Clinical manifestations of methylmercury (MeHg) intoxication include cerebellar ataxia, concentric constriction of visual fields, and sensory and auditory disturbances. The symptoms depend on the ...site of MeHg damage, such as the cerebellum and occipital lobes. However, the underlying mechanism of MeHg-induced tissue vulnerability remains to be elucidated. In the present study, we used a rat model of subacute MeHg intoxication to investigate possible MeHg-induced blood-brain barrier (BBB) damage. The model was established by exposing the rats to 20-ppm MeHg for up to 4 weeks; the rats exhibited severe cerebellar pathological changes, although there were no significant differences in mercury content among the different brain regions. BBB damage in the cerebellum after MeHg exposure was confirmed based on extravasation of endogenous immunoglobulin G (IgG) and decreased expression of rat endothelial cell antigen-1. Furthermore, expression of vascular endothelial growth factor (VEGF), a potent angiogenic growth factor, increased markedly in the cerebellum and mildly in the occipital lobe following MeHg exposure. VEGF expression was detected mainly in astrocytes of the BBB. Intravenous administration of anti-VEGF neutralizing antibody mildly reduced the rate of hind-limb crossing signs observed in MeHg-exposed rats. In conclusion, we demonstrated for the first time that MeHg induces BBB damage via upregulation of VEGF expression at the BBB in vivo. Further studies are required in order to determine whether treatment targeted at VEGF can ameliorate MeHg-induced toxicity.
Physical therapy (PT) is beneficial for critically ill patients, but the extent of its application in the intensive care unit (ICU) differs between countries. Here, we compared the extent of PT ...intervention in the ICU in Japan, the Philippines, and Taiwan by evaluating the sociodemographic and ICU-related profiles of ICU physical therapists. In this cross-sectional study, a semistructured nationwide online survey was distributed to ICU physical therapists in the three countries. We analyzed the responses of 164 physical therapists from Japan, Philippines, and Taiwan. Significant differences were observed between the countries in all sociodemographic variables and the following ICU-related profiles of physical therapists: ICU work experience, duration of the ICU posting, number of hours per day spent in the ICU, on-call ICU PT service engagement, source of ICU patient referral, therapist-patient ratio, and ICU-related PT training participation (p < 0.05). Medical, surgical, and neurologic ICUs were the most common ICU workplaces of the ICU physical therapists, but only surgical and neurologic ICUs exhibited significant differences between the countries (p < 0.05). Standard PT techniques in the ICU were passive and active-assisted range of motion, positioning, and breathing exercises but were implemented with significantly different frequencies between the countries (p < 0.05). The most common challenge faced in ICU PT service delivery by respondents from all three countries was lack of training prior to ICU duty, and lack of training was even bigger challenge in Japan than in other two countries after adjustment of age, highest educational attainment, and work experience. The differences in the health-care system between Japan, the Philippines, and Taiwan were related to differences in the compliance with internationally recommended PT practice standards in the ICU, differences in the type of PT intervention prioritized, and the challenges encountered in ICU PT service delivery.
The purpose of this study was to detect specific motor unit (MU) abnormalities in people with amyotrophic lateral sclerosis (ALS) compared to controls using high-density surface electromyography ...(HD-SEMG).
Sixteen people with ALS and 16 control subjects. The participants performed ramp up and sustained contractions at 30% of their maximal voluntary contraction. HD-SEMG signals were recorded in the vastus lateralis muscle and decomposed into individual MU firing behavior using a convolution blind source separation method.
In total, 339 MUs were detected (people with ALS; n = 93, control subjects; n = 246). People with ALS showed significantly higher mean firing rate, recruitment threshold, coefficient of variation of the MU firing rate, MU firing rate at recruitment, and motoneurons excitability than those of control subjects (p < 0.001). The number of MU, MU firing rate, recruitment threshold, and MU firing rate at recruitment were significantly correlated with disease severity (p < 0.001). Multivariable analysis revealed that an increased MU firing rate at recruitment was independently associated with ALS.
These results suggest increased excitability at recruitment, which is consistent with neurodegeneration results in a compensatory increase in MU activity.
Abnormal MU firing behavior provides an important physiological index for understanding the pathophysiology of ALS.
With the aging process, brain functions, such as attention, memory, and cognitive functions, degrade over time. In a super-aging society, the alteration of neural activity owing to aging is ...considered crucial for interventions for the prevention of brain dysfunction. The complexity of temporal neural fluctuations with temporal scale dependency plays an important role in optimal brain information processing, such as perception and thinking. Complexity analysis is a useful approach for detecting cortical alteration in healthy individuals, as well as in pathological conditions, such as senile psychiatric disorders, resulting in changes in neural activity interactions among a wide range of brain regions. Multi-fractal (MF) and multi-scale entropy (MSE) analyses are known methods for capturing the complexity of temporal scale dependency of neural activity in the brain. MF and MSE analyses exhibit high accuracy in detecting changes in neural activity and are superior with regard to complexity detection when compared with other methods. In addition to complex temporal fluctuations, functional connectivity reflects the integration of information of brain processes in each region, described as mutual interactions of neural activity among brain regions. Thus, we hypothesized that the complementary relationship between functional connectivity and complexity could improve the ability to detect the alteration of spatiotemporal patterns observed on electroencephalography (EEG) with respect to aging. To prove this hypothesis, this study investigated the relationship between the complexity of neural activity and functional connectivity in aging based on EEG findings. Concretely, MF and MSE analyses were performed to evaluate the temporal complexity profiles, and phase lag index analyses assessing the unique profile of functional connectivity were performed based on the EEGs conducted for young and older participants. Subsequently, these profiles were combined through machine learning. We found that the complementary relationship between complexity and functional connectivity improves the classification accuracy among aging participants. Thus, the outcome of this study could be beneficial in formulating interventions for the prevention of age-related brain dysfunction.
In recent years, there have been increasing knowledge gaps and biases in public health information. This has become especially evident during the COVID-19 pandemic and has contributed to the spread ...of misinformation. With constant exposure to disinformation and misinformation through television, the internet, and social media, even university students studying healthcare-related subjects lack accurate public health knowledge. This study aimed to assess university students’ knowledge levels of basic public health topics before they started their specialized education. Participants in this cross-sectional study were first-year students from medical schools, health-related colleges, and liberal arts colleges. A self-administered electronic survey was conducted from April to May 2021 at a private university in Japan, comprising six colleges with seven programs. Data analysis, conducted from June to December 2022, included students’ self-reported public health knowledge, sources of information, and self-assessment of knowledge levels. Among the 1,562 students who received the questionnaire, 549 (192 male 35%, 353 female 64.3%, and 4 undisclosed 0.7%) responded to one question (participants’ response rate for each question; 59.6%–100%). The results showed that students had limited public health knowledge, especially in sexual health topics, and 10% of students reported not learning in class before university admission the following 11 topics: two on Alcohol, Tobacco, and Other Drugs; eight on Growth, Development, and Sexual Health; and one on Personal and Community Health. These results indicate significant knowledge gaps and biases, as well as gender gaps, in public health education, especially in the area of sexual health, which may help educators and educational institutions to better understand and prepare for further specialized education. The findings also suggest a need to supplement and reinforce the foundation of public health knowledge for healthcare majors at the time of university admission.
Heated tobacco products (HTPs) have emerged as novel alternatives to conventional cigarettes (CCs), marketed by the tobacco industry as having a reduced potential for harm. Nevertheless, a ...significant dearth of information remains regarding the long-term effects of HTPs on the central nervous system (CNS). Here, we sought to shed light on the repercussions of prolonged exposure to HTPs on the CNS, employing a mouse model mimicking prodromal Alzheimer's disease (AD). Our study entailed subjecting App knock-in mice to 16 weeks of HTP exposure, administered 5 days per week, with serum cotinine concentration serving as confirmation of HTP exposure within this model. Histological analysis, aimed at assessing amyloid pathology, unveiled a minimal impact attributable to HTPs. However, exploration of differentially expressed genes in the cerebral cortex, using unadjusted p values, indicated an association between HTP exposure and non-inflammatory pathways, specifically linked to neurohypophyseal and neuropeptide hormone activity within the CNS. Of note, similar results have already been observed after exposure to CCs in vivo. Our study not only contributes insights into the potential non-inflammatory effects of HTPs within the context of AD pathogenesis but also underscores the significance of continued research to comprehend the full scope of their impact on the CNS.
•Synphilin-1 inhibited ROS production and cytochrome c release induced by MPP+ in vitro.•Synphilin-1 inhibited early steps in the intrinsic apoptotic pathway.•Synphilin-1 played a neuroprotective ...role in Parkinson’s disease model cells.
Synphilin-1, a cytoplasmic protein, interacts with α-synuclein which is one of the main constituents of Lewy bodies and plays an important role in the pathology of Parkinson’s disease (PD), in neurons. This interaction indicates that synphilin-1 may also play a central role in PD. However, the biological functions of synphilin-1 are not fully understood, and whether synphilin-1 is neurotoxic or neuroprotective remains controversial. This study examined the function of synphilin-1 in a PD model in vitro. We used an inhibitor of mitochondrial complex I, 1-methyl-4-phenylpyridinium (MPP+). We established human neuroblastoma SH-SY5Y cell lines that stably expressed human synphilin-1. We found that overexpression of synphilin-1 increased SH-SY5Y cell viability after MPP+ treatment. We further found that synphilin-1 significantly suppressed apoptotic changes in nuclei, including nuclear condensation and fragmentation, after MPP+ treatment. We showed that synphilin-1 significantly decreased MPP+-induced cleaved caspase-3 and cleaved poly-ADP-ribose polymerase levels by using western blotting. Production of reactive oxygen species (ROS) induced by MPP+ was significantly reduced in cells expressing synphilin-1 compared to those expressing empty vector. Synphilin-1 inhibited MPP+-induced cytochrome c release from mitochondria into the cytosol. These data suggested that synphilin-1 may function to protect against dopaminergic cell death by preserving mitochondrial function and inhibiting early steps in the intrinsic apoptotic pathway. Taken together, our results indicated that synphilin-1 may play neuroprotective roles in PD pathogenesis by inhibiting ROS production and apoptosis.
In the central nervous system, progranulin, a glycoprotein growth factor, plays a crucial role in maintaining physiological functions, and progranulin gene mutations cause TAR DNA-binding ...protein-43-positive frontotemporal lobar degeneration. Although several studies have reported that progranulin plays a protective role against ischaemic brain injury, little is known about temporal changes in the expression level, cellular localization, and glycosylation status of progranulin after acute focal cerebral ischaemia. In addition, the precise mechanisms by which progranulin exerts protective effects on ischaemic brain injury remains unknown. Furthermore, the therapeutic potential of progranulin against acute focal cerebral ischaemia, including combination treatment with tissue plasminogen activator, remains to be elucidated. In the present study, we aimed to determine temporal changes in the expression and localization of progranulin after ischaemia as well as the therapeutic effects of progranulin on ischaemic brain injury using in vitro and in vivo models. First, we demonstrated a dynamic change in progranulin expression in ischaemic Sprague-Dawley rats, including increased levels of progranulin expression in microglia within the ischaemic core, and increased levels of progranulin expression in viable neurons as well as induction of progranulin expression in endothelial cells within the ischaemic penumbra. We also demonstrated that the fully glycosylated mature secretory isoform of progranulin (∼88 kDa) decreased, whereas the glycosylated immature isoform of progranulin (58-68 kDa) markedly increased at 24 h and 72 h after reperfusion. In vitro experiments using primary cells from C57BL/6 mice revealed that the glycosylated immature isoform was secreted only from the microglia. Second, we demonstrated that progranulin could protect against acute focal cerebral ischaemia by a variety of mechanisms including attenuation of blood-brain barrier disruption, neuroinflammation suppression, and neuroprotection. We found that progranulin could regulate vascular permeability via vascular endothelial growth factor, suppress neuroinflammation after ischaemia via anti-inflammatory interleukin 10 in the microglia, and render neuroprotection in part by inhibition of cytoplasmic redistribution of TAR DNA-binding protein-43 as demonstrated in progranulin knockout mice (C57BL/6 background). Finally, we demonstrated the therapeutic potential of progranulin against acute focal cerebral ischaemia using a rat autologous thrombo-embolic model with delayed tissue plasminogen activator treatment. Intravenously administered recombinant progranulin reduced cerebral infarct and oedema, suppressed haemorrhagic transformation, and improved motor outcomes (P = 0.007, 0.038, 0.007 and 0.004, respectively). In conclusion, progranulin may be a novel therapeutic target that provides vascular protection, anti-neuroinflammation, and neuroprotection related in part to vascular endothelial growth factor, interleukin 10, and TAR DNA-binding protein-43, respectively.
Background The aim of this study is to explore the prevalence and overlap of physical, cognitive, psychological, and social frailty and their negative-interrelationships.
Methods We conducted a ...survey of people aged ≥75 years in the region with the oldest population in Japan. Frailty was divided into physical, cognitive, psychological, and social frailty, which were evaluated with the Japanese version of the Cardiovascular Health Study (J-CHS) criteria, J-CHS and the Japanese version of the Montreal Cognitive Assessment, the Geriatric Depression Scale-15 and the Lubben Social Network Scale, respectively.
Results Of the 268 participants (aged 81.5 ± 4.5 years), 48.1% and 8.6% had physical prefrailty and frailty; 68.3%, 13.0%, and 5.2% had mild cognitive impairment, dementia, and cognitive frailty; 25.7% and 5.2% had depressive mood and depression as psychological frailty; and 7.8% had social frailty, respectively. Path analysis showed that social frailty was associated with psychological frailty. Psychological frailty was associated with physical frailty. Physical frailty was associated with cognitive frailty. Multiple logistic regression analysis showed that independent determinants of physical robustness were female sex, age, and psychological robustness (odds ratio (OR) = 2.166, 0.831, 3.625, respectively). Determinants of cognitive robustness were age and psychological robustness (OR = 0.837, 7.079). Determinants of psychological robustness were physical, cognitive, and social robustness (OR = 3.759, 6.829, 5.037), and the determinant of social robustness was psychological robustness (OR = 4.489), respectively.
Conclusions We demonstrated the prevalence, overlap, and interrelationships of different types of frailty and clarified the factors that may help to reduce frailty.
Hypertension is a major public health problem among the aging population worldwide. It causes cardiac remodeling, including hypertrophy and interstitial fibrosis, which leads to development of ...hypertensive heart disease (HHD). Although microRNA-21 (miR-21) is associated with fibrogenesis in multiple organs, its contribution to cardiac remodeling in hypertension is poorly understood. Circulating miR-21 level was higher in patients with HHD than that in the control subjects. It also positively correlated with serum myocardial fibrotic markers. MiR-21 expression levels were significantly upregulated in the mice hearts after angiotensin II (Ang II) infusion or transverse aortic constriction (TAC) compared with control mice. Expression level of programmed cell death 4 (PDCD4), a main target of miR-21, was significantly decreased in Ang II infused mice and TAC mice compared with control mice. Expression levels of transcriptional activator protein 1 (AP-1) and transforming growth factor-β1 (TGF-β1), which were downstream targets of PDCD4, were increased in Ang II infused mice and TAC mice compared with control mice. In vitro, mirVana-miR-21-specific inhibitor attenuated Ang II-induced PDCD4 downregulation and contributed to subsequent deactivation of AP-1/TGF-β1 signaling pathway in neonatal rat cardiomyocytes. Thus, suppression of miR-21 prevents hypertrophic stimulation-induced cardiac remodeling by regulating PDCD4, AP-1, and TGF-β1 signaling pathway.
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