A Case of Refractory Vasospastic Angina Complicated by Bronchial Asthma with Eosinophilia1.

A 48-year-old woman with a history of bronchial asthma and allergic rhinitis presented with cardiac arrest due to ventricular fibrillation and was resuscitated by defibrillation. Coronary angiography revealed coronary vasospasm. Various antispastic agents were unable to control recurrent coronary spasms. We searched for other points of intervention and found a significant increase in the eosinophil count. The patient received mepolizumab for bronchial asthma with eosinophilia, which normalized the eosinophil count. Since then, the patient has remained free from coronary vasospasm, suggesting that mepolizumab may be a viable option for treating refractory coronary angina associated with bronchial asthma and eosinophilia.

[A case of high cervical cord infarction presenting with cardiopulmonary arrest due to respiratory dysfunction].

A 46-year-old man with neck pain and impaired physical mobility called for emergency medical services. The patient was able to communicate with the emergency medical team upon their arrival. However, he went into cardiopulmonary arrest 5 minutes later. Cardiopulmonary resuscitation was immediately performed, and the patient was admitted to our hospital with a Glasgow Coma Scale score of E1V1M1. His respiratory rate was 5 breaths/minute and his partial pressure of carbon dioxide in arterial blood (PaCO2) was 127 |mmHg, necessitating intubation and ventilation. His consciousness improved as the PaCO2 level decreased. However, he was unable to be weaned off the ventilator and breathe independently. Neurological examination revealed flaccid quadriplegia, pain sensation up to the C5 level, absence of deep tendon reflexes, indifferent plantar responses, and absence of the rectoanal inhibitory reflex. Magnetic resonance imaging showed a hyperintense lesion with slight enlargement of the anterior two-thirds of the spinal cord at the C2-C4 level on both T2-weighted and diffusion-weighted images, consistent with a diagnosis of spinal cord infarction. Although the quadriplegia and sensory loss partially improved, the patient was unable to be weaned from the ventilator. Cervical cord infarction of the anterior spinal artery can cause rapid respiratory failure leading to cardiopulmonary arrest. Therefore, cervical cord infarction should be included as a differential diagnosis when examining patients after cardiopulmonary resuscitation.

Driver gene KRAS aggravates cancer-associated stroke outcomes.

The incidence of cancer-associated stroke has increased with the prolonged survival times of cancer patients. Recent genetic studies have led to progress in cancer therapeutics, but relationships between oncogenic mutations and stroke remain elusive. Here, we focused on the driver gene KRAS, which is the predominant RAS isoform mutated in multiple cancer types, in cancer associated stroke study. KRASG13D/- and parental human colorectal carcinoma HCT116 cells were inoculated into mice that were then subjected to a photochemically-induced thrombosis model to establish ischemic stroke. We found that cancer inoculation exacerbated neurological deficits after stroke. Moreover, mice inoculated with KRASG13D/- cells showed worse neurological deficits after stroke compared with mice inoculated with parental cells. Stroke promoted tumor growth, and the KRASG13D/- allele enhanced this growth. Brain RNA sequencing analysis and serum ELISA showed that chemokines and cytokines mediating pro-inflammatory responses were upregulated in mice inoculated with KRASG13D/- cells compared with those inoculated with parental cells. STAT3 phosphorylation was promoted following ischemic stroke in the KRASG13D/- group compared with in the parental group, and STAT3 inhibition significantly ameliorated stroke outcomes by mitigating microglia/macrophage polarization. Finally, we compared the prognosis and mortality of colorectal cancer patients with or without stroke onset between 1 January 2007 and 31 December 2020 using a hospital-based cancer registry and found that colorectal cancer patients with stroke onset within 3 months after cancer diagnosis had a worse prognosis. Our work suggests an interplay between KRAS and ischemic stroke that may offer insight into future treatments for cancer-associated stroke.

Discontinuation of Oral Anticoagulants in Atrial Fibrillation Patients: Impact of Treatment Strategy and on Patients' Health Status.

AIMS: The discontinuation of oral anticoagulants (OACs) remains as a significant concern in the management of atrial fibrillation (AF). The discontinuation rate may vary depending on management strategy, and physicians may also discontinue OACs due to concerns about patient satisfaction with their care. We aimed to assess the incidence of OAC discontinuation and its relationship to patients' health in an outpatient AF registry. METHODS AND RESULTS: From a multicenter registry for newly recognized AF patients (n = 3313), we extracted 1647 (49.7%) patients with OACs and a CHA2DS2-Vasc score of ≥2. Discontinuation was defined as sustained cessation of OACs within a 1-year follow-up. We examined predictors associated with discontinuation and its relations to health status defined by the AFEQT questionnaire. Of the 1647 patients, 385 (23.6%) discontinued OACs after 1 year, with discontinuation rates varying across treatment strategies (15.3% for catheter ablation, 4.9% for rhythm control with antiarrhythmic drugs, and 3.0% for rate control). Successful rhythm control was associated with discontinuation in the catheter ablation (OR 6.61, 95% CI 3.00-14.6, p < 0.001) and antiarrhythmic drugs (OR 6.47, 95% CI 2.62-15.9, p < 0.001) groups, whereas the incidence of bleeding events within 1 year was associated with discontinuation in the rate control group. One-year AFEQT scores did not significantly differ between patients who discontinued OACs and those who did not in each treatment strategy group. CONCLUSIONS: OAC discontinuation was common among AF patients with significant stroke risk but varied depending on the chosen treatment strategy. This study also found no significant association between OAC discontinuation and patients' health status.

Importance of microRNAs by mRNA-microRNA integration analysis in acute ischemic stroke patients.

OBJECTS: The roles of mRNA and microRNA (miRNA) are well known in many diseases, including ischemic stroke; thus, integration analysis using mRNA and miRNA is important to elucidate pathogenesis. However, their contribution, especially that of miRNA-targeted mRNA, to the severity of acute ischemic stroke remains unclear. Therefore, we examined mRNA and miRNA integration analysis targeted for acute ischemic stroke to clarify the pathway related to acute stroke severity. MATERIAL AND METHODS: We performed Ingenuity Pathway Analysis (IPA) using RNA extracted from the whole blood of four healthy controls, six minor acute ischemic stroke patients (MS; National Institutes of Health Stroke Scale [NIHSS] < 8), and six severe acute ischemic stroke patients (SS; NIHSS ≥ 8) on admission. mRNA and miRNA were measured using RNA sequencing and RNA expression variation; canonical pathway analysis (CPA) and upstream regulator analyses were performed. RESULTS: Acute ischemic stroke patients demonstrated different RNA expressions to healthy controls. Compared to MS patients, in the SS patients, 1222 mRNA, 96 miRNA, and 935 miRNA-targeted mRNA expressions were identified among differentially expressed RNA expressions (p<0.05, |log2 fold change| >1.1). CPA by IPA using mRNAs or miRNA-targeted mRNAs showed that macrophage-stimulating protein (MSP)-recepteur d'origine nantais (RON) signaling was mostly activated in SS patients compared to in MS patients. In addition, upstream regulator analysis in IPA showed that most mRNAs located upstream are miRNAs. CONCLUSIONS: In severe acute stroke, integration of mRNA and microRNA analysis showed activated MSP-RON signaling in macrophages, and multiple miRNAs comprehensively controlled the overall pathophysiology of stroke.

Spontaneous resolution of inflammatory myopathy involving the masseter muscle following COVID-19 mRNA vaccination.

According to previous reports, most cases of inflammatory myopathy following messenger RNA (mRNA) vaccination can be classified as idiopathic inflammatory myopathy, particularly dermatomyositis, owing to their similar clinical features and courses. However, some patients have different clinical features and courses. We report a rare case of transient inflammatory myopathy involving the masseter muscle following the third dose of coronavirus disease 2019 (COVID-19) mRNA vaccination. An 80-year-old woman presented with a history of fever and fatigue for 3 months soon after receiving the third COVID-19 mRNA vaccination. Her symptoms progressed to jaw pain and inability to open her mouth. She also experienced mild proximal muscle weakness in the lower limbs but no skin manifestations or daily difficulties. Fat-saturated T2-weighted magnetic resonance imaging showed bilateral high-intensity signals for the masseter and quadriceps muscles. The patient experienced spontaneous resolution of fever and improvement of symptoms 5 months after onset. The timing of the onset of symptoms, the lack of detectable autoantibodies, and the atypical presentation of myopathy in the masseter muscles, in addition to the spontaneous mild course of the disease, all indicate the substantial role of mRNA vaccination in this myopathy. Since then, the patient has been followed up for 4 months without any recurrence of symptoms or any additional treatment. It is important to recognise that the course of myopathy after COVID-19 mRNA vaccination could be different from that of typical idiopathic inflammatory myopathies.

Role of Polymorphonuclear Myeloid-Derived Suppressor Cells and Neutrophils in Ischemic Stroke.

Background Immune cells play a vital role in the pathology of ischemic stroke. Neutrophils and polymorphonuclear myeloid-derived suppressor cells share a similar phenotype and have attracted increasing attention in immune regulation research, yet their dynamics in ischemic stroke remain elusive. Methods and Results Mice were randomly divided into 2 groups and intraperitoneally treated with anti-Ly6G (lymphocyte antigen 6 complex locus G) monoclonal antibody or saline. Distal middle cerebral artery occlusion and transient middle cerebral artery occlusion were applied to induce experimental stroke, and mice mortality was recorded until 28 days after stroke. Green fluorescent nissl staining was used to measure infarct volume. Cylinder and foot fault tests were used to evaluate neurological deficits. Immunofluorescence staining was conducted to confirm Ly6G neutralization and detect activated neutrophils and CD11b+Ly6G+ cells. Fluorescence-activated cell sorting was performed to evaluate polymorphonuclear myeloid-derived suppressor cell accumulation in brains and spleens after stroke. Anti-Ly6G antibody successfully depleted Ly6G expression in mice cortex but did not alter cortical physiological vasculature. Prophylactic anti-Ly6G antibody treatment ameliorated ischemic stroke outcomes in the subacute phase. Moreover, using immunofluorescence staining, we found that anti-Ly6G antibody suppressed activated neutrophil infiltration into parenchyma and decreased neutrophil extracellular trap formation in penumbra after stroke. Additionally, prophylactic anti-Ly6G antibody treatment reduced polymorphonuclear myeloid-derived suppressor cell accumulation in the ischemic hemisphere. Conclusions Our study suggested a protective effect of prophylactic anti-Ly6G antibody administration against ischemic stroke by reducing activated neutrophil infiltration and neutrophil extracellular trap formation in parenchyma and suppressing polymorphonuclear myeloid-derived suppressor cell accumulation in the brain. This study may provide a novel therapeutic approach for ischemic stroke.

The tight junction protein occludin modulates blood-brain barrier integrity and neurological function after ischemic stroke in mice.

Blood-brain barrier (BBB) disruption contributes to brain injury and neurological impairment. Tight junctions (TJs) and cell-cell adhesion complexes develop between endothelial cells in the brain to establish and maintain the BBB. Occludin, the first transmembrane protein identified in TJs, has received intense research interest because numerous in vitro studies have suggested its importance in maintaining BBB integrity. However, its role in maintaining BBB integrity after ischemic stroke is less clear owing to the lack of in vivo evidence. This study aimed to investigate the dynamics and function of occludin across the acute and chronic phases after stroke using occludin-deficient mice. By photochemically induced thrombosis model, the expression of occludin was decreased in brain endothelial cells from ischemic lesions. The neurological function of occludin-deficient mice was continuously impaired compared to that of wild-type mice. BBB integrity evaluated by Evans blue and 0.5-kDa fluorescein in the acute phase and by 10-kDa fluorescein isothiocyanate-labeled dextran in the chronic phase was decreased to a greater extent after stroke in occludin-deficient mice. Furthermore, occludin-deficient mice showed decreased claudin-5 and neovascularization after stroke. Our study reveals that occludin plays an important role from the acute to the chronic phase after ischemic stroke in vivo.

MDMX elevation by a novel Mdmx-p53 interaction inhibitor mitigates neuronal damage after ischemic stroke.

Mdmx and Mdm2 are two major suppressor factors for the tumor suppressor gene p53. In central nervous system, Mdmx suppresses the transcriptional activity of p53 and enhances the binding of Mdm2 to p53 for degradation. But Mdmx dynamics in cerebral infarction remained obscure. Here we investigated the role of Mdmx under ischemic conditions and evaluated the effects of our developed small-molecule Protein-Protein Interaction (PPI) inhibitors, K-181, on Mdmx-p53 interactions in vivo and in vitro. We found ischemic stroke decreased Mdmx expression with increased phosphorylation of Mdmx Serine 367, while Mdmx overexpression by AAV-Mdmx showed a neuroprotective effect on neurons. The PPI inhibitor, K-181 attenuated the neurological deficits by increasing Mdmx expression in post-stroke mice brain. Additionally, K-181 selectively inhibited HDAC6 activity and enhanced tubulin acetylation. Our findings clarified the dynamics of Mdmx in cerebral ischemia and provide a clue for the future pharmaceutic development of ischemic stroke.

Effect of Tricuspid Regurgitation on the Reported Quality of Life and Subsequent Outcomes in Patients With Atrial Fibrillation.

Background Atrial fibrillation and heart failure (HF) possess mutual risk factors and share a common pathophysiological pathway. Tricuspid regurgitation (TR) is a known predictor of adverse events in patients with HF. However, its implications on patients with atrial fibrillation in its early stage remain unknown. Methods and Results Data of 2211 patients without previous HF diagnosis were extracted from a prospective, multicenter registry of newly diagnosed patients with atrial fibrillation. TR was categorized as absent, mild, moderate, and severe based on the American Society of Echocardiography recommendations. The primary outcome was time to first hospitalization for HF after enrollment. The Atrial Fibrillation Effects on Quality-of-Life scores were compared. Overall, 1107 patients (50.1%) had TR (42.3%, 7.2%, and 0.6% for mild, moderate, and severe, respectively). During follow-up (median 730 [interquartile range, 366-731] days), 44 patients (2.0%) experienced HF hospitalization, and the incidence increased with severity of TR (P<0.001). TR was an associated predictor of the primary outcome (hazard ratio [HR]: 2.51, P=0.050; HR: 6.19, P=0.008; for moderate and severe TR versus no TR). Changes in AFEQT overall score were negatively related to TR severity (8.7±17.5 versus 8.5±17.0 versus 3.1±17.5 versus 1.4±11.8, absent versus mild versus moderate versus severe TR, respectively), although it was not an independent predictor after adjustments. Conclusions TR severity at atrial fibrillation diagnosis was an associated predictor of subsequent hospitalization for HF, which may warrant the need for a more intensive follow-up and HF-related management.

An Older Thrombus Delays Reperfusion after Mechanical Thrombectomy for Ischemic Stroke.

BACKGROUND: Thrombosis is a dynamic process, and a thrombus undergoes physical and biochemical changes that may alter its response to reperfusion therapy. This study assessed whether thrombus age influenced reperfusion quality and outcomes after mechanical thrombectomy for cerebral embolism. METHODS: We retrospectively evaluated 185 stroke patients and thrombi that were collected during mechanical thrombectomy at three stroke centers. Thrombi were pathologically classified as fresh or older based on their granulocytes' nuclear morphology and organization. Thrombus components were quantified, and the extent of NETosis (the process of neutrophil extracellular trap formation) was assessed using the density of citrullinated histone H3-positive cells. Baseline patient characteristics, thrombus features, endovascular procedures, and functional outcomes were compared according to thrombus age. RESULTS: Fresh thrombi were acquired from 43 patients, and older thrombi were acquired from 142 patients. Older thrombi had a lower erythrocyte content (p < 0.001) and higher extent of NETosis (p = 0.006). Restricted mean survival time analysis revealed that older thrombi were associated with longer puncture-to-reperfusion times (difference: 15.6 minutes longer for older thrombi, p = 0.002). This association remained significant even after adjustment for erythrocyte content and the extent of NETosis (adjusted difference: 10.8 minutes, 95% confidence interval [CI]: 0.6-21.1 minutes, p = 0.039). Compared with fresh thrombi, older thrombi required more device passes before reperfusion (p < 0.001) and were associated with poorer functional outcomes (adjusted common odds ratio: 0.49; 95% CI: 0.24-0.99). CONCLUSION: An older thrombus delays reperfusion after mechanical thrombectomy for ischemic stroke. Adding therapies targeting thrombus maturation may improve the efficacy of mechanical thrombectomy.

MiRNA-132/212 regulates tight junction stabilization in blood-brain barrier after stroke.

MicroRNA-132/212 has been supposed as a critical gene related to the blood-brain barrier (BBB) protection after stroke, but its regulation pathway including the upstream regulator and downstream targets is still unclear. Herein, we demonstrated the cAMP response element-binding protein (CREB)-regulated transcription coactivator-1 (CRTC1) to be the upstream regulator of miRNA-132/212 using CRTC1 knockout and wild-type mice. CRTC1 deletion led to the reduction of miRNA-132/212 expression in mice brain after ischemic stroke, significantly increased infarct volume, and aggravated BBB permeability with worsening neurological deficits. Furthermore, we identified that miRNA-132 repressed Claudin-1, tight junction-associated protein-1 (TJAP-1), and RNA-binding Fox-1 (RBFox-1) by directly binding to their respective 3'-untranslated regions, which alleviated the ischemic damage by enhancing neuronal survival and BBB integrity. Moreover, the co-culture of endothelial cells with CRTC1-deficient neurons aggravated the cell vulnerability to hypoxia, also supporting the idea that miRNA-132/212 cluster is regulated by CRTC1 and acts as a crucial role in the mitigation of ischemic damage. This work is a step forward for understanding the role of miRNA-132/212 in neurovascular interaction and may be helpful for potential gene therapy of ischemic stroke.

Stroke Severity and Outcomes in Patients With Newly Diagnosed Atrial Fibrillation.

Background and Purpose: Once a stroke occurs in a patient with atrial fibrillation (AF), it is likely to be severe. Patients with newly diagnosed AF after stroke and those with known AF before stroke have different background characteristics, yet the difference in stroke severity has not been sufficiently evaluated. In the current study, we compared the stroke severity and in-hospital outcomes between these patient groups. Methods: We retrospectively analyzed a database of 196 patients with acute ischemic stroke and AF between January 2010 and October 2019. We divided the patients into two groups: patients with "newly diagnosed AF" and those with "known AF." We assessed the stroke severity using the National Institutes of Health Stroke Scale (NIHSS) score on admission and in-hospital outcomes using the modified Rankin Scale (mRS) score at discharge. Results: The proportion of newly diagnosed AF was 33% (64/196). There were no differences in age, hypertension, diabetes mellitus, and past history of heart failure between patients with newly diagnosed AF and those with known AF. Patients with newly diagnosed AF were associated with a lower proportion of male sex (male; 50 vs. 67%, p < 0.05), a lower proportion of past history of stroke (12 vs. 35%, p < 0.01), a lower CHA2DS2-VASc score (median [interquartile range]; 3 [2-4] vs. 3.5 [3-5], p < 0.01), and a lower proportion of pre-stroke oral anticoagulation (5 vs. 59%, p < 0.01). There were no differences in the NIHSS score on admission (12 [4-19] vs. 9 [3-19]) or the mRS score at discharge (3 [1-5] vs. 3 [1-5]). After adjustment for relevant covariates, newly diagnosed AF was not associated with the NIHSS score on admission [adjusted common odds ratio (OR), 0.85; 95% confidence interval (CI), 0.45-1.60] or the mRS score at discharge (adjusted common OR, 1.67; 95% CI, 0.88-3.18). After propensity score matching, newly diagnosed AF was not associated with the NIHSS score on admission (adjusted common OR, 0.91; 95% CI, 0.48-1.73) and the mRS score at discharge (adjusted common OR, 1.77; 95% CI, 0.92-3.43). Conclusion: Stroke severity and in-hospital outcomes in patients with newly diagnosed AF did not differ from those in patients with known AF after adjustment for clinically relevant factors. The importance of detection of latent AF and subsequent anticoagulation in preventing severe stroke should be further emphasized.

High neutrophil/lymphocyte ratio at cancer diagnosis predicts incidence of stroke in cancer patients.

Although cancer increases the incidence and severity of ischaemic stroke, there is no reliable method for predicting ischaemic stroke in cancer patients. To evaluate the prognostic capacity of the neutrophil-to-lymphocyte ratio at cancer diagnosis for predicting the incidence of ischaemic stroke, we used a hospital-based cancer registry that contained clinical data from all patients treated for cancer at Osaka University Hospital between 2007 and 2015. The neutrophil-to-lymphocyte ratio was calculated after dividing absolute neutrophil counts by absolute lymphocyte counts. These counts were obtained within 1 month after cancer diagnosis. The primary endpoint was new-onset ischaemic stroke within 2 years after cancer diagnosis. Of the 18 217 included cancer patients (median age: 65.2 years), 69 (0.38%) had ischaemic stroke. Unadjusted Cox regression analysis stratified by cancer site demonstrated that each 1-unit increase in the neutrophil-to-lymphocyte ratio was associated with a significant 7.2% increase in the risk of an ischaemic stroke event (95% confidence interval 1.041-1.103, P < 0.001). Survival tree analysis and the Kaplan-Meier method suggested that patients with and without atrial fibrillation who had increased neutrophil-to-lymphocyte ratios had a higher risk of ischaemic stroke. Multivariate Cox proportional hazard models, adjusted for cancer site and stage, revealed that patients with high neutrophil-to-lymphocyte ratios (>15) had higher ischaemic stroke risk than patients with low neutrophil-to-lymphocyte ratios (<5). This was true among cancer patients both with (hazard ratio 11.598; 95% confidence interval 0.953-141.181) and without (hazard ratio 7.877; 95% confidence interval 2.351-26.389) atrial fibrillation. The neutrophil-to-lymphocyte ratio at cancer diagnosis is associated with the incidence of ischaemic stroke among cancer patients and might thus be useful for identifying patients at high risk of ischaemic stroke, allowing us to guide future preventive interventions.

Sinus Arrest and Bradycardia Induced by Carotid Baroreceptor Reflex Activation during Rotational Angiography: A Case Report.

Objective: We describe a rare patient with a cavernous sinus dural arteriovenous fistula (CS DAVF) in whom diagnostic rotational angiography (RA) caused sinus arrest and bradycardia. Case Presentation: A 79-year-old woman with no previous history of cardiovascular diseases presented with left oculomotor nerve paresis. Conventional angiography confirmed a bilateral CS DAVF. During a three-dimensional RA (3DRA) examination of the left internal carotid artery, sinus arrest occurred. Subsequently, the use of 3DRA to image the left external carotid artery and the use of cone beam computed tomography (CBCT) to image the left internal and external carotid artery also caused transient sinus bradycardia. Two weeks later, we inserted a temporary transvenous pacemaker and completed the transvenous embolization of the left CS DAVF. The left oculomotor paresis improved without any perioperative complications. Conclusion: RA is a standard radiological modality for the diagnosis of cerebrovascular disease. Although the physical force generated by the injection of the contrast medium at the carotid bifurcation can theoretically cause hemodynamic instability, no previous reports have described sinus arrest or bradycardia in association with diagnostic carotid angiography. The present case demonstrates that 3DRA and CBCT can provoke rare, but serious, incidences of cardiac arrhythmia.

Symptom burden and treatment perception in patients with atrial fibrillation, with and without a family history of atrial fibrillation.

Atrial fibrillation (AF) is known to aggregate within family and might be associated with a lower quality-of-life (QoL). We evaluated the association between a family history (FHx) of AF and patient-reported symptom burden and perception towards treatment. We performed a retrospective analysis in a cohort of 1285 newly diagnosed patients with AF. Patients completed the atrial fibrillation effect on quality of life (AFEQT) questionnaire at the time of registration and at the 1-year follow-up. Patients who had a first-degree relative with AF were classified into the FHx group. Baseline characteristics and AFEQT scores were compared between groups, and a multivariate analysis was used to evaluate the independent association between FHx and QoL. Overall, 15.9% of patients (n = 204) had a positive AF FHx. Compared to the non-FHx group, the FHx group had an earlier onset of AF (60.2 ± 12.0 years vs. 64.5 ± 12.1 years; P < 0.05) and lower AFEQT overall summary (AFEQT-OS) score at baseline (73.9 ± 17.8 vs. 77.0 ± 16.8; P < 0.05). After adjustment for clinical background, a positive FHx was independently associated with a worse QoL (changes in AFEQT-OS score = - 3.18; 95% confidence interval: - 5.67 to - 0.69; P = 0.012). No between-group difference in AFEQT-OS scores was noted at the 1-year follow-up. An FHx of AF was associated with a lower QoL, which could be improved by therapeutic intervention in patients with AF. Recognizing the presence of an FHx of AF is important to predict patient's symptom load and treatment acceptance.

CREB Coactivator CRTC2 Plays a Crucial Role in Endothelial Function.

The cAMP pathway is known to stabilize endothelial barrier function and maintain vascular physiology. The family of cAMP-response element binding (CREB)-regulated transcription coactivators (CRTC)1-3 activate transcription by targeting the basic leucine zipper domain of CREB. CRTC2 is a master regulator of glucose metabolism in liver and adipose tissue. However, the role of CRTC2 in endothelium remains unknown. The aim of this study was to evaluate the effect of CRTC2 on endothelial function. We focused the effect of CRTC2 in endothelial cells and its relationship with p190RhoGAP-A. We examined the effect of CRTC2 on endothelial function using a mouse aorta ring assay ex vivo and with photothrombotic stroke in endothelial cell-specific CRTC2-knock-out male mice in vivo CRTC2 was highly expressed in endothelial cells and related to angiogenesis. Among CRTC1-3, only CRTC2 was activated under ischemic conditions at endothelial cells, and CRTC2 maintained endothelial barrier function through p190RhoGAP-A expression. Ser171 was a pivotal regulatory site for CRTC2 intracellular localization, and Ser307 functioned as a crucial phosphorylation site. Endothelial cell-specific CRTC2-knock-out mice showed reduced angiogenesis ex vivo, exacerbated stroke via endothelial dysfunction, and impaired neurologic recovery via reduced vascular beds in vivo These findings suggest that CRTC2 plays a crucial protective role in vascular integrity of the endothelium via p190RhoGAP-A under ischemic conditions.SIGNIFICANCE STATEMENT Previously, the role of CRTC2 in endothelial cells was unknown. In this study, we firstly clarified that CRTC2 was expressed in endothelial cells and among CRTC1-3, only CRTC2 was related to endothelial function. Most importantly, only CRTC2 was activated under ischemic conditions at endothelial cells and maintained endothelial barrier function through p190RhoGAP-A expression. Ser307 in CRTC2 functioned as a crucial phosphorylation site. Endothelial cell-specific CRTC2-knock-out mice showed reduced angiogenesis ex vivo, exacerbated stroke via endothelial dysfunction, and impaired neurologic recovery via reduced vascular beds in vivo These results suggested that CRTC2 maybe a potential therapeutic target for reducing blood-brain barrier (BBB) damage and improving recovery.

Hematological Abnormalities and Malnutrition Mediate Pathway between Cancer and Outcomes in Ischemic Stroke Patients.

BACKGROUND: The present study aimed to examine whether variables including D-dimer, high-sensitivity C-reactive protein (hsCRP), hemoglobin, platelet count, and nutritional status mediate the pathway between cancer and ischemic stroke outcomes. METHODS: We reviewed data from consecutive patients with ischemic stroke admitted to Osaka University Hospital between January 1, 2006, and December 31, 2016. Patients with ischemic stroke were grouped according to the presence of cancer. Nutritional status was assessed using Controlling Nutritional Status (CONUT) scores. Mediation analyses were utilized to address the study aims. RESULTS: Among 1,570 patients with ischemic stroke, 185 (12%) had active cancer. Relative to patients with ischemic stroke in the non-cancer group, those in the cancer group exhibited higher National Institutes of Health Stroke Scale scores on admission, higher D-dimer and hsCRP levels, lower hemoglobin levels and platelet counts, higher CONUT scores, and poorer modified Rankin Scale scores at discharge. Mediation analysis revealed that D-dimer, hsCRP, hemoglobin, platelet count, and CONUT scores acted as mediators of poor prognosis in the cancer group. The association between the exposure and outcome variables was no longer significant in the models containing D-dimer and CONUT scores as mediator variables, suggesting that they were strong mediators. Regarding the association between the mediator and outcome variables, hemoglobin, platelet count, and CONUT exhibited non-linearity (p for non-linearity < 0.001). CONCLUSIONS: D-dimer, hsCRP, hemoglobin, platelet count, and CONUT score act as mediators of poor prognosis in patients with ischemic stroke with comorbid cancer. Such abnormalities can help to predict ischemic stroke outcomes.

Promising Effect of a New Ketogenic Diet Regimen in Patients with Advanced Cancer.

A ketogenic diet is expected to be an effective support therapy for patients with cancer, but the degree and duration of carbohydrate restriction are unclear. We performed a case series study of a new ketogenic diet regimen in patients with different types of stage IV cancer. Carbohydrates were restricted to 10 g/day during week one, 20 g/day from week two for three months, and 30 g/day thereafter. A total of 55 patients participated in the study, and data from 37 patients administered the ketogenic diet for three months were analyzed. No severe adverse events associated with the diet were observed. Total ketone bodies increased significantly, and both fasting blood sugar and insulin levels were suppressed significantly for three months after completion of the study. Five patients showed a partial response on Positron emission tomography-computed tomography (PET-CT) at three months. Three and seven patients showed complete and partial responses, respectively at one year. Median survival was 32.2 (maximum: 80.1) months, and the three-year survival rate was 44.5%. After three months on the ketogenic diet, the serum Alb, BS, and CRP (ABC) score could be used to stratify the patients into groups with significantly different survival rates (p < 0.001, log-rank test). Our ketogenic diet regimen is considered to be a promising support therapy for patients with different types of advanced cancer.

Reduced Plasma NT-proBNP Levels Months after Myocardial Infarction Postconditioned with Lactate-Enriched Blood.

BACKGROUND: We recently reported a new approach, namely postconditioning with lactate-enriched blood (PCLeB), for cardioprotection in patients with ST-segment elevation myocardial infarction (STEMI). OBJECTIVES: We examined the effects of PCLeB on plasma NT-proBNP levels months after myocardial infarction (MI). METHODS: The study included consecutive patients (n = 31) undergoing percutaneous coronary intervention (PCI) for anterior STEMI within 12 h of symptom onset in our hospital between March 2014 and August 2018. We retrospectively compared plasma NT-proBNP levels several months after MI in these patients with those in historical control patients (n = 32). The control patients included consecutive patients who underwent successful PCI without PCLeB for anterior STEMI within 12 h of symptom onset in our hospital between March 2009 and February 2014. We compared the highest plasma NT-proBNP values 6-10 months after MI in the postconditioned patients with the lowest plasma NT-proBNP values 6-10 months after MI in the control patients. In the PCLeB protocol, the duration of each brief reperfusion was increased stepwise from 10 to 60 s. Lactated Ringer's solution (30 mL) was injected directly in the culprit coronary artery at the end of each brief reperfusion. Each ischemic episode lasted 60 s. RESULTS: Plasma NT-proBNP levels in the postconditioned patients months after MI (211 ± 207 pg/mL) were significantly lower than those in the control patients (516 ± 598 pg/mL; p < 0.0001). CONCLUSION: PCLeB was associated with reduced plasma NT-proBNP levels months after MI.