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Medical Excellence JAPAN (MEJ) is a general incorporated association established in 2011 in Japan. It aims to serve as a central hub and a platform to promote international health business jointly with governments, medical communities, academic organizations, and healthcare industries. This article introduces the works of MEJ in the broader context of Japan Revitalization Strategy. The Act on Promotion of Healthcare Policy (2014 Act No. 48) established the Headquarters for Healthcare Policy, chaired by the Prime Minister and supported by dedicated secretariats in the Cabinet Office. The Headquarters aimed at policy coordination across ministries but learned hard lessons from COVID-19, such as delay of domestic vaccine production. This highlights our systematic weakness of the trajectory from R&D to public availability, and this is the field in which MEJ can play further roles. The value and feasibility of developing MEJ-like mechanisms in Asia with a rapidly growing healthcare sector is discussed.

Background: Cerebral small vessel disease (SVD) has received attention as a risk stratification tool for antithrombotic-related intracranial hemorrhage but may also be a predictor for bleeding in other organs. Purpose: To determine the excess risk of antithrombotic-related bleeding due to cerebral SVD burden. Methods: Patients with cerebrovascular or cardiovascular diseases taking oral antithrombotic agents were prospectively enrolled from 52 hospitals across Japan between 2016 and 2019. Multimodal brain MRI was acquired at baseline for all patients under prespecified conditions. All MRI examinations were interpreted by a central diagnostic radiology committee for cerebral microbleeds, lacunes, white matter hyperintensities, and enlarged basal ganglia perivascular spaces, for calculation of a total SVD score (range 0-4). The primary outcome was major bleeding during 2-year follow-up. Secondary outcomes included bleeding in each site and ischemic events. Event risks according to SVD score were estimated with multivariable Cox proportional hazards models. Results: Of the analyzed 5250 patients (1736 women; median age, 73 years; 9933 patient-years follow-up), antiplatelets and anticoagulants were administered at baseline in 3948 and 1565, respectively. Median of the total SVD score was 2 (IQR 1-3). As SVD score increased, advanced age, hypertension, anemia, and chronic kidney disease were more prevalent (P Conclusions: The total SVD score was predictive for intracranial hemorrhage and probably for extracranial bleeding, suggesting a broader clinical relevance of cerebral SVD as a marker for safe implementation of antithrombotic therapy.

Systemic sclerosis (SSc) is a chronic, heterogenous disease of connective tissue characterized by organ fibrosis together with vascular injury and autoimmunity. Transforming growth factor (TGF)-β plays a central role in generating fibrosis, including SSc. Periostin is a matricellular protein playing a key role in the generation of fibrosis by amplifying the TGF-β signals. SOX (SRY-related HMG box) 11 is a transcription factor playing several important roles in organ development in embryos. We have previously shown that SOX11 induces periostin expression. However, the roles of the interactions among the TGF-β signals, periostin, and SOX11 remain unknown in the pathogenesis of SSc. In this study, we found that most clones of dermal fibroblasts derived from SSc patients showed constitutive, high expression of SOX11, which is significantly induced by TGF-β1. SOX11 forms a positive loop with periostin to activate the TGF-β signals in SSc dermal fibroblasts. Genetic deletion of Sox11 in Postn-expressing fibroblasts impairs dermal fibrosis by bleomycin. Moreover, using the DNA microarray method, we identified several fibrotic factors dependent on the TGF-β/SOX11/periostin pathway in SSc dermal fibroblasts. Our findings, taken together, show that a positive loop formed by SOX11 and periostin in fibroblasts upregulates the TGF-β signals, leading to skin fibrosis.

Atopic dermatitis (AD) is a chronic relapsing skin disease accompanied by recurrent itching. Although type 2 inflammation is dominant in allergic skin inflammation, it is not fully understood how non-type 2 inflammation co-exists with type 2 inflammation or how type 2 inflammation causes itching. We have recently established the FADS mouse, a mouse model of AD. In FADS mice, either genetic disruption or pharmacological inhibition of periostin, a downstream molecule of type 2 inflammation, inhibits NF-κB activation in keratinocytes, leading to downregulating eczema, epidermal hyperplasia, and infiltration of neutrophils, without regulating the enhanced type 2 inflammation. Moreover, inhibition of periostin blocks spontaneous firing of superficial dorsal horn neurons followed by a decrease in scratching behaviors due to itching. Taken together, periostin links NF-κB-mediated inflammation with type 2 inflammation and promotes itching in allergic skin inflammation, suggesting that periostin is a promising therapeutic target for AD.

Previously, we reported that a direct thrombin inhibitor melagatran paradoxically increased thrombin generation in human plasma in the presence of thrombomodulin. The aim of this study is to test the hypothesis that melagatran may exert a deleterious effect on tissue-type plasminogen activator (t-PA)-induced fibrinolysis via enhancement of thrombin generation and subsequent activation of thrombin-activatable fibrinolysis inhibitor (TAFI) and factor XIII (FXIII). Clot formation in human plasma containing t-PA and thrombomodulin was induced by tissue factor. The absorbance at 405 nm was measured to obtain clot lysis time. Effects of melagatran and a factor Xa inhibitor edoxaban on clot lysis time were determined. In the presence of thrombomodulin, melagatran significantly prolonged clot lysis time, but edoxaban shortened it. In the absence of thrombomodulin, melagatran did not inhibit fibrinolysis. Prolongation of clot lysis time by melagatran was reversed by activated protein C (which suppressed thrombin generation increased by melagatran) and a TAFIa inhibitor. Melagatran significantly suppressed plasmin generation, while edoxaban significantly increased it. However, both melagatran and edoxaban suppressed FXIII activation. In the clot formed in the presence of melagatran and edoxaban, the fibrin fibre was thin compared with control, showing no clear difference in the clot structures between melagatran and edoxaban. These results indicated that melagatran, not edoxaban, prolonged clot lysis time through the paradoxical enhancement of thrombin generation, and subsequent TAFI activation and inhibition of plasmin generation. Neither FXIII activation nor change in fibrin clot structure contributed to the inhibition of fibrinolysis by melagatran.

Infection increases the risk of thrombosis through the activation of inflammation and coagulation. Edoxaban, a direct oral factor Xa inhibitor, is used for the prevention and treatment of thrombotic diseases. The aim of this study was to determine the effects of edoxaban on microvascular thrombus formation in a rat model of lipopolysaccharide (LPS)-induced coagulopathy. Rats were intravenously injected with 7.5 mg/kg of LPS (Escherichia coli 055:B5). Immediately after LPS injection, the rats were treated with subcutaneous injection of edoxaban. At 2 and 6 h after the injection of LPS, biomarkers of coagulation and organ damages and inflammatory cytokines were measured. Microvascular thrombus formation in organs was evaluated using 125I-fibrinogen (human) or by the pathological analysis. Mortality was examined 24 h after LPS injection. After the injection of LPS, D-dimer and thrombin-antithrombin complex increased and platelet numbers decreased, indicating the activation of coagulation. Microvascular thrombi were found in the liver. Markers of liver injury (aspartate aminotransferase and alanine aminotransferase) also increased. Treatment with edoxaban attenuated the changes in the coagulation markers and microvascular thrombus formation in the liver. Edoxaban suppressed the increase in the liver injury markers and reduced the mortality. Edoxaban did not affect the levels of inflammatory cytokines. In conclusions, edoxaban significantly inhibited the activation of coagulation, the formation of microvascular thrombus in the liver and the liver damage, and reduced mortality in rats injected with LPS. These results suggest that the FXa inhibition by edoxaban might be a beneficial therapy for the management of infection-associated thrombosis.

看護学生のコミュニケーション能力の縦断的変化について明らかにし、学習支援や授業改善の資料とするために、大学１年生から２年生にわたり縦断的に調査を行った。調査内容及び方法は、コミュニケーション技術評価尺度を、１年生で行うコミュニケーション授業の前後と基礎看護学実習Ⅰ終了後、加えて２年生時の基礎看護学実習Ⅱの終了後に測定した。毎回の授業後には理解度・関心度を調査し、授業終了後には授業評価を実施した。なお、１年生で行う基礎看護学実習Ⅰ終了後には、コミュニケーションに関する感想や学び、課題を自由記述で求めた。結果として、１年生ではコミュニケーションの基本技術が向上し、２年生では、対象との関係性に向かうため非言語コミュニケーション力が向上していた。学習支援上の課題は、グループ活動による学習では、学生の対人緊張を和らげる工夫が必要と考えられた。

Ventriculoperitoneal (VP) shunt placement is commonly performed for the treatment of hydrocephalus, and several complications of this procedure are well known. Radiating shoulder tip pain after VP shunt placement has been reported as an unusual complication in a few cases, associated with dislocation of the peritoneal catheter. We described the case of a 9-year-old girl who presented with recurrent radiating shoulder tip pain after VP shunt placement. The pain recurred after peritoneal catheter repositioning because of peritoneal inflammation and adhesion due to peritonitis with Propionibacterium acnes (P. acnes). This bacterium was isolated using 16S ribosomal RNA gene polymerase chain reaction (16S rRNA gene PCR), and anaerobic and prolonged culture tests. After antibacterial treatment, ventriculoarterial (VA) shunt placement was successfully performed. Hemidiaphragm irritation by the peritoneal catheter leads to radiating shoulder tip pain, and peritoneal inflammation and adhesion caused by infectious peritonitis may cause recurrence of this despite catheter repositioning. Clinicians should be aware of shoulder pain as a complication of VP shunt placement, and should consider VA shunt placement as an alternative treatment if this symptom recurs after catheter repositioning. Furthermore, 16S rRNA gene PCR and anaerobic and prolonged culture tests should be considered to detect P. acnes infection.

Patients with diabetes are known to have high salivary glucose levels. But the mechanisms are still unclear. We hypothesized that the topological changes of glucose transporters affect the salivary glucose level.We used adult Goto-Kakizaki (GK) rats, an animal model of advanced diabetes, and Wistar rats as a control, with or without glucose load. The sections of salivary glands from the animals were processed for standard histological, immunohistochemical, and immunofluorescent staining.Parotid acinar cells of GK rats appeared like mucous filled with low-eosin-stained granules and possessing a flat nucleus located basally, whereas those of Wistar rats appeared as a typical serous gland with eosin-rich cytoplasm and a spherical nucleus. Cytoplasmic granules of GK rat parotid acinar cells showed no reaction of polysaccharide staining. In acinar cell cytoplasm of GK rats, intense GLUT1 immunoreactivity was observed compared to Wistar rats. By double immunostaining for GLUT1 and Golgi apparatus-specific markers, it was determined that GLUT1 was localized to the Golgi apparatus. By glucose loading in starved GK rats, the distribution of GLUT1-immunoreactive signals was spread out clearly from the apical side of the nucleus to the basolateral side.In rat model of diabetes, highly localized GLUT1 at Golgi apparatus in acinar cells seems to increase taking up cytoplasmic glucose to form exocytotic vesicles. This phenomenon may transform parotid glands from serous to mucous-like and result in saccharide-rich saliva.

Fibrinolysis is regulated by the thrombin/thrombin-activatable fibrinolysis inhibitor (TAFI) system. Thus, anticoagulants and inhibitors of TAFI are expected to accelerate fibrinolysis. The combined effects of an anticoagulant and a TAFIa inhibitor on fibrinolysis remain unknown. The aim of this study was to evaluate the combined effect of edoxaban, an oral direct factor Xa (FXa) inhibitor, and a TAFIa inhibitor, potato tuber carboxypeptidase inhibitor (PCI) on tissue-type plasminogen activator (t-PA)-induced clot lysis in human plasma in vitro. Pooled human plasma (containing 180 ng/mL t-PA and 0.1 nM thrombomodulin) was mixed with edoxaban and/or PCI. Clot formation was induced by 2.5 pM tissue factor and 4 µM phospholipids and clot lysis time was examined. Plasma plasmin-α2 antiplasmin complex (PAP) concentration was measured as a marker of plasmin generation. Edoxaban or PCI alone significantly shortened the t-PA-induced clot lysis time and plasma PAP concentration. The combination of these compounds significantly accelerated the clot lysis compared with the inhibitors alone. Addition of PCI (0.3, 1, and 3 μg/mL) to 75 ng/mL edoxaban increased plasma PAP concentration compared with edoxaban alone; however, compared with PCI alone only the combination of 0.3 μg/mL PCI + 75 ng/mL edoxaban showed the significant increase in PAP concentration. Concomitant use of an oral direct FXa inhibitor, edoxaban, and a TAFIa inhibitor, PCI, significantly accelerate fibrinolysis via enhancement of plasmin generation. These results suggest that the combination of edoxaban and a TAFIa inhibitor might be beneficial for the treatment of thromboembolic diseases.

Juvenile myelomonocytic leukemia (JMML) is a pediatric hematological malignancy with a poor prognosis. Although several case series have been published describing hematological and molecular responses to azacitidine (AZA) treatment in patients with JMML, the efficacy and safety profile of AZA is not well investigated, especially in Asian children and children undergoing hematopoietic stem cell transplantation (HSCT). We retrospectively analyzed 5 patients who received a total of 12 cycles (median 2 cycles) of AZA treatment in Japan. All five patients were boys and their ages at the time of treatment were 21, 23, 24, 26, and 46 months, respectively. All five patients tolerated AZA treatment, including four patients who received AZA after HSCT. Therapeutic toxicity with AZA was mostly limited to hematological toxicity. The only serious non-hematological adverse event was hyperbilirubinemia (grades III-IV) observed in a patient who received AZA after a second HSCT. Two out of five patients treated with AZA achieved a partial response (PR), while three patients treated for post-transplant relapse did not have an objective response. Future prospective studies should be conducted to develop combination therapies with AZA and other molecular targeted drugs for high-risk patients.

In human hair follicles, the hair‐forming cells express 16 hair keratin genes depending on the differentiation stages. K85 and K35 are the first hair keratins expressed in cortical cells at the early stage of the differentiation. Two types of mutations in the gene encoding K85 are associated with ectodermal dysplasia of hair and nail type. Here, we transfected cultured SW‐13 cells with human K85 and K35 genes and characterized filament formation. The K85–K35 pair formed short filaments in the cytoplasm, which gradually elongated and became thicker and entangled around the nucleus, indicating that K85–K35 promotes lateral association of short intermediate filaments (IFs) into bundles but cannot form IF networks in the cytoplasm. Of the K85 mutations related to ectodermal dysplasia of hair and nail type, a two‐nucleotide (C1448T1449) deletion (delCT) in the protein tail domain of K85 interfered with the K85–K35 filament formation and gave only aggregates, whereas a missense mutation (233A>G) that replaces Arg78 with His (R78H) in the head domain of K85 did not interfere with the filament formation. Transfection of cultured MCF‐7 cells with all the hair keratin gene combinations, K85–K35, K85(R78H)–K35 and K85(delCT)–K35, as well as the individual hair keratin genes, formed well‐developed cytoplasmic IF networks, probably by incorporating into the endogenous cytokeratin IF networks. Thus, the unique de novo assembly properties of the K85–K35 pair might play a key role in the early stage of hair formation., We transfected SW‐13 cells with human hair keratin K85 and K35 genes. This pair formed short filaments in the cytoplasm, which gradually elongated, became thicker and entangled around the nucleus, indicating that K85–K35 promotes lateral association of short intermediate filaments into bundles but cannot form filament networks in the cytoplasm. Two K85 mutants related to ectodermal dysplasia were also tested.

Background Anticoagulation therapy, particularly subcutaneous heparin therapy, is recommended for cancer-associated thrombosis. However, not starting or discontinuing anticoagulation was not rare. The aim of the present study was to examine the practical issues related to anticoagulation therapy and effects of subcutaneous heparin therapy for cancer-associated stroke. Methods Patients with cancer-associated stroke in our stroke center between October 2014 and August 2017 who were diagnosed as having acute ischemic stroke based on diffusion-weighted imaging were retrospectively enrolled. Baseline clinical characteristics, heparin injection, reasons for no subcutaneous heparin therapy, and clinical outcomes were collected. Results A total of 59 patients with cancer-associated stroke (75 ± 10 years old, male 42%) were enrolled. Lung cancer was the most frequently observed cancer (n = 17, 29%), followed by gastric cancer (n = 8, 14%) and pancreatic cancer (n = 8, 14%). Of the 19 patients (32%) who underwent subcutaneous heparin therapy, it was discontinued in 9 (47%), mainly because of patients’ medical conditions (deterioration of cancer or hemorrhagic complication). Ten patients with long-term subcutaneous heparin therapy did not have stroke recurrence. In contrast, among nine patients who discontinued subcutaneous heparin therapy, three (33%) had recurrence of ischemic stroke. Of the 40 patients without subcutaneous heparin therapy, the main reasons for no subcutaneous heparin therapy were the patients’ medical conditions (n = 22, 55%). Conclusions Although subcutaneous heparin therapy was given to only one third of cancer-associated stroke patients, long-term subcutaneous heparin therapy might prevent recurrence of cancer-associated stroke.

Background/Aims: Stent thrombosis is a serious complication after percutaneous coronary intervention and femoropopliteal endovascular intervention. The aim of this study was to determine the antithrombotic effects of a direct factor Xa inhibitor edoxaban alone or in combination with antiplatelet agents in a rat model of stent thrombosis. Methods: Stainless steel stents (4 stents per rat) were placed in an extracorporeal arteriovenous shunt. The shunt was inserted into the carotid artery and the jugular vein in each rat to circulate blood. Stent thrombosis was induced by exposing the stents to arterial blood for 30 min. Protein content of the thrombus was measured. Edoxaban and antiplatelet agents (aspirin, clopidogrel, and ticagrelor) were orally administered before the thrombus induction. Results: Edoxaban (0.3–3 mg/kg), clopidogrel (1–10 mg/kg), aspirin (10–100 mg/kg), and ticagrelor (0.3–3 mg/kg) exerted significant and dose-dependent antithrombotic effects in a rat stent thrombosis model. The effect of edoxaban was comparable to that of antiplatelet agents. The combination of submaximal doses of edoxaban and clopidogrel or aspirin significantly potentiated the antithrombotic effects compared with antiplatelet agents alone. Conclusion: These results suggest that edoxaban alone and in combination with clopidogrel or aspirin are promising antithrombotic therapies for the prevention of stent thrombosis.

We report a pediatric case aged 10 years with Granulicatella adiacens-associated chronic mandibular osteomyelitis. The causative pathogen was uncertain because polymicrobial species were detected from the bacterial culture in bone marrow fluid. In contrast, G. adiacens was predominantly identified in the clone library analysis of the bacterial 16S rRNA gene sequence. Vancomycin to which G. adiacens was reported to be susceptible was not administrated sufficiently to this patient because of its adverse event, whereas linezolid and ciprofloxacin was alternatively effective for the treatment of chronic mandibular osteomyelitis.

In adults, meningiomas occasionally display aggressive behavior and may occasionally metastasize. By contrast, pediatric meningiomas are rare, and there is limited information regarding their clinical characteristics, treatment and prognosis. We herein report the case of a 3-year-old boy with anaplastic meningioma with a history of local recurrence and late pulmonary metastasis. At diagnosis, a 70-mm mass lesion in was identified in the right frontal lobe, with intratumoral hemorrhage. The tumor was attached to the falx cerebri and was completely resected. The histological diagnosis was anaplastic meningioma, World Health Organization grade III. Two months after the surgery, the meningioma recurred at the same site. Although the patient received radiotherapy after a second operation, the tumor metastasized to the lung and pleura 8 months after the initial operation. The metastasis was resistant to treatment, even after gross total resection, and the effectiveness of further radiotherapy was limited. The patient succumbed to the disease 1 year and 4 months after the initial diagnosis. The findings of the present case and a review of the relevant literature suggest that recurrence and metastasis of meningiomas are difficult to predict. Therefore, such patients should be carefully monitored throughout the follow-up period.

Introduction: Stroke is a relatively common in hospitalized patients. However, previous studies have shown delays in recognition and initial assessment of in-hospital stroke. We aimed to elucidate that reorganization of in-hospital stroke code protocol can improve process of acute stroke care and save the treatment time. Methods: Our reorganization of in-hospital stroke code comprises the development of in-hospital stroke code protocol and workshop for hospital medical staff. Before the intervention, if the medical staff identified patients with suspected stroke, they first contacted the attending physician, then the physician consulted the stroke neurologists immediately or after imaging. After the intervention, to quickly identify stroke patients, the medical staff can directly consult stroke neurologists when they identified patients with at least one of acute-onset symptoms, including face droop, arm drift, speech disturbance, eye deviation, aphasia, or neglect, within 6-hour from last seen well or stroke recognition. As an educational intervention, we held workshop for nurses and residents with an understanding of how to evaluate stroke symptoms, use the protocol, and manage stroke. Data were compared between 24-month period before and 12-month period after the intervention. Outcome measure included the time from stroke recognition to initial imaging, and evaluation by stroke neurologist, and from initial imaging to groin puncture. Results: One hundred four patients were included (before, 42; after, 62). Significant time savings were seen in the median time from stroke recognition to evaluation by stroke neurologist (91 vs. 56 minutes, p=0.015), and time from initial imaging to groin puncture (113 vs. 68, p=0.040). The rate of consultation to stroke neurologists before initial imaging was significantly increased (21% vs. 47%, p=0.012). The time from stroke recognition (234 vs. 103, p=0.126), and evaluation by stroke neurologist (135 vs. 81, p=0.056) to groin puncture tended to decrease. Conclusion: Reorganization of in-hospital stroke code protocol can improve the time for initial management of in-hospital stroke.

Here we report a case of a 12-year-old girl who was referred to our department because of marked short stature of more than -5 SD below the median. Although her growth failure began suddenly at 6 years of age, she never had an examination because she had no other symptoms. Brain MRI examination suggested a tumor in the suprasellar region, and endocrine examination revealed combined pituitery hormone deficiency due to the tumor. Before surgery, the supplementation with hydrocortisone and levothyroxine was initiated. The pathological diagnosis of the surgically removed tumor was xanthogranuloma. The pattern of her growth curve showed a growth failure with sudden onset, which is a typical pattern of short stature secondary to pituitary disfunction including growth hormone deficiency associated with brain tumors. This case suggests that growth failure could be the only symptom in pediatric cases with brain tumors. Improved awareness regarding the association of growth failure with brain tumors is needed for earlier diagnosis and treatment. Furthermore, the growth curves should be carefully evaluated in regular health examinations at school.

A direct oral anticoagulant, edoxaban, is as effective as vitamin K antagonists for the treatment of venous thromboembolism (VTE). However, the mechanism underlying the treatment effect on VTE remains to be determined. The aims of this study were to evaluate the effect of edoxaban on tissue plasminogen activator (t-PA)-induced clot lysis in human plasma and to determine the roles of plasmin and thrombin-activatable fibrinolysis inhibitor (TAFI) in the profibrinolytic effect by edoxaban. Pooled human normal plasma or TAFI-deficient plasma (containing 180 ng/mL t-PA and 0.1 nM thrombomodulin) was mixed with edoxaban or an activated TAFI inhibitor, potato tuber carboxypeptidase inhibitor (PCI). Clot was induced by adding tissue factor and phospholipids. Clot lysis time and plasma plasmin-α2 antiplasmin complex (PAP) concentration were determined. Clot structure was imaged with a scanning electron microscope. In normal plasma, edoxaban at clinically relevant concentrations (75, 150, and 300 ng/mL) and PCI significantly shortened clot lysis time. PCI increased PAP concentration and a correlation between PAP concentration and percent of clot lysis was observed. Edoxaban also dose-dependently elevated PAP concentration. In TAFI-deficient plasma, the effects of edoxaban and PCI on clot lysis and PAP concentration were markedly diminished as compared with normal plasma. Fibrin fibers were thinner in clots formed in the presence of edoxaban. In conclusion, edoxaban at clinically relevant concentrations accelerates t-PA-induced fibrinolysis via increasing plasmin generation in human plasma. The effects of edoxaban is mainly dependent on TAFI. The profibrinolytic effect of edoxaban might contribute to the efficacy for the treatment of VTE.

In addition to platelet aggregation, coagulation activation is considered to be involved in arterial thrombosis. In this study, we determined antithrombotic effects of edoxaban, an oral factor Xa (FXa) inhibitor, as both a monotherapy and in combination with antiplatelet agents in a rat model of arterial thrombosis. We further examined its effects on a procoagulant biomarker and bleeding. Arterial thrombosis was induced by topical application of 15% ferric chloride to rat abdominal aortas. Bleeding time was measured by a tail incision method. Edoxaban, clopidogrel, and aspirin were orally administered 30min, 4h, and 2h before thrombus or bleeding induction. As a biomarker of coagulation activation, plasma thrombin-antithrombin complex (TAT) was measured. Edoxaban dose-dependently prevented arterial thrombosis in a manner comparable to clopidogrel and aspirin. The combination of edoxaban plus clopidogrel or edoxaban plus aspirin significantly potentiated the antithrombotic effects compared with these drugs alone. The combination of edoxaban and clopidogrel was more potent than clopidogrel and aspirin. Plasma TAT concentration was elevated after thrombus induction and suppressed by edoxaban and clopidogrel, but not by aspirin, suggesting P2Y12 receptor-mediated platelet procoagulant activity. Bleeding time was prolonged by the coadministration of edoxaban and clopidogrel, but not by edoxaban and aspirin. In conclusion, the present study demonstrates that the monotherapy with edoxaban and combination therapy with edoxaban plus clopidogrel or edoxaban plus aspirin are promising options for the prevention of arterial thrombosis as effective as the standard antiplatelet agents; however, a combination of edoxaban and clopidogrel increased the risk of bleeding.

Background: The functional independence measure (FIM) is a standard tool to provide a detailed evaluation of ADL of patients with disabilities. This study aimed to show the differences in FIM scores as an outcome predictor between patients with anterior circulation (AC) and posterior circulation (PC) strokes. Methods: Consecutive patients with acute ischemic stroke hospitalized within 7 days after onset were investigated. Baseline NIHSS scores, 1st-FIM (< 72 h after ­admission to stroke unit), 2nd-FIM (< 72 h before discharge), and modified Rankin Scale (mRS) scores were collected. Logistic regression analyses were used to identify predictors of a favorable outcome (mRS 0–2) at 3-month after stroke. Results: Three hundred eighty-five patients (median age, 78 years; male, 59%; median length of stroke unit stay, 20 days) were included. The median baseline NIHSS, 1st- and 2nd-FIM scores were 4 (interquartile range 2–9), 65 (33–91), and 98 (54–122) respectively. Baseline NIHSS (3 vs. 4, p = 0.01) and mRS score at 3-month (1 vs. 2, p = 0.01) were lower, and 1st-FIM (75 vs. 64, p < 0.01) and 2nd-FIM (113 vs. 95, p = 0.01) were higher in 82 patients with PC than 303 patients with AC strokes. On multivariate logistic regression analysis, 2nd-FIM score was an independent predictor of favorable outcomes in both PC (OR 1.18, 95% CI 1.04–1.48, p < 0.01) and AC (OR 1.12, 95% CI 1.06–1.20, p < 0.01) strokes. The optimal cutoff scores of 2nd-FIM for predicting favorable outcome were 104 for PC (sensitivity 0.82, specificity 0.88) and 93 for AC (0.88–0.90) strokes. Conclusions: The differences in outcome predictability by FIM score between AC and PC strokes should be considered, although FIM scores at discharge from stroke unit were useful to predict a favorable outcome.

Acquired hemophilia A (AHA), a bleeding disorder caused by autoantibodies against FVIII, has the potential for life-threatening bleeding. The annual onset rate is said to be one in 4 million people, but diagnosis examples increase in adults because a disorder concept penetrated. AHA is quite rare in children, with an incidence rate of 0.045 per 1 million, but early detection is crucial because serious bleeding can happen, as in adults. We report a pediatric case who received an early diagnosis of AHA by an activated partial thromboplastin time (APTT) cross-mixing test. The 12-year-old girl had neither a past history nor a family history of bleeding episodes. She presented with intramuscular bleeding and epistaxis without trauma or medication. At diagnosis, her blood test showed prolonged APTT. Other hemostatic tests, such as the platelet count, prothrombin time and fibrinogen concentration, were within the normal range. We administered an APTT cross-mixing test that detected an inhibitor pattern and inhibitory antibodies against factors VIII. As a result, we administered prednisolone and the inhibitor disappeared after 1.5 months. In conclusion, AHA is a bleeding disorder which should be considered even in children due to the potential for life-threatening bleeding. Furthermore, the APTT cross-mixing test is useful for screening coagulation factor deficiencies and inhibitors.

Vascular injury activates the coagulation cascade. Some studies report that coagulation factor Xa and thrombin are implicated in proliferation of vascular smooth muscle cells and neointimal hyperplasia after vascular injury. The aim of this study was to determine the effect of an oral direct factor Xa inhibitor, edoxaban, on neointimal hyperplasia following the carotid artery injury in apolipoprotein E (ApoE)-deficient mice. Vascular injury was induced by the application of 10% ferric chloride to the carotid artery for 3 min in ApoE-deficient mice. After vascular injury, all animals were fed with high-cholesterol chow for 6 weeks. Edoxaban at 15 mg/kg was orally administered to the mice 1 h before (n = 10) or 1 h after (n = 9) ferric chloride injury, and thereafter 10 mg/kg edoxaban was orally administered b.i.d. for 6 weeks. Thrombus formation and neointimal hyperplasia were evaluated. Treatment with 15 mg/kg edoxaban before vascular injury almost completely inhibited thrombus formation, and following chronic administration of edoxaban significantly suppressed neointimal hyperplasia. In the mice treated with edoxaban after vascular injury, there was wide interindividual variability. In some mice (four out of nine) the neointimal hyperplasia was inhibited like in edoxaban-pretreated mice, but there was no statistical difference compared with control. This study demonstrated that inhibition of the coagulation and thrombosis by edoxaban ameliorated neointimal hyperplasia caused by vascular injury and high-cholesterol diets in ApoE-deficient mice. This suggests that factor Xa has a crucial role in the formation of neointima following vascular injury.The abstract should be followed by 3-4 bullet points that highlight major findings. The final bullet point should emphasize future directions for research.

Aim To clarify growth patterns, spatial distribution and risk factors of cerebral white matter hyperintensity (WMH) lesions on magnetic resonance imaging. Methods We analyzed volumes of cerebral WMH lesions in those who underwent brain magnetic resonance imaging as a hospital-based health check-up in 2012 and 2013 by using a computational quantitative image analysis software (Software for NeuroImage Processing in Experimental Research). After excluding subjects not suitable for volumetric analyses because of pathological brain conditions, a total of 1047 healthy participants (mean age 56.6 years) were included for the analyses. First, the relationship of computational volumetry and conventional qualitative visual evaluation by Shinohara grading was evaluated. Volumes of WMH lesions were analyzed according to age and the different cerebral lobes. Finally, clinical risk factors associated with WMH lesions were assessed. Results Volumes of WMH lesions were significantly correlated with Shinohara grading (P

We report the long-term morbidity and mortality of 105 pediatric patients who developed chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). According to the consensus criteria of the National Institutes of Health, the global severity of cGVHD was mild in 26 patients (25%), moderate in 30 patients (29%), and severe in 49 patients (47%). Patients with severe cGVHD had a significantly lower cumulative incidence of cGVHD remission and higher probability of continuing cGVHD at 8 years from cGVHD diagnosis compared with those with mild or moderate cGVHD. The 10-year cumulative incidence of nonrelapse mortality in severe cGVHD patients was significantly higher and the probability of disease-free survival was significantly lower than those among patients with mild and moderate cGVHD. Of the 59 patients who survived for more than 5 years, 20 (34%) (4 with moderate and 16 with severe cGVHD) had persistent functional impairment caused by cGVHD with a Karnofsky/Lansky performance score of 90% in 3 patients, 80% in 4 patients, and below 70% in 13 patients at the time of relapse, death, or last follow-up. Better therapeutic strategies are needed to lower the incidence of severe cGVHD, considering the longer life expectancy of pediatric HSCT survivors.

Background and Purpose: In patients with emergent large vessel occlusion (ELVO), fluid-attenuated inversion recovery (FLAIR) hyperintense vessel (FHV) has been linked to cerebral hypoperfusion. However, the association between FHV and infarction lesion after successful recanalization by endovascular thrombectomy (ET) remains unknown. In this study, we investigated the relationship baseline FHV and baseline or post-ET diffusion weighted imaging (DWI) positive lesions. Methods: From April 2012 to August 2016, fifty-nine patients were received ET for ELVO of the anterior circulation. We included twenty-five patients of them who obtained successful (Thrombolysis In Cerebral Infarction score 2b/3) recanalization of ICA or M1 occlusion. All patients had DWI before and after ET and FLAIR before ET. Infarct lesions and FHV were evaluated in seven cortical lesions which divided according to cortical area of Alberta Stroke Program Early CT (ASPECT) scoring (I, M1-M6). The association between baseline or post-ET DWI positive and baseline FHV was analyzed in each one hundred seventy-five lesions. Results: DWI positive lesions were present in 65/171 (37%) and 108/175 (62%) lesions on baseline and post-ET DWI, respectively. FHV was present in 89/175 (51%) lesions on baseline FLAIR. Baseline DWI positive lesion was significantly higher at FHV positive lesion than FHV negative lesion (FHV (+) vs. FHV (-): 56% vs. 17%, p Conclusion: Baseline FHV positive lesions have already been infarcted before ET and likely to become infarction after successful recanalization compared to FHV negative lesion. Because FHV positive lesion became infarct despite early successful recanalization, FHV seemed to suggest severe hypoperfusion.

Background and Purpose: Modified Rankin scale (mRS) score at 3-month after onset is widely used as clinical outcomes in stroke patients. Functional Independence Measure (FIM) is a valid tool to estimate the level of ADL. However, there were few studies whether FIM score in acute stroke patients can predict clinical outcomes at 3-month. Our aim is to reveal that FIM scores of acute stroke patients can predict favorable outcome (mRS 0-1 at 3-month). Method: We used data from a prospectively collected observational registry in single stroke center between January 2016 and March 2017. Baseline NIHSS score, acute FIM score (=within 3 days from admission to the stroke unit), discharge FIM score (=at discharge from the stroke unit), and mRS score (before stroke, at 3-month) were collected. The relationship between discharge FIM score and mRS score at 3-month were examined using Spearman’s rank correlation test. Logistic regression analyses were used to reveal the predictors of favorable outcome. Results: Of 678 patients were admitted to our stroke center due to acute stroke, 410 patients whose clinical data could be obtained (60%; mean age, 74±13 years; male, 57%; the median of length of hospital stay, 21 days; 75% with ischemic stroke) were enrolled. The median of the baseline NIHSS score, acute and discharge FIM scores were 5 (interquartile range [IQR], 2-16), 53 (IQR 22-83), and 86 (IQR 32-119), respectively. Discharge FIM score strongly correlated with mRS score at 3 month (ρ=-0.86; p Conclusions: FIM score at discharge from the stroke unit can predict favorable clinical outcome at three months. Our results can help stroke physicians to expect stroke patients’ status in the chronic phase.

Background and purpose: Functional Independence Measure (FIM) is a valid tool to estimate the level of ADL. However, there were few studies whether FIM score in acute stroke patients is associated with the short-term outcome. Our aim is to reveal whether FIM scores within 3 days from admission to a stroke unit can predict the short-term good outcome (discharge directly to home). Method: We used data from a prospectively collected observational registry in a single stroke center between January 2016 and March 2017. Baseline NIHSS score, acute FIM score (= within 3 days from admission to the stroke unit), discharge FIM score (= at discharge from the stroke unit) were collected. FIM efficiency was calculated from (discharge FIM - acute FIM)/ the length of hospital stay. Logistic regression analysis was used to determine the independent predictors of discharge directly to home. Results: Of 678 patients were admitted to our stroke center due to acute stroke, 410 patients whose clinical data could be obtained (60%; mean age, 74±13 years; male, 57%; the median of length of hospital stay, 21 days; 75% with ischemic stroke) were enrolled. The median of the baseline NIHSS score, acute FIM score, and FIM efficiency were 5 (interquartile range [IQR], 2-16), 53 (IQR 22-83), and 0.88 (IQR 0.10-1.73), respectively. In univariate logistic regression analysis, male sex, acute ischemic stroke, baseline NIHSS score, acute FIM score, discharge FIM score, the length of hospital stay, and FIM efficiency were associated with discharge directly to home. In multivariate logistic regression analysis, acute FIM score (odds ratio [OR] 1.04; 95% confidence interval [CI] 1.03-1.06; p71, with a sensitivity of 72%, specificity of 88%, and an area under the curve of 0.86 (p Conclusions: FIM scores within 3 days from admission to a stroke unit can predict discharge directly to home, which can help stroke physicians to expect the short-term outcomes.

Background/Aims: Agents to reverse the anticoagulant effect of edoxaban, an oral direct factor Xa inhibitor, would be desirable in emergency situations. The aim of this study is to determine the effect of tranexamic acid, an antifibrinolytic agent, on the anticoagulant activity and bleeding by edoxaban in rats. Methods: A supratherapeutic dose of edoxaban (3 mg/kg) was intravenously administered to rats. Three minutes after dosing, tranexamic acid (100 mg/kg) was given intravenously. Bleeding was induced by making an incision with a blade on the planta 8 min after edoxaban injection and bleeding time was measured. Prothrombin time (PT) and clot lysis were examined. Results: A supratherapeutic dose of edoxaban significantly prolonged PT and bleeding time. Tranexamic acid did not affect PT or bleeding time prolonged by edoxaban, although tranexamic acid significantly inhibited clot lysis in rat plasma. Conclusion: An antifibrinolytic agent tranexamic acid failed to reverse the anticoagulant effect and bleeding by edoxaban in rats.

Edoxaban is an oral and direct activated factor X inhibitor. In this study, the acute treatment effect of edoxaban on venous thrombosis is investigated in rats by single and multiple administrations, and compared to the conventional parenteral anticoagulants, enoxaparin and fondaparinux. Venous thrombus was induced in the inferior vena cava by partial stenosis plus topical application of 10% ferric chloride for 5min. After 1-h thrombus maturation, oral edoxaban and subcutaneous enoxaparin and fondaparinux were given. In the single administration experiment, thrombus weight was measured 1 or 4h after thrombus induction. In the multiple administration experiments, edoxaban was orally administered once daily (QD) and twice daily (BID) for 3 days. In the single administration experiment, oral administration of edoxaban (3.0 and 10mg/kg) 1h after thrombus formation significantly regressed the venous thrombus compared to the thrombus at 1h after thrombus formation. Similarly the significant venous thrombus regression was observed with enoxaparin (10mg/kg) and fondaparinux (0.30-3.0mg/kg). In the multiple administration experiment, both QD and BID administration of edoxaban at daily doses of 5 and 10mg/kg exerted significant treatment effects. QD administration of edoxaban including lower doses (1-10mg/kg) significantly reduced thrombus weight. Edoxaban administered QD and BID was effective in the treatment of venous thrombosis, and the treatment effect of edoxaban was comparable to the conventional parenteral anticoagulants. These data demonstrate the potential of edoxaban as an oral anticoagulant in the acute treatment of venous thromboembolism.

Multiple type I and II hair keratins are expressed in hair-forming cells but the role of each protein in hair fiber formation remains obscure. In this study, recombinant proteins of human type I hair keratins (K35, K36 and K38) and type II hair keratins (K81 and K85) were prepared using bacterial expression systems. The heterotypic subunit interactions between the type I and II hair keratins were characterized using two-dimensional gel electrophoresis and surface plasmon resonance (SPR). Gel electrophoresis showed that the heterotypic complex-forming urea concentrations differ depending on the combination of keratins. K35-K85 and K36-K81 formed relatively stable heterotypic complexes. SPR revealed that soluble K35 bound to immobilized K85 with a higher affinity than to immobilized K81. The in vitro intermediate filament (IF) assembly of the hair keratins was explored by negative-staining electron microscopy. While K35-K81, K36-K81 and K35-K36-K81 formed IFs, K35-K85 afforded tight bundles of short IFs and large paracrystalline assemblies, and K36-K85 formed IF tangles. K85 promotes lateral association rather than elongation of short IFs. The in vitro assembly properties of hair keratins depended on the combination of type I and II hair keratins. Our data suggest the functional significance of K35-K85 and K36-K81 with distinct assembly properties in the formation of macrofibrils.

In this study, oxytocin receptors (OTRs) in the islets of Langerhans were detected using real-time RT-PCR and immunohistochemical technique. Indeed, OTR mRNA was expressed in the rat pancreas. Double immunohistochemical staining for OTR and either glucagon or insulin demonstrated their co-localization in A-cells or B-cells, respectively. OTR-immunoreactivity in A-cells was stronger than that of B-cells. All A-cells and 94.8% of B-cells were OTR-immunoreactive. We reveal the statistically significant relations of OTR with A-cells and B-cells in the islets of Langerhans. This is the first demonstration of the OTR localization in the islets of Langerhans immunohistochemically. It suggests that oxytocin (OT) is involved in the release of insulin and glucagon.

SummaryEdoxaban, an oral, direct factor Xa inhibitor, has a similar or low incidence of bleeding events compared with other anticoagulants in clinical trials. Therefore, agents to reverse the anticoagulant effects of edoxaban could be desirable in emergency situations. In this study, the reversal effects of haemostatic agents were determined on prothrombin time (PT) prolongation in vitro and bleeding time prolongation in vivo by edoxaban. PT using human plasma was measured in the presence of edoxaban at therapeutic and excess concentrations with the haemostatic agents, prothrombin complex concentrate (PPSB-HT), activated prothrombin complex concentrate (Feiba), and recombinant factor VIIa (rFVIIa). In rats, rFVIIa and Feiba was given during intensive anticoagulation with edoxaban. The haemostatic effect was evaluated in a model of planta template bleeding and a potential prothrombotic effect was evaluated in a venous thrombosis model. PPSB-HT, Feiba, and rFVIIa concentration-dependently shortened PT prolonged by edoxaban. Among these, rFVIIa and Feiba showed potent activities in reversing the PT prolongation by edoxaban. rFVIIa (1 and 3 mg/kg, i.v.) and Feiba (100 U/kg, i.v.) significantly reversed edoxaban (1 mg/kg/h)-induced prolongation of bleeding time in rats. In a rat venous thrombosis model, no potentiation of thrombus formation was observed when the highest dose (3 mg/kg) of rFVIIa was added to edoxaban (0.3 and 1 mg/kg/h) compared with the control. The present study indicated that rFVIIa, Feiba, and PPSB-HT have the potential to be reversal agents for edoxaban.

SummaryEdoxaban is an oral, direct factor Xa (FXa) inhibitor under late-phase clinical development. This study compared the antithrombotic efficacy of edoxaban with that of an indirect FXa inhibitor, fondaparinux, in in vivo venous and arterial thrombosis models and in ex vivo perfusion chamber thrombosis model under low and high shear rates in rats. Venous and arterial thrombi were induced by platinum wire insertion into the inferior vena cava and by application of FeCl3 to the carotid artery, respectively. The perfusion chamber thrombus was formed by blood perfusion into a collagen-coated capillary at 150 s-1 (low shear rate) and 1,600 s-1 (high shear rate). Effective doses of edoxaban that reduced thrombus formation by 50% (ED50) in venous and arterial thrombosis models were 0.076 and 0.093 mg/kg/h, respectively. In contrast, ED50 of fondaparinux in the arterial thrombosis model (>10 mg/kg/h) was markedly higher compared to ED50 in the venous thrombosis model (0.021 mg/kg/h). In the perfusion chamber thrombosis model, the ratio of ED50 under high shear rate (1.13 mg/kg/h) to that under low shear rate (0.63 mg/kg/h) for edoxaban was 1.9, whereas that for fondaparinux was more than 66. While the efficacy of fondaparinux markedly decreased in arterial thrombosis and in a high-shear state, edoxaban exerted consistent antithrombotic effects regardless of flow conditions. These results suggest that shear rate is a key factor in different antithrombotic effects between edoxaban and fondaparinux.

Introduction: Direct oral anticoagulants are as effective as vitamin K antagonists for the treatment of venous thromboembolism and are associated with less bleeding. We have reported that a direct oral factor Xa inhibitor edoxaban exerts a thrombus resolution effect in a rat model of venous thrombosis and enhances tissue plasminogen activator (t-PA)-induced clot lysis in human plasma. However, the mechanism underlying the thrombus resolution effect and fibrinolysis enhancement by edoxaban remains to be determined. Purposes: To evaluate the effect of edoxaban on plasmin generation during clot lysis in human plasma in vitro. To determine the role of thrombin-activatable fibrinolysis inhibitor (TAFI) in the enhancement of fibrinolysis by edoxaban. Methods: Pooled human normal plasma or TAFI-deficient plasma (both containing 180 ng/mL t-PA and 0.1 nM thrombomodulin) was mixed with edoxaban, an activated TAFI (TAFIa) inhibitor (a fibrinolysis enhancer) potato tuber carboxypeptidase inhibitor (PCI), or vehicle. Clot was induced by adding 2.5 pM tissue factor and 4 µM phospholipids. To monitor the clot formation and lysis, the absorbance of plasma at 405 nm was measured every 30 sec. Clot lysis time was defined as the interval between the time of the midpoint of the clear to maximum turbidity transition and the midpoint of the maximum turbidity to clear transition. Plasmin-α2 antiplasmin complex (PAP) concentration was measured by ELISA as an indicator of plasmin generation. Results: In normal plasma, PCI accelerated clot lysis and increased plasma PAP concentration. There was a correlation between plasma PAP concentration and percent of clot lysis, indicating that plasma PAP concentration is an appropriate marker of fibrinolysis. Edoxaban at clinically relevant concentrations (75, 150, and 300 ng/mL) significantly shortened clot lysis time and elevated plasma PAP concentration. The additive combined effect of edoxaban and PCI was observed. In TAFI-deficient plasma, clot lysis time was shortened and plasma PAP concentration increased compared with normal plasma. In these samples, the effects of edoxaban and PCI on clot lysis and plasma PAP concentration were markedly diminished as compared with normal plasma. Conclusions: Edoxaban at clinically relevant concentrations enhanced t-PA-induced clot lysis with increasing plasma PAP concentration in human plasma. The effects of edoxaban on clot lysis and plasmin generation were diminished in TAFI-deficient plasma. A TAFIa inhibitor PCI exerted similar effects. These data suggest that edoxaban enhanced fibrinolysis via inhibition of TAFI activation and enhancement of plasmin generation. Disclosures Morishima: Daiichi Sankyo Co., Ltd.: Employment. Honda:Daiichi Sankyo Co., Ltd.: Employment. Furugohri:Daiichi Sankyo Co., Ltd.: Employment.

We investigated sex damage to the university student. and conducted question paper investigation about the uneasiness and the trouble about a sex for the second grader of a junior high school, and analyzed the result. The percentage of a college student's sex damage experience is 34.6%, and there was no difference between men and women. However, female students' (65.4%) sex damage experience rate was intentionally (P< 0.05) higher than the junior high school student boy (34.6%). The junior high school student who has the experience on which consulted with the Yogo teacher was 3.0% after entrance into a school. The contents on which the junior high school student consulted with the Yogo teacher were the following contents. Human relations with a\friend, a senior, etc. are 3.0%, consultation of the body are 2.4%, and activity of an after school are 2.1%.

To evaluate people's opinions concerning the release of the Japanese Crested Ibis Nipponia nippon, a questionnaire was mailed throughout Sado City, Niigata Prefecture, Japan. The 1,000 target individuals were selected randomly from within the 20 to 79 year age group. Results from the 591 respondents indicated almost 74% to have appreciated the release, and only 26% have neither agreed nor disagreed. The most common reason people gave for their appreciation was “they have lived here”, though only 16% of the people had actually seen the Japanese Crested Ibis in the wild. Their concerns related to the release were related mainly toward the success of the release rather than to any harm the birds might cause to crops. Especially, they worried about the released Japanese Crested Ibis survival. These results may be affected by the media like TV. Many people treated Japanese Crested Ibis as a local symbol, or a symbol of nature, and only a few viewed the bird as a potentially commercial venurte. Similar results were obtained from a questionnaire on the Oriental Storks Ciconia boyciana in Toyooka City. The releases in the past have been done far from the villages. This Japanese Crested Ibis release is the second case done near the villages, just after the release of the Oriental Storks. The sequential research will be done to compare the two questionnaires relating to the Oriental Stork and the Japanese Crested Ibis.