Corrigendum: NmFGF1-regulated glucolipid metabolism and angiogenesis improves functional recovery in a mouse model of diabetic stroke and acts via the AMPK signaling pathway.

[This corrects the article DOI: 10.3389/fphar.2021.680351.].

FGF17 protects cerebral ischemia reperfusion-induced blood-brain barrier disruption via FGF receptor 3-mediated PI3K/AKT signaling pathway.

Maintaining blood-brain barrier (BBB) integrity is critical components of therapeutic approach for ischemic stroke. Fibroblast growth factor 17 (FGF17), a member of FGF8 superfamily, exhibits the strongest expression throughout the wall of all major arteries during development. However, its molecular action and potential protective role on brain endothelial cells after stroke remains unclear. Here, we observed reduced levels of FGF17 in the serum of patients with ischemic stroke, as well as in the brains of mice subjected to middle cerebral artery occlusion (MCAO) injury and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced brain microvascular endothelial cells (bEnd.3) cells. Moreover, treatment with exogenous recombinant human FGF17 (rhFGF17) decreased infarct volume, improved neurological deficits, reduced Evans Blue leakage and upregulated the expression of tight junctions in MCAO-injured mice. Meanwhile, rhFGF17 increased cell viability, enhanced trans-endothelial electrical resistance, reduced sodium fluorescein leakage, and alleviated reactive oxygen species (ROS) generation in OGD/R-induced bEnd.3 cells. Mechanistically, the treatment with rhFGF17 resulted in nuclear factor erythroid 2-related factor 2 (Nrf2) nuclear accumulation and upregulation of heme oxygenase-1 (HO-1) expression. Additionally, based on in-vivo and in-vitro research, rhFGF17 exerted protective effects against ischemia/reperfusion (I/R) -induced BBB disruption and endothelial cell apoptosis through the activation of the FGF receptor 3/PI3K/AKT signaling pathway. Overall, our findings indicated that FGF17 may hold promise as a novel therapeutic strategy for ischemic stroke patients.

PRMT8 Attenuates Cerebral Ischemia/Reperfusion Injury via Modulating Microglia Activation and Polarization to Suppress Neuroinflammation by Upregulating Lin28a.

Activation and polarization of microglia are involved in neuroinflammation and regulate ischemic stroke-associated brain injury. Protein arginine methyltransferase 8 functions as a regulatory component of hypoxic stress-induced neuroinflammation. The protective effect of protein arginine methyltransferase 8 (PRMT8) against ischemic stroke-associated brain injury through regulation of microglia activation and polarization was investigated. First, PRMT8 was downregulated in middle cerebral artery occlusion (MCAO)-induced mice and oxygen-glucose deprivation/reoxygenation (OGD/R)-induced SH-SY5Y. Injection with AAV-PRMT8 reduced infarct volumes in MCAO-induced mice. Moreover, injection with AAV-PRMT8 promoted neuronal survival and ameliorated histopathological changes in the brains of MCAO-induced mice. The neuronal apoptosis and neuroinflammation in MCAO-induced mice were suppressed by AAV-PRMT8 injection. Second, PRMT8 overexpression increased cell viability and suppressed the cell apoptosis and inflammation of OGD/R-induced SH-SY5Y. Third, injection with AAV-PRMT8 reduced almost 50% of CD86 + M1 microglia and enhanced about 20% of CD206 + M2 microglia. Furthermore, PRMT8 overexpression attenuated OGD/R-induced M1 phenotype polarization of BV2. Lastly, PRMT8 upregulated Lin28a and loss of Lin28a attenuated PRMT8 overexpression-induced increase in cell viability and decrease in cell apoptosis and inflammation of OGD/R-induced SH-SY5Y. In conclusion, PRMT8 promoted M2 phenotype polarization of microglia and suppressed neuronal apoptosis to ameliorate cerebral ischemia/reperfusion injury through upregulation of Lin28a.

Hydroxychloroquine attenuates neuroinflammation following traumatic brain injury by regulating the TLR4/NF-κB signaling pathway.

BACKGROUND: After traumatic brain injury (TBI), an acute, robust inflammatory cascade occurs that is characterized by the activation of resident cells such as microglia, the migration and recruitment of peripheral immune cells and the release of inflammatory mediators that induce secondary cell death and impede neurological recovery. In addition, neuroinflammation can alter blood-brain barrier (BBB) permeability. Controlling inflammatory responses is considered a promising therapeutic approach for TBI. Hydroxychloroquine (HCQ) has already been used clinically for decades, and it is still widely used to treat various autoimmune diseases. However, the effects of HCQ on inflammation and the potential mechanism after TBI remain to be defined. The aim of the current study was to elucidate whether HCQ could improve the neurological recovery of mice post-TBI by inhibiting the inflammatory response via the TLR4/NF-κB signaling pathway. METHODS: C57BL/6 mice were subjected to controlled cortical impact (CCI) and randomly divided into groups that received intraperitoneal HCQ or vehicle daily after TBI. TAK-242 (3.0 mg/kg), an exogenous TLR4 antagonist, was injected intraperitoneally 1 h before TBI. Behavioral assessments were performed on days 1 and 3 post-TBI, and the gene expression levels of inflammatory cytokines were analyzed by qRT-PCR. The presence of infiltrated immune cells was examined by flow cytometry and immunostaining. In addition, BBB permeability, tight junction expression and brain edema were investigated. RESULTS: HCQ administration significantly ameliorated TBI-induced neurological deficits. HCQ alleviated neuroinflammation, the activation and accumulation of microglia and immune cell infiltration in the brain, attenuated BBB disruption and brain edema, and upregulated tight junction expression. Combined administration of HCQ and TAK-242 did not enhance the neuroprotective effects of HCQ. CONCLUSIONS: HCQ reduced proinflammatory cytokine expression, and the underlying mechanism may involve suppressing the TLR4/NF-κB signaling pathway, suggesting that HCQ is a potential therapeutic agent for TBI treatment.

NmFGF1-Regulated Glucolipid Metabolism and Angiogenesis Improves Functional Recovery in a Mouse Model of Diabetic Stroke and Acts via the AMPK Signaling Pathway.

Diabetes increases the risk of stroke, exacerbates neurological deficits, and increases mortality. Non-mitogenic fibroblast growth factor 1 (nmFGF1) is a powerful neuroprotective factor that is also regarded as a metabolic regulator. The present study aimed to investigate the effect of nmFGF1 on the improvement of functional recovery in a mouse model of type 2 diabetic (T2D) stroke. We established a mouse model of T2D stroke by photothrombosis in mice that were fed a high-fat diet and injected with streptozotocin (STZ). We found that nmFGF1 reduced the size of the infarct and attenuated neurobehavioral deficits in our mouse model of T2D stroke. Angiogenesis plays an important role in neuronal survival and functional recovery post-stroke. NmFGF1 promoted angiogenesis in the mouse model of T2D stroke. Furthermore, nmFGF1 reversed the reduction of tube formation and migration in human brain microvascular endothelial cells (HBMECs) cultured in high glucose conditions and treated with oxygen glucose deprivation/re-oxygenation (OGD). Amp-activated protein kinase (AMPK) plays a critical role in the regulation of angiogenesis. Interestingly, we found that nmFGF1 increased the protein expression of phosphorylated AMPK (p-AMPK) both in vivo and in vitro. We found that nmFGF1 promoted tube formation and migration and that this effect was further enhanced by an AMPK agonist (A-769662). In contrast, these processes were inhibited by the application of an AMPK inhibitor (compound C) or siRNA targeting AMPK. Furthermore, nmFGF1 ameliorated neuronal loss in diabetic stroke mice via AMPK-mediated angiogenesis. In addition, nmFGF1 ameliorated glucose and lipid metabolic disorders in our mouse model of T2D stroke without causing significant changes in body weight. These results revealed that nmFGF1-regulated glucolipid metabolism and angiogenesis play a key role in the improvement of functional recovery in a mouse model of T2D stroke and that these effects are mediated by the AMPK signaling pathway.

Lin28a attenuates cerebral ischemia/reperfusion injury through regulating Sirt3-induced autophagy.

Cerebral ischemia-reperfusion injury causes damage to local brain tissue and its function, but its specific pathogenesis is still unclear. Autophagy is an important catabolic pathway in eukaryotic cells, which is mainly used to remove damaged intracellular organelles, misfolded long-acting macromolecules and participate in cerebral ischemia-reperfusion injury. Lin28 is a highly conserved RNA-binding protein that plays a role in regulating gene translation, which is important for the growth and maintenance of pluripotent cells. Lin28a has been reported to have a clear protective effect on post-ischemic reperfusion injury of the heart. However, whether Lin28a has an effect on nerve injury after cerebral ischemia-reperfusion needs further study. In this study, we found that the expression of Lin28a was decreased in cerebral ischemia-reperfusion mice model. Upregulation of Lin28a could alleviate the nerve injury caused by ischemia-reperfusion, and promote autophagy of nerve cells. Upregulation of Lin28a reduced nerve cell apoptosis and relieved nerve cell injure induced by oxygen-glucose deprivation/reoxygenation. Lin28a increased the LC3-II levels in nerve cells, suggesting the promotion of autophagy. Mechanism studies indicated that Lin28a promoted autophagy mainly through regulating Sirt3 expression and activating AMPK-mTOR pathway. In conclusion, our study revealed the important role of Lin28a in cerebral ischemia-reperfusion and suggested that Lin28a was a protective factor for cerebral ischemia-induced injury.

FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages.

BACKGROUND: Resident microglia and macrophages are the predominant contributors to neuroinflammation and immune reactions, which play a critical role in the pathogenesis of ischemic brain injury. Controlling inflammatory responses is considered a promising therapeutic approach for stroke. Recombinant human fibroblast growth factor 21 (rhFGF21) presents anti-inflammatory properties by modulating microglia and macrophages; however, our knowledge of the inflammatory modulation of rhFGF21 in focal cerebral ischemia is lacking. Therefore, we investigated whether rhFGF21 improves ischemic outcomes in experimental stroke by targeting microglia and macrophages. METHODS: C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAO) and randomly divided into groups that received intraperitoneal rhFGF21 or vehicle daily starting at 6 h after reperfusion. Behavior assessments were monitored for 14 days after MCAO, and the gene expression levels of inflammatory cytokines were analyzed via qRT-PCR. The phenotypic variation of microglia/macrophages and the presence of infiltrated immune cells were examined by flow cytometry and immunostaining. Additionally, magnetic cell sorting (MACS) in combination with fluorescence-activated cell sorting (FACS) was used to purify microglia and macrophages. RESULTS: rhFGF21 administration ameliorated neurological deficits in behavioral tests by regulating the secretion of pro-inflammatory and anti-inflammatory cytokines. rhFGF21 also attenuated the polarization of microglia/macrophages toward the M1 phenotype and the accumulation of peripheral immune cells after stroke, accompanied by a temporal evolution of the phenotype of microglia/macrophages and infiltration of peripheral immune cells. Furthermore, rhFGF21 treatment inhibited M1 polarization of microglia and pro-inflammatory cytokine expression through its actions on FGF receptor 1 (FGFR1) by suppressing nuclear factor-kappa B (NF-κB) and upregulating peroxisome proliferator-activated receptor-γ (PPAR-γ). CONCLUSIONS: rhFGF21 treatment promoted functional recovery in experimental stroke by modulating microglia/macrophage-mediated neuroinflammation via the NF-κB and PPAR-γ signaling pathways, making it a potential anti-inflammatory agent for stroke treatment.

Predicting Long-Term Outcomes After Poor-Grade Aneurysmal Subarachnoid Hemorrhage Using Decision Tree Modeling.

BACKGROUND: Despite advances in the treatment of poor-grade aneurysmal subarachnoid hemorrhage (aSAH), predicting the long-term outcome of aSAH remains challenging, although essential. OBJECTIVE: To predict long-term outcomes after poor-grade aSAH using decision tree modeling. METHODS: This was a retrospective analysis of a prospective multicenter observational registry of patients with poor-grade aSAH with a World Federation of Neurosurgical Societies (WFNS) grade IV or V. Outcome was assessed by the modified Rankin Scale (mRS) at 12 mo, and an unfavorable outcome was defined as an mRS of 4 or 5 or death. Long-term prognostic models were developed using multivariate logistic regression and decision tree algorithms. An additional independent testing dataset was collected for external validation. Overall accuracy, sensitivity, specificity, and area under receiver operating characteristic curves (AUC) were used to assess model performance. RESULTS: Of the 266 patients, 139 (52.3%) had an unfavorable outcome. Older age, absence of pupillary reactivity, lower Glasgow coma score (GCS), and higher modified Fisher grade were independent predictors of unfavorable outcome. Modified Fisher grade, pupillary reactivity, GCS, and age were used in the decision tree model, which achieved an overall accuracy of 0.833, sensitivity of 0.821, specificity of 0.846, and AUC of 0.88 in the internal test. There was similar predictive performance between the logistic regression and decision tree models. Both models achieved a high overall accuracy of 0.895 in the external test. CONCLUSION: Decision tree model is a simple tool for predicting long-term outcomes after poor-grade aSAH and may be considered for treatment decision-making.

Poor-Grade Aneurysmal Subarachnoid Hemorrhage: Risk Factors Affecting Clinical Outcomes in Intracranial Aneurysm Patients in a Multi-Center Study.

Objective: Patients with poor-grade aneurysm subarachnoid hemorrhage (SAH) have commonly been considered to have a poor prognosis. The objective of this study was to investigate the independent risk factors affecting clinical outcomes in intracranial aneurysm patients with poor-grade aneurysm subarachnoid hemorrhage (aSAH) underwent different intervention therapies. Methods: A multicenter observational registry of 324 poor-grade aSAH patients treated at tertiary referral centers from October 2010 to March 2012 were enrolled in this study. The clinical data including patient characteristics on admission and during treatment course, treatment modality, aneurysm size and location, radiologic features, signs of cerebral herniation (dilated pupils), and functional neurologic outcome were collected. Clinical outcomes were assessed via a modified Rankin Scale at 12 months. Multivariate logistic regression models were used to develop prognostic models. The area under the receiver operator characteristic curves (AUC) and Hosmer-Lemeshow tests were used to assess discrimination and calibration. WAP score was developed to predict risk of poor outcome. Results: Older age, female gender, ventilated breathing status, non-reactive pupil response, pupil dilation, lower GCS score, a WFNS grade of V, intraventricular hemorrhage, a higher Fisher grade, a higher modified Fisher grade, and conservative treatment were calculated to be associated with a relatively poor outcome. Multivariate analyses revealed that older age, lower Glasgow coma scale score (GCS), the absence of pupillary reactivity, higher modified Fisher grade, and conservative treatment were independent predictors of poor outcome, showed good discrimination and calibration. Patients with WFNS grade V, older age and non-reactive pupillary reactivity were predicted to have a poor outcome by WAP risk score. Conclusions: A simple WAP risk score had good discrimination and calibration in the prediction of outcome. The risk score can be easily measured and may complement treatment decision-making.

Endovascular Coiling versus Surgical Clipping of Very Small Ruptured Anterior Communicating Artery Aneurysms.

BACKGROUND: Endovascular coiling of anterior communicating artery (ACoA) aneurysms has evolved dramatically. Ruptured ACoA aneurysms are more likely to be smaller. We aimed to investigate the safety and efficacy of endovascular coiling of very small ruptured ACoA aneurysms compared with surgical clipping. METHODS: We conducted a retrospective analysis of consecutive 111 patients with very small ruptured ACoA aneurysms treated with endovascular coiling or surgical clipping in our single center. Very small aneurysms were defined as aneurysm maximal size ≤3.0 mm. Patients were grouped into coiling and clipping groups. Baseline characteristics, postoperative complications, and clinical outcomes were compared between the 2 groups. RESULTS: Forty-six patients (41.1%) underwent successfully coiling, and 65 patients (58.0%) underwent surgical clipping, including 2 patients who failed coiling and crossed over to surgical clipping. The mean size of the ruptured ACoA aneurysms was 2.6 ± 0.5 mm (range, 1.0-3.0 mm). Patients with smaller aneurysms (P = 0.028) or A1 segment complete configuration (P = 0.009) more often underwent surgical clipping, and patients with A1 segment symmetric configuration more often underwent coiling (P = 0.011). There were not statistically significant differences in intraoperative rupture, early rebleeding, cerebral infarction, and seizure in patients treated with clipping and coiling. Clinical outcomes were similar between the 2 groups. There was no retreatment in both groups. CONCLUSIONS: Patients with very small ruptured ACoA aneurysms can be safely and effectively treated with endovascular coiling. However, smaller ACoA aneurysms still require surgical clipping. A smaller aneurysm size limits the use of endovascular coiling.

Intracranial Complex Ruptured Aneurysms Coiled with Overlapping Low-Profile Visualized Intraluminal Support Stents: Another Available Option for Complex Ruptured Intracranial Aneurysms.

BACKGROUND: Overlapping stents represent a new paradigm in endovascular interventions, especially for complex and wide-necked aneurysms. The low-profile visualized intraluminal support (LVIS) device is a new generation of self-expanding braided stents recently introduced in China for stent-assisted coiling of intracranial aneurysms. We report several cases of intracranial aneurysms coiled using overlapping LVIS stents to evaluate its efficacy and safety. METHODS: Patients with ruptured intracranial aneurysms treated with double LVIS stents at our center between November 2014 and May 2016 were reviewed. The clinical data and technical results are presented. RESULTS: Ten patients with 15 aneurysms were treated with double LVIS stents, with a 100% technical success rate. No mortality was observed. Immediate angiographic outcome evaluation showed complete occlusion in 13 aneurysms (86.7%) and neck remnants in 2 aneurysms (13.3%). CONCLUSIONS: Double LVIS stents are safe and effective in the treatment of intracranial aneurysms, especially complex aneurysms.

Comparison of Aggressive Surgical Treatment and Palliative Treatment in Elderly Patients with Poor-Grade Intracranial Aneurysmal Subarachnoid Hemorrhage.

OBJECTIVE: To compare the current treatment approach in elderly patients with poor-grade aneurysmal subarachnoid hemorrhage (SAH) and identify the independent predictors of the outcome after aggressive surgical treatment. METHOD: This prospective, multicenter cohort study included 104 poor-grade aneurysmal SAH elderly patients, 60 years or older, treated in our institution from October 2010 to March 2013. Patients were grouped according to three treatment arms. Neurological outcome was assessed using the Glasgow Outcome Scale (GOS) at baseline and at a 12-month follow-up. Univariate and multivariate analysis were performed using the following factors: sex, age, smoking history, breathing ability, alcohol consumption, cerebral hernia, aneurysm location, aneurysm diameter, WFNS grade, CT Fisher grade, treatment approach, and the timing of the aneurysm surgery. RESULTS: At the 12-month follow-up, patients in the coiling group and clipping group had better prognosis than patients in the palliative treatment group. Univariate analysis confirmed that the treatment approach, WFNS grade, CT Fisher grade, and age are critical factors for neurological outcomes in poor-grade SAH. Multivariate analysis indicated that WFNS grade V, CT Fisher grades 3-5, and palliative treatment were independent predictors of poor prognoses. CONCLUSION: Aggressive surgical treatment improves the prognoses in poor-grade aneurysm elderly patients with SAH. Elderly Patients of WFNS grade IV and CT Fisher grades 1-2 are more likely to have a better outcome.

Stent-assisted coiling versus coiling alone of poor-grade ruptured intracranial aneurysms: a multicenter study.

INTRODUCTION: Endovascular coiling is a valid treatment option for poor-grade ruptured aneurysms. However, little is known about stent-assisted coiling of poor-grade aneurysms. OBJECTIVE: To compare the safety and efficacy of stent-assisted coiling with coiling alone for poor-grade aneurysms. METHODS: Using multicenter data on poor-grade aneurysms, we performed a retrospective analysis of 131 consecutive patients treated with endovascular coiling within 14 days after ictus. Patients were split into two groups: stent-assisted coiling and coiling alone. Baseline characteristics, immediate angiographic results, perioperative complications, and clinical outcomes were compared between the two groups. RESULTS: Twenty-three (17.6%) patients were treated with stent-assisted coiling and 108 (82.4%) with coiling alone. There were no statistically significant differences in patient age, sex, clinical grade, Fisher grade, modified Fisher grade, aneurysm location, and size between the stent-assisted coiling and coiling alone groups. Intraprocedural aneurysm rupture, procedure-related ischemic complication, external ventricular drainage-related hemorrhagic complication, and symptomatic vasospasm did not differ between the two groups. Immediate angiographic results and clinical outcomes at discharge and at 6 and 12 months did not differ between the groups. Aneurysm rebleeding occurred in 4 (17.4%) patients after stent-assisted coiling compared with 2 (1.9%) patients after coiling alone (p<0.007). Multivariate analysis showed that incomplete aneurysm occlusion was independently associated with aneurysm rebleeding (p=0.016), and there was a trend toward aneurysm rebleeding after stent-assisted coiling (p=0.051). CONCLUSIONS: Stent-assisted coiling of poor-grade aneurysms is feasible and safe compared with coiling alone. However, the hemorrhagic complication and aneurysm rebleeding may not be negligible.

Preoperative and postoperative predictors of long-term outcome after endovascular treatment of poor-grade aneurysmal subarachnoid hemorrhage.

OBJECTIVE An increasing number of patients with poor-grade aneurysmal subarachnoid hemorrhage (aSAH) have received endovascular treatment. Endovascular treatment of poor-grade aSAH, however, is based on single-center retrospective studies, and predictors of long-term outcome have not been well defined. Using results from a multicenter prospective registry, the authors aimed to develop preoperative and postoperative prognostic models to predict poor outcome after endovascular treatment of poor-grade aSAH. METHODS A Multicenter Poor-grade Aneurysm Study (AMPAS) was a prospective and observational registry of consecutive patients with poor-grade aSAH. From October 2010 to March 2012, 366 patients were enrolled in the registry, and 136 patients receiving endovascular treatment were included in this study. Outcome was assessed by modified Rankin Scale (mRS) score at 12 months, and poor outcome was defined as an mRS score of 4, 5, or 6. Prognostic models were developed in multivariate logistic regression models. The area under receiver operating characteristic curves (AUC) was used to assess the model's discriminatory ability, and Hosmer-Lemeshow goodness-of-fit tests were used to assess the calibration. RESULTS At 12 months, 64 patients (47.0%) had a poor outcome: 9 (6.6%) had an mRS score of 4, 6 (4.4%) had an mRS score of 5, and 49 (36.0%) had died. Univariate analyses showed that older age (p = 0.001), female sex (p = 0.044), lower Glasgow Coma Scale score (p < 0.001), a World Federation of Neurosurgical Societies (WFNS) grade of V (p < 0.001), higher Fisher grade (p < 0.001), modified Fisher grade (p < 0.001), and wider neck aneurysm (p = 0.026) were associated with a poor outcome. There was a trend toward a worse outcome in patients with anterior communicating artery aneurysms (p = 0.080) and in those with incompletely occluded aneurysms (p = 0.063). After endovascular treatment, the presence of cerebral infarction (p = 0.039), symptomatic vasospasm (p = 0.039), and pneumonia (p = 0.006) were associated with a poor outcome. Multivariate analyses showed that the preoperative prognostic model including age, a WFNS grade of V, modified Fisher grade, and aneurysm neck size had excellent discrimination with an AUC of 0.86 (95% CI 0.80-0.92, p < 0.001), and a postoperative model that included these predictors as well as postoperative pneumonia had excellent discrimination (AUC = 0.87, 95% CI 0.81-0.93, p < 0.001). Both models had good calibration (p = 0.941 and p = 0.653, respectively). CONCLUSIONS Older age, WFNS Grade V, higher modified Fisher grade, wider neck aneurysm, and postoperative pneumonia were independent predictors of poor outcome after endovascular treatment of poor-grade aSAH. The preoperative model had almost the same discrimination as the postoperative model. Endovascular treatment should be carefully considered in patients with poor-grade aSAH with ruptured wide-neck aneurysms. ▪ CLASSIFICATION OF EVIDENCE Type of question: prognostic; study design: retrospective cohort trial; evidence: Class I.

Predicting intraprocedural rupture and thrombus formation during coiling of ruptured anterior communicating artery aneurysms.

BACKGROUND: Intraprocedural rupture and thrombus formation are serious complications during coiling of ruptured intracranial aneurysms, and they more often occur in patients with anterior communicating artery (ACoA) aneurysms. OBJECTIVE: To identify independent predictors of intraprocedural rupture and thrombus formation during coiling of ruptured ACoA aneurysms. METHODS: Between January 2008 and February 2015, 254 consecutive patients with 255 ACoA aneurysms were treated with coiling. We retrospectively reviewed intraoperative angiograms and medical records to identify intraprocedural rupture and thrombus formation, and re-measured aneurysm morphologies using CT angiography images. Multivariate logistic regression models were used to determine independent predictors of intraprocedural rupture and thrombus formation. RESULTS: Of the 231 patients included, intraprocedural rupture occurred in 10 (4.3%) patients, and thrombus formation occurred in 15 (6.5%) patients. Patients with smaller aneurysms more often experienced intraprocedural rupture than those with larger aneurysms (3.5±1.3 mm vs 5.7±2.3 mm). Multivariate analysis showed that smaller ruptured aneurysms (p=0.003) were independently associated with intraprocedural rupture. The threshold of aneurysm size separating rupture and non-rupture groups was 3.5 mm. Multivariate analysis showed that a history of hypertension (p=0.033), aneurysm neck size (p=0.004), and parent vessel angle (p=0.023) were independent predictors of thrombus formation. The threshold of parent vessel angle separating thrombus and non-thrombus groups was 60.0°. CONCLUSIONS: Ruptured aneurysms <3.5 mm were associated with an increased risk of intraprocedural rupture, and parent vessel angle <60.0°, wider-neck aneurysms, and a history of hypertension were associated with increased risk of thrombus formation during coiling of ruptured ACoA aneurysms.

Aneurysm rebleeding after poor-grade aneurysmal subarachnoid hemorrhage: Predictors and impact on clinical outcomes.

BACKGROUND: Aneurysm rebleeding is a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH) and more often occurs in patients with poor-grade aSAH. Limited data on predictors of rebleeding in these patients are available. OBJECTIVE: To investigate predictors of aneurysm rebleeding after poor-grade aSAH and the association of rebleeding with clinical outcomes. METHODS: A multicenter poor-grade aneurysm study was a prospective and observational registry of consecutive patients who presented with poor-grade aSAH defined as a World Federation of Neurosurgical Societies (WFNS) grade of IV or V. Rebleeding was defined as a new hemorrhage on computed tomography scan. Clinical outcomes were assessed with modified Rankin score. Multivariate logistic regression analyses were used to determine independent predictors of rebleeding and association between the rebleeding and clinical outcomes at 12months. RESULTS: Of the 297 patients included in this study, 30 (10.1%) patients experienced rebleeding. Most rebleeding occurred within 24h after ictus. 22 (73.3%) patients died at discharge. Aneurysm rebleeding was independently associated with poor outcome (odds ratio [OR] 36.37, p<0.001) and associated with mortality (OR 25.03, p<0.001) at 12months. The multivariate analysis showed that a lower Fisher grade (OR 0.49, 95% CI 0.31-0.77; p=0.002), ruptured anterior cerebral artery aneurysms (OR 4.26, 95% CI 1.07-16.90; p=0.039), external ventricular drainage (OR 4.62, 95% CI 1.46-14.59; p=0.009) were independently associated with aneurysm rebleeding. CONCLUSIONS: The outcome of aneurysm rebleeding remains very poor. A lower Fisher grade, ruptured anterior cerebral artery aneurysms, external ventricular drainage were associated with increased risk of rebleeding.

Alterations of caveolin-1 expression in a mouse model of delayed cerebral vasospasm following subarachnoid hemorrhage.

The aim of the present study was to evaluate the expression levels of caveolin-1 in the basilar artery following delayed cerebral vasospasm (DCVS) in a rat model of subarachnoid hemorrhage (SAH), in order to investigate the association between caveolin-1 and DCVS, and its potential as a treatment for DCVS of SAH. A total of 150 Sprague Dawley rats were randomly allocated into blank, saline and SAH groups. The SAH and saline groups were subdivided into days 3, 5, 7 and 14 following the establishment of the model. The murine model of SAH was established by double injection of autologous arterial blood into the cisterna magana and DCVS was detected using Bederson neurological severity scores. Hematoxylin and eosin (HE) staining was used to observe the inner perimeter of the basilar artery pipe and variations in the thickness of the basilar artery wall. Alterations in the levels of caveolin-1 protein in the basilar artery were measured using immunofluorescence and western blot analysis; whereas alterations in the mRNA expression levels of caveolin-1 were detected by reverse transcription-quantitative polymerase chain reaction. In the present study, 15 mice succumbed to SAH-induced DCVS in the day 3 (n=3), 5 (n=5) and 7 (n=2) groups. No mortality was observed in the blank control and saline groups during the process of observation in the SAH group, All mice in the SAH groups exhibited Bederson neurological severity scores ≥1; whereas no neurological impairment was detected in the blank and normal saline groups, demonstrating the success of the model. HE staining was used to assess vasospasm and the results demonstrated that the inner perimeter of the basal artery pipe decreased at day 3 in the SAH group; whereas values peaked in the day 7 group. The thickness of the basal artery wall significantly increased (P<0.05), as compared with the blank and saline groups, in which no significant alterations in the wall thickness and the inner perimeter of the basal artery pipe were detected. As detected by immunofluorescence and western blot analysis, the expression levels of caveolin-1 protein significantly decreased in the day 7 of SAH group, as compared with the blank and saline groups (P<0.01), in which no significant alterations were detected. Caveolin-1 mRNA expression levels significantly increased at the day 7 in the SAH group, as compared with the blank and the saline groups (P<0.01), as detected by RT-qPCR. Furthermore, significant differences were detected at day 14 in the SAH group, as compared with the blank and the saline groups (P>0.05), in which no significant alterations were detected. Therefore, the results of the present study demonstrated that caveolin-1 protein was downregulated in the basilar artery of a rat modeling SAH, which may be associated with DCVS. This suggested that caveolin-1 may be a potential target for the treatment of DCVS.

A Multicenter Analysis of Computed Tomography Angiography Alone Versus Digital Subtraction Angiography for the Surgical Treatment of Poor-Grade Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Poor-grade aneurysmal subarachnoid hemorrhage (aSAH) is associated with increased intracranial pressure, and these patients are unstable with a high risk of rebleeding. Computed tomography angiography (CTA) has been proposed as an examination tool for the rapid detection of ruptured aneurysms. We aimed to determine the safety and efficacy of CTA alone for surgical treatment of poor-grade aSAH compared with digital subtraction angiography (DSA). METHODS: We conducted a multicenter retrospective analysis of 144 patients with poor-grade aSAH who underwent surgical treatment for 2 different cohorts. Patients were grouped into CTA alone and DSA groups. Baseline characteristics, postoperative complications, and clinical outcomes at discharge and at last follow-up were compared between the 2 groups. Multivariate logistic regression models were used to assess the association between CTA alone and clinical outcomes after we adjusted for potential confounders. RESULTS: Of the 116 patients included, 42 (36.2%) patents received CTA alone and 74 patients (63.7%), including 12 patients with CTA and DSA and 62 patients with DSA alone, received DSA before surgical treatment. Patients with larger ruptured aneurysms (P = 0.006), aneurysm sizes of larger than 5 mm (P = 0.025), presence of single aneurysms (P = 0.018), and presence of intraventricular hemorrhage (P = 0.019) more often received CTA alone. All ruptured aneurysms were clipped successfully during surgery. There were no statistically significant differences in postoperative complications and clinical outcomes between the 2 groups. CONCLUSIONS: Although CTA alone can be safely and effectively used in most patients requiring surgical treatment, additional DSA may be considered in patients with smaller ruptured aneurysms or in those with multiple aneurysms.

Stent-assisted coiling versus coiling alone of ruptured anterior communicating artery aneurysms: A single-center experience.

OBJECTIVE: Endovascular coiling of anterior communicating artery (ACoA) aneurysms has evolved; however, stent-assisted coiling of ruptured aneurysms remains controversial. We aimed to compare periprocedural complications, angiographic and clinical outcomes after stent-assisted coiling with coiling alone of ruptured ACoA aneurysms. METHODS: We performed a retrospective review of consecutive 222 patients with ruptured ACoA aneurysms treated with endovascular coiling within 7 days after ictus. Patients were grouped into stent-assisted coiling and coiling alone groups. Baseline characteristics, periprocedural complications, clinical outcomes, and angiographic results were compared between the two groups. RESULTS: 63 (28.4%) patients underwent stent-assisted coiling and 159 (71.6%) underwent coiling alone. There were no statistically significant differences in age, sex, clinical grading and Fisher grade. Larger aneurysms (P=0.002) and wider-neck aneurysms (P<0.001) were more often treated with stent-assisted coiling within 72h (P=0.025). Intraprocedural aneurysm rupture occurred in 6 (9.5%) patients treated with stent-assisted coiling compared with in 5 (3.1%) treated with coiling alone (P<0.048). Thrombus formation occurred in 10 (15.9%) patients after stent-assisted coiling compared with 6 (3.8%) after coiling alone (P=0.002). Stent-assisted coiling achieved a lower rate of immediate occlusion than coiling alone (P=0.045). Postoperative complications, clinical outcomes, and follow-up aneurysm occlusion did not significantly differ. CONCLUSIONS: Stent-assisted coiling of ruptured ACoA aneurysms was associated with a higher rate of intraprocedural complications and associated with a lower immediate occlusion rate. However, Postoperative complications and clinical outcomes did not differ. Long-term angiographic results require further study.

Predictors of good functional outcomes and mortality in patients with severe rebleeding after aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Aneurysmal rebleeding is a major cause of morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH); however, limited data on severity of rebleeding and outcomes after severe rebleeding are available. We aimed to determine predictors of good outcome and mortality after severe rebleeding. MATERIALS AND METHODS: In a multicenter poor-grade aneurysm study, 60 patients with severe rebleeding, defined as new hemorrhage with poor clinical condition caused by rebleeding, were identified. Good functional outcome was defined as a modified Rankin scale (mRS) of ≤2, and mortality was defined as a mRS of 6. Multivariate logistic analyses were used to determine predictors of good outcome and mortality. RESULTS: Of the 58 patients included in this report, 24 (41.3%) patients experienced rebleeding within 24h after ictus. 42 (72.4%) patients had died at 12 months. The rate of good outcome increased from 5.2% at discharge to 13.8% at 6 months and 19.0% at 12 months. In multivariate analysis, World Federation of Neurosurgical Societies (WFNS) grade IV after rebleeding (P=0.007) and aggressive treatment (P=0.039) were independently associated with good outcome. A higher modified Fisher grade before rebledding (P=0.040), larger aneurysms (P=0.005), and lower Glasgow coma score after rebleeding (P=0.003) were independently associated with increased mortality. CONCLUSIONS: A better clinical condition after rebleeding were independently associated with good outcome and inversely associated with morality after severe rebleeding. Despite high mortality of rebleeding, patients with WFNS grade IV treated with aggressive treatment were more likely to have good outcomes regardless of their condition before rebleeding.