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Abstract T‐cell lymphoma in the gastrointestinal tract (intestinal T‐cell lymphoma, [ITCL]) is rare. ITCL, not otherwise specified (ITCL, NOS) which is a type of ITCL is particularly rare. There are few case reports of ITCL, NOS but no previous reports describe its endoscopic features. In this report, the 69‐year‐old man was diagnosed with ITCL, NOS. Colonoscopy revealed the elevated legion and edematous mucosa with focal depressions in the lower rectum. On the depressed legions, magnifying endoscopy combined with narrow‐band imaging detected the disappearance of glandular structure and branching abnormal blood vessels like a tree. These findings were similar to the tree‐like appearance, which has been described as a unique feature of gastric mucosal‐associated lymphoid tissue lymphoma. The targeted biopsy of the tree‐like appearance showed abnormal histopathological findings which fit the definition of ITCL, NOS. He was treated with chemotherapy and achieved complete remission. As is the case of gastric mucosal‐associated lymphoid tissue lymphoma, the tree‐like appearance is possibly the unique sign of ITCL, NOS. We report the endoscopic features of ITCL, NOS and show characteristic findings by magnifying endoscopy combined with narrow‐band imaging.

Abstract Background Intensity‐modulated radiotherapy (IMRT) has been increasingly used for patients with locally advanced non‐small cell lung cancer (LA‐NSCLC). However, there are some barriers to implementing IMRT for LA‐NSCLC, including the complexity of treatment plan optimization. This study aimed to evaluate the learning curve of lung dose optimization in IMRT for LA‐NSCLC and identify the factors that affect the degree of achievement of lung dose optimization. Methods We retrospectively evaluated 40 consecutive patients with LA‐NSCLC who received concurrent chemoradiotherapy at our institution. These 40 patients were divided into two groups: 20 initially treated patients (earlier group) and 20 subsequently treated patients (later group). Patient and tumor characteristics were compared between the two groups. The dose‐volume parameter ratio between the actually delivered IMRT plan and the simulated three‐dimensional conformal radiotherapy plan was also compared between the two groups to determine the learning curve of lung dose optimization. Results The dose‐volume parameter ratio for lung volume to receive more than 5 Gy (lung V5) and mean lung dose (MLD) significantly decreased in later groups. The spread of the beam path and insufficient optimization of dose coverage of planning target volume (PTV) might cause poor control of lung V5, MLD. Conclusions A learning curve for lung dose optimization was observed with the accumulation of experience. Appropriate techniques, such as restricting the beam path and ensuring dose coverage of PTV during the optimization process, are essential to control lung dose in IMRT for LA‐NSCLC.

Introduction: Recent advancements in genomic research have revealed that 9 individuals per 1,000 population in East Asia and 3.4 individuals per 1,000 population worldwide carry cysteine-altering NOTCH3 variants in the epidermal growth factor-like repeat domains, which are the underlying cause of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Compared to CADASIL patients in Western countries, Asian patients exhibit several differences, including: (1) different predominant pathogenic NOTCH3 variants, (2) a higher prevalence of hemorrhagic stroke, and (3) a lower prevalence of white matter hyperintensities in the anterior temporal pole. Therefore, it is necessary to conduct large- scale clinical studies in East Asia to establish clinical evidence for CADASIL patients in this region. We here investigate clinical, genetic, and neuroradiological characteristics of CADASIL patients in Japan, Korea, and Taiwan. Methods: The current CADREA (CADASIL Registry in East Asia) study will recruit 1,000 CADASIL patients diagnosed based on the results of NOTCH3 genetic testing. From September, 2023, physicians in participating facilities will register clinical data, including age, gender, race, medical history, social history, medication history, family history, scores of the Montreal Cognitive Assessment and Trail Making Test, and detailed information on stroke events, into an Electronic Data Capture system called Research Electronic Data Capture (REDCap). Brain MRI data will be independently evaluated by the Central Evaluation Committee. Each patient will undergo annual evaluations for two years. The study will examine genotype-phenotype correlations, particularly in the frequency of stroke events and changes in cognitive function and imaging biomarkers. Discussion: The CADREA study will uncover the natural history of CADASIL patients in East Asia, providing basic data for future clinical trials. Additionally, the findings may have implications for understanding the unique characteristics of CADASIL in Asian populations and inform potential interventions and treatments.

Interferon β and glatiramer acetate are the disease-modifying drugs (DMDs) considered relatively safe for use in pregnant women with multiple sclerosis (MS); however, the safety profile of dimethyl fumarate (DMF) and natalizumab (NTZ) in this population remains inconclusive. Here, we present four cases of pregnant women with MS who were treated with DMF and NTZ (n = 2 patients, each) during their pregnancy and discuss our observations with the use of these drugs and the clinical courses of the patients. We retrospectively examined relapse of MS during pregnancy and after delivery; duration of exposure to DMDs; maternal, fetal, and neonatal adverse events; breastfeeding; and timing of resumption of DMDs. The two patients treated with DMF discontinued treatment 5 or 6 weeks after the discovery of pregnancy. DMF was resumed 1 week postpartum, and mixed breastfeeding was initiated. Brain magnetic resonance imaging in one patient 9 months after delivery revealed a new lesion; however, it was not classified as a clinical relapse. In two patients treated with NTZ, the dosing interval was extended to 6 weeks after the discovery of pregnancy. One patient discontinued NTZ at 30 weeks and the other at 25 weeks of gestation, as a slight restriction in fetal growth was observed owing to hyperemesis gravidarum. Both patients opted for formula feeding, and no relapse was observed within 1 year postpartum. Additionally, no abnormalities were observed in any of the patients during the perinatal period, and their development was normal. Investigation of drug safety in pregnant and parturient women primarily relies on registries, postmarketing surveillance, and case reports due to ethical limitations on conducting randomized controlled trials. Our findings demonstrated that DMF and NTZ were not contraindicated during pregnancy or the perinatal period in women with MS; nevertheless, vigilant monitoring is essential to ensure the safety of these drugs.

The etiology of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) remains elusive and is believed to involve multiple contributing factors. There have been cases linking CIDP to the coronavirus disease 2019 (COVID-19) mRNA vaccine. However, there are no documented instances following alternative vaccines. We report a case of a 48-year-old woman, previously vaccinated with Pfizer-BioNTech’s COVID-19 vaccine (BNT162b2), who subsequently received the Moderna mRNA-1273 vaccine. Within 2 days postvaccination, she developed diplopia and numbness in the lower limbs’ distal extremities. Cerebrospinal fluid analysis exhibited protein-cell dissociation, while F-wave studies showed demyelinating activity in the bilateral tibial nerves. Given the disease’s progressive nature, the patient was presumed to have CIDP and commenced steroid pulse therapy and intravenous immunoglobulin therapy. The onset of CIDP may be associated with variations in mRNA sequences and vaccine constituents.

Background: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), the most common form of hereditary cerebral small vessel disease (SVD), currently lacks disease-modifying treatments. Adrenomedullin (AM), a vasoactive peptide with angiogenic, vasodilatory, anti-inflammatory, and anti-oxidative properties, shows potential effects on the neuro-glial-vascular unit. Objective: The AdrenoMedullin for CADASIL (AMCAD) study aims to assess the efficacy and safety of AM in patients with CADASIL. Sample size: Overall, 60 patients will be recruited. Methods: The AMCAD is a multicenter, investigator-initiated, single-arm phase II trial. Patients with a confirmed CADASIL diagnosis, based on NOTCH3 genetic testing, will receive an 8-h AM treatment (15 ng/kg/min) for 14 days following a baseline assessment (from day 1 to day 14). Follow-up evaluations will be performed on days 15, 28, 90, and 180. Study outcomes: The primary endpoint is the cerebral blood flow change rate in the frontal cortex, evaluated using arterial spin labeling magnetic resonance imaging, from baseline to day 28. Summary statistics, 95% confidence intervals, and a one-sample t-test will be used for analysis. Conclusion: The AMCAD study aims to represent the therapeutic potential of AM in patients with CADASIL, addressing an unmet medical need in this challenging condition. Clinical Trial Registration: jRCT 2,051,210,117 (https://jrct.niph.go.jp/en-latest-detail/jRCT2051210117).

Abstract Background In this study, we developed a simple method for evaluating achievement degree of lung dose optimization in individual patients with locally advanced non‐small cell lung cancer (NSCLC) treated with intensity modulated radiotherapy (IMRT). Methods Data of 28 patients with stage IIB to IIIC NSCLC were retrospectively analyzed. All patients were treated with IMRT and a simulated three‐dimensional conformal radiotherapy (3D‐CRT) plan created for them. Dose‐volume parameters of lung were analyzed for their correlation with radiation pneumonitis (RP). Results Over a median follow‐up of 14 months, grade 1 pneumonitis was diagnosed in 14 patients (50%), grade 2 pneumonitis in 11 (39%), and grade 3 pneumonitis in one (4%). Two patients did not develop pneumonitis. None of the patients developed grade 4 or 5 pneumonitis. Regarding dose‐volume parameter ratios between IMRT and simulated 3D‐CRT, receiver operating characteristic analysis showed that mean lung dose (MLD)IMRT/MLD3D‐CRT had the largest area under curve (0.750). Cumulative 6‐month incidences of grade 2 or greater RP were 78.4% versus 19.5% (MLDIMRT/MLD3D‐CRT, ≥1.0 or less); this difference was significant (p

Abstract The aim of this study was to determine the impact at 5 years of sodium‐glucose cotransporter 2 inhibitor (SGLT2i) in nonalcoholic fatty liver disease (NAFLD) with type 2 diabetes mellitus (T2DM) on liver histopathology and clinical features. In this retrospective study, the histological impacts at 5 years after the start of SGLT2i in NAFLD with T2DM were investigated. Six patients with NAFLD and T2DM were treated for the long term with canagliflozin of SGLT2i, and liver biopsies were obtained at the points of the pretreatment, 24 weeks, 3 years, and 5 years after the start of treatment. The primary outcome was liver histopathological changes at 5 years (defined as decrease in NAFLD activity score of one point or more without worsening in fibrosis stage, compared with the pretreatment). The additional treatment of glucagon‐like peptide 1 receptor agonist (GLP‐1RA) was performed in 2 patients after the point of 3 years, and evaluated as histological worsening. As the primary outcome, histological improvement, no change, and worsening were 50%, 17%, and 33% at 5 years, respectively. Overall, the scores of steatosis, lobular inflammation, ballooning, and fibrosis stage decreased at 5 years in 67%, 33%, 0%, and 33%, respectively. As the secondary outcomes, homeostasis model assessment of insulin resistance and serum ferritin decreased significantly at 5 years. None developed 3‐point major adverse cardiovascular events. Two patients with the addition of GLP‐1RA on SGLT2i did not show the worsening of steatosis, ballooning, and fibrosis stage at 5 years compared with 3 years. Conclusion: A 5‐year follow‐up study with SGLT2i indicated the favorable histological impact on NAFLD with T2DM.

Abstract Background This retrospective study was performed to evaluate the efficacy and toxicity of high-dose stereotactic body radiotherapy (SBRT) using a CyberKnife® for patients with stage I peripheral non-small cell lung cancer (NSCLC). Methods Ninety-six patients with stage I peripheral NSCLC who were treated with SBRT using a CyberKnife® from August 2010 to June 2019 were identified and included in this study. Local control (LC), local progression-free survival (LPFS), progression-free survival (PFS), overall survival (OS), and late toxicity were evaluated. Potential risk factors associated with LC, LPFS, PFS, or OS were investigated by univariate analyses. Results Data of 96 patients were examined. The prescribed dose to the tumor was 54 Gy in 3 fractions in 91 patients and 60 Gy in 3 fractions in 5 patients. The median follow-up duration was 27 months. The 2-year LC, LPFS, PFS, and OS rates were 97%, 88%, 84%, and 90%, respectively. The T factor was significantly correlated with LC, LPFS, and PFS. The 2-year LC rate for patients with T1a/T1b and T1c/T2a disease was 100% and 90%, respectively (p

Background We investigated the impact of the p.R4810K variant of RNF213 (ring finger protein 213) gene, a susceptibility gene of moyamoya disease in East Asia, on the outer diameter of cervical parts of carotid and vertebral arteries (VAs). Methods We examined consecutive Japanese patients with ischemic stroke who underwent carotid ultrasonography between 2015 and 2019. Patient background and the carotid ultrasonography‐measured outer diameter of extracranial cervical arteries, including the common carotid artery, internal carotid artery, external carotid artery, and cervical VA, were compared between variant carriers and noncarriers. Outer diameters of each artery were defined as the mean distance from far to near wall adventitia of right and left target arteries using carotid ultrasonography. The average diameter of both cervical portions of common carotid arteries, internal carotid arteries, external carotid arteries, and the dominant side diameter of both cervical VAs were used. Results Of the 617 adult patients (204 women; median age, 74 years) analyzed, 26 (4.2%) carried the RNF213 p.R4810K variant. Variant carriers were significantly younger (P

Background We investigated the impact of the ring finger protein 213 p.R4810K variant, a founder variant for moyamoya disease in East Asians, on endovascular therapy outcomes in patients with acute anterior‐circulation large‐vessel occlusion stroke in comparison with noncarriers. Methods Of the consecutive patients with ischemic stroke admitted to our institute from 2011 to 2021, patients who underwent endovascular therapy for acute occlusion of the intracranial internal carotid artery or M1 segment of the middle cerebral artery were included. Outcomes were instant reocclusion, final modified Thrombolysis in Cerebral Infarction reperfusion ≥2b, and early reocclusion. Instant reocclusion was defined as the occurrence of reocclusion during the procedure, and early reocclusion was defined as reocclusion detected on magnetic resonance angiography within 2 weeks after the confirmation of successful reperfusion. Results Of the 277 patients analyzed (128 women; median age, 76 years), 10 patients (3.6%) carried the ring finger protein 213 p.R4810K variant. Variant carriers were younger (P=0.01) and more frequently had intracranial atherosclerotic disease‐related large‐vessel occlusion as a cause of acute large‐vessel occlusion (P

ABSTRACT Introduction: We evaluated the outcomes of the selective intercostal artery reconstruction for preventing spinal cord injury during thoracoabdominal aortic aneurysm repair. Methods: We retrospectively assessed 84 consecutive patients who underwent thoracoabdominal aortic aneurysm repairs between 2004 and 2016. The mean age of the patients was 57.3 years. We performed preoperative multidetector computed tomography in 74 patients (88.0%) to identify the Adamkiewicz artery. Spinal cord injury preventive measures included motor evoked potential monitoring, hypothermia induction, Adamkiewicz artery or other intercostal artery reconstruction, and cerebrospinal fluid drainage. Results: The hospital death rate was 5.9%, and paraplegia occurred in four patients (4.7%). The Adamkiewicz artery or other intercostal arteries were reconstructed selectively in 46 patients (54.7%). Of these patients, 41 underwent postoperative multidetector computed tomography, which revealed occlusion of the reconstructed grafts in 23 patients (56.0%). There was no paraplegia in the patients who underwent reconstruction of the Adamkiewicz artery, which was patent on postoperative multidetector computed tomography. Univariate analysis showed no significant effect of various risk factors on the development of spinal cord injury. Conclusion: Outcome of open surgery for thoracoabdominal aortic aneurysm in our institution regarding spinal cord injury was satisfactory. The benefits of Adamkiewicz artery reconstruction remain inconclusive, and further larger studies are required to identify its validation for spinal cord protection in thoracoabdominal aortic aneurysm repair.

Type 2 diabetes mellitus is associated with an increased risk of dementia, potentially through multifactorial pathologies, including neuroinflammation. Therefore, there is a need to identify novel agents that can suppress neuroinflammation and prevent cognitive impairment in diabetes. In the present study, we demonstrated that a high-glucose (HG) environment elevates the intracellular reactive oxygen species (ROS) levels and triggers inflammatory responses in the mouse microglial cell line BV-2. We further found that thioredoxin-interacting protein (TXNIP), a ROS-responsive positive regulator of the nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, was also upregulated, followed by NLRP3 inflammasome activation and subsequent interleukin-1beta (IL-1β) production in these cells. Conversely, caspase-1 was not significantly activated, suggesting the involvement of noncanonical pathways in these inflammatory responses. Moreover, our results demonstrated that taxifolin, a natural flavonoid with antioxidant and radical scavenging activities, suppressed IL-1β production by reducing the intracellular ROS levels and inhibiting the activation of the TXNIP–NLRP3 axis. These findings suggest the novel anti-inflammatory effects of taxifolin on microglia in an HG environment, which could help develop novel strategies for suppressing neuroinflammation in diabetes.

Abstract We investigated the potential of mid-regional pro-adrenomedullin (MR-proADM) for use as a novel biomarker for arterial stiffness as the criterion for vascular failure and cardiometabolic disease (obesity, hypertension, dyslipidemia, diabetes, and metabolic syndrome) compared with high-sensitivity C-reactive protein (hsCRP). Overall, 2169 individuals (702 men and 1467 women) were enrolled. Multiple regression analysis was performed to assess the association of MR-proADM and hsCRP with brachial-ankle pulse wave velocity (baPWV), adjusting for other variables. The diagnostic performance (accuracy) of MR-proADM with regard to the index of vascular failure was tested with the help of receiver operating characteristic curve analysis in the models. MR-proADM was significantly higher in participants with vascular failure, as defined by baPWV and/or its risk factors (obesity, hypertension, dyslipidemia, diabetes, and metabolic syndrome), than in control groups. Independent of cardiovascular risk factors (age, drinking, smoking, body mass index, systolic blood pressure, lipid and glycol metabolism), MR-proADM was significantly associated with baPWV, and MR-proADM showed higher areas under the curve of baPWV than hsCRP showed. MR-proADM is more suitable for the diagnosis of higher arterial stiffness as the criterion for vascular failure than hsCRP. Because vascular assessment is important to mitigate the most significant modifiable cardiovascular risk factors, MR-proADM may be useful as a novel biomarker on routine blood examination.

IntroductionThe role of commensal microbiota in systemic diseases, including brain diseases, has attracted increasing attention. Oral infectious diseases, such as dental caries and periodontitis, are also involved in cerebrovascular diseases and cognitive impairment. Cerebral microbleeds (CMBs) and intracerebral hemorrhage due to small vessel disease (SVD), are presumably associated with a high risk of vascular cognitive impairment and stroke. We previously reported that Streptococcus mutans (S. mutans, the main pathogen of dental caries), harboring the cnm gene that encodes the collagen-binding protein Cnm, is associated with the development of hypertensive intracerebral hemorrhage and aggravation of CMBs. We also proposed a mechanism by which the circulating Cnm-expressing S. mutans causes intracerebral hemorrhage or CMBs; it binds to denuded basement membranes mainly composed of collagen IV through damaged tight junctions or it directly invades endothelial cells, resulting in blood-brain barrier injury. In November 2018, we initiated a multicenter, prospective cohort study (RAMESSES: Risk Assessment of Cnm-positive S. mutans in Stroke Survivors; UMIN Clinical Trials Registry: UMIN000045559) to explore the longitudinal association between Cnm-positive S. mutans and CMBs with comprehensive dental findings, which should determine the effect of Cnm-positive S. mutans in the oral cavity on the risk of CMB development and cognitive decline.MethodsFifteen domestic institutes will be enlisted to enroll 230 patients who have at least one CMB in the deep brain area and develop a stroke within the past year. The prevalence of Cnm-positive S. mutans based on oral specimens and dental hygiene will be examined. The primary outcome is the number of newly developed deep CMBs. The secondary outcomes include the new development of lobar, subtentorial, or any type of CMBs; symptomatic intracerebral hemorrhage or ischemic stroke; changes in cognitive function or frailty; major bleeding; all-cause mortality; and antibody titers against periodontal pathogens. The observation period will be 2 years.DiscussionThe 2-year longitudinal prospective cohort study is expected to establish the role of Cnm-positive S. mutans in SVD including CMBs and intracerebral hemorrhage from the perspective of the “brain-oral axis” and provide guidance for novel prophylactic strategies against Cnm-positive S. mutans-induced SVD.

Abstract Background The prognostic factors of morbidity and mortality in patients with lean NAFLD (body mass index

Abstract White matter hyperintensities (WMH) occur in association with dementia but the aetiology is unclear. Here we test the hypothesis that there is a combination of impaired elimination of interstitial fluid from the white matter together with a degree of hypoxia in WMH. One of the mechanisms for the elimination of amyloid-β (Aβ) from the brain is along the basement membranes in the walls of capillaries and arteries (Intramural Peri-Arterial Drainage – IPAD). We compared the dynamics of IPAD in the grey matter of the hippocampus and in the white matter of the corpus callosum in 10 week old C57/B16 mice by injecting soluble Aβ as a tracer. The dynamics of IPAD in the white matter were significantly slower compared with the grey matter and this was associated with a lower density of capillaries in the white matter. Exposing cultures of smooth muscle cells to hypercapnia as a model of cerebral hypoperfusion resulted in a reduction in fibronectin and an increase in laminin in the extracellular matrix. Similar changes were detected in the white matter in human WMH suggesting that hypercapnia/hypoxia may play a role in WMH. Employing therapies to enhance both IPAD and blood flow in the white matter may reduce WMH in patients with dementia.

Background and purpose: We investigated the incidence and dose-volume relationships of radiation pneumonitis (RP) after concurrent chemoradiotherapy (CCRT) followed by durvalumab for locally advanced non-small-cell lung cancer (LA-NSCLC). Materials and methods: We retrospectively analyzed records of 36 patients with LA-NSCLC who underwent CCRT followed by durvalumab. Incidence of RP was analyzed for correlations with clinical factors and dose-volume parameters of lung in radiotherapy. Results: All patients received 60 Gy in 30 fractions of radiotherapy with concurrent chemotherapy. Over a median follow-up period of 7 months, incidence of grade ≥2 RP was 36% (including grade 3 RP: 5% and grade 5 RP: 3%). Age, sex, Brinkman index, and blood test results did not significantly differ between patients with grade ≥2 RP and grade ≤1 RP. Dose-volume parameters (lung volumes that received 5 Gy, 10 Gy, 20 Gy, 30 Gy, 40 Gy, 50 Gy, and mean lung dose) were significantly higher among patients with grade ≥2 RP compared with patients with grade ≤1 RP. Conclusion: Incidence of grade ≥2 RP was 36% after CCRT followed by durvalumab for LA-NSCLC, but did not significantly differ from those of patients treated with CCRT alone. Lung dose-volume parameters were significantly correlated with RP.

Primary cardiac tumors are unusual, whereas lipomas are particularly rare. We successfully removed a very large posterior cardiac lipoma by transecting the ascending aorta and main pulmonary artery. Transecting both the ascending aorta and the main pulmonary artery facilitated surgical exposure and complete removal of the posterior cardiac lipoma.

The molecular pathogenesis of nonalcoholic steatohepatitis (NASH) includes a complex interaction of metabolic stress and inflammatory stimuli. Considering the therapeutic goals of NASH, it is important to determine whether the treatment can prevent the progression from NASH to hepatocellular carcinoma. Taxifolin, also known as dihydroquercetin, is a natural bioactive flavonoid with antioxidant and anti-inflammatory properties commonly found in various foods and health supplement products. In this study, we demonstrated that Taxifolin treatment markedly prevented the development of hepatic steatosis, chronic inflammation, and liver fibrosis in a murine model of NASH. Its mechanisms include a direct action on hepatocytes to inhibit lipid accumulation. Taxifolin also increased brown adipose tissue activity and suppressed body weight gain through at least two distinct pathways: direct action on brown adipocytes and indirect action via fibroblast growth factor 21 production in the liver. Notably, the Taxifolin treatment after NASH development could effectively prevent the development of liver tumors. Collectively, this study provides evidence that Taxifolin shows pleiotropic effects for the treatment of the NASH continuum. Our data also provide insight into the novel mechanisms of action of Taxifolin, which has been widely used as a health supplement with high safety.

Introduction: The ring finger protein 213 gene (RNF213) has been identified as a susceptibility gene for moyamoya disease, and the p.R4810K polymorphism as a founder variant commonly found in East Asian patients. 1 A recent large case‐control study including over 46,958 Japanese subjects reported that the RNF213 p.R4810K variant was a strong risk factor for Japanese cerebral infarction: the variant was found in 5.2% of patients with non‐cardioembolic stroke and in 2.1% of healthy controls. 2 Mechanical thrombectomy (MT) is a standard treatment for acute ischemic stroke due to occlusion of the internal carotid artery and M1 segment of the middle cerebral artery, but in East Asians, about 15–25% of LVOs for which MT was performed were reportedly caused by intracranial atherosclerotic disease (ICAD). 3 RNF213 p.R4810K variant may be involved to some extent in ICAD‐related LVO of Asian patients undergoing MT. In this study, we aimed to investigate the impact of RNF213 p.R4810K variant on EVT for anterior circulation LVO stroke. Methods: Of the consecutive ischemic stroke patients from 2011 to 2021 seen in our institute, patients who underwent EVT for acute occlusion of the intracranial ICA or M1 segment of MCA and signed a consent form for RNF213 genotyping were included. Outcomes were instant re‐occlusion, final modified Thrombolysis in Cerebral Infarction (mTICI) ≥2b reperfusion, early re‐occlusion, and modified Rankin Scale (mRS) score 0–2 at 90 days. Instant re‐occlusion was defined as occurrence of re‐occlusion during the procedure, whereas early re‐occlusion as re‐occlusion detected on magnetic resonance angiography within 2 weeks after confirmation of successful reperfusion at the end of the procedure. 4 Results: Of the 277 patients (128 women [46.2%]; median age, 76 years) analyzed, 10 (3.6%) patients had the RNF213 p.R4810K variant. The variant carriers were younger (67 years vs. 76 years, P

The rate of dementia continues to increase worldwide; however, there currently exist no therapeutic strategies for this condition [...]

IntroductionDysregulation of the RING finger protein 213 (RNF213) gene impairs vascular formation in experimental animal models. In addition, vascular abnormalities in the circle of Willis are associated with cerebrovascular disease. Here, we evaluated the relationship between the East Asian founder variant RNF213 p.R4810K and consequent anatomical variations in the circle of Willis in cerebrovascular disease.Patients and MethodsThe present study is an observational cross-sectional study. It included patients with acute anterior circulation non-cardioembolic stroke admitted to our institution within 7 days of symptom onset or last-known-well from 2011 to 2019, and those who participated in the National Cerebral and Cardiovascular Center Biobank. We compared anatomical variations of the vessels constituting the circle of Willis between RNF213 p.R4810K (c.14429G > A) variant carriers and non-carriers using magnetic resonance angiography and assessed the association between the variants and the presence of the vessels constituting the circle of Willis. Patients with moyamoya disease were excluded.ResultsFour hundred eighty-one patients [146 women (30%); median age 70 years; median baseline National Institutes of Health Stroke Scale score 5] were analyzed. The RNF213 p.R4810K variant carriers (n = 25) were more likely to have both posterior communicating arteries (PComAs) than the variant non-carriers (n = 456) (56% vs. 13%, P < 0.01). Furthermore, variant carriers were less likely to have an anterior communicating artery (AComA) than non-carriers (68% vs. 84%, P = 0.04). In a multivariate logistic regression analysis, the association of RNF213 p.R4810K variant carriers with the presence of both PComAs and the absence of AComA remained significant.ConclusionOur findings suggest that the RNF213 p.R4810K variant is an important factor in determining anatomical variations in the circle of Willis.

Cerebral amyloid angiopathy (CAA) is characterized by the accumulation of β-amyloid (Aβ) in the walls of cerebral vessels, leading to complications such as intracerebral hemorrhage, convexity subarachnoid hemorrhage and cerebral microinfarcts. Patients with CAA-related intracerebral hemorrhage are more likely to develop dementia and strokes. Several pathological investigations have demonstrated that more than 90% of Alzheimer’s disease patients have concomitant CAA, suggesting common pathogenic mechanisms. Potential causes of CAA include impaired Aβ clearance from the brain through the intramural periarterial drainage (IPAD) system. Conversely, CAA causes restriction of IPAD, limiting clearance. Early intervention in CAA could thus prevent Alzheimer’s disease progression. Growing evidence has suggested Taxifolin (dihydroquercetin) could be used as an effective therapy for CAA. Taxifolin is a plant flavonoid, widely available as a health supplement product, which has been demonstrated to exhibit anti-oxidative and anti-inflammatory effects, and provide protection against advanced glycation end products and mitochondrial damage. It has also been shown to facilitate disassembly, prevent oligomer formation and increase clearance of Aβ in a mouse model of CAA. Disturbed cerebrovascular reactivity and spatial reference memory impairment in CAA are completely prevented by Taxifolin treatment. These results highlight the need for clinical trials on the efficacy and safety of Taxifolin in patients with CAA

Adrenomedullin (AM) is an endogenous peptide mainly secreted from endothelial cells, which has multiple physiological actions such as anti-inflammation, vasodilation, vascular permeability regulation and angiogenesis. Blood AM levels are upregulated in a variety of pathological states including sepsis, severe COVID-19, acute ischemic stroke and vascular cognitive impairment with white matter changes, likely serving as a compensatory biological defense response against infection and ischemia. AM is currently being tested in clinical trials for ulcerative colitis, Crohn's disease, severe COVID-19 for its anti-inflammatory properties and in ischemic stroke for its additional angiogenic action. AM has been proposed as a therapeutic option for vascular cognitive impairment as its arteriogenic and angiogenic properties are thought to contribute to a slowing of cognitive decline in mice after chronic cerebral hypoperfusion. As AM promotes differentiation of oligodendrocyte precursor cells into mature oligodendrocytes under hypoxic conditions, AM could also be used in the treatment of CADASIL, where reduced oxygen delivery is thought to lead to the death of hypoxia-prone oligodendrocytes. AM therefore holds potential as an innovative therapeutic drug, which may regenerate blood vessels, while controlling inflammation in cerebrovascular diseases.

Abstract Introduction Cilostazol may be a novel therapeutic agent for Alzheimer's disease. Its metabolite, OPC‐13015, has a stronger inhibitory effect on type 3 phosphodiesterase than cilostazol. Methods We prospectively enrolled patients with mild cognitive impairment to whom cilostazol was newly prescribed. Patients underwent the Montreal Cognitive Assessment (MoCA) twice, at a 6‐month interval. Plasma cilostazol, OPC‐13015, OPC‐13213, and OPC‐13217 concentrations were determined using liquid chromatography‐tandem mass spectrometry. Results MoCA score changes from baseline to the 6‐month visit were positively correlated with ratios of OPC‐13015 to cilostazol and total metabolites (n = 19, P = .005). Patients with higher ratios of OPC‐13015 (≥0.18, median value; n = 10) had significantly higher MoCA scores (P = .036) than patients with lower ratios (the ratio

A 51-year-old man with type 2 diabetes mellitus was admitted with a 2-month history of repeated episodes of transient aphasia and right hemiparesis after food intake. His blood pressure (BP) fell when the neurological deficits developed. The fall in BP after each meal was confirmed by 24-h ambulatory blood pressure monitoring (ABPM), which established the diagnosis of postprandial hypotension (PPH). Diffusion-weighted magnetic resonance imaging of the brain showed multiple high-intensity lesions at the borderzone between the anterior and middle cerebral artery (MCA) territories in the left hemisphere. Digital subtraction angiography showed tapered occlusion at the origin of the left internal carotid artery (ICA). Despite sufficient antiplatelet therapy and medication for PPH, the transient symptoms remained. Positron emission tomography scanning using H215O showed decreased cerebral blood flow with increased oxygen extraction fraction in the left MCA territory. As the symptomatic left ICA occlusion was intractable, an extracranial-intracranial (EC-IC) bypass surgery was conducted without any perioperative complications. Although PPH remained, cerebrovascular ischemic events including repeated transient ischemic attack disappeared for 2 months after surgery. The coincidence of stroke with ABPM-proved transient hypotension suggested that the brain infarcts were caused by hemodynamic changes related to PPH co-existent with the chronic left ICA occlusion. ABPM is useful in evaluating hemodynamic infarcts associated with BP fluctuation, and should be considered for patients with chronic ICA occlusion. In addition, EC-IC bypass may be a treatment option for symptomatic chronic ICA occlusion due to PPH.

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Cerebral amyloid angiopathy (CAA) is characterised by the progressive accumulation of β-amyloid (Aβ) in the walls of cerebral capillaries and arteries representing a major cause of haemorrhagic stroke including lobar intracerebral haemorrhage (ICH) and convexity subarachnoid haemorrhage (SAH). Haemorrhaging from CAA predominantly involves smaller arteries rather than arterial aneurysm. Restricted bleeding into the subarachnoid space in CAA results in asymptomatic or mild symptomatic SAH. Herein, we present an autopsied case of massive SAH related to CAA. An 89-year-old male with a history of mild Alzheimer’s disease (AD) and advanced pancreatic cancer with liver metastasis developed sudden onset of coma. Head CT illustrated ICH located in the right frontal lobe and right insula, as well as SAH bilaterally spreading from the basal cistern to the Sylvian fissure, with hydrocephalus and brain herniation. He died about 24 h after onset and the post-mortem examination showed no evidence of arterial aneurysm. The substantial accumulation of Aβ in the vessels around the haemorrhagic lesions led to the diagnosis of ICH related to CAA and secondary SAH, which may have been aggravated by old age and malignancy. This case suggests that CAA can cause severe SAH resembling aneurysmal origin and thus may be overlooked when complicated by atypical cerebral haemorrhage.

ObjectivesClinical characteristics of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) include migraine, recurrent stroke, white matter lesions, and vascular dementia. CADASIL is one of the most common hereditary cerebral small vessel diseases. Clinical presentation of CADASIL varies and a racial gap may exist between the Asian and Caucasian populations. This is the first nationwide epidemiological survey which aimed to elucidate the clinical features of CADASIL in Japan. Moreover, the registration database of CADASIL was constructed.MethodsSubjects included CADASIL patients who visited the hospitals (totally 1,448 hospitals) certified by the Japanese Society of Neurology and/or Japan Stroke Society in 2016. This study consisted of a two-step survey; patients with CADASIL were identified genetically by the first questionnaire, and their clinical features were assessed by the second questionnaire. Selected 6 hospitals registered the data of all CADASIL patients using a Research Electronic Data Capture (REDCap) system for the second questionnaire.ResultsBased on the criteria, 88 patients (50 male and 38 female) with CADASIL were enrolled. The mean age of symptom onset was 49.5 years. Sixteen (18.2%) patients had an elderly onset (>60 years). Thirteen patients (13.6%) had history of migraine with aura and 33 patients (37.5%) had vascular risk factor(s). From among the 86 patients who were examined using magnetic resonance imaging, abnormal deep white matter lesions were detected in 85 patients (98.8%), WMLs extending to anterior temporal pole in 73 patients (84.9%), and cerebral microbleeds in 41 patients (47.7%). Anti-platelet therapy was received by 65 patients (73.9%). Thirty-eight patients (43.2%) underwent treatment with lomerizine hydrochloride. Thirty-four different mutations of NOTCH3 were found in exons 2, 3, 4, 5, 6, 8, 11, 14, and 19. Most of the mutations existed in exon 4 (n = 44, 60.3%). The prevalence rate of CADASIL was 1.20 to 3.58 per 100,000 adults in Japan.ConclusionThis questionnaire-based study revealed clinical features and treatment status in Japanese CADASIL patient, although it may not be an exhaustive search. We have constructed the REDCap database for these CADASIL patients.

Objectives: Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common hereditary small vessel disease, with reported frequencies of 2-5/100,000 individuals. Recently, it has been reported that some patients with NOTCH3 gene mutations show atypical clinical symptoms of CADASIL. Assuming that CADASIL is underdiagnosed in some cases of lacunar infarction, this study was designed to examine the prevalence of NOTCH3 gene mutations in the patients at highest risk who were admitted for lacunar infarctions.Methods: From January 2011 to April 2018, 1,094 patients with lacunar infarctions were admitted to our hospital, of whom 31 patients without hypertension but with white matter disease (Fazekas scale 2 or 3) were selected and genetically analyzed for NOTCH3 gene mutations (Phase 1). Furthermore, 54 patients, who were 60 years or younger, were analyzed for NOTCH3 mutations (Phase 2). NOTCH3 exons 2–24, which encode the epidermal growth factor-like repeat domain of the NOTCH3 receptor, were analyzed for mutations by direct sequencing of genomic DNA.Results: Three patients presented NOTCH3 p.R75P mutations: two in the Phase 1 and one in the Phase 2 cohort. Among patients aged 60 years or younger and those without hypertension but with moderate-to-severe white matter lesions, the carrier frequency of p.R75P was 3.5% (3/85), which was significantly higher than that in the Japanese general population (4.7KJPN) (odds ratio [95% CI] = 58.2 [11.6–292.5]). All three patients with NOTCH3 mutations had family histories of stroke, and the average patient age was 51.3 years. All three patients also showed white matter lesions in the external capsule but not in the temporal pole. The CADASIL and CADASIL scale-J scores of the three patients were 6, 17, 7 (mean, 10.0) and 13, 20, 10 (mean, 14.3), respectively.Conclusion: Among patients hospitalized for lacunar infarctions, the p.R75P prevalence may be higher than previously estimated. The NOTCH3 p.R75P mutation may be underdiagnosed in patients with early-onset lacunar infarctions due to the atypical clinical and neuroimaging features of CADASIL. Early-onset, presence of family history of stroke, external capsule lesions, and absence of hypertension may help predict underlying NOTCH3 mutations despite no temporal white matter lesions.

People with Down syndrome, which is a trisomy of chromosome 21, exhibit intellectual disability from infancy and neuropathology similar to Alzheimer’s disease, such as amyloid plaques, from an early age. Recently, we showed that cilostazol, a selective inhibitor of phosphodiesterase (PDE) 3, promotes the clearance of amyloid β and rescues cognitive deficits in a mouse model of Alzheimer’s disease. The objective of the present study was to examine whether cilostazol improves behaviors in the most widely used animal model of Down syndrome, i.e., Ts65Dn mice. Mice were supplemented with cilostazol from the fetal period until young adulthood. Supplementation significantly ameliorated novel-object recognition in Ts65Dn females and partially ameliorated sensorimotor function as determined by the rotarod test in Ts65Dn females and hyperactive locomotion in Ts65Dn males. Cilostazol supplementation significantly shortened swimming distance in Ts65Dn males in the Morris water maze test, suggesting that the drug improved cognitive function, although it did not shorten swimming duration, which was due to decreased swimming speed. Thus, this study suggests that early supplementation with cilostazol partially rescues behavioral abnormalities seen in Down syndrome and indicates that the effects are sex-dependent.

Abstract Two of the key functions of arteries in the brain are (1) the well‐recognized supply of blood via the vascular lumen and (2) the emerging role for the arterial walls as routes for the elimination of interstitial fluid (ISF) and soluble metabolites, such as amyloid beta (Aβ), from the brain and retina. As the brain and retina possess no conventional lymphatic vessels, fluid drainage toward peripheral lymph nodes is mediated via transport along basement membranes in the walls of capillaries and arteries that form the intramural peri‐arterial drainage (IPAD) system. IPAD tends to fail as arteries age but the mechanisms underlying the failure are unclear. In some people this is reflected in the accumulation of Aβ plaques in the brain in Alzheimer's disease (AD) and deposition of Aβ within artery walls as cerebral amyloid angiopathy (CAA). Knowledge of the dynamics of IPAD and why it fails with age is essential for establishing diagnostic tests for the early stages of the disease and for devising therapies that promote the clearance of Aβ in the prevention and treatment of AD and CAA. This editorial is intended to introduce the rationale that has led to the establishment of the Clearance of Interstitial Fluid (ISF) and CSF (CLIC) group, within the Vascular Professional Interest Area of the Alzheimer's Association International Society to Advance Alzheimer's Research and Treatment.

Abstract RNF213 is a susceptibility gene for moyamoya disease, yet its exact functions remain unclear. To evaluate the role of RNF213 in adaptation of cerebral blood flow (CBF) under cerebral hypoperfusion, we performed bilateral common carotid artery stenosis surgery using external microcoils on Rnf213 knockout (KO) and vascular endothelial cell-specific Rnf213 mutant (human p.R4810K orthologue) transgenic (EC-Tg) mice. Temporal CBF changes were measured by arterial spin-labelling magnetic resonance imaging. In the cortical area, no significant difference in CBF was found before surgery between the genotypes. Three of eight (37.5%) KO mice died after surgery but all wild-type and EC-Tg mice survived hypoperfusion. KO mice had a significantly more severe reduction in CBF on day 7 than wild-type mice (KO, 29.7% of baseline level; wild-type, 49.3%; p = 0.038), while CBF restoration on day 28 was significantly impaired in both KO (50.0%) and EC-Tg (56.1%) mice compared with wild-type mice (69.5%; p = 0.031 and 0.037, respectively). Changes in the subcortical area also showed the same tendency as the cortical area. Additionally, histological analysis demonstrated that angiogenesis was impaired in both EC-Tg and KO mice. These results are indicative of the essential role of RNF213 in the maintenance of CBF.

As climate change progresses, it is becoming more crucial to understand how timber species respond to increased drought frequency and severity. Photosynthetic traits in a 40-year-old clonal Japanese cedar (Cryptomeria japonica) plantation were assessed under artificial drought stress using a roof to exclude rainfall and a control with no exclusion. C. japonica is a commercial tree that is native to Japan and has high growth on mesic sites. The maximum carboxylation rate (Vcmax), maximum electron transfer rate (Jmax), and dark respiration rate (Rd) in current-year shoots in the upper canopy were determined from spring to autumn over two growing seasons. In addition, the photosynthetic rate at light saturation (Pmax), stomatal conductance (gs), and intrinsic water use efficiency (WUEi) were measured in the morning and afternoon during the same period. Leaf mass per unit area (LMA) and nitrogen concentration (N) were also measured. The values of Vcmax, Jmax, Rd, N, and LMA did not differ between the two plots. By contrast, significantly lower Pmax and gs and higher WUEi were found in the drought plot, and the reduction in Pmax was accompanied by low gs values. Midday depressions in Pmax and gs were more pronounced in the drought plot relative to the control and were related to higher WUEi. Under drought conditions, mature Japanese cedar experienced little change in photosynthetic capacity, foliar N, or LMA, but they did tend to close the stomata to regulate transpiration, thus avoiding drought-induced damage to the photosynthetic machinery and improving WUEi.

Abstract Deficits in the integration of motor prediction and its feedback have been reported in Parkinson’s disease. Conscious awareness of action is proposed to emerge under the integration of motor prediction and its feedback. Thus, it may lead to changes in the awareness of the authorship of action (in other words, the sense of agency) in Parkinson’s disease. We have employed both explicit and implicit measures to assess the awareness of action in Parkinson’s disease and matched controls. As an explicit measure, an action recognition task requiring explicit judgments was used. Patients showed less attribution of their movements to non-biased and angular-biased visual feedbacks. As an implicit measure, the temporal attraction between the perceived time of actions and their effects, which is known as intentional binding task, was used. While action-effect association was observed in the control group, actions were not experienced as having shifted towards their subsequent effects in the patient group. These tendencies were consistent regardless of the side of the asymmetrical motor symptoms. These results may reflect an underlying abnormality in the awareness of voluntary action in Parkinson’s disease.

Abstract Cerebral amyloid angiopathy (CAA) induces various forms of cerebral infarcts and hemorrhages from vascular amyloid-β accumulation, resulting in acceleration of cognitive impairment, which is currently untreatable. Soluble amyloid-β protein likely impairs cerebrovascular integrity as well as cognitive function in early stage Alzheimer’s disease. Taxifolin, a flavonol with strong anti-oxidative and anti-glycation activities, has been reported to disassemble amyloid-β in vitro but the in vivo relevance remains unknown. Here, we investigated whether taxifolin has therapeutic potential in attenuating CAA, hypothesizing that inhibiting amyloid-β assembly may facilitate its clearance through several elimination pathways. Vehicle- or taxifolin-treated Tg-SwDI mice (commonly used to model CAA) were used in this investigation. Cognitive and cerebrovascular function, as well as the solubility and oligomerization of brain amyloid-β proteins, were investigated. Spatial reference memory was assessed by water maze test. Cerebral blood flow was measured with laser speckle flowmetry and cerebrovascular reactivity evaluated by monitoring cerebral blood flow changes in response to hypercapnia. Significantly reduced cerebrovascular pan-amyloid-β and amyloid-β1-40 accumulation was found in taxifolin-treated Tg-SwDI mice compared to vehicle-treated counterparts (n = 5). Spatial reference memory was severely impaired in vehicle-treated Tg-SwDI mice but normalized after taxifolin treatment, with scoring similar to wild type mice (n = 10–17). Furthermore, taxifolin completely restored decreased cerebral blood flow and cerebrovascular reactivity in Tg-SwDI mice (n = 4–6). An in vitro thioflavin-T assay showed taxifolin treatment resulted in efficient inhibition of amyloid-β1-40 assembly. In addition, a filter trap assay and ELISA showed Tg-SwDI mouse brain homogenates exhibited significantly reduced levels of amyloid-β oligomers in vivo after taxifolin treatment (n = 4–5), suggesting the effects of taxifolin on CAA are attributable to the inhibition of amyloid-β oligomer formation. In conclusion, taxifolin prevents amyloid-β oligomer assembly and fully sustains cognitive and cerebrovascular function in a CAA model mice. Taxifolin thus appears a promising therapeutic approach for CAA.

22q11.2 heterozygous multigene deletions confer an increased risk of schizophrenia with marked impairment of cognition. We explored whether genes on 22q11.2 are associated with cognitive performance in patients with idiopathic schizophrenia. A total of 240 schizophrenia patients and 240 healthy controls underwent the Japanese-language version of the Brief Assessment of Cognition in Schizophrenia (BACS) and were genotyped for 115 tag single-nucleotide polymorphisms (tag SNPs) at the 22q11.2 region using the golden gate assay (Illumina®). Associations between z-scores of the BACS cognitive domains and SNPs and haplotypes were analyzed using linear regression in PLINK 1.07. An additional set of 149 patients with bipolar disorder were included for cognitive assessment and selected SNPs were genotyped using real-time PCR. Patients with schizophrenia and bipolar disorder showed qualitatively comparable profiles of cognitive impairment across BACS subdomains, as revealed by significant correlation between the two groups in the resulting cognitive effect sizes relative to controls. rs4819522 (TBX1) and rs2238769 (UFD1L) were significantly and nominally associated, respectively, with symbol coding in patients with schizophrenia. Haplotype analyses revealed that haplotypes containing the A allele at rs4819522 and G allele at rs2238769 showed significant negative associations with symbol coding in patients with schizophrenia. There was no effect of any haplotypes on cognition in patients with bipolar disorder. Our results have implications for the understanding of the role of haplotypes of UFD1L and TBX1 genes associated with symbol coding in patients with schizophrenia. Further replication studies in a cohort of newly diagnosed patients and other ethnicities are warranted. Keywords: Schizophrenia, 22q11.2, TBX1, UFD1L, BACS, Symbol coding

Recent advances in vascular risk management have successfully reduced the prevalence of Alzheimer's Disease (AD) in several epidemiologic investigations. It is now widely accepted that cerebrovascular disease is both directly and indirectly involved in AD pathogenesis. Herein, we review the non-pharmacological and pharmacological therapeutic approaches for AD treatment. MIND [Mediterranean and DASH (Dietary Approaches to Stop Hypertension) Intervention for Neurodegenerative Delay] diet is an important dietary treatment for prevention of AD. Multi domain intervention including diet, exercise, cognitive training, and intensive risk managements also prevented cognitive decline in the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) study. To confirm these favorable effects of life-style intervention, replica studies are being planned worldwide. Promotion of β-amyloid (Aβ) clearance has emerged as a promising pharmacological approach because insufficient removal of Aβ is more important than excessive Aβ production in the pathogenesis of the majority of AD patients. Most AD brains exhibit accompanying cerebral amyloid angiopathy, and Aβ distribution in cerebral amyloid angiopathy closely corresponds with the intramural periarterial drainage (IPAD) route, emphasizing the importance of Aβ clearance. In view of these facts, promotion of the major vascular-mediated Aβ elimination systems, including capillary transcytosis, the glymphatic system, and IPAD, have emerged as new treatment strategies in AD. In particular, the beneficial effects of cilostazol were shown in several clinical observation studies, and cilostazol facilitated IPAD in a rodent AD model. The COMCID (Cilostazol for prevention of Conversion from MCI to Dementia) trial, evaluating the efficacy of cilostazol for patients with mild cognitive impairment is currently ongoing in Japan. Such therapeutic approaches involving maintenance of cerebrovascular integrity and promotion of vascular-mediated Aβ clearance have the potential to be mainstream treatments for sporadic AD.

In recent years, attention has been focused on woody biomass energy from the viewpoint of reducing environmental burden and effective use of local energy resources. However, the knowledge concerning the drying of the wood which becomes the fuel is poor, and it depends on the experience of the technician. Therefore, it is beneficial to develop a method that can obtain optimum drying and combustion conditions. However, in the drying process, complicated phenomena must be considered, and analysis of the drying process is difficult. In this study, we focused attention on the viewpoint of heat transfer considering evaporation. To establish a simple analysis method of the drying process, a heat transfer analysis program modeling the drying of wood balls containing moisture was created and analyzed. An experimental apparatus was also fabricated, and a dry experiment of filling wood ball group containing moisture was carried out. Numerical analysis of the temperature responses of spheres and air currents when hot air is flowed through a filled wooden group containing moisture and the drying process of the filled wood ball group was investigated. We compared the numerical analysis results obtained from the simulation with the temperature response characteristics by experiments on wood balls. In addition to investigating the validity of the simulation, the predictability of the dry completion time was evaluated.

A 34-year-old woman was diagnosed with acute promyelocytic leukemia. Chemotherapy was administered following the JALSG APL204 protocol. Induction therapy with all-trans retinoic acid resulted in complete remission on day 49. She developed coccygeal pain from day 18, which spread to the spine and cheekbones and lasted 5 weeks. She had similar bone pain on days 7–10 of the first consolidation therapy and on days 4–12 of the second consolidation therapy. Oral loxoprofen was prescribed for pain relief. On day 33 of the third consolidation, white blood cell and neutrophil counts were 320/μL and 20/μL, respectively. After she developed epigastralgia and hematemesis, she developed septic shock. Gastroendoscopy revealed markedly thickened folds and diffusely damaged mucosa with blood oozing. Computed tomography revealed thickened walls of the antrum and the pylorus. Despite emergency treatments, she died. Bacterial culture of the gastric fluid yielded Enterobacter cloacae and enterococci growth. Collectively, she was diagnosed with phlegmonous gastritis. Retrospective examination of serial bone marrow biopsy specimens demonstrated progressive bone marrow fibrosis, which may have caused prolonged myelosuppression. Thus, evaluation of bone marrow fibrosis by bone marrow biopsy after each treatment cycle might serve as a predictor of persistent myelosuppression induced by chemotherapy.

Back ground: Theoretical investigations predicting the epidemic curves of seasonal influenza have been demonstrated so far; however, there is little empirical research using ever accumulated epidemic curves. The effects of vaccine coverage and information distribution on influenza epidemics were evaluated. Materials and Methods: Four indices for epidemics (i.e., onset-peak duration, onset-end duration, ratio of the onset-peak duration to onset-end duration and steepness of epidemic curves) were defined, and the correlations between these indices and anti-flu drug prescription dose, vaccine coverage, the volume of media and search trend on influenza through internet were analyzed. Epidemiological data on seasonal influenza epidemics from 2002/2003 to 2013/2014 excluding 2009/2010 season were collected from National Institute of Infectious Diseases of Japan. Results: The onset-peak duration and its ratio to onset-end duration correlated inversely with the volume of anti-flu drug prescription. Onset-peak duration correlated positively with media information volume on influenza. The steepness of the epidemic curve, and anti-flu drug prescription dose inversely correlated with the volume of media information. Pre-epidemic search trend and media volume on influenza correlated with the vaccine coverage in the season. Vaccine coverage had no strong effect on epidemic curve. Conclusion: Education through media has an effect on the epidemic curve of seasonal influenza.

Aims: Cerebral amyloid angiopathy (CAA) is the accumulation of amyloid beta (Aβ) in the walls of cerebral arterioles, arteries and capillaries. Changes in the white matter in CAA are observed as hyperintensities and dilated perivascular spaces on MRI suggesting impairment of fluid drainage but the pathophysiology behind these changes is poorly understood. We tested the hypothesis that proteins associated with clearance of Aβ peptides are upregulated in the white matter in cases of CAA. Methods: In this study, we compare the quantitative proteomic profile of white matter from post-mortem brains of patients with CAA and age-matched controls in order to gain insight into the cellular processes and key molecules involved in the pathophysiology of CAA. Results: Our proteomic analysis resulted in the profiling of 3,734 proteins (peptide FDR p

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disease directly implicated in Alzheimer’s disease (AD) pathogenesis through amyloid-β (Aβ) deposition, which may cause the development and progression of dementia. Despite extensive studies to explore drugs targeting Aβ, clinical benefits have not been reported in large clinical trials in AD patients or presymptomatic individuals at a risk for AD. However, recent studies on CAA and AD have provided novel insights regarding CAA- and AD-related pathogenesis. This work has revealed potential therapeutic targets, including Aβ drainage pathways, Aβ aggregation, oxidative stress, and neuroinflammation. The functional significance and therapeutic potential of bioactive molecules such as cilostazol and taxifolin have also become increasingly evident. Furthermore, recent epidemiological studies have demonstrated that serum levels of a soluble form of triggering receptor expressed on myeloid cells 2 (TREM2) may have clinical significance as a potential novel predictive biomarker for dementia incidence. This review summarizes recent advances in CAA and AD research with a focus on discussing future research directions regarding novel therapeutic approaches and predictive biomarkers for CAA and AD.

In the absence of lymphatics, fluid and solutes such as amyloid-β (Aβ) are eliminated from the brain along basement membranes in the walls of cerebral capillaries and arteries—the Intramural Peri-Arterial Drainage (IPAD) pathway. IPAD fails with age and insoluble Aβ is deposited as plaques in the brain and in IPAD pathways as cerebral amyloid angiopathy (CAA); fluid accumulates in the white matter as reflected by hyperintensities (WMH) on MRI. Within the brain, fluid uptake by astrocytes is regulated by aquaporin 4 (AQP4). We test the hypothesis that expression of astrocytic AQP4 increases in grey matter and decreases in white matter with onset of CAA. AQP4 expression was quantitated by immunocytochemistry and confocal microscopy in post-mortem occipital grey and white matter from young and old non-demented human brains, in CAA and in WMH. Results: AQP4 expression tended to increase with normal ageing but AQP4 expression in severe CAA was significantly reduced when compared to moderate CAA (p = 0.018). AQP4 expression tended to decline in the white matter with CAA and WMH, both of which are associated with impaired IPAD. Adjusting the level of AQP4 activity may be a valid therapeutic target for restoring homoeostasis in the brain as IPAD fails with age and CAA.