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Background: Alcoholic liver disease (ALD) significantly contributes to global liver-related morbidity and mortality. Natural products play a crucial role in the prevention and treatment of ALD. Hydroxysafflor yellow A (HSYA), a unique and primary component of Safflower (Carthamus tinctorius l.), exhibits diverse pharmacological activities. However, the impact and mechanism of HSYA on ALD have not been fully elucidated., Purpose: The purpose of this study was to employ an integrative pharmacology approach to assess the multi-targeted mechanism of HSYA against ALD., Methods: Network pharmacology and molecular docking techniques were used to analyze the potential therapeutic signaling pathways and targets of HSYA against ALD. An ALD model in zebrafish larvae was established. Larvae were pretreated with HSYA and then exposed to ethanol. Liver injury was measured by fluorescence expression analysis in the liver-specific transgenic zebrafish line Tg (fabp10a:DsRed) and liver tissue H&E staining. Liver steatosis was determined by whole-mount oil red O staining and TG level. Additionally, an ethanol-induced hepatocyte injury model was established in vitro to observe hepatocyte damage (cell viability, ALT level), lipid accumulation (oil red O staining, TC and TG), and oxidative stress (ROS, MDA, GPx and SOD) in HepG2 cells treated with or without HSYA. Finally, qRT-PCR combined with network pharmacology and molecular docking was employed to validate the effects of HSYA on targets., Results: HSYA exhibited a significant, dose-dependent improvement in ethanol-induced liver injury in zebrafish larvae and HepG2 cells. Network pharmacology analysis revealed that HSYA may exert pharmacological effects against ALD through 341 potential targets. These targets are involved in various signaling pathways, including lipid metabolism and atherosclerosis, PI3K-Akt signaling pathway, MAPK signaling pathway, and ALD itself. Molecular docking studies displayed that HSYA had a strong binding affinity toward the domains of IL1B, IL6, TNF, PPARA, PPARG, HMGCR and ADH5. qRT-PCR assays demonstrated that HSYA effectively reversed the ethanol-induced aberrant gene expression of SREBF1, FASN, ACACA, CPT1A, PPARA, IL1B, IL6, TNFα, ADH5, and ALDH2 in vivo and in vitro., Conclusion: This study offers a comprehensive investigation into the anti-ALD mechanisms of HSYA using an integrative pharmacology approach. The potential targets of HSYA may be implicated in enhancing ethanol catabolism, reducing lipid accumulation, mitigating oxidative stress, and inhibiting inflammatory response., Competing Interests: Declaration of competing interest The authors declared no conflict of interest. The authors declared that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024. Published by Elsevier GmbH.)

Aims: Erythropoiesis is controlled by several factors, including oxygen level under different circumstances. However, the role of hypoxia in erythroid differentiation and the underlying mechanisms are poorly understood. We studied the effect and mechanism of hypoxia on erythroid differentiation of K562 cells and observed the effect of hypoxia on early erythropoiesis of zebrafish. Results: Compared with normal oxygen culture, both hemin-induced erythroid differentiation of K562 cells and the early erythropoiesis of zebrafish were inhibited under hypoxic treatment conditions. Hypoxia-inducible factor 1 alpha (HIF1α) plays a major role in the response to hypoxia. Here, we obtained a stable HIF1α knockout K562 cell line using the CRISPR-Cas9 technology and further demonstrated that HIF1α knockout promoted hemin-induced erythroid differentiation of K562 cells under hypoxia. We demonstrated an HIF1-mediated induction of the nuclear factor interleukin-3 (NFIL3) regulated in K562 cells under hypoxia. Interestingly, a gradual decrease in NFIL3 expression was detected during erythroid differentiation of erythropoietin-induced CD34 + hematopoietic stem/progenitor cells (HSPCs) and hemin-induced K562 cells. Notably, erythroid differentiation was inhibited by enforced expression of NFIL3 under normoxia and was promoted by the knockdown of NFIL3 under hypoxia in hemin-treated K562 cells. In addition, a target of NFIL3, pim-1 proto-oncogene, serine/threonine kinase (PIM1), was obtained by RNA microarray after NFIL3 knockdown. PIM1 can rescue the inhibitory effect of NFIL3 on hemin-induced erythroid differentiation of K562 cells. Innovation and Conclusion: Our findings demonstrate that the HIF1α-NFIL3-PIM1 signaling axis plays an important role in erythroid differentiation under hypoxia. These results will provide useful clues for preventing the damage of acute hypoxia to erythropoiesis.

Aneurysmal recurrence after successful flow-diversion embolization is exceptionally rare. The rarity of recurrence has called into question the yield of interval surveillance imaging. Here we report the case of a recurrent intracranial aneurysm despite complete angiographic resolution after flow-diversion therapy with a Pipeline embolization device (PED). Given the absence of poor wall apposition, endoleak, and device migration, how this aneurysm recurred remains unclear, particularly given the recurrence was at a timepoint at which complete reendothelialization of the device would be expected. The patient ultimately underwent interval treatment with a second device placed across the neck of the aneurysm. Although rare, reports of aneurysmal recurrences support the use of interval non-invasive imaging surveillance to ensure successful embolization in this patient population., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Atrial fibrillation (AF) associated ischemic stroke is associated with worse functional outcomes, less effective recanalization, and increased rates of hemorrhagic complications after intravenous thrombolysis (IVT). Conversely, AF is not associated with hemorrhagic complications or functional outcomes in patients undergoing mechanical thrombectomy (MT). This differential effect of MT and IVT in AF associated stroke raises the question of whether bridging thrombolysis increases hemorrhagic complications in AF patients undergoing MT., Methods: This international cohort study of 22 comprehensive stroke centers analyzed patients with large vessel occlusion (LVO) undergoing MT between June 1, 2015 and December 31, 2020. Patients were divided into four groups based on comorbid AF and IVT exposure. Baseline patient characteristics, complications, and outcomes were reported and compared., Results: 6461 patients underwent MT for LVO. 2311 (35.8%) patients had comorbid AF. In non-AF patients, bridging therapy improved the odds of good 90 day functional outcomes (adjusted OR (aOR) 1.29, 95% CI 1.03 to 1.60, p=0.025) and did not increase hemorrhagic complications. In AF patients, bridging therapy led to significant increases in symptomatic intracranial hemorrhage and parenchymal hematoma type 2 (aOR 1.66, 1.07 to 2.57, p=0.024) without any benefit in 90 day functional outcomes. Similar findings were noted in a separate propensity score analysis., Conclusion: In this large thrombectomy registry, AF patients exposed to IVT before MT had increased hemorrhagic complications without improved functional outcomes, in contrast with non-AF patients. Prospective trials are warranted to assess whether AF patients represent a subgroup of LVO patients who may benefit from a direct to thrombectomy approach at thrombectomy capable centers., Competing Interests: Competing interests: RMS: consulting and teaching agreements with Penumbra, Abbott, Medtronic, InNeuroCo, and Cerenovus. MNP: travel grants/honoraria from Phenox, Stryker, and Siemens. ASA: consultant for Balt, Johnson and Johnson, Leica, Medtronic, Microvention, Penumbra, Scientia, Siemens, and Stryker; research support for Cerenovus, Microvention, Penumbra, and Siemens; and shareholder of Bendit, Cerebrotech, Endostream, Magneto, Marblehead, Neurogami, Serenity, Synchron, Triad Medical, and Vascular Simulations. LE: consultant for Balt, Cerenovuc, Medtronic, MicroVention, Penumbra, Sequent, and Stryker; and research support for Siemens. PJ: consultant for Medtronics and Microvention. AMS: consultant for Penumbra, Microvention, and Pulsar Vascular; and travel grants/honoraria from Penumbra, Pulsar Vascular, Microvention, and Stryker. KMF, JM, PK, and RDL are on the editorial board of Journal of Neurointerventional Surgery., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The early phase of the COVID-19 pandemic led to significant healthcare avoidance, perhaps explaining some of the excess reported deaths that exceeded known infections. The impact of the early COVID-19 era on aneurysmal subarachnoid hemorrhage (aSAH) care remains unclear., Objective: To determine the impact of the early phase of the COVID-19 pandemic on latency to presentation, neurological complications, and clinical outcomes after aSAH., Methods: We performed a retrospective cohort study from March 2, 2012, to June 30, 2021, of all patients with aSAH admitted to our center. The early COVID-19 era was defined as March 2, 2020, through June 30, 2020. The pre-COVID-19 era was defined as the same interval in 2012 to 2019., Results: Among 499 patients with aSAH, 37 presented in the early COVID-19 era. Compared with the pre-COVID-19 era patients, patients presenting during this early phase of the pandemic were more likely to delay presentation after ictus (median, interquartile range; 1 [0-4] vs 0 [0-1] days, respectively, P < .001). Radiographic-delayed cerebral ischemia (29.7% vs 10.2%, P < .001) was more common in the early COVID-19 era. In adjusted analyses, presentation in the early COVID-19 era was independently associated with increased inhospital death or hospice disposition (adjusted odds ratio 3.29 [1.02-10.65], P = .046). Both latency and adverse outcomes returned to baseline in 2021., Conclusion: aSAH in the early COVID-19 era was associated with delayed presentation, neurological complications, and worse outcomes at our center. These data highlight how healthcare avoidance may have increased morbidity and mortality in non-COVID-19-related neurosurgical disease., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Background: Atrial fibrillation (AF) associated ischemic stroke has worse functional outcomes, less effective recanalization, and increased rates of hemorrhagic complications after intravenous thrombolysis (IVT). Limited data exist about the effect of AF on procedural and clinical outcomes after mechanical thrombectomy (MT)., Objective: To determine whether recanalization efficacy, procedural speed, and clinical outcomes differ in AF associated stroke treated with MT., Methods: We performed a retrospective cohort study of the Stroke Thrombectomy and Aneurysm Registry (STAR) from January 2015 to December 2018 and identified 4169 patients who underwent MT for an anterior circulation stroke, 1517 (36.4 %) of whom had comorbid AF. Prospectively defined baseline characteristics, procedural outcomes, and clinical outcomes were reported and compared., Results: AF predicted faster procedural times, fewer passes, and higher rates of first pass success on multivariate analysis (p<0.01). AF had no effect on intracranial hemorrhage (aOR 0.69, 95% CI 0.43 to 1.12) or 90-day functional outcomes (aOR 1.17, 95% CI 0.91 to 1.50) after MT, although patients with AF were less likely to receive IVT (46% vs 54%, p<0.0001)., Conclusions: In patients treated with MT, comorbid AF is associated with faster procedural time, fewer passes, and increased rates of first pass success without increased risk of intracranial hemorrhage or worse functional outcomes. These results are in contrast to the increased hemorrhage rates and worse functional outcomes observed in AF associated stroke treated with supportive care and or IVT. These data suggest that MT negates the AF penalty in ischemic stroke., Competing Interests: Competing interests: RMS: consulting and teaching agreements with Penumbra, Abbott, Medtronic, InNeuroCo, and Cerenovus. MNP: travel grants/honoraria–Phenox, Stryker, Siemens. ASA: consultant–Balt, Johnson and Johnson, Leica, Medtronic, Microvention, Penumbra, Scientia, Siemens, and Stryker; research support–Cerenovus, Microvention, Penumbra, and Siemens; and shareholder–Bendit, Cerebrotech, Endostream, Magneto, Marblehead, Neurogami, Serenity, Synchron, Triad Medical, Vascular Simulations. PJ: consultant-Medtronics, Microvention. AMS: consultant–Penumbra, Microvention, and Pulsar Vascular; travel grants/honoraria–Penumbra, Pulsar Vascular, Microvention, Stryker. AR: consulting agreement with Stryker, Cerenovus, and Microvention., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Urokinase-type plasminogen activator (uPA) is a serine proteinase that catalyzes the generation of plasmin on the cell surface and activates cell signaling pathways that promote remodeling and repair. Neuronal cadherin (NCAD) is a transmembrane protein that in the mature brain mediates the formation of synaptic contacts in the II/III and V cortical layers. Our studies show that uPA is preferentially found in the II/III and V cortical laminae of the gyrencephalic cortex of the non-human primate. Furthermore, we found that in murine cerebral cortical neurons and induced pluripotent stem cell (iPSC)-derived neurons prepared from healthy human donors, most of this uPA is associated with pre-synaptic vesicles. Our in vivo experiments revealed that in both, the gyrencephalic cortex of the non-human primate and the lissecephalic murine brain, cerebral ischemia decreases the number of intact synaptic contacts and the expression of uPA and NCAD in a band of tissue surrounding the necrotic core. Additionally, our in vitro data show that uPA induces the synthesis of NCAD in cerebral cortical neurons, and in line with these observations, intravenous treatment with recombinant uPA three hours after the onset of cerebral ischemia induces NCAD-mediated repair of synaptic contacts in the area surrounding the necrotic core.

Background: The Woven EndoBridge (WEB) device was granted premarket approval in the United States following results of the Woven EndoBridge Intrasaccular Therapy (WEB-IT) study. WEB-IT reported excellent adequate angiographic occlusion of treated aneurysms with a high safety profile. These results were achieved, however, in the context of a prospective study with strict inclusion criteria and rigorous training support., Objective: To review early as-practiced clinical experience with the WEB device in the United States., Methods: Retrospective review across 6 institutions identified 91 patients undergoing 92 treatment sessions for WEB device placement in treatment of 91 intracranial aneurysms. Details regarding demographics, aneurysm characteristics, treatment considerations, clinical outcomes, and aneurysm occlusion were obtained and analyzed in a multicenter database. Angiograms from the index procedure and follow-up studies were reviewed by a blinded and independent adjudicator., Results: The middle cerebral, anterior communicating, and basilar artery complexes were the commonly treated locations. Eight patients presented with ruptured aneurysms. A mean of 1.2 devices were introduced per case. Technical failure without deployment of a WEB device occurred in 2% (2/92) of sessions. Complete aneurysm occlusion for patients with imaging follow-up was 49% (mean follow-up of 8 mo). Four aneurysms were retreated. 90% of patients had modified Rankin Scale ≤ 2 at last clinical follow-up with no mortalities., Conclusion: Immediate postmarket experience with the WEB device, newly introduced at American centers, confirms safe procedural use, but long-term efficacy remains unclear. Early challenges include accurate sizing and device selection., (© Congress of Neurological Surgeons 2021.)

Background: Ruptured aneurysms of the intracranial vertebral artery (VA) or posterior inferior cerebellar artery (PICA) are challenging to treat as they are often dissecting aneurysms necessitating direct sacrifice of the diseased segment, which is thought to carry high morbidity due to brainstem and cerebellar stroke. However, relatively few studies evaluating outcomes following VA or proximal PICA sacrifice exist. We sought to determine the efficacy and outcomes of endovascular VA/PICA sacrifice., Methods: A retrospective series of ruptured VA/PICA aneurysms treated by endovascular sacrifice of the VA (including the PICA origin) or proximal PICA is reviewed. Collected data included demographic, radiologic, clinical, and disability information., Results: Twenty-one patients were identified. Median age was 57 years (IQR 11); 15 were female. The Hunt and Hess grade was mostly 3 and 4 (18/21). Seven cases (33%) involved VA-V4 at the PICA take-off, and 14 cases (67%) involved the PICA exclusively. For VA pathology, V4 was sacrificed in all cases, while for PICA pathology, sacrificed segments included anterior medullary (4/14), lateral medullary (7/14), and tonsillomedullary (3/14) segments. Four patients went to hospice (19%). Twelve patients (57%) had evidence of stroke on follow-up imaging: cerebellar (8), medullary (1), and both (3). One patient required suboccipital decompression for brainstem compression. No aneurysm re-rupture occurred. Median discharge modified Rankin Scale score was 2.0 (IQR 2), which decreased to 1.0 (IQR 1) at median follow-up of 6.5 months (IQR 23)., Conclusions: Endovascular sacrifice of V4 or PICA aneurysms may carry less morbidity than previously thought, and is a viable alternative for poor surgical candidates or those with good collateral perfusion., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Purpose: Flow diversion is an established method to treat complex intracranial aneurysms. The natural history of flow-diversion treatment failure resulting in aneurysm remnants is not well-defined. We aimed to delineate the clinical and angiographic features of this entity., Materials and Methods: Review of a prospectively maintained Pipeline Embolization Device data base from inception to October 2017 was performed for aneurysms that demonstrated residual filling on follow-up imaging. Procedural and follow-up clinical details were recorded. Independent, blinded, angiographic assessment of occlusion was performed on the basis of the O'Kelly-Marotta scale. Aggregated outcomes were analyzed using the Fisher exact and Mann-Whitney U tests for categoric and continuous variables, respectively (statistical significance, α = .05)., Results: During the study period, 283 sequential patients were treated; 87% (246/283) were women. The median patient age was 55 years (interquartile range, 47-65 years). Six-month follow-up imaging was available in 83.7% (237/283) of patients, which showed 62.4% (148/237) complete occlusion (class D, O'Kelly-Marotta grading scale). Adjunctive coiling ( P = .06), on-label Pipeline Embolization Device use ( P = .04), and multiple device constructs ( P = .02) had higher rates of complete occlusion at 6 months. Aneurysm remnants were identified in 25 cases on long-term follow-up imaging (median, 16 months; interquartile range, 12-24 months). No patient with an aneurysm remnant after flow diversion presented with delayed rupture or other clinical sequelae, with a median clinical follow-up of 31 months (interquartile range, 23-33 months)., Conclusions: Aneurysm remnants after flow diversion are infrequent with minimal clinical impact. When appropriate, the presence of overlapping devices and possibly adjunctive coiling may result in higher rates of complete occlusion., (© 2019 by American Journal of Neuroradiology.)

Background: Aneurysmal subarachnoid hemorrhage is a potentially devastating condition, and among the first priorities of treatment is aneurysm occlusion to prevent re-hemorrhage. An emerging strategy to treat patients whose aneurysms are not ideal for surgical or endovascular treatment is subtotal coiling followed by flow diversion in the recovery phase or 'plug and pipe'. However, data regarding the safety and efficacy of this strategy are lacking., Methods: A retrospective cohort study was performed to evaluate the efficacy and safety of 'plug and pipe'. All patients with a ruptured intracranial aneurysm intentionally, subtotally treated by coiling in the acute stage followed by flow diversion after recovery, were included. The primary outcome was re-hemorrhage. Secondary outcomes included aneurysm occlusion and functional status. Complications were reviewed., Results: 22 patients were included. No patient suffered a re-hemorrhage, either in the interval between coiling and flow diversion or in follow-up. The median interval between aneurysm rupture and flow diversion was 3.5 months. Roy-Raymond (R-R) class I or II occlusion was achieved in 91% of target aneurysms at the last imaging follow-up (15/22(68%) R-R 1 and 5/22(23%) R-R 2). Complications occurred in 2 (9%) patients, 1 of which was neurological., Conclusions: Overall, these data suggest that subtotal coiling of ruptured intracranial aneurysms followed by planned flow diversion is both safe and effective. Patients who may most benefit from 'plug and pipe' are those with aneurysms that confer high operative risk and those whose severity of medical illness increases the risk of microsurgical clip ligation., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

An adult rhesus macaque developed seizures after the induction of ischemic stroke. Initially, on the day of surgery, a focal ischemic lesion was present exclusively in the right caudate nucleus. By 48 h after stroke induction, the lesion had extended into the putamen, when a seizure was observed. Our report highlights the temporal changes in infarction of unilateral basal ganglia after acute stroke and the accompanying clinical symptoms. This unusual case may provide additional information regarding the involvement of the basal ganglia in seizures, given that prior case reports and studies usually have not described the temporal and spatial evolution of the lesion before clinical symptoms emerge.

Background: Administration of ε-aminocaproic acid (εACA), as adjuvant therapy following incompletely embolized cranial dural arteriovenous (dAVFs) and direct carotid artery to cavernous sinus fistulae (CCFs), is a strategy to promote post-procedural thrombosis. However, the efficacy of εACA to treat incompletely obliterated dAVFs and CCFs has not been published. The purpose of this study was to determine if administration of εACA following incomplete embolization of cranial dAVFs or CCFs was associated with an increased likelihood of cure on follow-up imaging compared with patients not given adjuvant εACA., Methods: A retrospective cohort study was performed. All patients who underwent treatment of a dAVF or CCF at our institution between 1998 and 2016 were reviewed (n=262). Patients with residual shunting following the first attempted endovascular embolization were included in the analysis (n=52). The study groups were those treated with εACA following incomplete obliteration of the fistula and those who were not. The primary outcome was obliteration of the fistula on initial follow-up imaging. Complication rates between cohorts were compared., Results: 20 (38%) patients with incompletely obliterated fistulae were treated with adjuvant εACA. A trend towards an improved rate of complete obliteration on initial follow-up imaging was observed in the group treated with εACA (55% vs 34% in the group not treated with εACA, p=0.14). No difference in clinical outcomes or thromboembolic complications was observed between the groups., Conclusions: In summary, these data suggest that administration of εACA is a safe adjuvant therapy in the management of cranial dAVFs and CCFs that are incompletely treated endovascularly., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Purpose: The pipeline embolization device (PED) necessitates dual antiplatelet therapy (APT) to decrease thrombotic complications while possibly increasing bleeding risks. The role of APT dose, duration, and response in patients with hemorrhagic and thromboembolic events warrants further analysis., Methods: A PubMed and Google Scholar search from 2009 to 2014 was performed using the following search terms individually or in combination: pipeline embolization device, aneurysm(s), and flow diversion, excluding other flow diverters. Review of the bibliographies of the retrieved articles yielded 19 single and multicenter studies. A statistical meta-analysis between aspirin (ASA) dose (low dose ≤160 mg, high dose ≥300 mg), loading doses of APT agents, post-PED APT regimens, and platelet function testing (PFT) with hemorrhagic or thrombotic complications was performed., Results: ASA therapy for ≤6 months post-PED was associated with increased hemorrhagic events. High dose ASA ≤6 months post-PED was associated with fewer thrombotic events compared with low dose ASA. Post-PED clopidogrel for ≤6 months demonstrated an increased incidence of symptomatic thrombotic events. Loading doses of ASA plus clopidogrel demonstrated a decreased incidence of permanent symptomatic hemorrhagic events. PFT did not show a statistically significant relationship with symptomatic hemorrhagic or thrombotic complications., Conclusions: High dose ASA >6 months is associated with fewer permanent thrombotic and hemorrhagic events. Clopidogrel therapy ≤6 months is associated with higher rates of thrombotic events. Loading doses of ASA and clopidogrel were associated with a decreased incidence of hemorrhagic events. PFT did not have any significant association with symptomatic events., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background and Purpose: Current nonhuman primate stroke models are limited by either stroke variability or survivability. A new nonhuman primate stroke model was developed by using endovascular trapping techniques to limit collateral vessels with serial MR imaging and neurologic assessments., Materials and Methods: Eight adult rhesus monkeys (female, 7-13 years of age) underwent MR imaging and Spetzler neurologic assessment followed by endovascular stroke induction consisting of superselective endovascular placement of surgical silk sutures into the right MCA by using a trapping technique. Two initial subjects were euthanized immediately following postocclusion MR imaging. The subsequent 6 subjects recovered and underwent follow-up MR imaging and Spetzler neurologic assessments at 48 hours, with 4 being followed to 96 hours. Stroke infarct volumes were measured, and the longitudinal Spetzler clinical neurologic scores were assessed. The brain tissues were harvested and prepared with hematoxylin-eosin staining., Results: Focal permanent cerebral ischemia was induced in the targeted right MCA territory in all subjects. The volumes of the ischemic lesions at 6, 48, and 96 hours were 3.18 ± 1.007 mL (standard error of the mean) (n = 8), 6.70 ± 1.666 mL (standard error of the mean) (n = 6), and 7.23 ± 1.371 mL (standard error of the mean) (n = 4). For the survival animals, the immediate postsurgical Spetzler grading score improved from 60.7 at 24 hours to 68.7 at 48 hours., Conclusions: We report a trapping modification to an established endovascular suture stroke model that yielded reproducible ischemia and clinically quantifiable neurologic deficits with no strokes in nontarget areas. This technique may be useful in evaluating translational stroke and penumbral imaging research in addition to preclinical testing of neuroprotective therapies., (© 2015 by American Journal of Neuroradiology.)

Background: Spinal digital subtraction angiography (DSA) is the gold standard for diagnosis of spinal dural arterial venous fistulas (SDAVFs), but can require extensive time, radiation exposure and contrast dose. We hypothesize that contrast-enhanced time-resolved MR angiography (CE-TR MRA) will have utility for the non-invasive diagnosis and pre-angiographic localization of SDAVFs., Methods: Eighteen patients underwent both CE-TR MRA and DSA for suspected SDAVFs, with DSA performed a median of 11 days (range 0-41) after MRA. CE-TR MRA was performed on a 1.5 T GE unit using Time Resolved Imaging of Contrast Kinetics (TRICKS). CE-TR MRA and DSA images were evaluated for the presence of SDAVFs and location of the feeding arterial supply, with DSA as the reference standard. DSA was also evaluated for the number of vessels catheterized, contrast volume and fluoroscopic and procedure times., Results: Eight of the 18 patients were positive for SDAVF on DSA. Sensitivity, specificity, positive predictive value and negative predictive value for the 18 CE-TR MRAs were 88%, 90%, 88% and 90%, respectively. Localization of the SDAVF arterial supply on CE-TR MRA was within one vertebral level from DSA for 6/7 SDAVFs. Compared with patients with a SDAVF and feeding artery identified on CE-TR MRA, patients with negative or suboptimal CE-TR MRA had a significantly increased number of vessels catheterized (p=0.027) and larger contrast volumes (p=0.022)., Conclusions: CE-TR MRA is a useful initial examination for the diagnosis and localization of SDAVFs, with a high concordance rate with DSA. When CE-TR MRA demonstrates a SDAVF, the number of catheterized vessels and contrast dose can be decreased during DSA., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background and Purpose: Endovascular reconstruction and flow diversion by using the Pipeline Embolization Device is an effective treatment for complex cerebral aneurysms. Accurate noninvasive alternatives to DSA for follow-up after Pipeline Embolization Device treatment are desirable. This study evaluated the accuracy of contrast-enhanced time-resolved MRA for this purpose, hypothesizing that contrast-enhanced time-resolved MRA will be comparable with DSA and superior to 3D-TOF MRA., Materials and Methods: During a 24-month period, 37 Pipeline Embolization Device-treated intracranial aneurysms in 26 patients underwent initial follow-up by using 3D-TOF MRA, contrast-enhanced time-resolved MRA, and DSA. MRA was performed on a 1.5T unit by using 3D-TOF and time-resolved imaging of contrast kinetics. All patients underwent DSA a median of 0 days (range, 0-68) after MRA. Studies were evaluated for aneurysm occlusion, quality of visualization of the reconstructed artery, and measurable luminal diameter of the Pipeline Embolization Device, with DSA used as the reference standard., Results: The sensitivity, specificity, and positive and negative predictive values of contrast-enhanced time-resolved MRA relative to DSA for posttreatment aneurysm occlusion were 96%, 85%, 92%, and 92%. Contrast-enhanced time-resolved MRA demonstrated superior quality of visualization (P = .0001) and a higher measurable luminal diameter (P = .0001) of the reconstructed artery compared with 3D-TOF MRA but no significant difference compared with DSA. Contrast-enhanced time-resolved MRA underestimated the luminal diameter of the reconstructed artery by 0.965 ± 0.497 mm (27% ± 13%) relative to DSA., Conclusions: Contrast-enhanced time-resolved MRA is a reliable noninvasive method for monitoring intracranial aneurysms following flow diversion and vessel reconstruction by using the Pipeline Embolization Device., (© 2014 by American Journal of Neuroradiology.)

Spines are dendritic protrusions that receive most of the excitatory input in the brain. Early after the onset of cerebral ischemia dendritic spines in the peri-infarct cortex are replaced by areas of focal swelling, and their re-emergence from these varicosities is associated with neurological recovery after acute ischemic stroke (AIS). Urokinase-type plasminogen activator (uPA) is a serine proteinase that plays a central role in tissue remodeling via binding to the urokinase plasminogen activator receptor (uPAR). We report that cerebral cortical neurons release uPA during the recovery phase from ischemic stroke in vivo or hypoxia in vitro. Although uPA does not have an effect on ischemia- or hypoxia-induced neuronal death, genetic deficiency of uPA (uPA(-/-)) or uPAR (uPAR(-/-)) abrogates functional recovery after AIS. Treatment with recombinant uPA after ischemic stroke induces neurological recovery in wild-type and uPA(-/-) but not in uPAR(-/-) mice. Diffusion tensor imaging studies indicate that uPA(-/-) mice have increased water diffusivity and decreased anisotropy associated with impaired dendritic spine recovery and decreased length of distal neurites in the peri-infarct cortex. We found that the excitotoxic injury induces the clustering of uPAR in dendritic varicosities, and that the binding of uPA to uPAR promotes the reorganization of the actin cytoskeleton and re-emergence of dendritic filopodia from uPAR-enriched varicosities. This effect is independent of uPA's proteolytic properties and instead is mediated by Rac-regulated profilin expression and cofilin phosphorylation. Our data indicate that binding of uPA to uPAR promotes dendritic spine recovery and improves functional outcome following AIS., (Copyright © 2014 the authors 0270-6474/14/3414219-14$15.00/0.)

Background: Stable access to target lesions is foundational to endovascular therapy, be it in hemorrhagic or ischemic disease. Continued evolution in access technology has resulted in next generation catheters that afford improved trackability and proximal support., Objective: Assess safety and patterns of use at two high volume centers, and conceptualize usage patterns., Materials and Methods: A retrospective review of 608 cases in which a 'next generation' catheter was used during 2008-2010 at Cleveland Clinic (Cleveland, Ohio, USA) and throughout 2009-2010 at Emory University Hospital (Atlanta, Georgia, USA) was conducted, and the cases classified by indication. Catheter placement, distal most location, and related complications were recorded and experience summarized. We also reviewed the differences in the catheters and the rationale for catheter selection, as well as relative costs for each approach., Results: 311 Neuron 053, 166 Neuron 070, 36 distal access catheter (DAC) 3.9 F, 61 DAC 4.3 F, and 34 DAC 5.2 F catheters were deployed. Of these, 459 placements were in the anterior circulation, 130 in the posterior circulation, 11 in the external carotid artery, and eight were used intravenously. Complication rates were 9/131 (6.9%) for the DAC catheter group, 16/311 (5.1%) for the Neuron 053 group, and 14/166 (8.4%) for the Neuron 070 group (p=0.37, χ(2) test)., Conclusions: Next generation access catheters possess characteristics that blend qualities of traditional microcatheters and stiff guide catheters. There was no statistically significant difference in complication rates between the various catheter families in this small retrospective review, and the complication rates were similar to historical complication rates., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Adenosine monophosphate-activated protein kinase (AMPK) is an energy sensor that regulates cellular adaptation to metabolic stress. Tissue-type plasminogen activator (tPA) is a serine proteinase found in the intravascular space, where its main role is as thrombolytic enzyme, and in neurons, where its function is less well understood. Here, we report that glucose deprivation induces the mobilization and package of neuronal tPA into presynaptic vesicles. Mass spectrometry and immunohistochemical studies show that the release of this tPA in the synaptic space induces AMPK activation in the postsynaptic terminal, and an AMPK-mediated increase in neuronal uptake of glucose and neuronal adenosine 5'(tetrahydrogen triphosphate; ATP) synthesis. This effect is independent of tPA's proteolytic properties, and instead requires the presence of functional N-methyl-D-aspartate receptors (NMDARs). In agreement with these observations, positron emission tomography (PET) studies and biochemical analysis with synaptoneurosomes indicate that the intravenous administration of recombinant tPA (rtPA) after transient middle cerebral artery occlusion (tMCAO) induces AMPK activation in the synaptic space and NMDAR-mediated glucose uptake in the ischemic brain. These data indicate that the release of neuronal tPA or treatment with rtPA activate a cell signaling pathway in the synaptic space that promotes the detection and adaptation to metabolic stress.

During the rainy season (April-September) of 2012, the atmospheric particulate matter with a diameter less than 2.5 mm (PM2.5) were sampled from the forest parks in the urban area, suburban area, and rural area of Guangzhou City. The mass concentration of PM2.5 and its water-soluble ions (SO4(2-), NO3-, NO2-, Cl-, F-, Na+, NH4+, Ca2+, K+, and Mg2+) contents were also measured. In the forest parks in the urban area, suburban area, and rural area, the diurnal variation of PM2.5 mass concentration was 21.8-161.7, 19.4-156.3, and 17.2-66.5 microg x m(-3), with an arithmetic average being 55.9, 49.8, and 44.4 microg x m(-3), respectively. SO4(2-), Na+, and NH4+ were the main components of water-soluble ions in the PM2.5, and the SO4(2-) had the highest content and decreased gradually from urban to rural forest parks. The contribution of the SO2 and NOx in the PM2.5 from coal combustion to the forest parks was larger than that from vehicle exhaust, but presented a decreasing trend from urban to rural forest parks, indicating that vehicle exhaust had a greater contribution to the atmospheric SO2 and NOx in the urban forest park. In the sampling period, the contribution of sea salt to the water soluble fractions (especially K+) of the PM2.5 was greater for the suburban forest park than for the other two parks. The equivalent concentration of the NH4+ in the PM2.5 was far less than those of the SO4(2-) and NO3-, with a neutralization ratio being much lower than 1.0, which suggested that the PM2.5 had a higher acidity. The PM2.5 acidity had an increasing trend from rural to urban forest parks.

Background: There are limited data on the effect of an early aggressive risk factor modification program to achieve risk factor targets and its impact on clinical outcomes among patients with symptomatic intracranial stenosis., Methods: We prospectively identified patients with symptomatic intracranial stenosis of 50% to 99% (using computed tomographic angiography or cerebral angiography) who failed to qualify for or declined to participate in the Stenting and Aggressive Medical Management for Preventing Recurrent stroke in Intracranial Stenosis trial but elected to receive aggressive medical management. Aggressive medical management was defined as aspirin plus clopidogrel therapy for a minimum of 3 months, blood pressure control, statin use with a low-density lipoprotein (LDL) goal of <70 mg/dL, smoking cessation, and body mass index <25 kg/m(2)., Results: Of 22 patients, the mean age was 65.6 ± 7.7 years, 82% were male, 59% were white, and mean percent stenosis was 71.5 ± 9.5% (55% with 70% to 99% stenosis). Median time from symptomatic event to first evaluation was 3 days. All patients completed 3 months of dual antiplatelet therapy, and at last follow-up, 86% had met their blood pressure goal, all were on statin therapy although only 73% had met their LDL goal, 96% reported no active tobacco use, and 36% had lost weight, but only 23% had achieved the BMI target. Over a mean follow-up of 1.2 years, there was no ischemic stroke, brain hemorrhage, or death from other vascular causes., Conclusions: An early aggressive risk factor modification program achieved high levels of blood pressure and cholesterol targets for patients with symptomatic intracranial stenosis and when combined with dual antiplatelet therapy was effective for the prevention of recurrent vascular events in this cohort., (Copyright © 2013 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

The ability to sense and adapt to hypoxic conditions plays a pivotal role in neuronal survival. Hypoxia induces the release of tissue-type plasminogen activator (tPA) from cerebral cortical neurons. We found that the release of neuronal tPA or treatment with recombinant tPA promotes cell survival in cerebral cortical neurons previously exposed to hypoxic conditions in vitro or experimental cerebral ischemia in vivo. Our studies using liquid chromatography and tandem mass spectrometry revealed that tPA activates the mammalian target of rapamycin (mTOR) pathway, which adapts cellular processes to the availability of energy and metabolic resources. We found that mTOR activation leads to accumulation of the hypoxia-inducible factor-1α (HIF-1α) and induction and recruitment to the cell membrane of the HIF-1α-regulated neuronal transporter of glucose GLUT3. Accordingly, in vivo positron emission tomography studies with 18-fluorodeoxyglucose in mice overexpressing tPA in neurons show that neuronal tPA induces the uptake of glucose in the ischemic brain and that this effect is associated with a decrease in the volume of the ischemic lesion and improved neurological outcome following the induction of ischemic stroke. Our data indicate that tPA activates a cell signaling pathway that allows neurons to sense and adapt to oxygen and glucose deprivation.

Background: Intraprocedural rupture is a dangerous complication of endovascular treatment. Small ruptured anterior communicating artery (ACoA) aneurysms and microaneurysms present a challenge for both surgical and endovascular therapies to achieve obliteration. An understanding of the complication rates of treating ruptured ACoA microaneurysms may help guide therapeutic options., Objective: To report the largest cohort of ACoA microaneurysms treated with endovascular therapy over the course of the past 10 years., Methods: We performed a retrospective review of 347 ACoA aneurysms treated in 347 patients at Cleveland Clinic and Emory University over a 10-year period. Patient demographics, aneurysmal rupture, size, use of balloon remodeling, patient outcomes, intraprocedural rupture, and rerupture were reviewed., Results: Rupture rates were examined by size for all patients and subgroups and dichotomized to evaluate for size ranges associated with increased rupture rates. The highest risk of rupture was noted in aneurysms less than 4 mm. Of 347 aneurysms, 74 (21%) were less than 4 mm. The intraprocedural rupture rate was 5% (18/347) for ACoA aneurysms of any size. There was an intraprocedural rupture rate of 2.9% (8/273) among ACoA aneurysms greater than 4 mm compared with 13.5% (10/74) in less than 4-mm aneurysms. Procedural rupture was a statistically significant predictor of modified Rankin score after adjusting for Hunt and Hess grades (HH)., Conclusion: ACoA aneurysms less than 4 mm have a 5-fold higher incidence of intraprocedural rerupture during coil embolization. Outcome is negatively affected by intraprocedural rerupture after adjusting for HH grade.

Gadolinium chelates can be utilized as a fluoroscopic contrast agent when iodinated contrast is contraindicated. However, the nephrotoxicity of gadolinium at radiographic doses limits its role as fluoroscopic contrast. Gadolinium chelate-enhanced digital subtraction angiography (DSA) is particularly limited by the kV of DSA, where gadolinium chelates are relatively more radiolucent. Flat panel detectors improve conspicuity of gadolinium chelates during DSA and should be employed where possible.

Background and Purpose: Denser coil packing in intracranial aneurysms is believed to result in lower recanalization rates. Hydrogel-coated expandable coils (HydroCoil) improve volumetric packing of aneurysms in animal models and clinical studies, but data from large clinical series are limited. The objective of this retrospective analysis was to analyze immediate and follow-up angiographic results as well as complications in a large consecutive series of patients treated with HydroCoils at a single institution., Materials and Methods: Retrospective analysis was performed of periprocedural complications, immediate and follow-up angiograms, and retreatments of the first 200 consecutive intracranial aneurysms treated at Emory University Hospital., Results: One hundred eighty-seven patients with 200 intracranial aneurysms were treated with HydroCoils during a 3-year period. Immediate angiograms showed complete aneurysmal obliteration in 58.4% of small aneurysms and 42.7% of large aneurysms. Periprocedural complications included early rebleeding and thromboembolic events resulting in permanent neurologic morbidity and mortality in 6% of cases. Follow-up angiography during an average of 16.3 months demonstrated recanalization in 17.7% of small aneurysms and 28.6% of large aneurysms, requiring retreatment in 6.3% and 19.0% of cases, respectively. During the same time period, there was delayed angiographic improvement in aneurysm obliteration in 26.6% of small aneurysms and 26.2% of large aneurysms., Conclusions: First-generation HydroCoil treatment of intracranial aneurysms has a favorable rate of recanalization compared with most large series of pure platinum coils with similar complication rates.

Object: The introduction of the Neuroform microstent has facilitated the embolization of complex cerebral aneurysms, which were previously not amenable to endovascular therapy. Typically, the use of this stent necessitates the administration of dual antiplatelet therapy to minimize thromboembolic complications. Such therapy may increase the risk of hemorrhage in patients who require concurrent external ventricular drainage and/or subsequent permanent cerebrospinal fluid diversion., Methods: The authors' neurosurgical database was queried for all patients who underwent stent-assisted coil embolization for cerebral aneurysms and who required an external ventricular drain (EVD) or ventriculoperitoneal (VP) shunt placement for management of hydrocephalus., Results: Thirty-seven patients underwent stent-assisted coil embolization for intracranial aneurysms at the authors' institution over a recent 2-year period. Seven of these patients required placement of an EVD and/or a VP shunt. Three of the 7 patients suffered an immediate intraventricular hemorrhage (IVH) associated with placement or manipulation of an EVD; 1 experienced a delayed intraparenchymal hemorrhage and an IVH; 1 suffered an aneurysmal rehemorrhage; and the last patient had a subdural hematoma (SDH) that resulted from placement of a VP shunt. This patient required drainage of the SDH and exchange of the valve., Conclusions: The necessity of dual antiplatelet therapy in the use of stent-assisted coil embolization increases the risk of intracranial hemorrhage and possibly rebleeding from a ruptured aneurysm. This heightened risk must be recognized when contemplating the appropriate therapy for a cerebral aneurysm and when considering the placement or manipulation of a ventricular catheter in a patient receiving dual antiplatelet therapy. Further study of intracranial procedures in patients receiving dual antiplatelet therapy is indicated.

This report describes a series of patients for whom dural arteriovenous fistulae (DAVFs) of the cavernous sinus were successfully embolized using a percutaneous, transorbital technique to directly cannulate the cavernous sinus. A vascular access needle and catheter are percutaneously advanced along the inferolateral aspect of the orbit to access the cavernous sinus via the superior orbital fissure. Safe and effective embolization is achieved without the need for a surgical cut-down.

Background and Purpose: After an initial series of basilar artery stent angioplasty indicated a high technical success rate and minimal morbidity, subsequent reports suggested significant procedural risks. We retrospectively reviewed our experience with basilar artery stent placement to assess complications and clinical outcomes., Materials and Methods: Ten consecutive patients with symptomatic intracranial athero-occlusive disease underwent stent placement of the basilar artery at our institution (1999-2003). We collected clinical data by chart review and determined outcomes (modified Rankin Scale [mRS]) by telephone interview. Angiographic data were analyzed by 2 blinded investigators. Clinical and angiographic variables were tested for correlation with outcome and complications using the Pearson correlation test., Results: Of 10 patients (mean follow-up time, 31 months), 4 patients suffered 6 ischemic complications that were immediate in 1, early delayed (<2 weeks) in 4, and late delayed (>2 weeks) in 1. Complications included basilar artery rupture in 1 patient, access site complications in 1 patient, and other non-neurologic complications in 5. Symptomatic restenosis occurred in 1 patient. Outcomes (mRS) were excellent (0-2) in 5 patients, good (3) in 4, and poor (4-6) in 1 patient, who died. Ischemic complications were associated with lesion lumen 45 degrees (P<.05). Less favorable clinical outcomes were associated with few ischemic complications and the presence of fewer than 2 patent vertebral arteries (P<.05)., Conclusions: Despite a significant incidence of ischemic and nonischemic complications after basilar artery stent placement, most patients in this small series achieved freedom from vertebrobasilar ischemia and good to excellent clinical outcomes at late midterm follow-up (12-46 months). Ischemic complications usually had an early delayed presentation and procedural risks correlated with lesion characteristics.

Background and Purpose: Thromboembolic events are a common source of complications during Guglielmi detachable coil (GDC) treatment of intracranial aneurysms. Thrombus formation at the coil-parent artery interface is not commonly reported but is an important potential source of emboli. We describe nine cases in which thrombus propagated from GDCs into the parent artery during coil therapy of cerebral aneurysms and subsequent treatment of the thrombus., Methods: A retrospective review of a procedural database was performed to identify cases in which thrombus occurred during GDC treatment of cerebral aneurysms during a 30-month period. All images were reviewed at the time of the procedure. Nine cases of thrombus forming at the coil-parent artery interface and five cases of distal emboli were identified among 210 cases. All patients underwent anticoagulation with heparin during GDC treatment procedures., Results: Thrombus was identified at the coil-parent artery interface during GDC treatment in nine (4.3%) of 210 cases. In each case, the thrombus was recognized before distal embolic complication occurred and was successfully treated with heparin alone (five patients) or with heparin plus a glycoprotein IIb-IIIa inhibitor (four patients)., Conclusion: Potential clinical complications can be avoided by early recognition of thrombus at the coil-parent artery interface and by administering appropriate medical therapy.

Summary: We present a case of recurrent carotid-cavernous fistula after prior ipsilateral carotid artery ligation. Due to lack of endovascular access, embolization was performed by direct puncture of the cavernous sinus via a transorbital approach. Operative technique and an anatomical basis for treatment are described.

Summary: A 74-year-old woman with a direct carotidcavernous fistula secondary to aneurysm rupture was treated by endovascular balloon occlusion of the fistula. Two days later, she suffered an intracerebral hemorrhage ipsilateral to the treated carotid cavernous fistula, perhaps due to normal perfusion pressure breakthrough. Normal perfusion pressure breakthrough has been described as a cause of hemorrhage following treatment of arteriovenous malformations (1) and carotid stenosis (2,3). We report an unusual case of therapeutic endovascular occlusion of a direct carotid-cavernous fistula complicated by hemorrhage presumably caused by normal pressure perfusion breakthrough.

Thrombin injection as a means of inducing thrombus formation has recently received wide attention as an alternative treatment for pseudoaneurysm. We present a case of a 67-year-old man in whom a large mycotic pseudoaneurysm developed in the ascending aorta because of sternal osteomyelitis and mediastinitis after coronary artery bypass grafting. Transcatheter intra-arterial thrombin injection was performed, and it successfully induced pseudoaneurysm thrombosis. However, the procedure was complicated by a sudden transient ischemic attack caused by thrombus propagation into the cerebral circulation. Complete thrombus dissolution in the cerebral circulation with the resolution of neurologic symptoms was achieved by means of intravenous abciximab.

We describe four cases in which abciximab was used as a thrombolytic rescue agent in the setting of thrombotic events complicating interventional neuroradiologic procedures. After IV administration of abciximab, the thrombus resolved within 30 min in three cases, whereas no thrombolysis occurred in the fourth case despite the addition of intraarterial tissue plasminogen activator. Further evaluation of glycoprotein IIb-IIIa inhibitors in patients with cerebral thromboembolic events is necessary to prove clinical efficacy.

Occlusion of an internal carotid artery stent was identified immediately post placement in a patient who had restenosis after prior angioplasty. An IV dose of abciximab was administered, and serial angiograms were performed. This resulted in partial resolution of the thrombus at 10 minutes and complete resolution at 20 minutes.

A three-dimensional Guglielmi detachable coil (3D-GDC) has been developed that is designed specifically to bridge the neck of an aneurysm with coil loops, thereby facilitating retention of additional coils placed within the aneurysm. Nine wide-necked cerebral aneurysms were successfully embolized using the 3D-GDC, provided that the dome-to-neck ratio was 1.5 or greater.

Endovascular therapy for intracranial aneurysms has evolved since Serbinenko pioneered embolisation with latex balloons in the 1970s. The focus of modern endovascular therapy has shifted to the use of Guglielmi Detachable Coils (GDC; Boston Scientific Corporation, Natick, MA, USA) which are retrievable until the operator is satisfied with placement and they are detached. GDC therapy has been shown to be most efficacious in smaller aneurysms with relatively large dome:neck ratios which allow maximal coil packing within the aneurysm lumen. Wide neck aneurysms with dome:neck ratios of less than 2.0 and large aneurysms have a significantly lower incidence of complete treatment, with higher rates of repeat rupture following GDC therapy. The geometry of wide neck aneurysms is less favourable for retention of coils within the aneurysm lumen, resulting in greater risk of parent vessel compromise from coil herniation and difficulty obtaining maximal coil packing. This chapter will summarise GDC therapy for intracranial aneurysms including newer techniques designed to address the problem of wide neck aneurysms., (Copyright 2000 Harcourt Publishers Ltd.)