A cavernous sinus dural arteriovenous fistula treated by direct puncture of the superior ophthalmic vein with craniotomy: illustrative case.

BACKGROUND: The authors report a case of symptomatic cavernous sinus (CS) dural arteriovenous fistula (dAVF) that was successfully treated using direct puncture of the superior ophthalmic vein (SOV) with craniotomy. CS dAVF is commonly treated using transvenous embolization (TVE), with the most common access route via the inferior petrosal sinus (IPS). However, this route is sometimes unavailable because of an occluded, hypoplastic, aplastic, or tortuous IPS. The SOV is an alternative, albeit tortuous and long, route to the CS; therefore, direct SOV puncture is occasionally performed. Direct SOV puncture is mostly percutaneous; however, in this case, it was difficult because of subcutaneous SOV narrowing. OBSERVATIONS: As the patient experienced increased intraocular pressure, decreased vision, and eye movement disorders, CS embolization was performed via direct puncture with a craniotomy because of other access difficulties. LESSONS: Several reports have described CS dAVF in patients receiving endovascular treatment via direct SOV puncture using a transorbital approach. However, to the best of the authors' knowledge, this is the first reported case of a CS dAVF treated using TVE with craniotomy. This approach is useful when the SOV cannot be reached intravenously and its distance from the epidermis is long.

Percutaneous transluminal angioplasty for persistent primitive hypoglossal artery stenosis: illustrative case.

BACKGROUND: We report a case of symptomatic, progressive stenosis of a persistent primitive hypoglossal artery (PPHA), which was successfully treated with percutaneous transluminal angioplasty (PTA) of the origin of the PPHA. The PPHA is a type of carotid-basilar anastomosis with an incidence of 0.02% to 0.10%. It originates from the internal carotid artery (ICA), passes through the hypoglossal canal, and merges with the basilar artery. In many cases, the ipsilateral vertebral artery is hypoplastic; therefore, PPHA stenosis causes cerebral infarction in the posterior circulation territory, as in this case. OBSERVATIONS: The patient's right PPHA had severe and progressive stenosis; therefore, he experienced cerebral infarction despite medical treatment. Therefore, PTA for the stenosis was performed, which ceased the recurrence of cerebral infarction and dizziness by improving blood flow in the posterior circulation. LESSONS: Several reports have described ICA stenosis accompanied by PPHA or PPHA stenosis in patients receiving endovascular treatments. Almost all cases were nonprogressive, and the treatment procedure was stenting. However, in our case, the PPHA stenosis was progressive, and we performed PTA because the patient experienced resistance to antiplatelet drugs and had poor collateral flow.

Machine Learning Risk Prediction for Incident Heart Failure in Patients With Atrial Fibrillation.

Background: Atrial fibrillation (AF) increases the risk of heart failure (HF); however, little focus is placed on the risk stratification for, and prevention of, incident HF in patients with AF. Objectives: This study aimed to construct and validate a machine learning (ML) prediction model for HF hospitalization in patients with AF. Methods: The Fushimi AF Registry is a community-based prospective survey of patients with AF in Fushimi-ku, Kyoto, Japan. We divided the data set of the registry into derivation (n = 2,383) and validation (n = 2,011) cohorts. An ML model was built to predict the incidence of HF hospitalization using the derivation cohort, and predictive ability was examined using the validation cohort. Results: HF hospitalization occurred in 606 patients (14%) during a median follow-up period of 4.4 years in the entire registry. Data of transthoracic echocardiography and biomarkers were frequently nominated as important predictive variables across all 6 ML models. The ML model based on a random forest algorithm using 7 variables (age, history of HF, creatinine clearance, cardiothoracic ratio on x-ray, left ventricular [LV] ejection fraction, LV end-systolic diameter, and LV asynergy) had high prediction performance (area under the receiver operating characteristics curve [AUC]: 0.75) and was significantly superior to the Framingham HF risk model (AUC: 0.67; P < 0.001). Based on Kaplan-Meier curves, the ML model could stratify the risk of HF hospitalization during the follow-up period (log-rank; P < 0.001). Conclusions: The ML model revealed important predictors and helped us to stratify the risk of HF, providing opportunities for the prevention of HF in patients with AF.

Hemodynamic Risk Factors for the Development of Carotid Stenosis in Patients with Unilateral Carotid Stenosis.

BACKGROUND: It is difficult to predict the development of carotid stenosis by means of the known risk factors. Using a computational fluid dynamics analysis, we examined the hemodynamic risks for carotid stenosis, focusing on wall shear stress (WSS) disturbances. METHODS: In 59 patients with unilateral carotid stenosis, the plaque was removed from the original three-dimensional computed tomography angiographic images, and the vessel shape before stenosis was artificially reproduced. A multivariate regression analysis was performed to determine the associations between the degree of area stenosis and hemodynamic and morphologic factors after adjustment for 6 known risk factors. RESULTS: Metrics for WSS disturbances were higher at and distal to a bifurcation in the carotid arteries after plaque removal compared with the normal carotid arteries, and metrics for WSS magnitudes were lower. In the plaque-removed arteries, the degree of stenosis was significantly negatively correlated with the ratio of stenotic to distal values of metrics for WSS disturbances and the diameter ratio of the external to common carotid artery, and positively correlated with the ratio of proximal to stenotic values of metrics for WSS magnitudes. CONCLUSIONS: Rapid increases in WSS from the common carotid artery toward the bifurcation, rapid decreases in WSS disturbance from the bifurcation toward the internal carotid artery, and lower diameter ratio of the external to common carotid artery are more likely than other risk factors to cause future severe stenosis. In patients with these hemodynamic risks, underlying diseases should be controlled more strictly, with imaging examinations at shorter intervals.

Predicting cerebral infarction in patients with atrial fibrillation using machine learning: The Fushimi AF registry.

The CHADS2 and CHA2DS2-VASc scores are widely used to assess ischemic risk in the patients with atrial fibrillation (AF). However, the discrimination performance of these scores is limited. Using the data from a community-based prospective cohort study, we sought to construct a machine learning-based prediction model for cerebral infarction in patients with AF, and to compare its performance with the existing scores. All consecutive patients with AF treated at 81 study institutions from March 2011 to May 2017 were enrolled (n = 4396). The whole dataset was divided into a derivation cohort (n = 1005) and validation cohort (n = 752) after excluding the patients with valvular AF and anticoagulation therapy. Using the derivation cohort dataset, a machine learning model based on gradient boosting tree algorithm (ML) was built to predict cerebral infarction. In the validation cohort, the receiver operating characteristic area under the curve of the ML model was higher than those of the existing models according to the Hanley and McNeil method: ML, 0.72 (95%CI, 0.66-0.79); CHADS2, 0.61 (95%CI, 0.53-0.69); CHA2DS2-VASc, 0.62 (95%CI, 0.54-0.70). As a conclusion, machine learning algorithm have the potential to perform better than the CHADS2 and CHA2DS2-VASc scores for predicting cerebral infarction in patients with non-valvular AF.

Characteristics and clinical outcomes in atrial fibrillation patients classified using cluster analysis: the Fushimi AF Registry.

AIMS: The risk of adverse events in atrial fibrillation (AF) patients was commonly stratified by risk factors or clinical risk scores. Risk factors often do not occur in isolation and are often found in multimorbidity 'clusters' which may have prognostic implications. We aimed to perform cluster analysis in a cohort of AF patients and to assess the outcomes and prognostic implications of the identified comorbidity cluster phenotypes. METHODS AND RESULTS: The Fushimi AF Registry is a community-based prospective survey of the AF patients in Fushimi-ku, Kyoto, Japan. Hierarchical cluster analysis was performed on 4304 patients (mean age: 73.6 years, female; 40.3%, mean CHA2DS2-VASc score 3.37 ± 1.69), using 42 baseline clinical characteristics. On hierarchical cluster analysis, AF patients could be categorized into six statistically driven comorbidity clusters: (i) younger ages (mean age: 48.3 years) with low prevalence of risk factors and comorbidities (n = 209); (ii) elderly (mean age: 74.0 years) with low prevalence of risk factors and comorbidities (n = 1301); (iii) those with high prevalence of atherosclerotic risk factors, but without atherosclerotic disease (n = 1411); (iv) those with atherosclerotic comorbidities (n = 440); (v) those with history of any-cause stroke (n = 681); and (vi) the very elderly (mean age: 83.4 years) (n = 262). Rates of all-cause mortality and major adverse cardiovascular or neurological events can be stratified by these six identified clusters (log-rank test; P < 0.001 and P < 0.001, respectively). CONCLUSIONS: We identified six clinically relevant phenotypes of AF patients on cluster analysis. These phenotypes can be associated with various types of comorbidities and associated with the incidence of clinical outcomes. CLINICAL TRIAL REGISTRATION INFORMATION: https://www.umin.ac.jp/ctr/index.htm. Unique identifier: UMIN000005834.

Fluid shear stress-mediated mechanotransduction in circulating leukocytes and its defect in microvascular dysfunction.

Leukocytes (neutrophils, monocytes) in the active circulation exhibit multiple phenotypic indicators for a low level of cellular activity, like lack of pseudopods and minimal amounts of activated, cell-adhesive integrins on their surfaces. In contrast, before these cells enter the circulation in the bone marrow or when they recross the endothelium into extravascular tissues of peripheral organs they are fully activated. We review here a multifaceted mechanism mediated by fluid shear stress that can serve to deactivate leukocytes in the circulation. The fluid shear stress controls pseudopod formation via the FPR receptor, the same receptor responsible for pseudopod projection by localized actin polymerization. The bioactivity of macromolecular factors in the blood plasma that interfere with receptor stimulation by fluid flow, such as proteolytic cleavage in the extracellular domain of the receptor or the membrane actions of cholesterol, leads to a defective ability to respond to fluid shear stress by actin depolymerization. The cell reaction to fluid shear involves CD18 integrins, nitric oxide, cGMP and Rho GTPases, is attenuated in the presence of inflammatory mediators and modified by glucocorticoids. The mechanism is abolished in disease models (genetic hypertension and hypercholesterolemia) leading to an increased number of activated leukocytes in the circulation with enhanced microvascular resistance and cell entrapment. In addition to their role in binding to biochemical agonists/antagonists, membrane receptors appear to play a second role: to monitor local fluid shear stress levels. The fluid shear stress control of many circulating cell types such as lymphocytes, stem cells, tumor cells remains to be elucidated.

Disruption of P2X4 purinoceptor and suppression of the inflammation associated with cerebral aneurysm formation.

OBJECTIVE: There are no effective therapeutic drugs for cerebral aneurysms, partly because the pathogenesis remains unresolved. Chronic inflammation of the cerebral arterial wall plays an important role in aneurysm formation, but it is not clear what triggers the inflammation. The authors have observed that vascular endothelial P2X4 purinoceptor is involved in flow-sensitive mechanisms that regulate vascular remodeling. They have thus hypothesized that shear stress-associated hemodynamic stress on the endothelium causes the inflammatory process in the cerebral aneurysm development. METHODS: To test their hypothesis, the authors examined the role of P2X4 in cerebral aneurysm development by using P2X4-/- mice and rats that were treated with a P2X4 inhibitor, paroxetine, and subjected to aneurysm-inducing surgery. Cerebral aneurysms were induced by unilateral carotid artery ligation and renovascular hypertension. RESULTS: The frequency of aneurysm induction evaluated by light microscopy was significantly lower in the P2X4-/- mice (p = 0.0488) and in the paroxetine-treated male (p = 0.0253) and female (p = 0.0204) rats compared to control mice and rats, respectively. In addition, application of paroxetine from 2 weeks after surgery led to a significant reduction in aneurysm size in the rats euthanized 3 weeks after aneurysm-inducing surgery (p = 0.0145), indicating that paroxetine suppressed enlargement of formed aneurysms. The mRNA and protein expression levels of known inflammatory contributors to aneurysm formation (monocyte chemoattractant protein-1 [MCP-1], interleukin-1ß [IL-1ß], tumor necrosis factor-α [TNFα], inducible nitric oxide synthase [iNOS], and cyclooxygenase-2 [COX-2]) were all significantly elevated in the rats that underwent the aneurysm-inducing surgery compared to the nonsurgical group, and the values in the surgical group were all significantly decreased by paroxetine administration according to quantitative polymerase chain reaction techniques and Western blotting. Although immunolabeling densities for COX-2, iNOS, and MCP-1 were not readily observed in the nonsurgical mouse groups, such densities were clearly seen in the arterial wall of P2X4+/+ mice after aneurysm-inducing surgery. In contrast, in the P2X4-/- mice after the surgery, immunolabeling of COX-2 and iNOS was not observed in the arterial wall, whereas that of MCP-1 was readily observed in the adventitia, but not the intima. CONCLUSIONS: These data suggest that P2X4 is required for the inflammation that contributes to both cerebral aneurysm formation and growth. Enhanced shear stress-associated hemodynamic stress on the vascular endothelium may trigger cerebral aneurysm development. Paroxetine may have potential for the clinical treatment of cerebral aneurysms, given that this agent exhibits efficacy as a clinical antidepressant.

Daily Habit of Water Intake in Patients with Cerebral Infarction before its Onset; Comparison with a Healthy Population: A Cross-Sectional Study.

BACKGROUND: While water intake is frequently recommended to prevent cerebral infarction (CI), only few studies have been published on this topic. OBJECTIVES: This study retrospectively estimated the daily non-alcohol drink (NAD) intake in CI patients before CI onset and compared it with NAD in healthy subjects. METHODS: We performed a cross-sectional study on CI patients in 3 hospitals and healthy subjects in the Kobe Orthopedic and Biomedical Epidemiologic (KOBE) study. Data from 1,287 subjects (274 CI patients and 1,013 healthy subjects) were used for the analyses. By dividing the CI patients into "increased", "unchanged", and "decreased" groups according to their current NAD intake, we compared the NAD intake between these 3 groups and healthy subjects by analyses of covariance and the post hoc test, adjusting for sex, age, surveyed month, body mass index, alcohol drinking history, and smoking history. Under the assumption that the NAD intake in the "unchanged" group was equal to the NAD intake before CI onset, the OR of less NAD intake for CI adjusting for the relevant variables in the "unchanged" group and the healthy subjects was calculated; the cut-off point was chosen using Youden's index. RESULTS: The mean age (mean ± SD) of the participants was 62.8 ± 9.3 years. One hundred and fifty-one patients (36 women) were included in the "increased" group; 105 (30 women), in the "unchanged" group; 18 (2 women), in the "decreased" group; and 1,013 (706 women), in the "healthy" group. The mean NAD intake was 1,702.5 ± 670.2 mL in the "increased" group, 1,494.2 ± 611.2 mL in the "unchanged" group, 1,268.0 ± 596.1 mL in the "decreased" group, and 1,720.6 ± 686.0 mL in the "healthy" group. After adjusting for the relevant variables, a significant difference in NAD intake between the groups was observed (F = 6.1, p < 0.001), and a post hoc test demonstrated significant differences (p < 0.05) in NAD intake between the "healthy" and "unchanged" groups, and between the "increased" and "unchanged" groups. The OR of less NAD intake (<1,570 mL/day, chosen using Youden's index) for CI was 2.48 (95% CI 1.52-4.07). CONCLUSION: This study showed that daily NAD intake before CI onset in CI patients was less than that in healthy persons, indicating that sufficient intake of NAD may be protective for CI.

Postoperative ischemic events in patients undergoing carotid artery stenting using algorithmic selection for embolic protection.

PURPOSE: Carotid artery stenting (CAS) is a valuable alternative to carotid endarterectomy, especially in high-risk patients. However, the reported incidences of perioperative stroke and death remain higher than for carotid endarterectomy, even when using embolic protection devices (EPDs) during CAS. Our purpose was to evaluate 30-day major adverse events after CAS when selecting the most appropriate EPD. METHODS: We reviewed the clinical outcomes of 61 patients with 64 lesions who underwent CAS with EPDs. Patients who underwent CAS associated with thrombectomy and who had a preoperative modified Rankin scale score >3 were excluded from the analysis. The EPD was selected based on symptoms, carotid wall magnetic resonance imaging and lesion length, and we analyzed combined 30-day complication rates (transient ischemic attack, minor stroke, major stroke or death). RESULTS: Forty-nine patients were men and 12 were women. The median age was 72 years (range: 59-89 years) and 44 lesions were asymptomatic. A filter-type EPD was selected in 23 procedures, distal-balloon protection in 14 procedures and proximal-occlusive protection in 27 procedures. Two patients (3.1%) experienced a transient ischemic attack and one patient (1.6%) had a minor stroke within 30 days of the procedure. No patients experienced procedure-related morbidities (modified Rankin score >2) or death. CONCLUSIONS: The perioperative stoke rate was low when we selected a proximal-occlusive-type EPD in high-risk patients with vulnerable carotid artery disease. Our algorithm for EPD selection was an effective tool in the perioperative management of carotid artery stenosis.

Endovascular treatment of acute ischaemic stroke in octogenarians and nonagenarians compared with younger patients.

Purpose: Endovascular therapy for emergent large vessel occlusion has been established as the standard approach for acute ischaemic stroke. However, the effectiveness and safety of endovascular therapy in the very elderly population has not been proved. Objective: To determine the safety and effectiveness of endovascular therapy in octogenarians and nonagenarians. Methods: We retrospectively reviewed all patients who underwent endovascular therapy at two stroke centres between April 2012 and July 2018. Functional outcome was assessed using the modified Rankin scale at 90 days after stroke or at discharge. A favourable outcome was defined as a modified Rankin scale score of 0-2 or not worsening of the modified Rankin scale score before stroke. Outcome was compared between younger patients (aged 46-79 years, n = 40) and octogenarians and nonagenarians (aged 80-97 years, n = 19). Results: Octogenarian and nonagenarian patients had pre-stroke functional deficit (modified Rankin scale score >1) more frequently than younger patients (57.9% vs. 20.0%, respectively, P = 0.0059). No difference was observed between very elderly and younger patients in the rate of successful reperfusion (89.5% vs. 67.5%, respectively, P = 0.11), favourable functional outcome (47.4% vs. 45.0%, respectively, P = 1.00) and mortality (21.1% vs. 27.5%, respectively, P = 1.00). On multiple regression analysis, successful reperfusion, concomitant use of intravenous thrombolysis, and out-of-hospital onset were independent predictors of favourable outcome (P = 0.0003, 0.015 and 0.028, respectively). Conclusions: Successful reperfusion, concomitant use of intravenous thrombolysis, and out-of-hospital onset were clinical predictors of favourable outcome. However, we did not observe an age-dependent effect of clinical outcome after endovascular therapy.

Predictors of Cardioembolic Stroke in Japanese Patients with Atrial Fibrillation in the Fushimi AF Registry.

BACKGROUND: Large-scale clinical trials have analyzed risk factors for any ischemic stroke in patients with atrial fibrillation (AF). However, the risk factors for cardioembolic stroke (CES), specifically, have not been reported. To clarify the risk factors for CES and clinically significant cardioembolic infarction, we examined the incidence of CES and larger infarct volume (IV) (> 30 mL) CES, employing the Fushimi AF Registry, a community-based prospective cohort of AF patients in the Fushimi ward, Kyoto, Japan. METHODS: A total of 4,182 Fushimi AF patients were enrolled from March 2011 to December 2014. The risk factors for CES were evaluated using multivariate analysis. RESULTS: Of 4,182 patients enrolled, 3,749 patients were observed for ≥1 year. During the follow-up period (mean duration, 979 ± 7.7 days), 91/3,749 patients experienced a CES (2.43%). Significant risk factors associated with CES were older age (odds ratio [OR], 1.31; 95% confidence interval [CI], 1.01-1.72; p = 0.046), low body weight (OR, 1.30; 95% CI, 1.03-1.65; p = 0.033), sustained AF (OR, 1.67; 95% CI, 1.05-2.71; p = 0.034), and previous stroke or transient ischemic attack (TIA) (OR, 1.94; 95% CI, 1.22-3.06; p = 0.004). Predictors of a large IV were chronic kidney disease (CKD) (OR, 2.08; 95% CI, 1.09-4.05; p = 0.027) and previous stroke/TIA (OR, 2.27; 95% CI, 1.19-4.24; p = 0.011). CONCLUSIONS: In this population-based cohort of Japanese patients with AF, in addition to previous stroke/TIA and older age, sustained AF and low body weight emerged as risk factors for CES, as opposed to any stroke, which may have a different risk profile. Patients with CKD or previous stroke/TIA who developed cardioembolic infarction exhibited more advanced severity. There is a need for direct oral anticoagulants that can be used safely in patients with comorbid AF and CKD.

Pazopanib-mediated Long-term Disease Stabilization after Local Recurrence and Distant Metastasis of Primary Intracranial Leiomyosarcoma: A Case Report on the Efficacy of Pazopanib as a Salvage Therapy.

Primary intracranial leiomyosarcoma (LMS) is an extremely rare tumor of the central nervous system. Only sporadic case reports have been published, and therefore data regarding long-term prognosis remain scarce. A 76-year-old woman presented with a right parietal mass, which had grown rapidly in the month prior to admission. Neuroimaging showed a resemblance to intraosseous meningioma. Gross total resection of the tumor was achieved, and histological diagnosis confirmed LMS. Because positron emission tomography (PET) with fluorodeoxyglucose (FDG) just after the resection showed no abnormal uptake, we diagnosed the tumor as primary intracranial LMS. Follow-up PET at 16 months after treatment showed two foci of FDG uptake in the bilateral lungs. Histological diagnosis by surgical resection identified the lesions as lung metastases of LMS. In addition, follow-up head magnetic resonance imaging (MRI) at 31 months showed local recurrence, and we conducted salvage therapy using CyberKnife system (Accuray incorporated) and pazopanib. To date, for 15 months after local recurrence, she is alive with intracranial recurrent disease remained inactive.

Endovascular embolization of branch-incorporated cerebral aneurysms.

Objectives The aim of this study was to examine the feasibility, technique, and clinical and angiographic outcomes of endovascular coiling to treat a cerebral aneurysm with a branch incorporated into the aneurysmal wall. Methods From 2012 to 2016, 25 patients with 26 cerebral aneurysms having a branch incorporated into the aneurysm (9 unruptured, 17 ruptured) were treated to prevent rupture or re-bleeding from the sac while preserving the incorporated branch by using single-catheter ( n = 18), balloon-remodeling ( n = 4), stent-assisted coiling ( n = 3), or double-catheter ( n = 1) techniques. Results Endovascular coiling was conducted in 26 procedures without angiographic occlusion of the incorporated branch. Post-embolization angiography revealed near-complete occlusion ( n = 8; 30.7%), neck remnant ( n = 13; 50%), and incomplete occlusion ( n = 5; 19.3%) aneurysms. Thromboembolisms were observed in four (15.4%) patients during or after the procedure. A procedure-related neurological deficit was observed in one (3.8%) patient. When patients with a preictal modified Rankin Scale (mRS) score of 3 presenting with grade 5 subarachnoid hemorrhage were excluded, all patients had favorable outcomes (mRS 0-2). Six (23.1%) recurrent aneurysms were observed during follow-up, five of which were treated endovascularly at 5-22 months without complication. The location of an aneurysm at the ICA-posterior communicating artery associated with the dominant-type posterior communicating artery was significantly associated with recurrence ( p = 0.041). Conclusions Cerebral aneurysms with an incorporated branch were safely treated using conventional endovascular coiling. However, treatment durability was unsatisfactory, especially for dominant-type ICA-posterior communicating artery aneurysms.

Fluid shear-induced cathepsin B release in the control of Mac1-dependent neutrophil adhesion.

There is compelling evidence that circulatory hemodynamics prevent neutrophil activation, including adhesion to microvessels, in the microcirculation. However, the underlying mechanism or mechanisms by which that mechanoregulation occurs remain unresolved. Here, we report evidence that exposure to fluid shear stress (FSS) promotes neutrophils to release cathepsin B (ctsB) and that this autocrine regulatory event is antiadhesive for neutrophils on endothelial surfaces through Mac1-selective regulation. We used a combined cell-engineering and immunocytochemistry approach to find that ctsB was capable of cleaving Mac1 integrins on neutrophils and demonstrated that this proteolysis alters their adhesive functions. Under no-flow conditions, ctsB enhanced neutrophil migration though a putative effect on pseudopod retraction rates. We also established a flow-based cell detachment assay to verify the role of ctsB in the control of neutrophil adhesion by fluid flow stimulation. Fluid flow promoted neutrophil detachment from platelet and endothelial layers that required ctsB, consistent with its fluid shear stress-induced release. Notably, compared with leukocytes from wild-type mice, those from ctsB-deficient (ctsB -/- ) mice exhibited an impaired CD18 cleavage response to FSS, significantly elevated baseline levels of CD18 surface expression, and an enhanced adhesive capacity to mildly inflamed postcapillary venules. Taken together, the results of the present study support a role for ctsB in a hemodynamic control mechanism that is antiadhesive for leukocytes on endothelium. These results have implications in the pathogenesis of chronic inflammation, microvascular dysfunction, and cardiovascular diseases involving sustained neutrophil activation in the blood and microcirculation.

Sustained expression of MCP-1 by low wall shear stress loading concomitant with turbulent flow on endothelial cells of intracranial aneurysm.

INTRODUCTION: Enlargement of a pre-existing intracranial aneurysm is a well-established risk factor of rupture. Excessive low wall shear stress concomitant with turbulent flow in the dome of an aneurysm may contribute to progression and rupture. However, how stress conditions regulate enlargement of a pre-existing aneurysm remains to be elucidated. RESULTS: Wall shear stress was calculated with 3D-computational fluid dynamics simulation using three cases of unruptured intracranial aneurysm. The resulting value, 0.017 Pa at the dome, was much lower than that in the parent artery. We loaded wall shear stress corresponding to the value and also turbulent flow to the primary culture of endothelial cells. We then obtained gene expression profiles by RNA sequence analysis. RNA sequence analysis detected hundreds of differentially expressed genes among groups. Gene ontology and pathway analysis identified signaling related with cell division/proliferation as overrepresented in the low wall shear stress-loaded group, which was further augmented by the addition of turbulent flow. Moreover, expression of some chemoattractants for inflammatory cells, including MCP-1, was upregulated under low wall shear stress with concomitant turbulent flow. We further examined the temporal sequence of expressions of factors identified in an in vitro study using a rat model. No proliferative cells were detected, but MCP-1 expression was induced and sustained in the endothelial cell layer. CONCLUSIONS: Low wall shear stress concomitant with turbulent flow contributes to sustained expression of MCP-1 in endothelial cells and presumably plays a role in facilitating macrophage infiltration and exacerbating inflammation, which leads to enlargement or rupture.

Successful endovascular treatment of a dissecting aneurysm of vertebral artery associated with double origin of the posterior inferior cerebellar artery.

BACKGROUND: Double origin of the posterior inferior cerebellar artery (DOPICA) has been rarely reported in the literature, with a reported incidence of 1.45%. In contrast, a high concurrence rate of DOPICA and vertebral artery dissecting aneurysm has been reported. CLINICAL PRESENTATION: A 61-year old woman presented with vomiting and diplopia with preceding headache. Magnetic resonance imaging (MRI) showed fresh infarction of the left lateral medulla and a vertebral artery dissecting aneurysm of the left vertebral artery. The next day, she exhibited transient loss of consciousness and worsening of headache, and MRI depicted subarachnoid hemorrhage. Four-vessel digital subtraction angiography showed a posterior inferior cerebellar artery (PICA) arising both intracranially and extracranially from the left vertebral artery. Although the dissecting lesion involved the V3 and V4 portion, it did not involve an extracranially originating PICA. Internal trapping of the V3 and V4 portion was chosen as the extracranial channel was expected to supply the PICA territory. This procedure was safely performed. CONCLUSION: Early endovascular intervention should be considered in the treatment of dissecting aneurysm of vertebral artery associated with DOPICA for patients with relatively long lesions even in unruptured cases.

Cathepsin L acutely alters microvessel integrity within the neurovascular unit during focal cerebral ischemia.

During focal cerebral ischemia, the degradation of microvessel basal lamina matrix occurs acutely and is associated with edema formation and microhemorrhage. These events have been attributed to matrix metalloproteinases (MMPs). However, both known protease generation and ligand specificities suggest other participants. Using cerebral tissues from a non-human primate focal ischemia model and primary murine brain endothelial cells, astrocytes, and microglia in culture, the effects of active cathepsin L have been defined. Within 2 hours of ischemia onset cathepsin L, but not cathepsin B, activity appears in the ischemic core, around microvessels, within regions of neuron injury and cathepsin L expression. In in vitro studies, cathepsin L activity is generated during experimental ischemia in microglia, but not astrocytes or endothelial cells. In the acidic ischemic core, cathepsin L release is significantly increased with time. A novel ex vivo assay showed that cathepsin L released from microglia during ischemia degrades microvessel matrix, and interacts with MMP activity. Hence, the loss of microvessel matrix during ischemia is explained by microglial cathepsin L release in the acidic core during injury evolution. The roles of cathepsin L and its interactions with specific MMP activities during ischemia are relevant to strategies to reduce microvessel injury and hemorrhage.

Practical approaches to diagnose and treat for T0 malignant pleural mesothelioma: a proposal for diagnostic total parietal pleurectomy.

Malignant pleural mesothelioma (MPM) remains suffering poor prognosis in spite of recent diagnostic and therapeutic progress. Although there is currently no established evidence, early diagnosis and early intervention may play a key role to improve prognosis of MPM, similarly to other malignancies. As pleural effusion is usually the first clinical sign of MPM, pleural effusion cytology is often the first diagnostic examination to be carried out. Since the sensitivity of pleural effusion cytology is approximately 60%, however, false-negative diagnosis is given to almost half of true MPM patients at this clinical step. One practical way to reduce the number of misdiagnosed MPM is to encourage performing thoracoscopic pleural biopsy unless definitive diagnosis other than MPM is established. There still remain a considerable number of patients with radiological/thoracoscopic T0 MPM who are misdiagnosed with nonspecific pleuritis after a complete investigation including thoracoscopic biopsies. Such patients will turn out to be malignant during follow-up period, although they have the best opportunity for long-term survival if only early therapeutic intervention is given. Currently, we are performing diagnostic total parietal pleurectomy in highly selected patients, who are characterized with strong clinical suspicion, positive pleural effusion cytology but uncertain pathological diagnosis, excellent cardiopulmonary reserve, and with written informed consent for highly invasive diagnostic surgery for pathologically unproven disease.

Characteristics of carotid plaque findings on ultrasonography and black blood magnetic resonance imaging in comparison with pathological findings.

BACKGROUND: Criteria to decide whether carotid endarterectomy (CEA) or carotid artery stenting (CAS) is the best mode of therapy in a specific case of cervical carotid stenosis have not been established. Overall, recent randomized clinical trials have reported that the effect on the prevention of stroke is not significantly different between CEA and CAS. CEA is more appropriate than CAS for soft atherosclerotic plaques, since such soft plaques are associated with a high incidence of ischemic complications during CAS. Therefore identification of the plaque type with noninvasive preoperative examinations plays an important role for selecting the suitable surgical method, CEA or CAS. OBJECTIVE: The objective of this study was to evaluate the association among findings of carotid ultrasonography (carotid US), black blood magnetic resonance imaging (BB-MRI), and the histopathological findings of plaque specimens removed during CEA, and secondly to consider whether these diagnostic tools are useful to predict the characteristics of carotid plaques. METHOD: We investigated a total of 25 consecutive patients who underwent CEA from November 2008 to June 2010 at Kyoto Medical Center. We examined carotid plaque in 17 patients employing both carotid US and BB-MRI, 7 patients by carotid US, and 1 patient by BB-MRI. The plaque echogenicity was qualitatively assessed as low, intermediate, or high, and the MR signal intensity of the carotid plaque was classified as low or high compared with the intensity of the ipsilateral sternocleidomastoid muscle. The plaque specimens were macroscopically and pathophysiologically classified as soft or hard plaque. RESULTS: All low-echogenic plaques on carotid US were histologically soft plaques. The high-intensity plaques on T1-weighted imaging (T1WI) showed a tendency toward soft plaque. Thirteen of 14 plaques with high signal intensity on T1WI were morphologically soft. Eleven of 14 plaques with an intermediate echogenicity on carotid US were also morphologically soft. CONCLUSION: The findings of carotid ultrasonography and BB-MRI are closely associated with the CEA specimen's morphology. Ultrasonography alone is insufficient to diagnose the plaque type accurately in some patients. Employing both carotid US and BB-MRI is useful for evaluating the characteristics of carotid plaque.