Hypothermia and focal brain cooling (FBC) demonstrate neuroprotective effects in ischemic stroke, but their invasiveness limits clinical use. We explored transient receptor potential (TRP) channels as an alternative, focusing on TRP Ankyrin 1 (TRPA1), which operates within the temperature range of FBC. Activation of TRPA1 has been reported to offer neuroprotection, suggesting it may contribute to the effects seen with FBC. We hypothesized that pharmacological activation of TRPA1 could replicate the neuroprotective effects of FBC, providing a less invasive treatment for cerebral infarction. We examined the effects of a TRPA1 agonist and FBC in focal cerebral ischemia induced by photochemically triggered thrombosis in wild-type (WT) and TRPA1 knockout (KO) mice. In WT mice, intracerebroventricular administration of the TRPA1 agonist allyl isothiocyanate reduced infarct size by approximately half, comparable to FBC. TRPA1 KO mice had larger infarcts than WT, but FBC significantly reduced infarct size in both groups. Furthermore, Evans blue extravasation, used to assess the extent of blood-brain barrier disruption, was approximately twice as high in TRPA1KO mice compared to WT mice. These findings underscore the neuroprotective potential of TRPA1 agonists and the increased vulnerability against ischemia with TRPA1 deficiency. However, the neuroprotective effects of TRPA1 activation are likely mediated by a mechanism distinct from that of FBC. Our study suggests TRPA1 channels are crucial for ischemic stroke protection and may offer a novel therapeutic approach.

Focal brain cooling (FBC) at 15℃ and transient receptor potential vanilloid 4 (TRPV4) deficiency relieve brain infarction. TRPV4 channels are inactivated by cooling (< 27℃), suggesting that the anti-ischemic effects of FBC include those of TRPV4 inactivation. However, the extent to which TRPV4 inactivation contributes to the anti-ischemic, anti- blood-brain barrier (BBB) disruption, and anti-apoptosis effects of FBC on cerebral infarction remains unclear. We investigated the contribution and mechanisms of RN1734, a TRPV4 antagonist, in FBC for cerebral infarction using TRPV4 knockout and wild-type mice. Focal cerebral infarction was induced by photochemically induced thrombosis. Infarct volume, BBB disruption, and number of apoptotic cells were evaluated. The TRPV4 antagonist or deficiency showed similar anti-ischemic and anti-BBB disruptive effects to those of FBC. Intracerebroventricular injection of RN1734 showed a similar reduction in the number of apoptotic cells to that of FBC. These anti-ischemic and -apoptotic effects were completely inhibited with injection of GSK1016790A, a TRPV4 agonist, immediately before FBC. Our results showed that TRPV4 modulation is the primary factor contributing to the antiischemic effects of FBC, and TRPV4 channel inactivation relieve focal ischemic infarction by relieving BBB disruption and preventing apoptosis. Therefore, FBC treatment improves ischemic stroke through the modulation of TRPV4 channels.

A 70-year-old woman presented with acute fever, impaired consciousness, leukopenia, thrombocytopenia, and right inguinal lymphadenopathy. A lymph node biopsy was diagnosed as diffuse large B-cell lymphoma (DLBCL). However, her symptoms were consistent with severe fever with thrombocytopenia syndrome (SFTS), and RT-PCR for SFTS virus (SFTSV) RNA was positive. The patient’s condition and lymphadenopathy gradually improved with supportive measures and short-term steroid treatment and no lymphadenopathy recurrence was observed. Lymph node pathological examination revealed SFTSV-infected cells, leading to the final diagnosis of necrotizing lymphadenitis associated with SFTS. Careful consideration is required to differentiate necrotizing lymphadenitis associated with SFTS from that associated with DLBCL.

Blood-brain barrier (BBB) dysfunction found in the multiple sclerosis (MS) cases is generally considered as a consequence of neuroinflammation. In this study we challenge this view by developing and analyzing novel BBB model from MS patients using induced pluripotent stem cells (iPSCs). We differentiated iPSCs into brain microvascular endothelial cell (BMEC)-like cells to establish an in vitro BBB model. We found that BMEC-like cells from MS patients exhibited compromised barrier integrity, characterized by weakened junctions, heightened permeability, and an elevated inflammatory profile when compared to cells from healthy individuals. Notably, the activation of the Wnt/β-catenin signaling pathway led to improvements in barrier function and a reduction in inflammatory responses, indicating potential therapeutic targets for reinforcing BBB stability in MS.

Cardiac hypertrophy is widely recognized as a significant risk factor contributing to adverse outcomes in individuals with cardiovascular conditions. The disruption of intracellular calcium ( Ca^{2+} ) balance has been implicated in the development of cardiac hypertrophy, though the precise mechanisms remain poorly understood. In this research, we explored whether hypertrophy induced by pressure overload may arise from the destabilization of the cardiac ryanodine receptor (RyR2) triggered by the dissociation of calmodulin (CaM), leading to subsequent Ca^{2+} leakage. We also assessed whether genetically strengthening the binding affinity between CaM and RyR2 could potentially reverse this process. In the early phases of cardiac hypertrophy caused by pressure overload—when contractile function is still intact—we observed that RyR2 destabilization mediated by reactive oxygen species (ROS) coincides with impaired relaxation. Moreover, stabilizing RyR2 through enhanced CaM binding was found to completely inhibit hypertrophic signaling and improve survival rates. Our findings reveal a crucial connection between RyR2 destabilization and the progression of cardiac hypertrophy.

This study explores the innovative applications of depth cameras combined with Graph Convolutional Networks (GCN) for action recognition in two critical domains: elderly care and smart education. We harness the capabilities of depth cameras to capture spatial and temporal features, alongside our robust GCN algorithm, to develop models capable of accurately recognizing and classifying human actions. In elderly care, our model is particularly focused on detecting and analyzing falls, which are crucial for enhancing care safety and supporting the independence of elderly individuals. Experimental results demonstrate that our depth camera-based action recognition model achieved an impressive average accuracy of 96.3% in fall detection within real-world scenarios, while also maintaining low rates of false positives and false negatives. In the realm of smart education, our depth camera-based model is specifically designed to recognize students’ hand-raising actions in real-time, which is crucial for comprehensively assessing student engagement in the class, and accordingly adjusting teaching strategies. Experimental results show that our model achieves an average accuracy of 89.7% in realworld scenarios, while maintaining low rates of false positives and false negatives. Overall, this study showcases the powerful potential of integrating depth cameras with GCNs for action recognition, significantly enhancing both the safety and efficiency of elderly care, as well as the interactivity and educational quality of smart education.

Access to high-quality care at the end-of-life is a fundamental human right; therefore, it is necessary to examine how end-of-life care should be taught in nursing education to prepare for a super-aging society. Japan and Hong Kong are both in the East Asian region and are facing similar super-aging challenges, such as increased mortality and declining birth rates. This paper explores the literature on this topic and discusses how end-of-life care is taught in undergraduate nursing education in both Japan and Hong Kong. A comprehensive literature search was performed using end-of-life care keywords. Subsequently, the authors engaged in a discourse on expert perspectives, insights, and results from the literature. It is necessary to bridge the gap between the desired manner of spending oneʼs final days and the practical reality of considering patientsʼ best interests by referring to the existing policies, laws, guidelines, and frameworks of healthcare systems. This study suggests the importance of understanding patientsʼ views on life, death, values, and cultural backgrounds and educating healthcare personnel to apply these principles flexibly in their practice.

I, Professor Nobuaki Tanaka, gave a Farewell Lecture on February 29, 2024. First, I talked about the episode that led me to start researching aortic stenosis, and reflected on my own lectures on this topic to students aiming to become medical laboratory scientist. Lastly, I spoke to students majoring in medical laboratory scientist about the importance of practical clinical training.

Dementia, a leading cause of death, often initiates with spatial cognitive impairment. Assisting spatial cognition may not only address challenges faced by individuals with spatial cognitive impairment but also facilitate the prevention of dementia. While previous studies have explored voice navigation for the visually impaired, its utility for those without visual impairment remains unexamined. To provide insights for spatial navigation in the elderly, in the present study, we evaluated the usefulness of voice navigation in healthy university students. In a randomized controlled trial, forty students were assigned to either a paper map only group or a paper map and Google Maps voice navigation group and instructed to navigate a predetermined 800-meter route in a park. The effectiveness of voice navigation was evaluated through various means, including time taken to reach the destination, accuracy of the route followed, and participantsʼ experience. The results show that the two groups did not differ in terms of goal completion and time consumed. Nor did they differ in feelings of drowsiness, instability, uneasiness, pleasure, and relaxation. However, participants in the paper map only group demonstrated a decrease in local pain and eyestrains together with improved feelings of vigor at the goal compared to the start, which was absent in participants using both paper map and voice navigation. Although the effectiveness of the voice navigation was not confirmed, our study did provide important insights regarding in what ways voice navigation can be improved. Moreover, we were able to observe mood improvements in participants with a paper map only, which may indicate the effect of physical activity and exposure to the natural environment.

Purpose: We investigated sex differences in heart rate variability (HRV; a non-invasive indicator of autonomic nervous system) and its frequency-specific responses to whole-body vibration (WBV) at three distinct frequencies among elderly subjects. Methods: Data from 11 males and 13 females were analyzed across four randomized sessions of exposure: WBV at 15, 20, or 25 Hz with a 4 mm peak-to-peak displacement, or control (0 Hz) condition comprising three bouts of 1-minute exposure with 1-minute between-bout rests. HRV measurements were taken before and during the exposure. Results: At baseline, low-frequency power/LF (ms^{2}) were significantly lower in females than males (P < 0.05). During exposure, LF (ms^{2}), high-frequency power (ms^{2}), standard deviation of normal-to-normal intervals, root mean square of successive differences between RR intervals, standard deviation of the Poincaré plot perpendicular to the line-of-identity, and standard deviation of the Poincaré plot along the line-of-identity significantly increased at 20 Hz for males and 25 Hz for females (P < 0.05 to 0.005) compared to respective baselines. Conclusions: Elderly females tend to exhibit reduced autonomic nervous system function compared to males. Furthermore, our results indicate that WBV at 20 Hz for males and 25 Hz for females may be considered beneficial for enhancing HRV in the elderly.

This study investigated the potential of adalimumab (ADA), a monoclonal antibody targeting TNF-alfa, to protect the inner ear from intense sound exposure, given that inflammatory cytokines, including TNF-alfa, are linked to hearing loss in acoustic disorders. In this study, adalimumab was administered to mice, and its effect on the inner ear was assessed. We examined the translocation of ADA to the inner ear and its ototoxicity and impact on acoustic exposure. The results showed that adalimumab partially reached the cochlea after administration but increased the susceptibility to acoustic exposure, resulting in higher hair cell loss in the inner ear. While TNF-alfa had been considered a potential therapeutic target, the results suggested that excessive TNF-alfa suppression could harm the inner ear. We acknowledged some limitations, such as the use of adalimumab instead of an anti-mouse TNF-alfa antibody and the need to explore the suppression of other cytokines for better inner ear protection. In conclusion, adalimumab administration was found to increase the inner earʼs susceptibility to acoustic exposure, potentially leading to more significant hair cell damage, possibly due to excessive TNF-alfa suppression.

Vestibular hair cells are susceptible to damage from various stimuli such as infections, ischemia, and certain therapeutic drugs, including aminoglycoside antibiotics and the antineoplastic agent cisplatin. In mammals, damage to the vestibular hair cells is permanent. This study aimed to evaluate the protective effects of nobiletin (NOB) against aminoglycoside-induced hair cell death using utricles collected from adult mice. The utricles removed from CBA/N mice were assigned to eight groups according to the dose of NOB and the administration or not of neomycin. Hair cells in the utricles were counted by double labeling with calmodulin and calbindin. NOB inhibited hair cell death in utricles exposed to neomycin. The protective effect of NOB on hair cells in the utricles was also suggested to have resulted from the inhibition of the production and accumulation of 4-hydroxy-2-nonenal, the final product of lipid peroxide aldehyde. NOB suppressed neomycin-induced hair cell death. The principle of hair cell protection from aminoglycoside-induced hair cell death suggests that NOB inhibits reactive oxygen species formation in the utricles exposed to neomycin.

Objective: The objective was to explore the potential existence and nature of the relationship between serum of uric acid (SUA) and serum uric acid to serum creatinine ratio (SUA/SCr) with reduced estimated glomerular filtration rate (eGFR) in patients with non-alcoholic fatty liver disease (NAFLD). Methods: A cross-sectional study was conducted among apparently healthy subjects with NAFLD (n=485). The association between tertiles of SUA and SUA/SCr with reduced eGFR (n=56) were investigated after adjustments for potentially relevant confounders. Also, the diagnostic performances of SUA and SUA/SCr were evaluated with the receiver operating characteristic (ROC) curve analysis. Results: In the adjusted models, SUA showed a significant positive association with reduced eGFR in the highest tertile (OR 5.65, 95% CI 2.48-12.86, p<0.001), and SUA/SCr, in the lowest tertile (4.21, 95% CI 1.76-10.07, p=0.001). The ROC curve analysis did not reveal any significant difference between the corresponding values of area under the curve for SUA and SUA/SCr (0.70 and 0.67, respectively; p=0.521). Conclusions: We revealed significant and independent associations of elevated SUA and reduced SUA/SCr with kidney function decline in NAFLD. However, the clinical utility of these two biomarkers seemed to be limited for the mentioned purpose and needs further investigations.

Benign paroxysmal positional vertigo (BPPV) is the most common vertigo disease and is more likely to occur in perimenopausal women, suggesting an association with osteoporosis. Since otoconia are primarily composed of calcium carbonate, abnormal calcium metabolism may lead to otoconia dislocation. However, the detailed mechanism is currently unknown. In this study, we investigated the effects of drugs (cadmium and dexamethasone) that cause abnormal calcium metabolism on otolith formation in zebrafish larvae. Here, otolith size was clearly reduced in the cadmium group, and the calcium content of the larvae was also markedly reduced. In contrast, in the dexamethasone group, which also had a lower calcium content than the control group, otolith size increased. Our results suggest that, as in bone, calcium metabolism influences the repeated dissolution and recrystallization of otoliths and maintains homeostasis in response to calcium concentrations in the endolymphatic fluid.

中国では、2000万人の新生児のうち約80万人に先天性疾患があり、そのうち20万人近くの胎児に深刻な欠陥や病気がある。これらの病気の胎児の誕生は、家族、さらには社会に深刻な経済的負担と社会問題をもたらす。したがって、胎児の欠陥や病気をできるだけ早期に発見するために、早期胎児モニタリングを実施することが重要である。臍帯動脈血信号には胎児の成長と発育に関する重要な情報が含まれており、子宮内発育遅延（IUGR）、低酸素症、母体の高血圧など妊娠中の様々な問題を、臍帯動脈血信号によって判断することができる。したがって、臍帯血信号の分析は、出生前のモニタリングと胎児の健康状態の診断にとって重要である。 超音波を用いた音響スペクトルパラメータ法は、臍帯動脈の血液信号を分析するための従来の手法であり、臨床診断基準となる3つのパラメータ、抵抗指数（RI）、脈動指数（PI）、および収縮期／拡張期臍帯血流速の最大値（S/D）から構成される。しかし、これらのパラメータは、位相遅延、位相周波数、位相モードといった信号の位相特性を無視し、最大値、最小値、平均値といった血流速度の基本的な統計パラメータのみに焦点を当てている。これは臨床的な誤診をもたらすことがある。 臍動脈の血液信号には、信号の振幅揺らぎに加えて、信号の複雑な構造と非線形特性も含まれている。本研究では、これらの信号の複雑な構造と非線形特性に着目し、フラクタル理論とカオス理論を用いて、胎児臍帯動脈血の測定信号に対して特徴パラメータの抽出および分類を包括的に行う新しい方法を提案する。まず、臍帯血信号のフラクタル特徴に着目し、フラクタル次元(BD)と相関次元(CD)を求め、BDは妊娠週数と正の相関があり、CDは正常と異常の判別に有効であることを検証する。次に、臍帯血時系列のカオス的特徴に対して、最大リャプノフ指数(MLE)を求め、同様に正常と異常判別への有効性を確認する。最後に、従来の特徴パラメータ(RI, PI, S/D）と新たに得られたパラメータ(BD,CD,MLE)に対して粒子群最適化サポートベクターマシン(PSO SVM)を適用し、４つの状態（正常、羊水過少、首周りの臍帯、胎児位置異常）における臍帯血信号の分類・診断モデルを提案する。 この博士論文は6章からなる。 第1章では、臍帯血研究の背景と手段を紹介し、現在の研究状況を概説する。また、本論文の概要を述べる。 第2章では，胎児血行動態の基礎を述べ、臍帯血信号パラメータの臨床的意義と正常基準値を概説する。臍帯動脈信号収集装置、データ分類、収集プロセスを概説する。 第3章では、フラクタル理論に基づき、フラクタル次元ボックスカウント法(BD)と相関次元(CD)を用いて臍帯動脈血信号の非線形特性を調べる。まず，臍帯血信号のフラクタル次元を計算し，その信号のフラクタル特性を解析する。結果として、臍帯動脈血信号のフラクタル次元と妊娠週数との間には正の相関があることが示された。次に、異常な臍帯動脈信号と正常な臍帯動脈信号を異常群と対照群に分類した。Grassberg-procacciaアルゴリズム（G-Pアルゴリズム）を用いて、2つのグループのCDを計算・分析する。正常臍帯血流信号のCDは異常信号のCDよりも全体的に大きい。CDは、従来の特徴パラメータに比べ、臍帯血流信号の正常性判別に有意的に優れている。さらに、臍帯血流信号のハースト指数をLo法により計算・解析する。その結果、臍帯血信号は非定常信号に属し、明らかな「1/fゆらぎ」特性を示すことがわかった。 第4章では，カオス位相空間図法と最大リアプノフ指数(MLE)を用いて，臍帯血信号のカオス特性を定性的・定量的に決定する。臍帯動脈血信号のアトラクター再構成を3次元(3D)および2次元(2D)位相空間で行う。その結果、異常な臍帯動脈信号の時系列のカオス位相図は、「毛糸玉」のようなごちゃごちゃした状態を示し、カオスの「形」は収束するように見えることがわかった。求めた最大リアプノフ指数(MLE)に対してROC曲線（ROC）を適用した結果、臍帯血流信号の正常性を識別する率が従来の特徴パラメータよりも有意に優れていることを示された。 第5章では，臍帯血信号の4つの状態（正常，絨毛膜羊膜症，臍帯頸部周囲，胎児位置異常）を分類する人工知能分類法を提案する。従来の特徴パラメータであるS/D、PI、RIに対してサポートベクターマシン(SVM)による分類器を構築する。」また、第3章と第4章で導出したフラクタル次元(BD)、相関次元(CD)、最大リアプノフ指数(MLE)を特徴パラメータとして、粒子群最適化-サポートベクターマシン（PSO-SVM）分類器を構築する。分類テストの結果から、PSO-SVM分類器の方が精度高く、本提案の分類法の有用性と有効性が確認された。 第6章では、本論文のまとめと今後の課題について述べる。

Native English scholarly writers use interactional metadiscourse markers in their research articles to indicate their stance and negotiate their claims with readers. Hedges are a type of interactional metadiscourse marker often used in scientific research articles to soften writers’ claims and protect themselves from criticism (Hyland, 2005a). When Japanese researchers write research articles in English, they tend to use fewer English hedges than native English writers. Although hedges are used in research articles written in Japanese, their usage appears to differ from that of English hedges. This study analyses the use of hedges in research articles by Japanese writers in both English and Japanese in comparison with English hedges employed by native English writers in order to reveal the differences in the use of hedges between the two languages. The analysis focuses not only on the discrepancies in usage between native English and Japanese writers, but also on the characteristics of hedges used in academic articles written in English and Japanese. Furthermore, this study investigates the impact of Japanese writers’ first language on their use of English hedges in articles written in English. A total of 30 published empirical research articles in soft science disciplines in English and Japanese were used for the quantitative and qualitative analyses of the use of hedges, revealing both the writing and linguistic differences between the two languages. Thus, this study aims to offer pedagogical suggestions for Japanese learners of English to use hedges more effectively in their research papers written in English.

Right ventricular (RV) dysfunction and its linked arrhythmias play a crucial role in determining the prognosis of pulmonary arterial hypertension (PAH). Our paper aimed to explore the potential protective effects of direct pharmacological intervention in the RV muscle using dantrolene (DAN), a stabilizer of the cardiac ryanodine receptor (RyR2), against RV dysfunction and arrhythmia in a rat model of monocrotaline (MCT)-induced PAH. To induce PAH, male 8-week-old Sprague-Dawley rats received MCT injections. The study also assessed the induction of ventricular tachycardia (VT) by catecholamines, examining RyR2-mediated Ca^{2+} release properties in isolated cardiomyocytes. Additionally, a pulmonary artery-banding model was established to evaluate the independent effects of chronic pressure overload on RV morphology and function. In the MCT-induced PAH rat model, findings revealed RV hypertrophy, dilation, and functional decline, resulting in 0% survival rate two months post-MCT induction. Conversely, chronic DAN treatment demonstrated improvements in these RV parameters and an 80% increase in survival. Furthermore, chronic DAN treatment prevented the dissociation of calmodulin from RyR2, inhibiting Ca^{2+} sparks and spontaneous Ca^{2+} transients in MCT-induced hypertrophied RV cardiomyocytes. Epinephrine induced VT in over 50% of rats with MCT-induced PAH, while chronic DAN treatment achieved complete suppression of VT. The paper concludes that stabilizing RyR2 with DAN holds promise as a novel therapeutic approach against the development of RV dysfunction and fatal arrhythmias associated with PAH.

To investigate whether dantrolene (DAN), cardiac ryanodine receptor (RyR2) stabilizer, improves impaired diastolic function in an early pressure-overloaded hypertrophied heart, pressure-overload hypertrophy was induced by transverse aortic constriction (TAC) in mice. Wild-type (WT) mice were divided into four groups: sham-operated mice (Sham), sham-operated mice treated with DAN (DAN+Sham), TAC mice (TAC), and TAC mice treated with DAN (DAN+TAC). The mice were then followed up for 2 weeks. Left ventricular (LV) hypertrophy was induced in TAC, but not DAN+TAC mice, 2 weeks after TAC. There were no differences in LV fractional shortening among the four groups. Catheter tip micromanometer showed that the time constant of LV pressure decay, an index of diastolic function, was significantly prolonged in TAC but not in DAN+TAC mice. Diastolic function was significantly impaired in TAC, but not in DAN+TAC mice as determined by cell shortening and Ca^{2+} transients. An increase in diastolic Ca^{2+} leakage and a decrease in calmodulin (CaM) binding affinity to RyR2 were observed in TAC mice, while diastolic Ca^{2+} leakage improved in DAN+TAC mice. Thus, DAN prevented the progression of hypertrophy and improved the impairment of LV relaxation by inhibiting diastolic Ca^{2+} leakage through RyR2 and the dissociation of CaM from RyR2.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is caused by a single point mutation in the cardiac type 2 ryanodine receptor (RyR2). Using knock-in mouse (KI) model (R2474S/+), we previously reported that a single point mutation within the RyR2 sensitized the channel to agonists, primarily mediated by defective inter-domain interaction within the RyR2 and subsequent dissociation of calmodulin (CaM) from the RyR2. Here, we examined whether CPVT can be genetically rescued by enhancing the binding affinity of CaM to the RyR2. We first determined whether there was a possible amino-acid substitution within the CaM-binding domain in the RyR2 (3584-3603) that can enhance its binding affinity to CaM, and found that V3599K substitution showed the highest binding affinity of CaM to CaM-binding domain. Hence, we generated a heterozygous KI mouse model (V3599K/+) with a single amino acid substitution in the CaM-binding domain of the RyR2, and crossbred it with the heterozygous CPVT –associated R2474S/+ KI mouse to obtain a double heterozygous R2474S/V3599K KI mouse model. The CPVT phenotypes, bidirectional or polymorphic ventricular tachycardia, were inhibited in the R2474S/V3599K mice. Thus, enhancement of the CaM binding affinity of the RyR2 is essential to prevent CPVT-associated arrhythmogenesis.