 medical facilities that had posted advertisements on their websites for the provision of APOE genetic testing, of which 85% were small clinics. Contact information, details, and costs of testing were described in most of the websites. Meanwhile, features such as "explaining APOE as a risk gene," "notes on interpreting APOE results," or "explaining examination methods" (e.g., blood sampling) were described to a variable degree depending on individual facilities. "Notes on genetic testing" or "referring to genetic counseling" were hardly referred to, and specialists with appropriate expertise were considered to participate in clinical practice in approximately one-third of these facilities providing APOE testing services. These website evaluation results showed moderate to substantial reliability between independent raters. These results suggest that self-determination of pursuing out-of-insurance APOE testing at some medical facilities in Japan may possibly be influenced in an inappropriate manner, at least in its entry route of taking the test.

Combining plasma Aß and p-tau217 improves detection of brain amyloid in non-demented elderly.

BACKGROUND: Maximizing the efficiency to screen amyloid-positive individuals in asymptomatic and non-demented aged population using blood-based biomarkers is essential for future success of clinical trials in the early stage of Alzheimer's disease (AD). In this study, we elucidate the utility of combination of plasma amyloid-ß (Aß)-related biomarkers and tau phosphorylated at threonine 217 (p-tau217) to predict abnormal Aß-positron emission tomography (PET) in the preclinical and prodromal AD. METHODS: We designed the cross-sectional study including two ethnically distinct cohorts, the Japanese trial-ready cohort for preclinica and prodromal AD (J-TRC) and the Swedish BioFINDER study. J-TRC included 474 non-demented individuals (CDR 0: 331, CDR 0.5: 143). Participants underwent plasma Aß and p-tau217 assessments, and Aß-PET imaging. Findings in J-TRC were replicated in the BioFINDER cohort including 177 participants (cognitively unimpaired: 114, mild cognitive impairment: 63). In both cohorts, plasma Aß(1-42) (Aß42) and Aß(1-40) (Aß40) were measured using immunoprecipitation-MALDI TOF mass spectrometry (Shimadzu), and p-tau217 was measured with an immunoassay on the Meso Scale Discovery platform (Eli Lilly). RESULTS: Aß-PET was abnormal in 81 participants from J-TRC and 71 participants from BioFINDER. Plasma Aß42/Aß40 ratio and p-tau217 individually showed moderate to high accuracies when detecting abnormal Aß-PET scans, which were improved by combining plasma biomarkers and by including age, sex and APOE genotype in the models. In J-TRC, the highest AUCs were observed for the models combining p-tau217/Aß42 ratio, APOE, age, sex in the whole cohort (AUC = 0.936), combining p-tau217, Aß42/Aß40 ratio, APOE, age, sex in the CDR 0 group (AUC = 0.948), and combining p-tau217/Aß42 ratio, APOE, age, sex in the CDR 0.5 group (AUC = 0.955), respectively. Each subgroup results were replicated in BioFINDER, where the highest AUCs were seen for models combining p-tau217, Aß42/40 ratio, APOE, age, sex in cognitively unimpaired (AUC = 0.938), and p-tau217/Aß42 ratio, APOE, age, sex in mild cognitive impairment (AUC = 0.914). CONCLUSIONS: Combination of plasma Aß-related biomarkers and p-tau217 exhibits high performance when predicting Aß-PET positivity. Adding basic clinical information (i.e., age, sex, APOE Îµ genotype) improved the prediction in preclinical AD, but not in prodromal AD. Combination of Aß-related biomarkers and p-tau217 could be highly useful for pre-screening of participants in clinical trials of preclinical and prodromal AD.

From the Cover: Neurons in the anterior olfactory nucleus pars externa detect right or left localization of odor sources.

Rodents can localize odor sources by comparing odor inputs to the right and left nostrils. However, the neuronal circuits underlying such odor localization are not known. We recorded neurons in the anterior olfactory nucleus (AON) while administering odors to the ipsilateral or contralateral (ipsi- or contra-) nostril. Neurons in the AON pars externa (AONpE) showed respiration phase-locked excitatory spike responses to ipsinostril-only stimulation with a category of odorants, and inhibitory responses to contranostril-only stimulation with the same odorants. Simultaneous odor stimulation of the ipsi- and contranostrils elicited significantly smaller responses than ipsinostril-only stimulation, indicating that AONpE neurons subtract the contranostril odor inputs from ipsinostril odor inputs. An ipsilateral odor source induced larger responses than a centrally located source, whereas an odor source at the contralateral position elicited inhibitory responses. These results indicate that individual AONpE neurons can distinguish the right or left position of an odor source by referencing signals from the two nostrils.

Regenerative medicine for epilepsy: from basic research to clinical application.

Epilepsy is a chronic neurological disorder, which presents with various forms of seizures. Traditional treatments, including medication using antiepileptic drugs, remain the treatment of choice for epilepsy. Recent development in surgical techniques and approaches has improved treatment outcomes. However, several epileptic patients still suffer from intractable seizures despite the advent of the multimodality of therapies. In this article, we initially provide an overview of clinical presentation of epilepsy then describe clinically relevant animal models of epilepsy. Subsequently, we discuss the concepts of regenerative medicine including cell therapy, neuroprotective agents, and electrical stimulation, which are reviewed within the context of our data.

Neuroprotective effects of liraglutide for stroke model of rats.

The number of diabetes mellitus (DM) patients is increasing, and stroke is deeply associated with DM. Recently, neuroprotective effects of glucagon-like peptide-1 (GLP-1) are reported. In this study, we explored whether liraglutide, a GLP-1 analogue exerts therapeutic effects on a rat stroke model. Wistar rats received occlusion of the middle cerebral artery for 90 min. At one hour after reperfusion, liraglutide or saline was administered intraperitoneally. Modified Bederson's test was performed at 1 and 24 h and, subsequently, rats were euthanized for histological investigation. Peripheral blood was obtained for measurement of blood glucose level and evaluation of oxidative stress. Brain tissues were collected to evaluate the level of vascular endothelial growth factor (VEGF). The behavioral scores of liraglutide-treated rats were significantly better than those of control rats. Infarct volumes of liraglutide-treated rats at were reduced, compared with those of control rats. The level of derivatives of reactive oxygen metabolite was lower in liraglutide-treated rats. VEGF level of liraglutide-treated rats in the cortex, but not in the striatum significantly increased, compared to that of control rats. In conclusion, this is the first study to demonstrate neuroprotective effects of liraglutide on cerebral ischemia through anti-oxidative effects and VEGF upregulation.

[Survey on the Current Advertising and Sales of Mucuna pruriens in Consumer-to-consumer Internet Trading in Japan].

Mucuna pruriens (MP) is leguminous plant which contains 5% of L-3,4-dihydroxyphenylalanine (levodopa) in its seeds. It may have a potential to be used as an alternative therapy for Parkinson's disease (PD). Meanwhile, there is a concern in terms of public health that MP products can be overused by patients with PD. As an entry for patients with PD to acquire MP products in Japan, they are often purchased via internet auctions or free markets. MP products are not reagrded as 'pharmatheutical' by Japanese law as long as the specific legal requirements on advertisements are met, so that the MP products can be advertised or sold without any permission from the authorities. In this study, we aimed to conduct internet survey as to the complianse status of these legal requirements. Several major internet auction or free market websites in Japan were surveyed in May-June 2023 by the authors, and 1157 MP product pages were examined. We found approximately 30-40% of the MP products were suspected to have potential legal risks in terms of their advertisements in their website descriptions, such as claiming pharmatheutical efficacy or describing pharmatheutical-like dosages. In addition, approximately 30-40% of the MP products also did not refer to cautions not to take MP products excessively because of the levodopa ingredients. Current study suggested the need of careful description of the MP products in the auction or free market websites for the MP products exhibitors or sellers, in order to fullfill legal requirements as well as to prevent MP abuse.

Perceptions of older adults and generativity among older citizens in Japan: a descriptive cross-sectional study.

BACKGROUND: As the population ages worldwide, including in Japan, there is a growing expectation for older adults to remain active participants in society. The act of sharing one's experiences and knowledge with younger generations through social engagement not only enriches the lives of older individuals, but also holds significant value for our society. In this study, we examined both positive and negative perceptions of older adults and investigated the correlation between these perceptions and generativity among older citizens. Additionally, we evaluated the impact of life satisfaction on these factors. METHODS: We conducted a survey of 100 older adults in Japan (mean age, 71.68 years) and utilized multiple regression analyses, using positive and negative perceptions of older adults, life satisfaction, and demographic factors as independent variables. The sub-categories of generativity-namely, generative action, concern, and accomplishment-were used as dependent variables. RESULTS: Participants who held a more positive perception of older adults demonstrated a higher level of generative actions and concerns. Additionally, participants who reported higher levels of life satisfaction also exhibited more generative actions, concerns, and accomplishments. Conversely, those who held a more negative perception of older adults were found to have higher levels of generative actions. CONCLUSION: Enhancing positive perceptions of older adults among them can boost the sub-categories of generativity. This study, which was conducted from an exploratory perspective, has several limitations, including a potential sampling bias. A more comprehensive examination of the relationship between perceptions of older adults and generativity is anticipated in future research.