Rice SRO1a Contributes to Xanthomonas TAL Effector-mediated Expression of Host Susceptible Genes.

Xanthomonas species infect many important crops and cause huge yield loss. These pathogens deliver transcription activator-like (TAL) effectors into the cytoplasm of plant cells. TAL effectors move to host nuclei, directly bind to the promoters of host susceptible genes, and activate their transcription. However, the molecular mechanisms by which TAL effectors induce host transcription remain unclear. We herein demonstrated that TAL effectors interacted with the SIMILAR TO RCD ONE (SRO) family proteins OsSRO1a and OsSRO1b in nuclei. A transactivation assay using rice protoplasts indicated that OsSRO1a and OsSRO1b enhanced the activation of the OsSWEET14 promoter by the TAL effector AvrXa7. The AvrXa7-mediated expression of OsSWEET14 was significantly reduced in ossro1a mutants. However, the overexpression of OsSRO1a increased disease resistance by up-regulating the expression of defense-related genes, such as WRKY62 and PBZ1. This was attributed to OsSRO1a and OsSRO1b also enhancing the transcriptional activity of WRKY45, a direct regulator of WRKY62 expression. Therefore, OsSRO1a and OsSRO1b appear to positively contribute to transcription mediated by bacterial TAL effectors and rice transcription factors.

Beyond i.i.d. in the Resource Theory of Asymmetry: An Information-Spectrum Approach for Quantum Fisher Information.

Energetic coherence is indispensable for various operations, including precise measurement of time and acceleration of quantum manipulations. Since energetic coherence is fragile, it is essential to understand the limits in distillation and dilution to restore damage. The resource theory of asymmetry (RTA) provides a rigorous framework to investigate energetic coherence as a resource to break time-translation symmetry. Recently, in the independent and identically distributed (i.i.d.) regime where identical copies of a state are converted into identical copies of another state, it was shown that the convertibility of energetic coherence is governed by a standard measure of energetic coherence, called the quantum Fisher information (QFI). This fact means that QFI in the theory of energetic coherence takes the place of entropy in thermodynamics and entanglement entropy in entanglement theory. However, distillation and dilution in realistic situations take place in regimes beyond i.i.d., where quantum states often have complex correlations. Unlike entanglement theory, the conversion theory of energetic coherence in pure states in the non-i.i.d. regime has been an open problem. In this Letter, we solve this problem by introducing a new technique: an information-spectrum method for QFI. Two fundamental quantities, coherence cost and distillable coherence, are shown to be equal to the spectral QFI rates for arbitrary sequences of pure states. As a consequence, we find that both entanglement theory and RTA in the non-i.i.d. regime are understood in the information-spectrum method, while they are based on different quantities, i.e., entropy and QFI, respectively.

Association of Microluminal Structures Assessed by Optical Coherence Tomography With Local Inflammation in Adjacent Epicardial Adipose Tissue and Coronary Plaque Characteristics in Fresh Cadavers.

BACKGROUND: Coronary intraplaque microluminal structures (MS) are associated with plaque vulnerability, and the inward progression of vascular inflammation from the adventitia towards the media and intima has also been demonstrated. Therefore, in the present study we investigated the relationships among MS, local inflammation in adjacent epicardial adipose tissue (EAT), and coronary plaque characteristics.Methods and Results: Optical coherence tomography (OCT) revealed MS in the left anterior descending coronary artery in 10 fresh cadaveric hearts. We sampled 30 lesions and subdivided them based on the presence of MS: MS (+) group (n=19) and MS (-) group (n=11). We measured inflammatory molecule levels in the adjacent EAT and percentage lipid volume assessed by integrated backscatter intravascular ultrasound in each lesion. The expression levels of vascular endothelial growth factor B and C-C motif chemokine ligand 2 were significantly higher in the MS (+) group than in the MS (-) group (0.9±0.7 vs. 0.2±0.2 arbitrary units (AU), P=0.04 and 1.5±0.5 vs. 0.6±0.7 AU, P=0.02, respectively). Percentage lipid volume was significantly higher in the MS (+) group than in the MS (-) group (38.7±16.5 vs. 23.7±10.9%, P=0.03). CONCLUSIONS: Intraplaque MS observed on OCT were associated with lipid-rich plaques and local inflammation in the adjacent EAT. Collectively, these results suggest that local inflammation in the EAT is associated with coronary plaque vulnerability via MS.

The rice OsERF101 transcription factor regulates the NLR Xa1-mediated immunity induced by perception of TAL effectors.

Plant nucleotide-binding leucine-rich repeat receptors (NLRs) initiate immune responses by recognizing pathogen effectors. The rice gene Xa1 encodes an NLR with an N-terminal BED domain, and recognizes transcription activator-like (TAL) effectors of Xanthomonas oryzae pv oryzae (Xoo). Our goal here was to elucidate the molecular mechanisms controlling the induction of immunity by Xa1. We used yeast two-hybrid assays to screen for host factors that interact with Xa1 and identified the AP2/ERF-type transcription factor OsERF101/OsRAP2.6. Molecular complementation assays were used to confirm the interactions among Xa1, OsERF101 and two TAL effectors. We created OsERF101-overexpressing and knockout mutant lines in rice and identified genes differentially regulated in these lines, many of which are predicted to be involved in the regulation of response to stimulus. Xa1 interacts in the nucleus with the TAL effectors and OsERF101 via the BED domain. Unexpectedly, both the overexpression and the knockout lines of OsERF101 displayed Xa1-dependent, enhanced resistance to an incompatible Xoo strain. Different sets of genes were up- or downregulated in the overexpression and knockout lines. Our results indicate that OsERF101 regulates the recognition of TAL effectors by Xa1, and functions as a positive regulator of Xa1-mediated immunity. Furthermore, an additional Xa1-mediated immune pathway is negatively regulated by OsERF101.

Prediction of Cross-Clamp-Induced Cerebral Ischemia During Carotid Endarterectomy Using Arterial Blood Flow Assessment.

BACKGROUND: Cross-clamping during carotid endarterectomy (CEA) is associated with the risk of cerebral ischemia. Various studies have evaluated different criteria for detecting cerebral ischemia, but difficulties arise when ischemic changes appear after the carotid artery is cross-clamped and incised. Here, we explored a parameter that can predict cerebral ischemia prior to cross-clamping during CEA using a blood-flow meter. METHODS: The carotid arterial blood flow was measured directly (direct ABF) in the common carotid artery prior to cross-clamping. The anatomical information in preoperative magnetic resonance imaging, cerebral blood flow in xenon-enhanced computed tomography, and carotid peak systolic flow velocity by carotid echo from the skin surface were also evaluated. A decrease in the short-latency somatosensory evoked potentials (SSEP) during cross-clamping to insert a shunt was assessed, and a decrease in amplitude of ≥ 50% was considered an indicator for cerebral ischemia. Surgery was performed under general anesthesia, and a shunt was inserted in all cases. RESULTS: Of 156 CEA patients between April 2013 and March 2020, 30 had decreased SSEP during cross-clamping. The baseline characteristics and intra- and postoperative findings were not significantly different between patients with and without a decrease in SSEP. Among the evaluated parameters, only the direct-ABF ratio (ABF-internal carotid artery/ABF-common carotid artery) differed significantly between the 2 groups (P = 0.011). The direct-ABF ratio ≤ 0.58 was predictive of cerebral ischemia during CEA. CONCLUSIONS: Direct-ABF measurement with an ultrasonic blood-flow meter can be useful for predicting cerebral ischemia prior to carotid artery cross-clamping during CEA.

STING, a cytosolic DNA sensor, plays a critical role in atherogenesis: a link between innate immunity and chronic inflammation caused by lifestyle-related diseases.

AIMS: Lifestyle-related diseases promote atherosclerosis, a chronic inflammatory disease; however, the molecular mechanism remains largely unknown. Endogenous DNA fragments released under over-nutrient condition provoke sterile inflammation through the recognition by DNA sensors. Here, we investigated the role of stimulator of interferon genes (STING), a cytosolic DNA sensor, in atherogenesis. METHODS AND RESULTS: Apolipoprotein E-deficient (Apoe-/-) mice fed a western-type diet (WTD), a hypercholesterolaemic mouse model, showed higher STING expression and markers for DNA damage such as γH2AX, p53, and single-stranded DNA (ssDNA) accumulation in macrophages in the aorta compared with wild-type (WT) mice. The level of cGAMP, a STING agonist, in the aorta was higher in Apoe-/- mice. Genetic deletion of Sting in Apoe-/- mice reduced atherosclerotic lesions in the aortic arch, lipid, and macrophage accumulation in plaques, and inflammatory molecule expression in the aorta compared with the control. Pharmacological blockade of STING using a specific inhibitor, C-176, ameliorated atherogenesis in Apoe-/- mice. In contrast, bone marrow-specific STING expression in Apoe-/- mice stimulated atherogenesis. Expression or deletion of STING did not affect metabolic parameters and blood pressure. In vitro studies revealed that STING activation by cGAMP or mitochondrial DNA accelerated inflammatory molecule expression (e.g. TNF-α or IFN-ß) in mouse and human macrophages. Activation of nuclear factor-κB and TANK binding kinase 1 was involved in STING-associated vascular inflammation and macrophage activation. Furthermore, human atherosclerotic lesions in the carotid arteries expressed STING and cGAMP. CONCLUSION: Stimulator of interferon genes stimulates pro-inflammatory activation of macrophages, leading to the development of atherosclerosis. Stimulator of interferon genes signalling may serve as a potential therapeutic target for atherosclerosis.

Clinical clerkship students' preferences and satisfaction regarding online lectures during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has caused an unprecedented disruption in medical education. Students and lecturers had to adapt to online education. The current study aimed to investigate the level of satisfaction and future preference for online lectures among clinical clerkship students and elucidated the factors that affect these outcomes. METHODS: We selected a sample of 114 medical students undergoing clinical clerkship during the COVID-19 pandemic. We conducted onsite lectures before the pandemic and online lectures after the outbreak. A survey was conducted, and the sample included students and 17 lecturers. The average scores of total satisfaction and future preference related to online lectures were computed. RESULTS: Students' scores on total satisfaction with online lectures and their future preference were higher than those for onsite lectures. Scores on the ease of debating dimension were low and those on accessibility of lectures in online lectures were higher than those in onsite lectures. There was no difference between the two groups in the scores on the comprehensibility and ease of asking questions dimensions. Results of the multiple regression analysis revealed that accessibility determined total satisfaction, and future preference was determined by comprehensibility as well as accessibility. Contrary to students' future preferences, lecturers favored onsite lectures to online ones. CONCLUSION: Online lectures are an acceptable mode of teaching during the COVID-19 pandemic for students undergoing clinical clerkship. Online lectures are expected to become more pervasive to avoid the spread of COVID-19.

Triple bypass for multisystem smooth muscle dysfunction syndrome due to Arg179His ACTA2 mutation.

Missense mutations in the smooth muscle-specific isoform of the alpha-actin (ACTA2) gene, which encodes smooth muscle actin, congenitally cause systemic smooth muscle dysfunction, leading to multiple systemic smooth muscle dysfunction syndrome. This disease is often diagnosed through the development of congenital mydriasis, patent ductus arteriosus, or thoracic aortic aneurysm at a young age. Some patients develop cerebrovascular lesions, also known as ACTA2 cerebral arteriopathy, which cause ischemic stroke and require surgical revascularization. However, an effective and safe treatment has not yet been established owing to the rarity of the disease. Furthermore, most reports of this disease involve children, with only a few reports on adults and few detailed reports on treatment outcomes published to date. We report a 46-year-old woman with ACTA2 cerebral arteriopathy caused by Arg179His, the most common mutation in this disease; she is the oldest patient reported with this disease to the best of our knowledge. The patient was diagnosed with multiple systemic smooth muscle dysfunction syndrome and ACTA2 cerebral arteriopathy after experiencing a stroke in the right cingulate gyrus. She underwent direct triple bypass with three anastomoses of the right superficial temporal artery to the middle and anterior cerebral arteries. She developed an ischemic stroke as a postoperative complication.The efficacy and safety of this procedure have not been clearly confirmed owing to the frailty of the donor superficial temporal artery and the poor development of collateral circulation; however, direct bypass should be considered a treatment option for patients experiencing progressive multiple strokes.

Clinical Utility of Overlap Time for Incomplete Relaxation to Predict Cardiac Events in Heart Failure.

BACKGROUND: The overlap time of transmitral flow can be a novel marker of subclinical left ventricular dysfunction for predicting adverse events in heart failure (HF). We aimed to (1) investigate the role of overlap time of the E-A wave in association with clinical parameters and (2) evaluate whether the overlap time could add prognostic information with respect to other conventional clinical prognosticators in HF. METHODS: We prospectively evaluated 153 patients hospitalized with HF (mean age 68 ± 15 years; 63% male). The primary endpoint was readmission following HF or cardiac death. RESULTS: During a median period of 25 months, 43 patients were readmitted or died. Overlap time appeared to be associated with worse outcomes. After adjustment for readmission scores and ratios of diastolic filling period and cardiac cycle length in a Cox proportional-hazards model, overlap time was associated with event-free survival, independent of elevated left atrial pressure based on guidelines. When overlap time was added to the model based on clinical variables and elevated left atrial pressure, the C-statistic significantly improved from 0.70 (95% CI: 0.63-0.77) to 0.77 (95% CI: 0.69-0.83, compared) (P = 0.035). CONCLUSION: This preliminary study suggested that prolonged overlap time may have potential for predicting readmission and cardiac mortality risk assessment in patients with HF.

Activated Factor X Signaling Pathway via Protease-Activated Receptor 2 Is a Novel Therapeutic Target for Preventing Atrial Fibrillation.

BACKGROUND: Activated factor X (FXa), which contributes to chronic inflammation via protease-activated receptor 2 (PAR2), might play an important role in atrial fibrillation (AF) arrhythmogenesis. This study aimed to assess whether PAR2 signaling contributes to AF arrhythmogenesis and whether rivaroxaban ameliorates atrial inflammation and prevents AF.Methods and Results:In Study 1, PAR2 deficient (PAR2-/-) and wild-type mice were infused with angiotensin II (Ang II) or a vehicle via an osmotic minipump for 2 weeks. In Study 2, spontaneously hypertensive rats (SHRs) were treated with rivaroxaban, warfarin, or vehicle for 2 weeks after 8 h of right atrial rapid pacing. The AF inducibility and atrial remodeling in both studies were examined. Ang II-treated PAR2-/- mice had a lower incidence of AF and less mRNA expression of collagen1 and collagen3 in the atrium compared to wild-type mice treated with Ang II. Rivaroxaban significantly reduced AF inducibility compared with warfarin or vehicle. In SHRs treated with a vehicle, rapid atrial pacing promoted gene expression of inflammatory and fibrosis-related biomarkers in the atrium. Rivaroxaban, but not warfarin, significantly reduced expression levels of these genes. CONCLUSIONS: The FXa-PAR2 signaling pathway might contribute to AF arrhythmogenesis associated with atrial inflammation. A direct FXa inhibitor, rivaroxaban, could prevent atrial inflammation and reduce AF inducibility, probably by inhibiting the pro-inflammatory activation.

A case of idiopathic extracranial carotid artery pseudoaneurysm with a rare clinical course and pathological features.

Extracranial carotid artery aneurysms (ECAAs) are rare, with the etiology mainly classified as degeneration or dissection. Pseudoaneurysms in the region are even rarer and are seen following trauma, iatrogenic injury, or infection. We report a case of extracranial carotid artery pseudoaneurysm (pseudo-ECAA) with a rare clinical course and pathological features. A 58-year-old man presented with swelling and purpura on the left side of his neck after sneezing. Radiological examinations suggested a ruptured left common carotid artery aneurysm. The operative findings were consistent with a pseudoaneurysm. Pathological examination revealed disarrangement and degeneration of smooth muscle fibers in the media, in addition to scattered foci of mucoid accumulation and irregular-shaped cavitation in the medial extracellular matrix, raising the possibility of an intrinsic dysfunction of the vascular wall in the pathological process of pseudoaneurysm formation.

Aspirin use and platelet aggregation in ischemic onset-type pediatric moyamoya patients with intractable headaches (moya-ache).

BACKGROUND: NSAIDs (nonsteroidal anti-inflammatory drugs) were administered to patients with ischemic onset-type moyamoya disease who experience headaches, but their therapeutic effect was very poor and resulted in a drop in quality of life (QOL). On the other hand, patients who were administered aspirin initially to prevent transient ischemic attacks (TIA) were observed to have a better QOL with the absence of headaches. Here, we report on patients with ischemic onset-type moyamoya disease experiencing headaches who received aspirin in order to verify its safety and effectiveness. METHODS: From October 2012 to July 2014, 35 patients (male: 19, female: 16 average age: 10.5 ± 3.9) with ischemic onset-type pediatric moyamoya disease and who were admitted or commuted to hospital and had surgical treatment were evaluated for background, moyamoya staging (Suzuki), presence/absence of TIA, and platelet aggregation activity by adenosine diphosphate (ADP)/collagen turbidity test. The patients were divided into four groups depending on the intensity of headache prior to being administered aspirin, and the Kruskal-Wallis test was carried out for platelet aggregation activity and moyamoya staging. Also, the 4 × 2 χ2 test was carried out for the presence/absence of TIA. Next, the items which were significant in these tests were used as independent variables to analyze the risk of headache onset, using logistic regression analysis. RESULTS: One item with statistical significance was the platelet aggregation test(PAT) value (on collagen) (P < 0.0001). A logistic regression analysis was carried out, using this value as an independent variable and headache intensity-as a dependent variable. As a result, an increase in PAT value by 1 translated into 4.43 times higher risk of the onset of intractable headache, and the onset of intractable headaches was predicted at 58.8% with collagen. The risk of developing a headache decreased as a result of aspirin administration, and the decrease was dependent on the collagen-induced aggregation suppression effect of aspirin. Aspirin was administered in the range of 1.6~9.5 mg/kg/day, and the PAT value decreasing rate was 42.9% on average. One case alone experienced nasal bleeding, and all cases showed an improvement in the intractable headaches. CONCLUSIONS: In patients with ischemic onset-type pediatric moyamoya disease who experience headaches, the platelet aggregation activity is accelerated, and aspirin administration is effective in alleviating headaches by inhibiting platelet activation, detected by the collagen PAT.

Maximum Nidus Depth as a Risk Factor of Surgical Morbidity in Eloquent Brain Arteriovenous Malformations.

BACKGROUND: Eloquent location of a brain arteriovenous malformation (BAVM) is known to increase the surgical risk. Surgical removal of such BAVMs is challenging. Useful indicators for the safe removal of eloquent BAVMs are needed. The aim of this study was to determine the surgical risk factors for these challenging entities. METHODS: The authors retrospectively reviewed 29 motor and/or sensory BAVM patients who underwent surgeries. The risk factors for surgical morbidity were analyzed. As a new risk factor, maximum nidus depth, was evaluated. RESULTS: Complete obliteration was achieved in 28 patients (96.6%). Postoperative transient and permanent neurological deteriorations were seen in nine patients (31.0%) and five patients (17.2%), respectively. In univariate analysis, maximum nidus depth (p = 0.0204) and asymptomatic onset (p = 0.0229) were significantly correlated with the total morbidity. In multivariate analysis, only maximum nidus depth was significantly correlated with total morbidity (p = 0.0357; odds ratio, 2.78598; 95% confidence interval, 0.8866-8.7535). The cut-off value for the maximum nidus depth was 36 mm for total morbidity (area under the curve [AUC], 0.7428) and 41 mm for permanent morbidity (AUC, 0.8833). The cutoff value of the maximum nidus size was 30 mm for total morbidity (AUC, 0.5785) and 30 mm for permanent morbidity (AUC, 0.7625). AUC was higher for the maximum nidus depth than it was for the maximum nidus size. CONCLUSIONS: Maximum nidus depth was significantly associated with surgical morbidity of eloquent BAVMs. The maximum nidus depth is a novel and a simpler indicator of the risk of surgical morbidity.

The Arabidopsis CERK1-associated kinase PBL27 connects chitin perception to MAPK activation.

Perception of microbe-associated molecular patterns by host cell surface pattern recognition receptors (PRRs) triggers the intracellular activation of mitogen-activated protein kinase (MAPK) cascades. However, it is not known how PRRs transmit immune signals to MAPK cascades in plants. Here, we identify a complete phospho-signaling transduction pathway from PRR-mediated pathogen recognition to MAPK activation in plants. We found that the receptor-like cytoplasmic kinase PBL27 connects the chitin receptor complex CERK1-LYK5 and a MAPK cascade. PBL27 interacts with both CERK1 and the MAPK kinase kinase MAPKKK5 at the plasma membrane. Knockout mutants of MAPKKK5 compromise chitin-induced MAPK activation and disease resistance to Alternaria brassicicola PBL27 phosphorylates MAPKKK5 in vitro, which is enhanced by phosphorylation of PBL27 by CERK1. The chitin perception induces disassociation between PBL27 and MAPKKK5 in vivo Furthermore, genetic evidence suggests that phosphorylation of MAPKKK5 by PBL27 is essential for chitin-induced MAPK activation in plants. These data indicate that PBL27 is the MAPKKK kinase that provides the missing link between the cell surface chitin receptor and the intracellular MAPK cascade in plants.

Association Between Right Ventricular Contractile Function and Cardiac Events in Isolated Postcapillary and Combined Pre- and Postcapillary Pulmonary Hypertension.

BACKGROUND: Recent studies have shown that patients with combined pre- and postcapillary pulmonary hypertension (CpcPH) had worse outcomes than those with isolated postcapillary pulmonary hypertension (IpcPH). However, the prognostic factors including right ventricular (RV) function have not been well documented. The aim of this study was to assess the differentiation of PH phenotypes, using echocardiography, and the association between RV longitudinal strain and cardiac events. METHODS AND RESULTS: We prospectively recruited consecutive patients who had undergone right heart catheterization. The primary endpoint was cardiovascular death or readmission due to heart failure. We included 137 patients with Group 2 PH. A RV longitudinal strain of 17% was sensitive (85%) and specific (70%) to determine the CpcPH. During a median period of 31 months, 43 patients experienced the primary endpoint during follow-up. In a multivariate analysis, RV longitudinal strain was associated with the primary endpoint in both CpcPH and IpcPH (HR: 0.84, P = 0.003; HR: 0.86, P = 0.001). CONCLUSIONS: Lower RV longitudinal strain was independently associated with worse outcomes in CpcPH and IpcPH. RV longitudinal strain may play a prognostic role in PH phenotypes.

Atherosclerotic Coronary Plaque Is Associated With Adventitial Vasa Vasorum and Local Inflammation in Adjacent Epicardial Adipose Tissue in Fresh Cadavers.

BACKGROUND: The coronary adventitia has recently attracted attention as a source of inflammation because it harbors nutrient blood vessels, termed the vasa vasorum (VV). This study assessed the link between local inflammation in adjacent epicardial adipose tissue (EAT) and coronary arterial atherosclerosis in fresh cadavers.Methods and Results:Lesion characteristics in the left anterior descending coronary artery of 10 fresh cadaveric hearts were evaluated using integrated backscatter intravascular ultrasound (IB-IVUS), and the density of the VV and levels of inflammatory molecules from the adjacent EAT were measured for each of the assessed lesions. The lesions were divided into lipid-rich, lipid-moderate, and lipid-poor groups according to percentage lipid volume assessed by IB-IVUS. Higher expression of inflammatory molecules (i.e., vascular endothelial growth factor A [VEGFA] andVEGFB) was observed in adjacent EAT of lipid-rich (n=11) than in lipid-poor (n=11) lesions (7.99±3.37 vs. 0.45±0.85 arbitrary units [AU], respectively, forVEGFA; 0.27±0.15 vs. 0.11±0.07 AU, respectively, forVEGFB; P<0.05). The density of adventitial VV was greater in lipid-rich than lipid-poor lesions (1.50±0.58% vs. 0.88±0.23%; P<0.05). CONCLUSIONS: Lipid-rich coronary plaques are associated with adventitial VV and local inflammation in adjacent EAT in fresh cadavers. This study suggests that local inflammation of EAT is associated with coronary plaque progression via the VV.

Do Direct Bypasses Really Resolve Capillary Vessels in Moyamoya Disease? Delayed Hemorrhage Potentially Relevant to Direct Bypasses: A Pathological Investigation.

OBJECTIVE: Moyamoya disease is a chronic but progressive obliterative cerebrovascular disease of bilateral internal carotid arteries (ICAs) causing hemorrhagic or ischemic cerebral strokes. Surgical revascularization has the potential for resolving the capillary vessels, but the effect on the occlusive ICA and the moyamoya vessels after a direct bypass remains unclear. PATIENT: A 2-year-old girl with a history of repeated transient ischemic attacks and direct bypasses but demonstrating improvement and associated anomaly is reported. A year and a half later, after a bilateral revascularization, an intracerebral capsulized hematoma growth was identified, and it was removed surgically. Neovascularization including many microvessels similar to capillary telangiectasia were identified by pathological investigation despite the reduction of moyamoya vessels on the repeated angiograms after the revascularization surgeries. In the present case, proliferation of capillary vessels was clearly confirmed by direct bypasses. CONCLUSION: There is no doubt that direct bypasses prevent further ischemic stroke by improving cerebral blood flow. However, they may result in failure in reducing the load of moyamoya vessels, albeit decreasing the potential risk of hemorrhagic strokes.

Can Moyamoya Disease Susceptibility Gene Affect Extracranial Systemic Artery Stenosis?

Diseases associated with the RNF213 gene include moyamoya disease, with the p.R4810K (c.14429G>A, rs112735431) homozygous variant thought to be the most pathogenic and significantly associated with severe manifestation such as early onset or cerebral infarction at onset. We report a case of a unique Japanese pedigree associated with RNF213. A 53-year-old woman with no arteriosclerotic risk factors experienced coronary artery disease, followed by coronary artery bypass surgery. In 8 years, she suffered sudden abdominal pain. Her abdominal contrast computed tomography revealed stenosis of abdominal artery and superior mesenteric artery. Though her 2 children and uncle had a typical moyamoya disease with RNF213 p.R4810K heterozygous variant, she has had no clinical and radiological evidence of moyamoya disease. Due to a family history of moyamoya disease, a genetic investigation was performed and revealed RNF213 p.R4810K homozygous variant. A possible role of RNF213 influencing systemic artery stenosis can be further be understood from this rare case harboring the homozygous variant carrier.

Association between Sarcopenia/Lower Muscle Mass and Short-Term Regression of Deep Vein Thrombosis Using Direct Oral Anticoagulants.

Advanced age, obesity, and muscle weakness are independent factors in the onset of deep vein thrombosis (DVT). Recently, an association between sarcopenia and DVT has been reported. We hypothesized that sarcopenia related factors, observed by ultrasonography, are associated with the regression effect on the thrombus following anticoagulation therapy. The present study focused on gastrocnemius muscle (GCM) thickness and the GCM's internal echogenic brightness. We examined the association with DVT regression following direct oral anticoagulants (DOACs) treatment.The prospective cohort study period was between October 2017 and August 2018. We enrolled 46 patients diagnosed with DVT by ultrasonography, who were aged >60 years old and treated with DOACs. Sarcopenia was evaluated using the Asian Working Group for Sarcopenia flowchart. The average DOACs treatment period was 94 days, and 29 patients exhibited thrombus regression. On univariate logistic regression analysis, sarcopenia, average GCM diameter index, and gastrocnemius integrated backscatter index were significantly associated with thrombus regression. In a multivariate model, only the average GCM diameter index correlated with thrombus regression.The average GCM diameter index is associated with DVT regression treated with DOACs. Considering the GCM diameter during DVT treatment can be a marker to make a decision for the treatment of DVT.

Protease-Activated Receptor-2 Plays a Critical Role in Vascular Inflammation and Atherosclerosis in Apolipoprotein E-Deficient Mice.

BACKGROUND: The coagulation system is closely linked with vascular inflammation, although the underlying mechanisms are still obscure. Recent studies show that protease-activated receptor (PAR)-2, a major receptor of activated factor X, is expressed in both vascular cells and leukocytes, suggesting that PAR-2 may contribute to the pathogenesis of inflammatory diseases. Here we investigated the role of PAR-2 in vascular inflammation and atherogenesis. METHODS: We generated apolipoprotein E-deficient ( ApoE-/-) mice lacking systemic PAR-2 expression ( PAR-2-/- ApoE-/-). ApoE-/- mice, which lack or express PAR-2 only in bone marrow (BM) cells, were also generated by BM transplantation. Atherosclerotic lesions were investigated after 20 weeks on a Western-type diet by histological analyses, quantitative reverse transcription polymerase chain reaction, and Western blotting. In vitro experiments using BM-derived macrophages were performed to confirm the proinflammatory roles of PAR-2. The association between plasma activated factor X level and the severity of coronary atherosclerosis was also examined in humans who underwent coronary intervention. RESULTS: PAR-2-/- ApoE-/- mice showed reduced atherosclerotic lesions in the aortic arch ( P<0.05) along with features of stabilized atherosclerotic plaques, such as less lipid deposition ( P<0.05), collagen loss ( P<0.01), macrophage accumulation ( P<0.05), and inflammatory molecule expression ( P<0.05) compared with ApoE-/- mice. Systemic PAR2 deletion in ApoE-/-mice significantly decreased the expression of inflammatory molecules in the aorta. The results of BM transplantation experiments demonstrated that PAR-2 in hematopoietic cells contributed to atherogenesis in ApoE-/- mice. PAR-2 deletion did not alter metabolic parameters. In vitro experiments demonstrated that activated factor X or a specific peptide agonist of PAR-2 significantly increased the expression of inflammatory molecules and lipid uptake in BM-derived macrophages from wild-type mice compared with those from PAR-2-deficient mice. Activation of nuclear factor-κB signaling was involved in PAR-2-associated vascular inflammation and macrophage activation. In humans who underwent coronary intervention, plasma activated factor X level independently correlated with the severity of coronary atherosclerosis as determined by Gensini score ( P<0.05) and plaque volume ( P<0.01). CONCLUSIONS: PAR-2 signaling activates macrophages and promotes vascular inflammation, increasing atherosclerosis in ApoE-/- mice. This signaling pathway may also participate in atherogenesis in humans.