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Continuous and careful management is necessary after revascularization surgery for moyamoya disease (MMD). The postoperative information has been shared in person or by telephone and emails among doctors; however, this is not always efficient. We aimed to describe the feasibility of remote diagnosis and text chats using a smartphone application on postoperative MMD management. Twenty consecutive patients who underwent combined direct and indirect revascularization for MMD were prospectively investigated in this study. In ten patients, the operator viewed postoperative images uploaded on a smartphone screen using the Join application (Allm Inc., Tokyo, Japan). The doctors shared the radiological findings and treatment plans using the group text chat function and performed postoperative management. We evaluated the intermodality agreements of radiological findings between the smartphone screen and conventional viewer. Postoperative courses were compared between the two patient groups that used or did not use the application. All postoperative images were uploaded to the cloud server and the operator viewed them remotely on the smartphone screen without restriction of location. Detected abnormal findings were cerebral hyperperfusion (CHP), CHP-related watershed shift phenomenon, fluid-attenuated inversion recovery cortical hyperintensity, high signal intensity on diffusion-weighted imaging, CHP-related crossed cerebellar diaschisis, and hypoperfusion. Radiological agreement between the modalities was good in all cases, and additional findings were not obtained on the conventional viewer. The postoperative courses of the Join group were as good as those of the control group. Remote radiological diagnosis and text chat using a smartphone application were feasible and useful for efficient and safe postoperative MMD management.

Background: Recent advances are in the genetics, diagnosis, pathophysiology, and management of moyamoya disease (MMD), and moyamoya syndrome (MMS), a term used to describe moyamoya-like vasculopathy associated with various systemic diseases or conditions. Summary: Ring finger protein (RNF213) has been reported to be a susceptibility gene not only for MMD but also for atherosclerotic intracranial arterial stenosis and ischemic stroke attributable to large artery atherosclerosis. The latest guidelines by the Research Committee on MMD of the Japanese Ministry of Health, Labor, and Welfare, removed limitations of the previous definition that required bilateral involvement of the intracranial carotid artery to make the diagnosis, given the increasing evidence of progression to bilateral involvement in unilateral MMD. 3-dimensional constructive interference in steady-state MRI is useful for the differential diagnosis of MMD from atherosclerosis. Recent advances in the pathophysiology of MMD suggest that genetic and environmental factors play important roles in vascular angiogenesis and remodeling via complex mechanisms. The latest Japanese Guidelines and American Scientific Statement described that antiplatelet therapy can be considered reasonable. Endovascular interventional stent placement fails to prevent ischemic events and does not halt MMD progression. In the Japan Adult Moyamoya trial, a randomized controlled trial for bilateral extracranial-intracranial direct bypass versus conservative therapy in patients with MMD, who had intracranial hemorrhage, recurrent bleeding, completed stroke, or crescendo transient ischemic attack was significantly fewer with direct bypass than with conservative care. Key Messages: This review presents updated information on genetics, diagnosis, pathophysiology, and treatment of adult MMD and MMS. Despite recent advances, many mysteries still exist in the etiologies of moyamoya vasculopathy. The diagnostic criteria and treatment guidelines have been updated but not yet been globally established. Ongoing and future studies investigating underlying pathophysiological mechanisms of MMD and MMS may clarify potentially effective medical, surgical, or endovascular treatments.

Abstract Background In Japan, home hemodialysis (HHD) has several benefits, including a favorable prognosis, enhanced quality of life (QOL) of patients, and cost-effectiveness. However, the caregiver’s burden in assisting patients on HHD is significant, which influences their decision to continue HHD. This study focused on the relationship between medical and nursing interventions, caregiver resolve to continue HHD, and caregiver quality of life, aiming to create support strategies for caregivers. Methods A multicenter cross-sectional survey was conducted on caregivers of patients on HHD from 150 HHD facilities in Japan. The caregiver’s intent to continue HHD was assessed using a four-tier response scale that evaluated aspects such as caregiver–healthcare provider meetings, caregiver breaks, treatment discussions, difficulty in HHD initiation, and post-initiation medical support. Caregiver QOL was evaluated using the Short-form Health Survey, eight domains (SF-8). Statistical analysis involved χ-squared tests, independent t-tests, and propensity score matching. Results The study achieved a caregiver participation rate of 55.6%. Results indicated that caregivers who were inclined to continue HHD were significantly more likely to receive respite outpatient dialysis and had a better understanding of HHD mechanics as explained by healthcare professionals; however, propensity score matching revealed limited generalizability. There was no significant difference in the SF-8 scores before and after propensity score matching among the groups. Conclusions This study highlights that there are a small number of caregivers who have little motivation to continue HHD and emphasizes the crucial role of support from healthcare professionals. Comprehensive support, including respite dialysis and detailed HHD information, may affect HHD sustainability.

Abstract Background The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has had a profound global impact, with millions of confirmed cases and deaths worldwide. While most cases are mild, a subset progresses to severe respiratory complications and death, with factors such as thromboembolism, age, and underlying health conditions increasing the risk. Vascular endothelial damage has been implicated in severe outcomes, but specific biomarkers remain elusive. This study investigated syndecan-1 (SDC-1), a marker of endothelial damage, as a potential prognostic factor for COVID-19, focusing on the Japanese population, which is known for its aging demographics and high prevalence of comorbidities. Methods A multicenter retrospective study of COVID-19 patients in Fukushima Prefecture in Japan who were admitted between February 2020 and August 2021 was conducted. SDC-1 levels were measured along with other clinical and laboratory parameters. Outcomes including thrombosis, 28-day survival, and disease severity were assessed, and disease severity was categorized according to established guidelines. Results SDC-1 levels were correlated with disease severity. Patients who died from COVID-19 had greater SDC-1 levels than survivors, and the area under the receiver operating characteristic curve (AUC) analysis suggested the potential of the SDC-1 level as a predictor of mortality (AUC 0.714). K‒M analysis also revealed a significant difference in survival based on an SDC-1 cutoff of 10.65 ng/mL. Discussion This study suggested that SDC-1 may serve as a valuable biomarker for assessing COVID-19 severity and predicting mortality within 28 days of hospitalization, particularly in the Japanese population. However, further investigations are required to assess longitudinal changes in SDC-1 levels, validate its predictive value for long-term survival, and consider its applicability to new viral variants. Conclusions SDC-1 is emerging as a potential biomarker for assessing the severity and life expectancy of COVID-19 in the Japanese population, offering promise for improved risk stratification and patient management in the ongoing fight against the virus.

Arterial spin-labeling magnetic resonance imaging (ASL-MRI) is widely used for evaluating collateral development in patients with acute ischemic stroke (AIS). This study aimed to characterize the findings of multiphase ASL-MRI between embolic and atherosclerotic large vessel occlusion (LVO) to aid in the differential diagnosis. Among 982 patients with AIS, 44 who were diagnosed with acute, symptomatic, and unilateral occlusion of the horizontal segment of the middle cerebral artery (MCA) were selected and categorized into embolic stroke (ES) and atherosclerosis (AT) groups. Using ASL-MRI (postlabeling delay [PLD] of 1.5, 2.0, and 2.5 s) at admission, the ipsilateral to contralateral ratio (ICR) of the signal intensity and its time-course increasing rate (from PLD 1.5 to 2.0 and 2.5, ΔICR) were measured and compared between the two groups. The mean ICR was significantly higher in the AT group than in the ES group (AT vs. ES: 0.49 vs. 0.27 for ICR1.5, 0.73 vs. 0.32 for ICR2.0, and 0.92 vs. 0.37 for ICR2.5). The ΔICR of PLD 1.5-2.0 (ΔICR2.0) and 2.5 (ΔICR2.5) were also significantly higher in the AT group than in the ES group (AT vs. ES: 50.9% vs. 26.3% for ΔICR2.0, and 92.6% vs. 42.9% for ΔICR2.5). Receiver operating characteristic curves showed moderate-to-strong discriminative abilities of each ASL-MRI parameter in predicting MCA occlusion etiology. In conclusion, multiphase ASL-MRI parameters may aid in differentiating intracranial LVO etiology during the acute phase. Thus, it is applicable to AIS management.

Abstract Background Ipilimumab (Ipi) plus nivolumab (Nivo) is the recommended first-line treatment for renal cell carcinoma (RCC). This report describes a case where pancreatic metastases disappeared after only two courses of Ipi + Nivo therapy. The primary tumor was cured by surgery, and a pathological Complete Response (pCR) was observed despite multiple serious immune-related Adverse Events (irAEs). Case presentation A 54-year-old woman with RCC and pancreatic metastasis at stage IV, diagnosed with intermediate risk according to the International Metastatic RCC Database Consortium classification, underwent initiation of Ipi + Nivo therapy. On day 26, she developed hyperthyroidism accompanied by tachycardia, leading to the commencement of metoprolol tartrate treatment. Following the resolution of tachycardia, a second course of Ipi + Nivo therapy was administered on day 50. By day 70, the patient exhibited Grade 3 hepatic dysfunction, followed by the onset of hypothyroidism on day 75, necessitating treatment with steroids and levothyroxine. After positive treatment, a Grade 3 skin disorder emerged on day 87 while tapering steroids, prompting treatment with methylprednisolone (mPSL) pulse therapy. The skin disorder responded to steroids, allowing for tapering. However, on day 113, a recurrence of Grade 3 skin disorder occurred, necessitating another mPSL pulse. The patient responded well to treatment, exhibiting improvement in her condition. On day 131, she presented at the hospital with complaints of respiratory distress, prompting a Computed Tomography (CT) scan that revealed interstitial pneumonia. By day 272, subsequent CT imaging showed the disappearance of pancreatic metastasis and shrinkage of the primary tumor. On day 294, she underwent a laparoscopic left nephrectomy. Pathological analysis confirmed a pCR in the primary tumor, indicating successful eradication of RCC through surgical intervention. Conclusions This case report presents a scenario where multiple severe irAEs appeared in a patient, yet metastases disappeared after only two courses of Ipi + Nivo therapy. The patient was ultimately cured by surgery and achieved a pCR. This case highlights that despite the occurrence of severe irAEs during RCC treatment with Ipi + Nivo therapy, they can be managed appropriately to maximize the therapeutic effects of checkpoint inhibitors.

The major focus of the present paper is All Alone (2013), an Iranian film by Ehsan Abdipour which narrates the life of a boy from Boushehr, whose friendship with the son of a Russian engineer at a nuclear plant has to end as the result of the sanctions against Iran’s nuclear capacity at the time. Using the lens of young adults and children, the film tangibly illustrates the impact of the sanctions on the lives of individuals. The power of cinematic representation in highlighting the significance of child perspectives is that it can reveal the human effect of sanctions not directly addressed in the adult world. In addition, the liminal position of the pre-adolescent can provide new space for negotiating the ‘unspoken’ or unrecognized effects of the sanctions. At the same time, as an Iranian who followed the progress of nuclear talks closely between 2013-2015, the recent release of Christopher Nolan’s Oppenheimer (2023) triggered an immediate association with recollections about the Joint Comprehensive Plan of Action (JCPOA), known more commonly as Iran’s Nuclear Deal. In particular, Oppenheimer’s self-reflexive recollections of the questions he grappled with as a youth about the nature of the universe struck a chord with the dilemma faced by the young protagonist in All Alone. In the light of this, the paper will also briefly consider the controversies around nuclear talks at the time All Alone was made.

Some flowering plants signal the abundance of their rewards by changing their flower colour, scent or other floral traits as rewards are depleted. These floral trait changes can be regarded as honest signals of reward states for pollinators. Previous studies have hypothesized that these signals are used to maintain plant-level attractiveness to pollinators, but the evolutionary conditions leading to the development of honest signals have not been well investigated from a theoretical basis. We examined conditions leading to the evolution of honest reward signals in flowers by applying a theoretical model that included pollinator response and signal accuracy. We assumed that pollinators learn floral traits and plant locations in association with reward states and use this information to decide which flowers to visit. While manipulating the level of associative learning, we investigated optimal flower longevity, the proportion of reward and rewardless flowers, and honest- and dishonest-signalling strategies. We found that honest signals are evolutionarily stable only when flowers are visited by pollinators with both high and low learning abilities. These findings imply that behavioural variation in learning within a pollinator community can lead to the evolution of an honest signal even when there is no contribution of rewardless flowers to pollinator attractiveness. [ABSTRACT FROM AUTHOR]

The chromosomes in multicellular eukaryotes are organized into a series of topologically independent loops called TADs. In flies, TADs are formed by physical interactions between neighboring boundaries. Fly boundaries exhibit distinct partner preferences, and pairing interactions between boundaries are typically orientation-dependent. Pairing can be head-to-tail or head-to-head. The former generates a stem-loop TAD, while the latter gives a circle-loop TAD. The TAD that encompasses the Drosophila even skipped (eve) gene is formed by the head-to-tail pairing of the nhomie and homie boundaries. To explore the relationship between loop topology and the physical and regulatory landscape, we flanked the nhomie boundary region with two attP sites. The attP sites were then used to generate four boundary replacements: λ DNA, nhomie forward (WT orientation), nhomie reverse (opposite of WT orientation), and homie forward (same orientation as WT homie). The nhomie forward replacement restores the WT physical and regulatory landscape: in MicroC experiments, the eve TAD is a ‘volcano’ triangle topped by a plume, and the eve gene and its regulatory elements are sequestered from interactions with neighbors. The λ DNA replacement lacks boundary function: the endpoint of the ‘new’ eve TAD on the nhomie side is ill-defined, and eve stripe enhancers activate a nearby gene, eIF3j. While nhomie reverse and homie forward restore the eve TAD, the topology is a circle-loop, and this changes the local physical and regulatory landscape. In MicroC experiments, the eve TAD interacts with its neighbors, and the plume at the top of the eve triangle peak is converted to a pair of ‘clouds’ of contacts with the next-door TADs. Consistent with the loss of isolation afforded by the stem-loop topology, the eve enhancers weakly activate genes in the neighboring TADs. Conversely, eve function is partially disrupted.

Two different models have been proposed to explain how the endpoints of chromatin looped domains (‘TADs’) in eukaryotic chromosomes are determined. In the first, a cohesin complex extrudes a loop until it encounters a boundary element roadblock, generating a stem-loop. In this model, boundaries are functionally autonomous: they have an intrinsic ability to halt the movement of incoming cohesin complexes that is independent of the properties of neighboring boundaries. In the second, loops are generated by boundary:boundary pairing. In this model, boundaries are functionally non-autonomous, and their ability to form a loop depends upon how well they match with their neighbors. Moreover, unlike the loop-extrusion model, pairing interactions can generate both stem-loops and circle-loops. We have used a combination of MicroC to analyze how TADs are organized, and experimental manipulations of the even skipped TAD boundary, homie, to test the predictions of the ‘loop-extrusion’ and the ‘boundary-pairing’ models. Our findings are incompatible with the loop-extrusion model, and instead suggest that the endpoints of TADs in flies are determined by a mechanism in which boundary elements physically pair with their partners, either head-to-head or head-to-tail, with varying degrees of specificity. Although our experiments do not address how partners find each other, the mechanism is unlikely to require loop extrusion.

Disparities in accessing advanced stroke treatment have been recognized as a policy challenge in multiple countries, including Japan, necessitating priority solutions. Nevertheless, more practical healthcare policies must be implemented due to the limited availability of healthcare staff and financial resources in most nations. This study aimed to evaluate the supply and demand balance of mechanical thrombectomy (MT) and identify areas with high priority for enhancing stroke centers. The target area of this study was Hokkaido, Japan. We adopted the capacitated maximal covering location problem (CMCLP) to propose an optimal allocation without increasing the number of medical facilities. Four realistic scenarios with varying levels of total MT supply capacity for Primary stroke centers and assuming a range of 90 minutes by car from the center were created and simulated. From scenarios 1 to 4, the coverage increased by approximately 53% to 85%, scenarios 2 and 3 had 5% oversupply, and scenario 4 had an oversupply of approximately 20%. When the supply capacity cap was eliminated and 8 PSCs received 31 or more patients, they became priority enhancement targets. The CMCLP estimates demand coverage considering the supply and demand balance and indicates areas and facilities where MT supply capacity enhancement is a priority.

The opportunity to treat older patients with Moyamoya disease (MMD) is increasing. However, the surgical outcomes after combined direct and indirect revascularization for elderly patients with MMD are not fully understood, especially for those 60 years old. This retrospective study examined 232 consecutive hemispheres of 165 adults with MMD who underwent combined revascularization. Clinical features and surgical outcomes were compared between the elderly (60 years) and nonelderly group (

Exosomes, lipid bilayer-enclosed small cellular vesicles, are actively secreted by various cells and play crucial roles in intercellular communication. These nanosized vesicles transport internalized proteins, mRNA, miRNA, and other bioactive molecules. Recent findings have provided compelling evidence that exosomes derived from stem cells hold great promise as a therapeutic modality for central nervous system disorders. These exosomes exhibit multifaceted properties including anti-apoptotic, anti-inflammatory, neurogenic, and vasculogenic effects. Furthermore, exosomes offer several advantages over stem cell therapy, such as high preservation capacity, low immunogenicity, the ability to traverse the blood-brain barrier, and the potential for drug encapsulation. Consequently, researchers have turned their attention to exosomes as a novel therapeutic avenue. Nonetheless, akin to the limitations of stem cell treatment, the limited accumulation of exosomes in the injured brain poses a challenge to their clinical application. To overcome this hurdle, intranasal administration has emerged as a non-invasive and efficacious route for delivering drugs to the central nervous system. By exploiting the olfactory and trigeminal nerve axons, this approach enables the direct transport of therapeutics to the brain while bypassing the blood-brain barrier. Notably, exosomes, owing to their small size, can readily access the nerve pathways using this method. As a result, intranasal administration has gained increasing recognition as an optimal therapeutic strategy for exosome-based treatments. In this comprehensive review, we aim to provide an overview of both basic and clinical research studies investigating the intranasal administration of exosomes for the treatment of central nervous system diseases. Furthermore, we elucidate the underlying therapeutic mechanisms and offer insights into the prospect of this approach.

Abstract Although novel techniques for avoiding incontinence during robot-assisted radical prostatectomy have been developed, long-term oncological outcomes are unknown. The objective of this study was to determine the long-term oncological outcomes and functional outcomes of novel nerve-sparing robot-assisted radical prostatectomy with endopelvic fascia preservation for a single surgeon. Data from 100 patients who underwent structure-preserving prostatectomies performed by a single surgeon were retrospectively analyzed. The median console time was 123 min. Bilateral nerve-sparing was performed in 43% of patients underwent, and 57% underwent unilateral nerve-sparing surgery. Most patients (96%) reached complete pad-zero urinary continence by one year after surgery. Satisfactory erectile function was achieved in 97% of patients who underwent bilateral nerve-sparing surgery, and 80% of patients who underwent unilateral nerve-sparing surgery. The surgical margin was positive for 25% of patients, and the biochemical recurrence-free rate at 5 years was 77%. The cancer-specific survival rate was 100% during the median follow-up period of 4.5 years. Clavien-Dindo grade III complications occurred in 1% of cases. The outcomes for novel nerve-sparing robot-assisted radical prostatectomy with endopelvic fascia preservation were similar to previously reported oncological outcomes, with satisfactory functional outcomes. This operative method may be useful for patients who are eligible for nerve-sparing surgery.

BackgroundOlfactory neuroblastoma (ONB) is a rare malignant tumor arising from the olfactory neuroepithelium. The standard of care for ONB is surgical resection; however, detailed treatment protocols vary by institution. Our treatment protocol consists of endoscopic skull base surgery (ESBS) for endoscopically resectable cases and induction chemotherapy followed by craniotomy combined with ESBS for locally advanced cases, with postoperative radiotherapy performed for all cases. Chemoradiotherapy (CRT) is performed in unresectable cases. In this study, we evaluate our treatment protocol and outcomes for ONB.MethodsA retrospective review of patients with ONB was conducted. Outcomes included survival outcomes and perioperative data.ResultsFifteen patients (53.6%) underwent ESBS, 12 (42.9%) underwent craniotomy combined with ESBS, and 1 (3.6%) received CRT. The 5- and 10-year overall survival rates for all patients were 92.9% and 82.5%, respectively, with a median follow-up period of 81 months. The 5- and 10-year disease-free survival rates were 77.3% and 70.3%, respectively, and the 5- and 10-year local control rates were 88.2% and 80.2%, respectively. Patients undergoing ESBS demonstrated a significantly shorter operating time, period from operation to ambulation, hospitalization period, and less blood loss than those undergoing craniotomy combined with ESBS.ConclusionOur treatment protocol was found to afford favorable outcomes. Patients who underwent endoscopic resection showed lower complication rates and better perioperative data than those who underwent craniotomy combined with ESBS. With appropriate case selection, ESBS is considered a useful approach for ONB.

Abstract ATP-dependent chromatin remodeling SWI/SNF complexes exist in three subcomplexes: canonical BAF (cBAF), polybromo BAF (PBAF), and a newly described non-canonical BAF (ncBAF). While cBAF and PBAF regulate fates of multiple cell types, roles for ncBAF in hematopoietic stem cells (HSCs) have not been investigated. Motivated by recent discovery of disrupted expression of BRD9, an essential component of ncBAF, in multiple cancers, including clonal hematopoietic disorders, we evaluate here the role of BRD9 in normal and malignant HSCs. BRD9 loss enhances chromatin accessibility, promoting myeloid lineage skewing while impairing B cell development. BRD9 significantly colocalizes with CTCF, whose chromatin recruitment is augmented by BRD9 loss, leading to altered chromatin state and expression of myeloid-related genes within intact topologically associating domains. These data uncover ncBAF as critical for cell fate specification in HSCs via three-dimensional regulation of gene expression and illuminate roles for ncBAF in normal and malignant hematopoiesis.

We examined whether U46619 (a prostanoid TP receptor agonist) could enhance the contractions of guinea pig urinary bladder smooth muscle (UBSM) in response to acetylcholine (ACh) and an ATP analog (α,β-methylene ATP (αβ-MeATP)) through stimulation of the UBSM TP receptor and whether protein kinase C (PKC) is involved. U46619 (10−7 M) markedly enhanced UBSM contractions induced by electrical field stimulation and ACh/αβ-MeATP (3 × 10−6 M each), the potentiation of which was completely suppressed by SQ 29,548 (a TP receptor antagonist, 6 × 10−7 M). PKC inhibitors did not attenuate the ACh-induced contractions enhanced by U46619 although they partly suppressed the U46619-enhanced, αβ-MeATP-induced contractions. While phorbol 12-myristate 13-acetate (PMA, a PKC activator, 10−6 M) did not enhance ACh-induced contractions, it enhanced αβ-MeATP-induced contractions, an effect that was completely suppressed by PKC inhibitors. αβ-MeATP-induced contractions, both with and without U46619 enhancement, were strongly inhibited by diltiazem. U46619/PMA enhanced 50 mM KCl-induced contractions, the potentiation of which was partly/completely attenuated by PKC inhibitors. These findings suggest that U46619 potentiates parasympathetic nerve-associated UBSM contractions by stimulating UBSM TP receptors. PKC-increased Ca2+ influx through voltage-dependent Ca2+ channels may partially play a role in purinergic receptor-mediated UBSM contractions enhanced by TP receptor stimulation.

Delayed foreign body reactions to either or both clipping and coating materials have been reported in several small series; however, studies in the titanium clip era are scarce. This study aims to survey the contemporary status of such reactions to titanium clips and coating materials. Among patients who received a total of 2327 unruptured cerebral aneurysmal surgeries, 12 developed delayed intraparenchymal reactions during outpatient magnetic resonance imaging (MRI) follow-up. A retrospective investigation was conducted. The patients' average age was 58.6 (45-73) years, and 11 were women. The aneurysms were located in the middle cerebral artery (n = 7), internal carotid artery (n = 4), or anterior communicating artery (AComA, n = 1). In 10 patients, additional coating with tiny cotton fragments was applied to the residual neck after clipping with titanium clips; however, only the clipping with titanium clips was performed in the remaining two. The median time from surgery to diagnosis was 4.5 (0.3-60) months. Seven (58.3%) patients were asymptomatic, and three developed neurological deficits. MRI findings were characterized by a solid- or rim-enhancing lobulated mass adjacent to the clip with surrounding parenchymal edema. In 11 patients, the lesions reduced in size or disappeared; however, in one patient, an AComA aneurysm was exacerbated, necessitating its removal along with optic nerve decompression. In conclusion, cotton material is a strongly suspected cause of delayed foreign body reactions, and although extremely rare, titanium clips alone may also induce such a reaction. The prognosis is relatively good with steroid therapy; however, caution is required when the aneurysm is close to the optic nerve, as in AComA aneurysms.

Abstract Proton (H+) release is linked to aluminum (Al)‐enhanced organic acids (OAs) excretion from the roots under Al rhizotoxicity in plants. It is well‐reported that the Al‐enhanced organic acid excretion mechanism is regulated by SENSITIVE TO PROTON RHIZOTOXICITY1 (STOP1), a zinc‐finger TF that regulates major Al tolerance genes. However, the mechanism of H+ release linked to OAs excretion under Al stress has not been fully elucidated. Recent physiological and molecular‐genetic studies have implicated the involvement of SMALL AUXIN UP RNAs (SAURs) in the activation of plasma membrane H+‐ATPases for stress responses in plants. We hypothesized that STOP1 is involved in the regulation of Al‐responsive SAURs, which may contribute to the co‐secretion of protons and malate under Al stress conditions. In our transcriptome analysis of the roots of the stop1 (sensitive to proton rhizotoxicity1) mutant, we found that STOP1 regulates the transcription of one of the SAURs, namely SAUR55. Furthermore, we observed that the expression of SAUR55 was induced by Al and repressed in the STOP1 T‐DNA insertion knockout (KO) mutant (STOP1‐KO). Through in silico analysis, we identified a functional STOP1‐binding site in the promoter of SAUR55. Subsequent in vitro and in vivo studies confirmed that STOP1 directly binds to the promoter of SAUR55. This suggests that STOP1 directly regulates the expression of SAUR55 under Al stress. We next examined proton release in the rhizosphere and malate excretion in the T‐DNA insertion KO mutant of SAUR55 (saur55), in conjunction with STOP1‐KO. Both saur55 and STOP1‐KO suppressed rhizosphere acidification and malate release under Al stress. Additionally, the root growth of saur55 was sensitive to Al‐containing media. In contrast, the overexpressed line of SAUR55 enhanced rhizosphere acidification and malate release, leading to increased Al tolerance. These associations with Al tolerance were also observed in natural variations of Arabidopsis. These findings demonstrate that transcriptional regulation of SAUR55 by STOP1 positively regulates H+ excretion via PM H+‐ATPase 2 which enhances Al tolerance by malate secretion from the roots of Arabidopsis. The activation of PM H+‐ATPase 2 by SAUR55 was suggested to be due to PP2C.D2/D5 inhibition by interaction on the plasma membrane with its phosphatase. Furthermore, RNAi‐suppression of NtSTOP1 in tobacco shows suppression of rhizosphere acidification under Al stress, which was associated with the suppression of SAUR55 orthologs, which are inducible by Al in tobacco. It suggests that transcriptional regulation of Al‐inducible SAURs by STOP1 plays a critical role in OAs excretion in several plant species as an Al tolerance mechanism.

Abstract Pharmacologic depletion of RNA-binding motif 39 (RBM39) using aryl sulfonamides represents a promising anti-cancer therapy but requires high levels of the adaptor protein DCAF15. Consequently, novel approaches to deplete RBM39 in an DCAF15-independent manner are required. Here, we uncover that RBM39 autoregulates via the inclusion of a poison exon into its own pre-mRNA and identify the cis-acting elements that govern this regulation. We also determine the NMR solution structures of RBM39’s tandem RNA recognition motifs (RRM1 and RRM2) bound to their respective RNA targets, revealing how RRM1 recognises RNA stem loops whereas RRM2 binds specifically to single-stranded N(G/U)NUUUG. Our results support a model where RRM2 selects the 3’-splice site of a poison exon and the RRM3 and RS domain stabilise the U2 snRNP at the branchpoint. Our work provides molecular insights into RBM39-dependent 3’-splice site selection and constitutes a solid basis to design alternative anti-cancer therapies.

Although postoperative neurological events due to brain compression by the swollen temporal muscle are a rare complication, the chronological volume changes of the temporal muscle pedicle and their clinical impact have not yet been documented. This prospective observational study aimed to investigate the chronological volume changes in the temporal muscle pedicle in Moyamoya disease (MMD). Eighteen consecutive combined revascularization procedures using the temporal muscle were performed for symptomatic MMD in 2021. The postoperative pedicle volume was quantified using repeated computed tomography images on postoperative days (PODs) 0, 1, 7, 14, and 30. Postoperative neurological events with radiological evaluations and collateral development evaluated using magnetic resonance angiography obtained 6 months after surgery were studied. On average, the postoperative temporal muscle pedicle volume was most significantly increased by as much as 112% ± 9.6% on POD 7 (P < 0.001) and decreased by as little as 52% ± 21% on POD 30 (P < 0.0001) relative to POD 0. One exceptional patient (overall incidence, 5.6%) demonstrated postoperative transient neurological events due to brain compression by the swollen temporal muscle with decreased focal cerebral blood flow in the adjacent cortical area. The postoperative collateral development via direct and indirect revascularizations was confirmed in 16 (89%) and 12 (67%) hemispheres, respectively. All patients, except for one rebleeding case, showed independent outcomes at the mean latest follow-up period on 290 ± 96 days after surgery. Our observations confirmed the temporal profile of muscle pedicle volume changes after combined revascularization. Through routine attempts to avoid the unfavorable effects of temporal muscle swelling, combined revascularization can provide favorable outcomes in symptomatic MMD.

Abstract Background While cancer is a risk factor for developing thromboembolism, so is the use of molecularly targeted therapies. This study aimed to determine whether thromboembolism incidence differed between vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) inhibitor use in patients with unresectable advanced or recurrent colorectal cancer, and to compare the risk of thromboembolism caused by cancer and the use of molecular targeted therapy drugs. Main body We retrospectively evaluated patients with unresectable advanced or recurrent colorectal cancer who were treated with a cytotoxic anticancer drug and a VEGF or EGFR inhibitor combination between April 2016 and October 2021. Patients were compared in terms of the regimen administered, thromboembolism occurrence during the first-line treatment period, patient background, and clinical laboratory values. Of the 179 included patients, 12 of 134 (8.9%) in the VEGF-inhibitor group and 8 of 45 (17.8%) in the EGFR-inhibitor group developed thromboembolism, with no significant difference between the groups (P = 0.11). There was no significant difference in time to thromboembolism between patients in the VEGF- inhibitor group and patients in the EGFR-inhibitor group (P = 0.206). The cutoff value determined by a receiver operating characteristic analysis for the occurrence of thromboembolism was one point. Multivariate analysis using the occurrence of thromboembolism as the response variable identified at least one risk factor for thromboembolism (odds ratio = 4.17, P = 0.006, 95% confidence interval = 1.51–11.50). Molecular targeted therapies were not identified as a risk factor. Conclusions Although the small sample size, there was no difference in the incidence of thromboembolism between the two molecular-targeted therapies in first-line treatment of patients with unresectable advanced or recurrent colorectal cancer. Our results suggest that risk factors for thromboembolism may be more strongly influenced by cancer itself than by the use of molecularly targeted therapies.

Purpose: The aim of this study was to investigate the effects of exercise therapy on physical function and quality of life (QOL) in older patients with non-Hodgkin lymphoma undergoing inpatient chemotherapy, including differences between patients with and without sarcopenia. Methods: Thirty-one inpatients aged 70 years or older participated in this study. Grip and knee extensor strength, 6-minute walking test, body composition, nutritional status, fatigue and health-related QOL at admission and discharge were compared. In addition, the patients were classified into sarcopenic and non-sarcopenic groups, and a comparison between admission and discharge and 2-way ANOVA were performed. Results: Overall, grip strength and skeletal muscle mass were significantly lower at discharge than at admission ( P < .05); however, QOL significantly improved ( P < .05). In the non-sarcopenia group, grip strength, right knee extension muscle strength, and skeletal muscle mass were all significantly lower at discharge than at admission ( P < .05); however, this was not the case in the sarcopenia group. In terms of QOL, improvements were observed in different items in the non-sarcopenia and sarcopenia groups. There was a significant interaction between admission to discharge time period and sarcopenia regarding left grip strength, right knee extensor strength, and QOL. Conclusion: Exercise therapy is effective in improving QOL in older non-Hodgkin lymphoma patients undergoing inpatient chemotherapy. However, the effect of exercise therapy and optimal exercise load may differ between non-sarcopenia and sarcopenia patients. Therefore, it is necessary to consider exercise therapy in the future, taking into account the presence or absence of sarcopenia.

Objective Although cervical spondylotic myelopathy (CSM) can be easily diagnosed using magnetic resonance imaging (MRI), prediction of surgical effect using preoperative radiological examinations remains difficult. In previous studies, it was reported that diffusion tensor imaging (DTI) may be used for the prediction of surgical effect; however, these studies did not consider the influences of spinal cord compression even though the values of DTI indexes can be distorted by compressive lesions in patients with CSM. Therefore, it is uncertain whether preoperative DTI indexes can actually predict the surgical effect. The aim of this study was to investigate DTI metrics that are hardly affected by spinal cord compression and can accurately predict neurological status after decompressive surgery. Methods Twenty-one patients with CSM who underwent surgery and 10 healthy volunteers were enrolled in this study. The subjects underwent cervical MRI, and values of DTI indexes including axial diffusivity (AD), radial diffusivity (RD), apparent diffusion coefficient (ADC), and fractional anisotropy (FA) were recorded at each intervertebral level. Further, the Japanese Orthopaedic Association (JOA) score of each patient with CSM was recorded before and after surgery for neurological status evaluation. Preoperative and postoperative values of DTI indexes were compared, and correlations between preoperative DTI parameters and postoperative neurological recovery were assessed. Results After surgery, the lesion-adjacent (LA) ratios of RD and ADC increased (p = 0.04 and p = 0.062, respectively), while the LA ratio of FA decreased (p = 0.075). In contrast, the LA ratio of AD hardly changed. A negative correlation was observed between preoperative LA ratio of AD and JOA recovery rate 6 months after surgery (r = -0.379, p = 0.091). Based on preoperative LA ratio of AD, the patients were divided into a low AD group and a high AD group, and JOA recovery rate 6 months after surgery was found to be higher in the low AD group than in the high AD group (p = 0.024). Conclusion In patients with CSM, preoperative LA ratio of AD is seldom affected by spinal cord compression, and it negatively correlates with JOA recovery rate 6 months after surgery.

Abstract Background The left ventricular (LV) vent is commonly inserted via the right superior pulmonary vein (RSPV) and directed toward the LV cavity through the mitral valve. We report a rare case in which the tip of the LV vent was misplaced into the aortic root across the aortic valve. Case presentation An 88-year-old man was scheduled to undergo the Bentall procedure. After initiation of cardiopulmonary bypass, the LV vent was inserted via the RSPV. Anterograde cardioplegia was administered via the aortic root cannula after the ascending aorta was cross-clamped. The electrocardiogram did not result in complete cardiac arrest, even after delivery of two-thirds of the planned dose. A transesophageal echocardiographic examination showed that the tip of the LV vent was misplaced into the aortic root across the aortic valve. Conclusions It is important to confirm the tip position by transesophageal echocardiography to prevent severe complications associated with the LV vent.

Abstract Background No laws or official guidelines govern voluntary assisted dying (VAD) in Japan. A legislative bill on the termination of life-sustaining measures has yet to be sent to deliberations for legislation, due to strong opposition that has prevented it from being submitted to the Diet. However, Japan has recently witnessed several cases involving VAD. Main text Against this backdrop, we argue that Japan should begin discussion on VAD legislation, referring to the Voluntary Assisted Dying Act 2017 (VADA2017), which was established in 2017 in Victoria, Australia. VADA2017 puts in place a wide range of stringent safeguards and is considered worldwide to be the safest and most conservative policy on a physician offering assisted dying based on the patient’s premeditated request. We consider what opposing opinions from society would arise in response to the VADA2017. Among these will include arguments against VAD itself, those against the validation of this act, and opinions that oppose even the initiation of the dialogue on VAD. Conclusions We conclude that to protect the right to life among those placed in vulnerable positions and, at the same time, to respect decision-making of those who wish for immediate death due to unbearable suffering, the dialogue must immediately begin with that on introducing a policy more conservative than that of the VADA2017, which solidly considers arguments against VAD.

Hypoxic-ischemic brain injury arises from inadequate oxygen delivery to the brain, commonly occurring following cardiac arrest, which lacks effective treatments. Recent studies have demonstrated the therapeutic potential of exosomes released from mesenchymal stem cells. Given the challenge of systemic dilution associated with intravenous administration, intranasal delivery has emerged as a promising approach. In this study, we investigate the effects of intranasally administered exosomes in an animal model. Exosomes were isolated from the cell supernatants using the ultracentrifugation method. Brain injury was induced in Sprague-Dawley rats through a transient four-vessel occlusion model. Intranasal administration was conducted with 3 × 108 exosome particles in 20 µL of PBS or PBS alone, administered daily for 7 days post-injury. Long-term cognitive behavioral assessments, biodistribution of exosomes, and histological evaluations of apoptosis and neuroinflammation were conducted. Exosomes were primarily detected in the olfactory bulb one hour after intranasal administration, subsequently distributing to the striatum and midbrain. Rats treated with exosomes exhibited substantial improvement in cognitive function up to 28 days after the insult, and demonstrated significantly fewer apoptotic cells along with higher neuronal cell survival in the hippocampus. Exosomes were found to be taken up by microglia, leading to a decrease in the expression of cytotoxic inflammatory markers.

Spinal cord injury (SCI) leads to devastating sequelae, demanding effective treatments. Recent advancements have unveiled the role of neutrophil extracellular traps (NETs) produced by infiltrated neutrophils in exacerbating secondary inflammation after SCI, making it a potential target for treatment intervention. Previous research has established that intravenous administration of stem cell-derived exosomes can mitigate injuries. While stem cell-derived exosomes have demonstrated the ability to modulate microglial reactions and enhance blood–brain barrier integrity, their impact on neutrophil deactivation, especially in the context of NETs, remains poorly understood. This study aims to investigate the effects of intravenous administration of MSC-derived exosomes, with a specific focus on NET formation, and to elucidate the associated molecular mechanisms. Exosomes were isolated from the cell supernatants of amnion-derived mesenchymal stem cells using the ultracentrifugation method. Spinal cord injuries were induced in Sprague-Dawley rats (9 weeks old) using a clip injury model, and 100 μg of exosomes in 1 mL of PBS or PBS alone were intravenously administered 24 h post-injury. Motor function was assessed serially for up to 28 days following the injury. On Day 3 and Day 28, spinal cord specimens were analyzed to evaluate the extent of injury and the formation of NETs. Flow cytometry was employed to examine the formation of circulating neutrophil NETs. Exogenous miRNA was electroporated into neutrophil to evaluate the effect of inflammatory NET formation. Finally, the biodistribution of exosomes was assessed using 64Cu-labeled exosomes in animal positron emission tomography (PET). Rats treated with exosomes exhibited a substantial improvement in motor function recovery and a reduction in injury size. Notably, there was a significant decrease in neutrophil infiltration and NET formation within the spinal cord, as well as a reduction in neutrophils forming NETs in the circulation. In vitro investigations indicated that exosomes accumulated in the vicinity of the nuclei of activated neutrophils, and neutrophils electroporated with the miR-125a-3p mimic exhibited a significantly diminished NET formation, while miR-125a-3p inhibitor reversed the effect. PET studies revealed that, although the majority of the transplanted exosomes were sequestered in the liver and spleen, a notably high quantity of exosomes was detected in the damaged spinal cord when compared to normal rats. MSC-derived exosomes play a pivotal role in alleviating spinal cord injury, in part through the deactivation of NET formation via miR-125a-3p.

In this report, we, the Research Committee on Moyamoya Disease (Spontaneous Occlusion of the circle of Willis), describe in detail the changes in the new “Diagnostic Criteria 2021” for moyamoya disease and its scientific basis to make it widely known to the world. The revised criteria cover all aspects of the disease, including a definition of the disease concept, diagnostic imaging, and the concept of quasi-moyamoya disease (moyamoya syndrome).

Abstract This study was performed to elucidate whether eicosapentaenoic acid (EPA) suppresses spasm-prone blood vessel contractions induced by a thromboxane mimetic (U46619) and prostaglandin F2α (PGF2α) and determine whether the primary target of EPA is the prostanoid TP receptor. Accordingly, we assessed: (1) the tension changes in porcine basilar and coronary arteries, and (2) changes in the Fura-2 (an intracellular Ca2+ indicator) fluorescence intensity ratio at 510 nm elicited by 340/380 nm excitation (F340/380) in 293T cells expressing the human TP receptor (TP-293T cells) and those expressing the human prostanoid FP receptor (FP-293T cells). EPA inhibited both porcine basilar and coronary artery contractions induced by U46619 and PGF2α in a concentration-dependent manner, but it did not affect the contractions induced by 80 mM KCl. EPA also inhibited the increase in F340/380 induced by U46619 and PGF2α in TP-293T cells. In contrast, EPA showed only a marginal effect on the increase in F340/380 induced by PGF2α in FP-293T cells. These findings indicate that EPA strongly suppresses the porcine basilar and coronary artery contractions mediated by TP receptor and that inhibition of TP receptors partly underlies the EPA-induced inhibitory effects on these arterial contractions.

We report a fatal subdural empyema caused by Campylobacter rectus in a 66-year-old female who developed acute onset of confusion, dysarthria, and paresis in her left extremities. A CT scan showed hypodensity in a crescentic formation with a mild mid-line shift. She had a bruise on her forehead caused by a fall several days before admission, which initially raised subdural hematoma (SDH) diagnosis, and a burr hole procedure was planned. However, her condition deteriorated on the admission night, and she died before dawn. An autopsy revealed that she had subdural empyema (SDE) caused by Campylobacter rectus and Slackia exigua. Both microorganisms are oral microorganisms that rarely cause extra-oral infection. In our case, head trauma caused a skull bone fracture, and sinus infection might have expanded to the subdural space causing SDE. CT/MRI findings were not typical for either SDH or SDE. Early recognition of subdural empyema and prompt initiation of treatment with antibiotics and surgical drainage is essential for cases of SDE. We present our case and a review of four reported cases.

Abstract Early brain injury after aneurysmal subarachnoid hemorrhage (SAH) worsens the neurological outcome. We hypothesize that a longer duration of depolarization and excessive release of glutamate aggravate neurological outcomes after SAH, and that brain hypothermia can accelerate repolarization and inhibit the excessive release of extracellular glutamate and subsequent neuronal damage. So, we investigated the influence of depolarization time and extracellular glutamate levels on the neurological outcome in the ultra-early phase of SAH using a rat injection model as Experiment 1 and then evaluated the efficacy of brain hypothermia targeting ultra-early brain injury as Experiment 2. Dynamic changes in membrane potentials, intracranial pressure, cerebral perfusion pressure, cerebral blood flow, and extracellular glutamate levels were observed within 30 min after SAH. A prolonged duration of depolarization correlated with peak extracellular glutamate levels, and these two factors worsened the neuronal injury. Under brain hypothermia using pharyngeal cooling after SAH, cerebral perfusion pressure in the hypothermia group recovered earlier than that in the normothermia group. Extracellular glutamate levels in the hypothermia group were significantly lower than those in the normothermia group. The early induction of brain hypothermia could facilitate faster recovery of cerebral perfusion pressure, repolarization, and the inhibition of excessive glutamate release, which would prevent ultra-early brain injury following SAH.

Despite recent developments in the treatments for ischemic stroke, such as tissue plasminogen activator (t-PA) and thrombectomy, effective therapies for intracerebral hemorrhage (ICH) remain scarce. Stem cell therapies have attracted considerable attention owing to their potential neuro-regenerative ability; preclinical and clinical studies have been conducted to explore strategies for achieving functional recovery following ICH. In this review, we summarize the findings of preclinical studies on stem cell therapies of ICH, with a focus on different animal models, stem cell sources, transplantation methods, and their potential mechanisms of action. We also provide an overview of data from clinical trials to discuss the current status and future perspectives. Understanding the effectiveness and limitations of stem cell therapy and the future prospects could expand the applications of this novel therapeutic approach for ICH.

Introduction: The aim of this study was to clarify whether magnetic resonance angiography (MRA)-based road mapping of the para-aortic transfemoral access route can reduce the procedural time of mechanical thrombectomy in patients with acute ischemic stroke. We further investigated the role of pre-procedural MRA-based road mapping in optimal initial catheter selection for rapid mechanical thrombectomy. Materials and Methods: We retrospectively reviewed 57 consecutive patients with acute ischemic stroke who underwent mechanical thrombectomy at our hospital between April 2018 and May 2021. Twenty-nine patients underwent MRA-based road mapping to visualize the para-aortic access route, whereas 28 patients only underwent routine head magnetic resonance imaging/angiography without MRA-based road mapping before neuro-interventional procedures. We then compared the basic procedural times required for mechanical thrombectomy, such as the time from femoral artery puncture to recanalization (“puncture to recanalization time”) and the time from the admission to recanalization (“door to recanalization time”), between the groups. Results: MRA-based road mapping significantly reduced the “puncture to recanalization time” (52.0 min vs. 70.0 min; p = 0.019) and the “door to recanalization time” (146 min vs. 183 min; p = 0.013). Conclusion: MRA-based road mapping of the para-aortic access route is useful to reduce the procedural time of mechanical thrombectomy in acute stroke patients, possibly by enabling optimal initial catheter selection during the procedure.

Mechanical stimulation of cultured keratinocytes and a living epidermis increases intracellular calcium ion concentrations ([Ca2+]i) in stimulated cells. This action propagates a Ca2+ wave to neighboring keratinocytes via ATP/P2Y2 receptors. Recent behavioral, pharmacological studies revealed that exogenous ATP induces itching via P2X3 receptors in mice. We previously showed that alloknesis occurs when an external stimulus is applied to the skin with increased epidermal histamine in the absence of spontaneous pruritus. Based on these results, we investigated the effects of histamine at a concentration that does not cause itching on ATP-induced itching. The mean number of scratching events induced by the mixture of ATP and histamine increased by 28% over the sum of that induced by histamine alone or ATP alone. A317491, a P2X3 receptor antagonist, suppressed the mixture-induced scratching more often than the ATP-induced scratching. Next, we examined the ATP-induced [Ca2+]i change before and after histamine stimulation using normal human epidermal keratinocytes. Some cells did not respond to ATP before histamine stimulation but responded to ATP afterward, the phenomenon suppressed by chlorpheniramine maleate. These findings suggest that histamine enhances ATP-induced itching and that a potential mechanism could involve increased responsiveness to ATP in keratinocytes.

Combining highly concentrated electrolytes with a polymer network is a valid approach to simultaneously achieve fast Li+ ion transport, high thermal stability, and a wide electrochemical window in a quasi-solid-state form. In this work, flexible gel electrolytes comprising commercially available poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF–HFP) and highly concentrated electrolytes of Li salts/sulfolane (SL) were prepared by a simple solution casting method. The anionic effects of the gel electrolytes on the Li-ion conductivity and charge transfer kinetics at the gel/electrode interface were investigated. The SL-based gel electrolyte with lithium bis(fluorosulfonyl)amide (LiFSA) showed an ionic conductivity of 0.7 mS cm−1 and a high Li transference number (>0.5) at 30 °C. The charge transfer resistance in a [Li/gel/LiCoO2] cell with LiFSA was lower than that of the cells with lithium bis(trifluoromethanesulfonyl)amide (LiTFSA) or LiBF4, indicating faster interfacial charge transfer kinetics in the gel electrolyte with FSA. The Li/LiCoO2 cell with the LiFSA/SL gel electrolyte exhibited a higher capacity than that of the cells with the LiTFSA/SL and LiBF4/SL gel electrolytes. Hence, rationally designed gel electrolytes containing highly concentrated SL-based electrolytes enable the high rate performance of Li batteries.