Decreased PDLIM1 expression in endothelial cells contributes to the development of intracranial aneurysm.

INTRODUCTION: Intracranial aneurysm (IA) is a common vascular enlargement that occurs in the wall of cerebral vessels and frequently leads to fatal subarachnoid hemorrhage. PDZ and LIM domain protein 1 (PDLIM1) is a cytoskeletal protein that functions as a platform for multiple protein complex formation. However, whether PDLIM is involved in the pathogenesis of IA remains poorly understood. METHODS: Loss-of-function and gain-of-function strategies were employed to determine the in vitro roles of PDLIM1 in vascular endothelial cells (VECs). A rat model of IA was generated to study the role of PDLIM1 in vivo. Gene expression profiling, Western blotting, and dual luciferase reporter assays were performed to uncover the underlying cellular mechanism. Clinical IA samples were used to determine the expression of PDLIM1 and its downstream signaling molecules. RESULTS: PDLIM1 expression was reduced in the endothelial cells of IA and was regulated by Yes-associated protein 1 (YAP1). Genetic silencing of PDLIM1 inhibited the viability, migratory ability, and tube formation ability of VECs. Opposite results were obtained by ectopic expression of PDLIM1. Additionally, PDLIM1 overexpression mitigated IA in vivo. Mechanistic investigations revealed that PDLIM1 promoted the transcriptional activity of ß-catenin and induced the expression of v-myc myelocytomatosis viral oncogene homolog (MYC) and cyclin D1 (CCND1). In clinical settings, reduced expression of PDLIM1 and ß-catenin downstream target genes was observed in human IA samples. CONCLUSION: Our study indicates that YAP1-dependent expression of PDLIM1 can inhibit IA development by modulating the activity of the Wnt/ß-catenin signaling pathway and that PDLIM1 deficiency in VECs may represent a potential marker of aggressive disease.

How we do it? The surgical resection of a medial parietal arteriovenous malformation under multimodal imaging technology-guided hybrid operation.

BACKGROUND: This report described the surgical resection of a challenging medial parietal lobe arteriovenous malformation (AVM) using the hybrid operation theater with a multimodal imaging-guided technology. METHOD: A 29-year-old male was admitted to treat a ruptured medial parietal AVM. The deep and diffusive compartment of the nidus was embolized before resection. Preoperatively and intraoperatively, mixed reality technology with multimodality imaging was utilized for surgical planning and navigation. The nidus was totally resected and confirmed by intraoperative angiography. The patient recovered without sequella. CONCLUSION: We hope this report provides new insights into applying multimodal imaging technology-guided hybrid operation for brain AVM.

The Safety and Efficacy of Leo Stents with Coiling or Alone for Anterior Cerebral Artery Aneurysms.

INTRODUCTION: Treatment of anterior cerebral artery (ACA) aneurysms is still not well established. The Leo stent with blood flow direction is a retrievable stent for intracranial aneurysms, whereas it needs to be studied clearly in patients with ACA aneurysms. METHODS: Consecutive patients with ACA aneurysms were retrospectively enrolled in three neurosurgical centers between January 2016 and October 2021. The data on demographics, aneurysm characteristics, symptom resolution, and postoperative course were collected and analyzed. The aneurysm occlusion status was appraised by Raymond-Ray Occlusion Class (RROC). RESULTS: A total of 57 patients with ACA aneurysms were included in our study. Immediate postprocedural angiograms showed that 20 aneurysms (35.1%) were in complete occlusion (RROC 1), 26 aneurysms (45.6%) were in near-complete occlusion (RROC 2), 11 aneurysms (19.3%) were in incomplete occlusion (RROC 3). The angiographic follow-up found that the rate of complete occlusion increased to 57.9%, and near-completion and incomplete occlusion dropped to 29.8% and 12.3%, respectively. The angiographic result of the last follow-up improved significantly (Z=- 2.805, P=0.005). Univariate analysis indicated that distal location of aneurysms (Z=4.538, P=0.033) and ruptured aneurysms (χ2=.6120, P=0.032) were potential risk factors for intra-parent artery narrowing. Furthermore, multivariate logistic regression analysis found that A3 aneurysms (95% CI 1.427~32.744, P=0.016) are the key risk factor for intra-parent artery narrowing. CONCLUSIONS: The Leo stent is safe and effective for aneurysms located in ACA circulations. The overall occlusion degree improved during follow-up. A distal, small artery was the risk factor for intra-parent artery narrowing.

Resveratrol inhibits cerebral aneurysms in mice via downregulating the NF-κB pathway.

OBJECTIVES: Cerebral aneurysm (CA) is one of the most common cerebrovascular diseases. The study was conducted to investigate the effect of resveratrol (RES) on the CA formation and its possible mechanisms. MATERIALS AND METHODS: Murine model of CA was constructed by induced hypertension and fed without (model group) or with RES (RES group). A Sham group was used as a control. The CA formation and inflammatory response were examined morphologically and histochemically. The expression of nuclear factor-κB (NF-κB), matrix metalloproteinase (MMP)-2, and MMP-9 was analyzed using qRT-PCR and Western blots. RESULTS: CA was induced in mice after the left common carotid artery was ligated and fed with high sodium chloride. Compared with the model, mice fed with RES had significantly fewer CA with smaller size, normal thickness of the arterial wall (P<0.05), and fewer infiltrated macrophages in the aneurysm wall (P<0.05). qRT-PCR and Western blot analyses showed that the expression of MMP-2, MMP-9 and NF-κB was significantly elevated in the model as compared with the control and significantly decreased after RES treatments (P<0.05). CONCLUSIONS: RES can inhibit the CA formation in mice subjected to induced hypertension and this inhibition is likely mediated via downregulating the NF-κB pathway.

The Long-Term Outcome in a Cohort of 52 Patients With Symptomatic Intramedullary Spinal Cavernous Hemangioma After Microsurgery and Emergency Rescue Surgery.

Background: Surgery is the mainstay treatment for patients with symptomatic intramedullary spinal cavernous hemangioma (ISCH), however the time of surgical intervention remains controversial. In this study, we proposed emergency rescue surgery (ERS) for patients in deteriorative type. The prognostic factors of patients with ISCH after microsurgery and the clinical effect of ERS were analyzed. Methods: From January 2013 to November 2019, 52 patients with symptomatic ISCH treated by microsurgical treatment were collected, ranging in age from 17 to 66 years old (mean: 45.8 ± 13.5 years). The course of the disease ranged from 2 days to 20 years. Of 52 lesions, 17 lesions were in the cervical segment, 25 in the thoracic segment, and 10 in the lumbosacral segment; while seven cases were at the ventral surface, 25 cases at the dorsal surface, and 20 cases at the central spinal cord. The sagittal diameter ranged from 1 to 58 mm (median: 17.3 mm). The transverse diameter ratio ranged from 20 to 80% (median: 50.7%). Thirty-two patients were diagnosed as deteriorative type and 22 were treated by ERS. Results: At 12 months after surgery, all patients were followed up, and no residual or recurrence was found in all patients. Twenty-five patients (48.1%) showed spinal cord functional improvement after surgery; 25 (48.1%) had no functional change; 2 (3.8%) got worse. For deteriorative patients, ERS group had a significantly higher improvement rate than the non-ERS group (χ2 = 5.393, P = 0.02); For all 52 patients, the factors as a lesion at the ventral surface (Z = 10.453, P = 0.015), or lumbosacral segment (χ2 = 9.259, P = 0.010) and longer course of disease (Z = -2.021, P = 0.043) were potential risks in functional recovery in univariate analysis; and in multiple-factor analysis, the lesion at the lumbosacral segment (OR = 4.004, 95% CI: 1.341~11.961, P = 0.013) was the independent risk factors for the functional recovery. Conclusions: Microsurgical resection is safe and effective for symptomatic ISCH. The ERS is an effective way to improve deteriorative patients' spinal cord function at long-term follow-up. The lesion at the lumbosacral segment is one of the poor prognostic factors.

Flow diversion effect of the leo braided stent for aneurysms in the posterior and distal anterior circulations: A multicenter cohort study.

Background and purpose: The treatment of aneurysms located in the posterior and distal anterior circulations remains a challenge. Leo stents with a flow diversion (FD) effect may be a potential option, which needs to be clearly studied. Methods: From January 2016 to October 2021, 133 patients with 145 aneurysms in the posterior and distal anterior circulations, treated with Leo stents, were retrospectively analyzed in three neurosurgical centers. Data on demographic information, aneurysm characteristics, procedural outcomes, postoperative course, and aneurysm occlusion were retrospectively analyzed. Results: After immediate surgery, 90 aneurysms (60.1%) were in complete occlusion [Raymond-Ray Occlusion Class (RROC) 1 and O'Kelly Marotta (OKM) grade D], 29 aneurysms (20%) in good occlusion (RROC 2 and OKM grade C), 17.9% in incomplete occlusion (RROC 3a or OKM grade B), and no aneurysms in invalid occlusion (RROC 3b and OKM grade A). A total of 112 patients with 117 aneurysms received angiographic follow-up (mean 11.4 months), and the degree of occlusion showed a significant improvement (Z = 3.900, p < 0.001). The complete occlusion rate increased to 84.6% (99/117), while good and incomplete occlusion decreased to 6.8% (8/117) and 8.6% (10/117), respectively. A total of 14 cases (10.5%) presented narrowing of the parent artery, and nine cases (6.8%) had injured side branches. Cerebral hemorrhage occurred in four patients (3.0%), and symptomatic ischemic infarction occurred in six patients (4.5%). The final permanent morbidity (mCS ≥3) and mortality were 2.8% (3/133) and 0.8% (1/133), respectively. For 82 aneurysms treated by stent-assisted with coiling (SAC), large-sized, ruptured aneurysms (χ2 = 7.767, p = 0.005) occurred. For 63 aneurysms treated by LEO stent monotherapy (LSM), multiple aneurysms, fusiform aneurysms (χ2 = 18.958, p < 0.01), and/or small-sized aneurysms (Z = -2.692, p = 0.007) occurred. Conclusions: Leo stents are safe and effective for aneurysms located in the posterior and distal anterior circulations. The overall degree of occlusion improved during a follow-up because of the FD effect of Leo stents. Aneurysms in these areas should be treated with personalized measures.

miR-139-5p Suppresses Proliferation and Angiogenesis of Intracranial Aneurysm via FGB.

Intracranial aneurysm (IA) is a common cerebrovascular disease. Understanding the mechanism regulating the progression of IA could help to develop novel therapeutic methods for this disease. In this study, we confirmed FGB is one of the targets of miR-139-5p. Moreover, miR-139-5p expression in intracranial aneurysm specimens was suppressed compared with normal tissues. However, we found that FGB in intracranial aneurysm samples was remarkedly enhanced compared to normal tissues. Moreover, we found miR-139-5p overexpression and FGB silencing inhibit HBMEC proliferation and tube formation and suppressed α-SMA and CXCR4 levels in HBMEC cells. Furthermore, a rescue experiment confirmed miR-139-5p affected the proliferation and angiogenesis of HBMEC through FGB. Despite further research being needed to determine the exact functions of miR-139-5p in the formation of CA, our new findings contribute to a comprehensive understanding of the treatment mechanism of IA.

Endovascular treatment of complex intracranial aneurysms using intra/extra-aneurysmal stent.

BACKGROUND: Intra/extra-aneurysmal stent placement for treatment of complex and wide-necked bifurcation aneurysms has been previously described. However, this technique has been rarely reported in the treatment of dissecting aneurysms with incorporated vessels. We assess the feasibility and effectiveness of intra/extra-aneurysmal stent-assisted coil embolization in the treatment of those complex intracranial aneurysms. METHODS: Between January 2009 and April 2010, nine consecutive patients with wide-necked or dissecting aneurysms with incorporated vessels underwent endovascular treatment using intra/extra-aneurysmal stent-assisted coiling at our institution. We assessed the clinical history, morphologic features of the aneurysms, treatment results, and follow-up. RESULTS: All Neuroform stents were successfully deployed in this series. Of the nine aneurysms treated with stent-assisted embolization, complete occlusion was achieved in seven aneurysms, nearly complete in one, and incomplete was present in one. There was no procedure-related complication in this series. Angiographic follow-up results of eight patients (mean, 8.6 months) showed continued obliteration of the aneurysms in six patients, incomplete occlusion in two patients, and the two patients received second treatment. On the modified Rankin Scale applied in follow-up, all patients were assessed as functionally improved or of stable clinical status. CONCLUSIONS: Intra/extra-aneurysmal stent placement and subsequent coil embolization may be effective for the treatment of selected patients with complex intracranial aneurysms. Short-term follow-up data indicate good durability of stent-assisted aneurysm occlusion. However, further study with longer follow-up and larger case series is necessary for validation of the efficacy of this treatment modality.

A New Classification of Anterior Choroidal Artery Aneurysms and Its Clinical Application.

Background and Purpose: The aim of this study was to compare the different subtypes of anterior choroidal artery (AChoA) aneurysm based on a new classification and to analyze the risk factors according to individual endovascular treatment (EVT). Methods: In the new classification, AChoA aneurysms are classified into independent type (I type) and dependent type (II type) based on the relationship between the AChoA and the aneurysm. II type aneurysms have three subtypes, IIa (neck), IIb (body), and IIc (direct). We retrospectively analyzed 52 cases of AChoA aneurysm treated in our center between 2015 to 2019. There were 13 (25.0%) I type aneurysms, 24 (46.2%) IIa aneurysms, 15 (28.8%) IIb aneurysms, and no IIc type; 28 cases had a subarachnoid hemorrhage. According to our preoperative EVT plan for the different subtypes: II type should achieve Raymond-Roy Occlusion Class 1 (RROC 1) where possible. To protect the AChoA, it is best to preserve the neck of the IIa type aneurysms (RROC 2), and RROC 3 is enough for IIb type. Results: Ten asymptomatic cases with minimal aneurysms were treated conservatively. Of the other cases, 42 were treated with individualized EVT (26 with a simple coil, 6 with balloon-assisted coiling, 7 with stent-assisted coiling, and 3 by flow diverter. Different subtypes had different RROC (Z = 14.026, P = 0.001). IIb type aneurysms (χ2 = 7.54, P = 0.023) were one of the factors related to temporary or permanent AChoA injury during surgery. Overall, two patients (IIa = 1, IIb = 1) developed contralateral hemiparesis. Conclusions: The new classification diagram clearly shows the features of all types of AChoA aneurysm and makes EVT planning more explicit. The II type (particularly IIb) was a potential risk factor for AChoA injury.

Model-Based Reasoning of Clinical Diagnosis in Integrative Medicine: Real-World Methodological Study of Electronic Medical Records and Natural Language Processing Methods.

BACKGROUND: Integrative medicine is a form of medicine that combines practices and treatments from alternative medicine with conventional medicine. The diagnosis in integrative medicine involves the clinical diagnosis based on modern medicine and syndrome pattern diagnosis. Electronic medical records (EMRs) are the systematized collection of patients health information stored in a digital format that can be shared across different health care settings. Although syndrome and sign information or relative information can be extracted from the EMR and content texts can be mapped to computability vectors using natural language processing techniques, application of artificial intelligence techniques to support physicians in medical practices remains a major challenge. OBJECTIVE: The purpose of this study was to investigate model-based reasoning (MBR) algorithms for the clinical diagnosis in integrative medicine based on EMRs and natural language processing. We also estimated the associations among the factors of sample size, number of syndrome pattern type, and diagnosis in modern medicine using the MBR algorithms. METHODS: A total of 14,075 medical records of clinical cases were extracted from the EMRs as the development data set, and an external test data set consisting of 1000 medical records of clinical cases was extracted from independent EMRs. MBR methods based on word embedding, machine learning, and deep learning algorithms were developed for the automatic diagnosis of syndrome pattern in integrative medicine. MBR algorithms combining rule-based reasoning (RBR) were also developed. A standard evaluation metrics consisting of accuracy, precision, recall, and F1 score was used for the performance estimation of the methods. The association analyses were conducted on the sample size, number of syndrome pattern type, and diagnosis of lung diseases with the best algorithms. RESULTS: The Word2Vec convolutional neural network (CNN) MBR algorithms showed high performance (accuracy of 0.9586 in the test data set) in the syndrome pattern diagnosis of lung diseases. The Word2Vec CNN MBR combined with RBR also showed high performance (accuracy of 0.9229 in the test data set). The diagnosis of lung diseases could enhance the performance of the Word2Vec CNN MBR algorithms. Each group sample size and syndrome pattern type affected the performance of these algorithms. CONCLUSIONS: The MBR methods based on Word2Vec and CNN showed high performance in the syndrome pattern diagnosis of lung diseases in integrative medicine. The parameters of each group's sample size, syndrome pattern type, and diagnosis of lung diseases were associated with the performance of the methods. TRIAL REGISTRATION: ClinicalTrials.gov NCT03274908; https://clinicaltrials.gov/ct2/show/NCT03274908.

The Role of Matrix Metalloproteinase-3 in the Doxycycline Attenuation of Intracranial Venous Hypertension-Induced Angiogenesis.

BACKGROUND: The molecular mechanism of brain arteriovenous malformation (BAVM) is largely unknown. Intracranial venous hypertension (VH) may enhance focal angiogenesis and promote BAVM development and progression. A rat VH model effectively simulates the hemodynamic microenvironment of this disease. OBJECTIVE: To explore the effect of doxycycline in VH-related angiogenesis, as well as the role of matrix metalloproteinase-3 (MMP-3) and other molecular factors. METHODS: A rat VH model was generated by common carotid artery and distal external jugular vein anastomosis. Microvessel density (MVD) in the perisinus area and expression of MMP-3/2/9, VEGF, TIMP-1, TGF-ß, and HIF-1α were examined, with and without daily doxycycline treatment for 4 wk. The effects of doxycycline were verified in Vitro using human brain microvascular endothelial cells (HBMECs). MMP-3 overexpression or knockdown in HBMECs was used to confirm the role of MMP-3 in cell functions. RESULTS: MVD in the perisinus cortex was greatly increased after VH. Doxycycline decreased MVD, suppressed MMP-3 overexpression, and reduced VEGF, TGF-ß, and TIMP-1 levels compared with the controls (P < .05). In Vitro, doxycycline decreased HBMEC migration, tube formation, and the mRNA, protein, and enzymatic activity levels of MMP-3. MMP-3 overexpression in HBMECs promoted migration, while knockdown of MMP-3 significantly attenuated proliferation, migration, and tube formation (P < .05). CONCLUSION: Our findings indicate that MMP-3 plays an important role in VH-related angiogenesis and the promotion of vascular remodeling. Suppression of MMP-3 overexpression by doxycycline may provide a potential strategy for inhibiting BAVM development.

Endovascular treatment of posterior cerebral artery aneurysms: a single center's experience of 55 cases.

OBJECTIVE Aneurysms of the posterior cerebral artery (PCA) are uncommon. To date, a limited number of studies have examined the outcomes of endovascular treatment for PCA aneurysms. The authors' aim in this study is to report their experience with the endovascular treatment of PCA aneurysms. METHODS Between January 2007 and December 2014, 55 patients with 59 PCA aneurysms were treated using the endovascular approach at the authors' institution. Twenty-three patients had 25 saccular aneurysms, and 32 patients had 34 fusiform/dissecting aneurysms. The endovascular modalities included the following: 1) selective occlusion of the aneurysm (n = 22); 2) complete occlusion of the aneurysm and the parent artery (n = 20); 3) parent artery occlusion (n = 6); 4) partial coiling of the aneurysm and the parent artery (n = 5); and 5) occlusion of the dissecting aneurysm sac (n = 2). RESULTS The immediate angiographic results included 45 complete occlusions (82%), 2 nearly complete occlusions (4%), and 8 incomplete occlusions (14%). The mean follow-up period of 21.8 months in 46 patients showed 37 stable results, 6 further thromboses, and 3 recurrences. The final results included 41 complete occlusions (89%), 2 nearly complete occlusions (4%), and 3 incomplete occlusions (7%). Procedure-related complications included the following: 1) rebleeding (n = 1); 2) infarction (n = 4); and 3) perforation (n = 1). There was 1 (1.8%) procedure-related death due to rebleeding, and 2 (3.6%) non-procedure-related deaths due to severe subarachnoid hemorrhage. Clinical outcomes were excellent (Glasgow Outcome Scale 5) in 47 of 49 patients at the long-term follow-up. CONCLUSIONS PCA aneurysms may be effectively treated by different endovascular approaches with favorable clinical and radiological outcomes. However, patients who present with severe SAH still have an overall poor prognosis. Partial coiling of the aneurysm and the parent artery is an attractive alternative treatment for patients who may not tolerate parent artery occlusion. Further study with a larger case series is necessary for validation of the durability and efficacy of this treatment.

Tentorial dural arteriovenous fistula manifesting as contralateral trigeminal neuralgia: resolution after transarterial Onyx embolization.

Tentorial dural arteriovenous fistula (DAVF) as a cause of trigeminal neuralgia is extremely rare. Although less than 10 cases have been reported in the literature, all cases presented with ipsilateral trigeminal neuralgia. Here we report a unique case of tentorial DAVF manifesting as contralateral trigeminal neuralgia. A 58-year-old man presented with right-sided trigeminal neuralgia. Cerebral angiography revealed a left tentorial DAVF and the MR imaging demonstrated a variceal venous dilatation occupying the left lateral pontine cistern and multiple venous flow voids adjacent to the right trigeminal nerve root entry zone. Transarterial Onyx embolization resulted in near complete obliteration of the fistula with immediate resolution of facial pain. The patient remains symptom free and without evidence of recurrence during 9 months of follow-up. Transarterial Onyx embolization may be an effective treatment modality for such an usual case.

Ginkgolide B prevents cathepsin-mediated cell death following cerebral ischemia/reperfusion injury.

Ginkgolide B (GB) has been shown to exert neuroprotective effects against cerebral ischemia/reperfusion (I/R) injury. However, the underlying mechanism by which GB prevents ischemic cell death remains unclear. Lysosomal proteases, including cathepsins B and L, have been implicated in ischemic cell death following reperfusion. Therefore, in the present study, we investigated the role of GB with respect to cathepsin-mediated cell death following I/R. Both the expression and enzymatic activity of cathepsins B and L were significantly increased in the ischemic cortex following cerebral I/R injury. We found that GB treatment markedly decreased the activity and expression of cathepsins B and L following I/R. Moreover, GB reduced necrotic and apoptotic cell death following I/R. These data strongly suggest that GB prevents cathepsin-mediated cell death following focal cerebral I/R injury, and they might provide new insights into the mechanism of the neuroprotective effects of GB.

Tentorial dural arteriovenous fistula manifesting as contralateral trigeminal neuralgia: resolution after transarterial Onyx embolization.

Tentorial dural arteriovenous fistula (DAVF) as a cause of trigeminal neuralgia is extremely rare. Although less than 10 cases have been reported in the literature, all cases presented with ipsilateral trigeminal neuralgia. Here we report a unique case of tentorial DAVF manifesting as contralateral trigeminal neuralgia. A 58-year-old man presented with right-sided trigeminal neuralgia. Cerebral angiography revealed a left tentorial DAVF and the MR imaging demonstrated a variceal venous dilatation occupying the left lateral pontine cistern and multiple venous flow voids adjacent to the right trigeminal nerve root entry zone. Transarterial Onyx embolization resulted in near complete obliteration of the fistula with immediate resolution of facial pain. The patient remains symptom free and without evidence of recurrence during 9 months of follow-up. Transarterial Onyx embolization may be an effective treatment modality for such an usual case.

Allelic variation of the MMP3 promoter affects transcription activity through the transcription factor C-MYB in human brain arteriovenous malformations.

MMPs comprise a family of proteolytic enzymes that degrade pericellular substances, which may result in the destabilization of vessels and related to the development of brain arteriovenous malformations (BAVM). MMP3 is a key member of this family, overexpressed in BAVM tissues, and a single nucleotide polymorphism within MMP3, -709A>G (rs522616), is significantly associated with the risk of BAVM. In this study, we aimed to investigate the mechanism through which the polymorphism rs522616 regulates the expression of MMP3. Our results showed that -709A led to a over 2-fold higher transcriptional activity compared with the G allele (P<0.05) and this transcriptional activity can be depressed by co-transfecting cells with competitive DNA fragments containing -709A but not -709G. Bioinformatics analyses suggested that the transcription factor C-MYB might bind to the area around rs522616. Overexpressed C-MYB significantly increased the transcriptional activity of -709A compared with -709G or controls that did not overexpress c-myb (P<0.01) in HEK293 and HUVEC cells. ChIP assays indicated that C-MYB bound to the SNP region in the two cell lines and three BAVM tissue samples. Together, these data indicated that C-MYB can bind to the -709A allele of the MMP3 promoter, activate its transcription and lead to a higher expression of this gene. This novel hypothesis, supported by molecular evidence, explains how this SNP affects MMP3 promoter function and results in a risk of BAVM development.