Genetic causal relationship between tea intake and cerebral aneurysm: a two-sample Mendelian Randomization Study

Background:Prior research has established a strong link between cerebral aneurysm(CA)occurrence and inflammation.Tea intake(TI)has been found to have anti-inflammatory properties through multiple mechanisms,potentially lowering CA incidence.This study aims to employ Mendelian Randomization(MR)methodology to explore the genetic causality between TI and CA.Methods:We collected Genome-wide association study(GWAS)data for CA,TI,Green tea intake(GTI),Herbal tea intake(HTI),and Rooibos tea intake(RTI).The MR analysis employed the TwoSampleMR package and utilized the inverse variance-weighted(IVW)method.Results:The findings suggest no genetic causal relationship between TI and CA(IVW:OR=1.10,95%CI:0.59–2.05,P=0.772).Similarly,there is no genetic causal association between GTI and CA(IVW:OR=1.07,95%CI:0.91–1.26,P=0.388),HTI and CA(IVW:OR=1.00,95%CI:0.89–1.13,P=0.943),or RTI and CA(IVW:OR=1.02,95%CI:0.96–1.09,P=0.472).Conclusion:There is no genetic causal relationship between TI and CA,and the different types of tea do not change this result.Further MR analysis is needed to investigate whether there is a potential genetic causal association between the quantity of TI and CA.

Outcomes of early physiotherapy in patients with cerebral aneurysms treated by surgical clipping or endovascular embolization

Early physiotherapy was given to 124 patients with ruptured or unruptured cerebral aneurysms who were treated by surgical clipping or endovascular embolization.Patients were divided into four groups according to their Hunt and Hess grade at admission and aneurysm treatment modality： Group 1,Hunt and Hess grade≤II and surgical clipping;Group 2,Hunt and Hess grade≤II and endovascular embolization;Group 3,Hunt and Hess grade≥III and surgical clipping;Group 4,Hunt and Hess grade≥III and endovascular embolization.Level of consciousness was evaluated using the Glasgow Coma Scale,functional status using the Glasgow Outcome Scale,level of the mobility using the Mobility Scale for acute stroke patients,and independence in activities of daily living using the Barthel Index.After early physiotherapy,the level of consciousness and functional status improved significantly in Groups 1,3,and 4;mobility improved significantly in all groups;and independence in activities of daily living improved significantly in Groups 1 and 3.At discharge, Groups 1 and 2 had better functional status than Groups 3 and 4.Level of consciousness,functional status,mobility and independence in activities of daily living improved after early physiotherapy. These findings suggest that early physiotherapy improved the prognosis of patients with cerebral aneurysms who were treated by surgical clipping or endovascular embolization.Patients with a worse clinical status at presentation had a poorer functional status at discharge.The outcome of physiotherapy was not affected by whether surgical clipping or endovascular embolization was chosen for treatment of the aneurysm.

Biomechanical Considerations in the Unruptured Cerebral Aneurysm Study (UCAS Japan): Rupture Risk and True Stress of Wall

When an unruptured aneurysm is found, deciding whether to operate or follow up is one of the most important issues. There are guidelines for making the best final decision on treatment, taking into account the effectiveness of diagnostic and therapeutic devices and the risk-benefit ratio of patients, caregivers, and healthcare professionals. The guidelines evidence-based of large clinical data for this purpose are presented by national medical societies. As one of the rupture risk indicators, there is the hazard risk ratio derived by the UCAS Japan research group based on the statistical method of 6697 aneurysms in 5720 patients with cerebral aneurysms of 3 mm or more. Therefore, we investigated the biomechanical significance of this hazard risk ratio using a spherical aneurysm model. It was revealed that 1) the reason why the frequency of aneurysm rupture is relatively high up to about 10 mm, 2) the UCAS hazard risk ratio corresponds to stress of the aneurysm wall, and the true stress can be calculated by multiplying the patient’s blood pressure, and 3) the factors that cause the daughter’s sac (irregular protrusion of the aneurysm wall). In addition, our two methods for measuring the strength of the blood vessel wall of an individual patient were described.

Interventional Therapy for Cerebral Aneurysms Under the Guidance of 3D Printing Technology

Objective:To explore the clinical method and effect of 3D printing in the treatment of cerebral aneurysms.Methods:The authors research work on the hospital,work time in February 2019-February 2020,this study selected patients of cerebral aneurysms,this period are selected for treatment of 100 cases of patients,randomly divided into two groups,a group to give simple intervention,named as the control group,another group for the interventional therapy under the guidance of 3 D printing,named as experimental group,analyze the effect of two groups of patients with clinical intervention.Results:The length of hospital stay in the experimental group was shorter than that in the control group.Meanwhile,the incidence of complications and adverse reactions in the experimental group and the control group were 6.00%and 18.00%,the experimental group was better(P<0.05).Conclusion:3D printing technology can be applied in the treatment of patients with cerebral aneurysms to provide guidance for interventional surgical treatment.It has significant effect,can reduce the incidence complications in patients,has significant clinical effect,and can be popularized.

NON-NEWTONIAN COMPUTATIONAL HEMODYNAMICS IN TWO PATIENT-SPECIFIC CEREBRAL ANEURYSMS WITH DAUGHTER SACCULES

Hemodynamic factors play important roles in the formation, progression and rupture of cerebral aneurysms, and the Wall Shear Stress （WSS） and Oscillatory Shear Index （OSI） on the aneurysms are considered to be correlated with their growth and rupture. In this article, two computational models based on patient-specific cerebral aneurysms with daughter saccule are constructed from 3D-RA image data, one is lateral aneurysm located in middle cerebral artery （CA1） and the other is terminal aneurysm located in anterior communicating artery （CA2）, The corresponding models of the two aneurysms by removing daughter saccule are established in order to investigate the initiation and growth of the daughter saccule. The flow patterns and the distributions of hemodynamic factors in the two aneurysms before and after daughter saccule is removed are obtained by solving the governing equations with the commercial CFD software Ansys CFX11.0 under the non-Newtonian fluid assumption. By analyzing the flow patterns, it is concluded that the aneurysms with daughter saccules have more complex and unstable flow patterns and hence are prone to rupture. By comparing the distribution of OSI, a hypothesis that a high OSI causes the growth of the daughter saccule is presented.

Finite element modeling and simulation of the implantation of braided stent to treat cerebral aneurysm

Braided stents were widely used to treat cerebral aneurysms and computational fluid dynamics(CFD)was used to evaluate the therapeutic effects.But the aneurysm-artery geometry used in CFD were usually undeformed which is inconsistent with clinical findings.Our team developed a finite element modeling workflow to simulate implantation of braided stents in patient-specific aneurysm-artery model.An LVIS-based braided stent was deployed into an aneurysm-artery model.The stent fully expanded,causing obvious deformation on the aneurysm-artery model.The workflow which we developed could provide reasonable deformed geometries of aneurysm-artery and braided stent for CFD computation and possibly assist surgical planning.

Non-Newtonian Effect on Hemodynamic Characteristics of Blood Flow in Stented Cerebral Aneurysm

Stent placement is considered as a promising and minimally invasive technique to prevent rupture of aneurysm and favor coagulation mechanism inside the aneurysm.Many scholars study the effect of the stent on blood flow in cerebral aneurysm by numerical simulations,and usually regard blood as the Newtonian fluid,blood,however,is a kind of non-Newtonian fluid in practice.The main purpose of the present paper is to investigate the effect of non-Newtonian behavior on the hemodynamic characteristics of blood flow in stented cerebral aneurysm with lattice Boltzmann method.The Casson model is used to describe the blood non-Newtonian character,which is one of the most popular models in depicting blood fluid.In particular,hemodynamic characteristics derived with Newtonian and non-Newtonian models are studied,and compared in detail.The results show that the non-Newtonian effect gives a great influence on hemodynamic characteristics of blood flow in stented cerebral aneurysm,especially in small necked ones.

Inflammation mediates the pathogenesis of cerebral aneurysm and becomes therapeutic target

The treatment of cerebral aneurysms(CAs)is of social importance,because poor outcomes result in subarachnoid hemorrhages after rupture.However,there is currently no medical treatment available to prevent the progression and rupture of CAs,which results in a large number of patients without receiving treatment.Recent studies using human samples have revealed the presence of inflammatory responses in lesions and also the possible correlation of inflammation with CA progression or rupture.Furthermore,experimental studies using animal models of CAs have supported the notion from human studies and have clarified the crucial contribution of inflammation to the pathogenesis.In this process,a vicious cycle/positive feedback loop includes the nuclear factor-kappa B(NF-kB)activation,which plays a role in amplifying inflammatory responses to the point of chronicity.In addition,the infiltration of macrophages via NF-kB-mediated monocyte chemotactic protein 1 induction expands inflammation in whole arterial walls and contributes to the degeneration of media by producing various cytokines and tissue-destructive proteases.These series of studies have provided an important insight-antiinflammatory drugs can be therapeutically significant in the treatment of CAs.Indeed,in animal models,some drugs with an antiinflammatory effect effectively suppressed CA formation and progression,which supports this hypothesis.In addition,in human cases,some case-control studies have reported the preventive effect of statins and nonsteroidal antiinflammatory drugs on CA rupture.Therefore,the development of novel medical treatment for preventing the progression and rupture of CAs is needed in the near future.In this literature review,articles were selected by performing a PubMed search using the key words“cerebral aneurysm”and“inflammation”.

Cerebral aneurysms and inflammation

Multiple inflammatory factors,playing a crucial role in cerebral aneurysm formation,have been identified.Tumor necrosis factor‑alpha(TNF‑α)has been revealed to have a close connection with several risk factors that affect aneurysm formation.Remarkable expression in aneurysm walls of mRNA for TNF‑αhas been observed in humans.Possible therapeutic interventions to reduce the formation of cerebral aneurysms may include the inhibition of mediators of inflammation.

Computational methods applied to analyze the hemodynamic effects of flow-diverter devices in the treatment of cerebral aneurysms:Current status and future directions

Flow diverter(FD)devices have been widely employed to treat cerebral aneurysms.Despite the well-documented clinical benefits,considerable inter-patient variability in clinical outcome has been reported,which implies the necessity of patient-specifically evaluating hemodynamic changes following FD treatment,especially those associated with posttreatment intra-aneurysmal thrombus formation or complications.Computational fluid dynamics(CFD)methods,owing to the advantages in hemodynamic quantification,cost,and flexibility over traditional in vivo measurement or in vitro experiment methods,have increasingly become a major means for addressing hemodynamic problems related to FD treatment.Relevant CFD-based studies have extensively demonstrated that the results of hemodynamic computation can reasonably explain the clinical outcomes in different patient cohorts and provide useful insights for guiding the selection or optimization of FD devices.Nevertheless,CFD models are inherently unable to predict FD implantation-induced mechanical changes in the walls of aneurysm and its parent artery.In addition,the boundary conditions of most existing CFD models were not fully personalized for purpose of simplicity or due to the difficulty of measuring flow velocity in nearaneurysm regions,which may however considerably compromise the fidelity of the models in reproducing in vivo hemodynamics.To address these issues,the following studies would be expected:(1)perform fluid structure interaction simulations to explore the associations between wall stress/tension and posttreatment adverse vascular remodeling or aneurysm rupture,and(2)develop geometrical multiscale models based on available in vivo data to generate patient-specific boundary conditions for CFD models localized to aneurysm regions.

Microsurgical treatment on distal anterior cerebral artery aneurysms (9 cases report)

Objective To report the clinical diagnosis and microsurgical treatment of ruptured distal anterior cerebral artery aneurysm (DACAA) patients treated over the last 3 years. Methods 9 consecutive cases of ruptured DACAA operated from October 2007 to March 2010 were reviewed and followed up. Results 11 aneurysms were clipped

Clinical application of retrograde cerebral perfusion for brain protection during the surgery of ascending aortic aneurysm:50 cases report

Objective To assess retrospectively the effects of different protective methods on brain in ascending aortic aneurysm surgery. Methods In 65 patients, aneurysm was dissected to the aortic arch or right arch. To protect brain, deep hypotermic circulatory arrest ( DHCA.) combined with retrograde cerebral perfusion ( RCP) June 2003 Vol11 No2 through the superior vena cava ( n = 50) and simple DHCA ( n = 15) were used during the procedure. Blood samples for lactic acid level from the jugular vein were compared in both groups at different plase, and perfusion blood distribution and oxygen content difference between the perfused and returned blood were measured in some RCP patients. Results The DHCA time was 35.9 ± 8 min (10. 0 - 63. 0 min) and DHCA+ RCP time was 45.5 ± 17. 2 min (16. 0 - 81. 0 min)The resuscitationtime was 7.1 ± 1.6 h (4.4 - 9.4H)in DHCA patients and 5.4±2.2h(2.0-9.0 h)in RCP patients. Operation death was 3/15 in the DHCA group and 1/50 in the RCP patients. Central nervous complication

Toll-like receptor 4 as a possible therapeutic target for delayed brain injuries after aneurysmal subarachnoid hemorrhage

Neuroinflammation is a well-recognized consequence of subarachnoid hemorrhage（SAH）, and Toll-like receptor（TLR） 4 may be an important therapeutic target for post-SAH neuroinflammation. Of the TLR family members, TLR4 is expressed in various cell types in the central nervous system, and is unique in that it can signal through both the myeloid differentiation primary-response protein 88-dependent and the toll receptor associated activator of interferon-dependent cascades to coordinate the maximal inflammatory response. TLR4 can be activated by many endogenous ligands having damage-associated molecular patterns including heme and fibrinogen at the rupture of an intracranial aneurysm, and the resultant inflammatory reaction and thereby tissue damages may furthermore activate TLR4. It is widely accepted that the excreted products of TLR4 signaling alter neuronal functions. Previous studies have focused on the pathway through nuclear factor（NF）-κΒ signaling among TLR4 signaling pathways as to the development of early brain injury（EBI） such as neuronal apoptosis and blood-brain barrier disruption, and cerebral vasospasm. However, many findings suggest that both pathways via NF-κΒ and mitogen-activated protein kinases may be involved in EBI and cerebral vasospasm development. To overcome EBI and cerebral vasospasm is important to improve outcomes after SAH, because both EBI and vasopasm are responsible for delayed brain injuries or delayed cerebral ischemia, the most important preventable cause of poor outcomes after SAH. Increasing evidence has shown that TLR4 signaling plays an important role in SAH-induced brain injuries. Better understanding of the roles of TLR4 signaling in SAH will facilitate development of new treatments.

Hydrocephalus after subarachnoid hemorrhage:A metaanalytic comparison of aneurysm treatments

AIM: To compare two treatments for ruptured cerebral aneurysm with reference to the relative risk of developing hydrocephalus.METHODS: We reviewed the English language literature on the risk of developing hydrocephalus after aneurysm treatment.Data were divided by type of study(randomized controlled trial,cohort trial,nonrandomized comparison,prospectively- and retrospectively-collected observational study).They were also divided by type of aneurysm treatment(microvascular- clipping,or endovascular- coiling).Additional predictive variables collected for each publication were average age,gender distribution,measures of hemorrhage volume and subarachnoid hemorrhage severity,aneurysm locations,time to treatment,duration of follow-up and date of publication.We employed meta-analysis to calculate pooled risk ratios of developing hydrocephalus in cases receiving aneurysm clipping vs those receiving coiling.Meta-regression was used to correct pooled results for covariates.RESULTS: Because indications for the two treatments are different,there is little clinical equipoise for treating most cases.The single randomized,controlled trial dealt with a small subset of ruptured aneurysms.Neither this nor pooled values from other studies which compared the two treatments had the power to demonstrate significant differences between the two treatments.Nor was there an apparent difference when observational data were meta-analytically pooled.However,when meta-regression was used to correct for predictive variables known to differ between the two treatment groups,a highly-significant difference appeared.Coiling is used more commonly in older,sicker patients with aneurysms in certain locations.These cases are more likely to develop hydrocephalus.When corrected for these covariates,the risk of hydrocephalus was found to be significantly lower in coiled vs clipped cases(P = 0.014).CONCLUSION: Pooled observational data were necessary to demonstrate that coiling ruptured cerebral aneurysms is associated with a lower risk of developing hydrocephalus than is clipping.

CEREBRAL ARTERY RECONSTRUCTION IN THE TREATMENT OF LARGE AND GIANT INTRACRANIAL ANEURYSMS

From 1978 to 1988, 14 giant intracranial aneurysms(more than 2.4 cm in diameter) and one large aneurysm (1.5cm in diameter) were treated by extracranial/intracranial(EC/IC) bypass or cerebral artery reconstruction. Of theaneurysms, 10 were located at the intracavernous carotid ar-tery (CCA). One of the 10 anourysms was posttraumatic andlocated at both the carotid-ophthalmic artery segment and thebifurcation of the internal carotid artery (ICA). Three wereseen at the middle cerebral artery (MCA) trunk.Theaneurysms were demonstrated by angiography and CTscanning. They were treated with trapping of the aneurysm andsuperficial temporal artery (STA)/middle cerebral artery(STA-MCA) bypass with/without a graft (6 cases), cervicalICA ligation and STA-MCA bypass with / without a graft (6)aneurysm excision with an end-to-end anastomosis of theMCA and a STA-MCA bypass with a graft (1), proximal

Treatment Strategy for Middle Cerebral Artery Dissecting Aneurysm with Severe Stenosis

A 62-year-old male patient was presented to the First Affiliated Hospital,Zhejiang University,School of Medicine with right hemiparesis and aphasia.No obvious infections were found.The magnetic resonance imaging demonstrated multiple infarctions in the area supplied by the left middle cerebral artery.The diagnosis was made as left middle cerebral artery dissecting aneurysm with stenosis.After adequate preoperative preparation,the patient received interventional therapy and then exhibited good prognosis.This paper introduces the interventional procedures for the treatment of the left middle cerebral artery dissecting aneurysm with stenosis.

Pathological observation of brain arteries and spontaneous aneurysms in hypertensive rats

Objective To investigate the role of hypertension in the pathogenesis of cerebral aneurysms in rats.Methods Twenty spontaneous hypertensive rats (SHR) and 10 Wistar-Kyoto rats (WKY) were included in this observational study. Animals were fed with normal diet and drinking water. No experimental modifications were undertaken in either group. They were sacrificed at one year of age, the bifurcations of the circle of Willis were dissected and longitudinal serial sections were prepared for light microscopic and transmission electron microscopic study.Results In the SHR group, 2 of the 20 rats formed an aneurysm respectively at the bifurcations of the basilar artery. As revealed by electron microscopy, injury at the bifurcation of the artery first occurred on the steeper side of the intimal pad. Furthermore, loss of endothelial cells, small depressions on the intima, disruptive internal elastic lamina and lymphocytes or red blood cells infiltration were noted at the steeper side of the intimal pad. No significant changes were observed in WKY group.Conclusions Cerebral aneurysms can form spontaneously in SHR without ligation of the common carotid artery and without a diet containing β-aminoproprionitrile. Long-standing systemic arterial hypertension is one of the etiological factors that contributes to aneurysm formation in SHR rats.

Delayed-onset adenosine deaminase deficiency with a novel synonymous mutation and a case series from China

Background Adenosine deaminase(ADA)is a key enzyme in the purine salvage pathway.Genetic defects of the ADA gene can cause a subtype of severe combined immunodeficiency.To date,few Chinese cases have been reported.Methods We retrospectively reviewed the medical records of patients diagnosed with ADA deficiency in Beijing Children's Hospital and summarized the previously published ADA deficiency cases from China in the literature.Results Nine patients were identified with two novel mutations(W272X and Q202=).Early-onset infection,thymic abnor-malities and failure to thrive were the most common manifestations of Chinese ADA-deficient patients.The ADA genotype has a major effect on the clinical phenotype.Notably,a novel synonymous mutation(c.606G>A,p.Q202=)was identified in a delayed-onset patient,which affected pre-mRNA splicing leading to a frameshift and premature truncation of the protein.Furthermore,the patient showed γδT cells expansion with an increased effect or phenotype,which may be associated with the delayed onset of disease.In addition,we reported cerebral aneurysm and intracranial artery stenosis for the first time in ADA deficiency.Five patients died with a median age of four months,while two patients received stem cell transplantation and are alive.Conclusions This study described the first case series of Chinese ADA-deficient patients.Early-onset infection,thymic abnormalities and failure to thrive were the most common manifestations in our patients.We identified a synonymous muta-tion that affected pre-mRNA splicing in the ADA gene,which had never been reported in ADA deficiency.Furthermore,we reported cerebral aneurysm in a delayed-onset patient for the first time.Further study is warranted to investigate the underlying mechanisms.

EFFECTS OF PARENT ARTERY SEGMENTATION AND ANEURISMALWALL ELASTICITY ON PATIENT-SPECIFIC HEMODYNAMIC SIMULATIONS

It is well known that hemodynamics and wall tension play an important role in the formation, growth and rupture of aneurysms. In the present study, the authors investigated the influence of parent artery segmentation and aneurismal-wall elasticity on patient-specific hemodynamic simulations with two patient-specific cases of cerebral aneurysms. Realistic models of the aneurysms were constructed from 3-D angiography images and blood flow dynamics was studied under physiologically representative waveform of inflow. For each aneurysm three computational models were constructed： Model 1 with more extensive upstream parent artery with the rigid arterial and aneurismal wall, Model 2 with the partial upstream parent artery with the elastic arterial and aneurismal wall, Model 3 with more extensive upstream parent artery with the rigid wall for arterial wall far from the aneurysm and the elastic wall for arterial wall near the aneurysm. The results show that Model 1 could predict complex intra-aneurismal flow patterns and wall shear stress distribution in the aneurysm, but is unable to give aneurismal wall deformation and tension, Model 2 demonstrates aneurismal wall deformation and tension, but fails to properly model inflow pattern contributed by the upstream parent artery, resulting in local misunderstanding Wall Shear Stress （WSS） distribution, Model 3 can overcome limitations of the former two models, and give an overall and accurate analysis on intra-aneufismal flow patterns, wall shear stress distribution, aneurismal-wall deformation and tension. Therefore we suggest that the proper length of extensive upstream parent artery and aneurismal-wall elasticity should be considered carefully in establishing computational model to predict the intra-aneurismal hemodynamic and wall tension.