Serum myelin basic protein as a marker of brain injury in aneurysmal subarachnoid haemorrhage.

BACKGROUND: Myelin basic protein (MBP) is the second most abundant protein in central nervous system myelin. Since the 1980s, it has been regarded as a marker of brain tissue injury in both trauma and disease. There have been no recent reports regarding MBP in aneurysmal subarachnoid haemorrhage (SAH). METHODS: One hundred four SAH patients with ruptured aneurysms underwent endovascular treatment within 24 h of rupture, and 156 blood samples were collected: 104 on days 0-3, 32 on days 4-6 and 20 on days 9-12 post-SAH. MBP levels were assayed using ELISA and compared with the clinical status on admission, laboratory results, imaging findings and treatment outcome at 3 months. RESULTS: MBP levels on days 0-3 post-SAH were significantly higher among poor outcome patients (p < 0.001), non-survivors (p = 0.005), patients who underwent intracranial intervention (p < 0.001) and patients with intracerebral haemorrhage (ICH; p < 0.001). On days 4-6 post-SAH, significantly higher levels were found following intracranial intervention (p = 0.009) and ICH (p = 0.039). There was clinically relevant correlation between MBP levels on days 0-3 post-SAH and 3-month Glasgow Outcome Scale (cc = - 0.42) and also ICH volume (cc = 0.48). All patients who made a full recovery had MBP levels below detection limit on days 0-3 post-SAH. Following endovascular aneurysm occlusion, there was no increase in MBP in 86 of the 104 patients investigated (83%). CONCLUSIONS: The concentration of MBP in peripheral blood after intracranial aneurysm rupture reflects the severity of the brain tissue injury (due to surgery or ICH) and correlates with the treatment outcome. Endovascular aneurysm occlusion was not followed by a rise in MBP in most cases, suggesting the safety of this technique.

Clinical Relevance of Changes in Peripheral Blood Cells After Intracranial Aneurysm Rupture.

BACKGROUND: The rupture of an intracranial aneurysm (IA) causes a systemic response that involves an immune/inflammatory reaction. We sought to characterize the systemic response to IA rupture. METHODS: We included 19 patients in the acute phase of IA rupture and 20 control subjects. Flow cytometry was used to analyze alterations in the level of mononuclear leukocytes. Cell-related parameters, including the neutrophil-to-lymphocyte ratio (NL-R), lymphocyte-to-monocyte ratio (LM-R), platelet-to-lymphocyte ratio (PL-R), and systemic immune-inflammation index (SII), were calculated, and the relationship between the analyzed hematological parameters and clinical status was investigated. RESULTS: Patients with ruptured IAs presented with significantly higher white blood cells (WBC) and neutrophil counts but lower lymphocyte counts than control subjects. NL-R and SII values were higher and the LM-R was lower in the acute phase after IA rupture. Analyzing the severity of clinical status and the outcome of patients with subarachnoid hemorrhage, we found that patients with poor clinical status, as measured by the Glasgow Coma Scale (GCS) and the Hunt and Hess scale, had significantly lower lymphocyte counts and higher NL-R, PL-R and SII values than those with good clinical status. Additionally, patients with lower GCS scores presented a lower proportion of CD3+CD4-CD8- cells. Worse outcomes assessed at discharge were associated with lower lymphocyte counts but higher PL-R values. CONCLUSIONS: The current study pointed to the significance of systemic immune and inflammatory responses after IA rupture and the potential clinical utility of hematological parameters, which can be easily calculated. In particular, the role of DN T cells and the significance of the SII as a marker related to clinical status should be further investigated.

Low Serum Calcium and Magnesium Levels and Rupture of Intracranial Aneurysms.

BACKGROUND AND PURPOSE: Both low serum calcium and magnesium levels have been associated with the extent of bleeding in patients with intracerebral hemorrhage, suggesting hypocalcemia- and hypomagnesemia-induced coagulopathy as a possible underlying mechanism. We hypothesized that serum albumin-corrected total calcium and magnesium levels are associated with ruptured intracranial aneurysms. METHODS: The medical records of 4701 patients, including 1201 prospective patients, diagnosed at the Brigham and Women's Hospital and Massachusetts General Hospital between 1990 and 2016 were reviewed and analyzed. One thousand two hundred seventy-five patients had available serum calcium, magnesium, and albumin values within 1 day of diagnosis. Individuals were divided into cases with ruptured aneurysms and controls with unruptured aneurysms. Univariable and multivariable logistic regression analyses were performed to determine the association between serum albumin-corrected total calcium and magnesium levels and ruptured aneurysms. RESULTS: In multivariable analysis, both albumin-corrected calcium (odds ratio, 0.33; 95% confidence interval, 0.27-0.40) and magnesium (odds ratio, 0.40; 95% confidence interval, 0.28-0.55) were significantly and inversely associated with ruptured intracranial aneurysms. CONCLUSIONS: In this large case-control study, hypocalcemia and hypomagnesemia at diagnosis were significantly associated with ruptured aneurysms. Impaired hemostasis caused by hypocalcemia and hypomagnesemia may explain this association.

Elevated International Normalized Ratio Is Associated With Ruptured Aneurysms.

Background and Purpose- The effects of anticoagulation therapy and elevated international normalized ratio (INR) values on the risk of aneurysmal subarachnoid hemorrhage are unknown. We aimed to investigate the association between anticoagulation therapy, elevated INR values, and rupture of intracranial aneurysms. Methods- We conducted a case-control study of 4696 patients with 6403 intracranial aneurysms, including 1198 prospective patients, diagnosed at the Massachusetts General Hospital and the Brigham and Women's Hospital between 1990 and 2016 who were on no anticoagulant therapy or on warfarin for anticoagulation. Patients were divided into ruptured and nonruptured groups. Univariable and multivariable logistic regression analyses were performed to evaluate the association of anticoagulation therapy, INR values, and presentation with a ruptured intracranial aneurysm, taking into account the interaction between anticoagulant use and INR. Inverse probability weighting using propensity scores was used to minimize differences in baseline demographics characteristics. The marginal effects of anticoagulant use on rupture risk stratified by INR values were calculated. Results- In unweighted and weighted multivariable analyses, elevated INR values were significantly associated with rupture status among patients who were not anticoagulated (unweighted odds ratio, 22.78; 95% CI, 10.85-47.81 and weighted odds ratio, 28.16; 95% CI, 12.44-63.77). In anticoagulated patients, warfarin use interacts significantly with INR when INR ≥1.2 by decreasing the effects of INR on rupture risk. Conclusions- INR elevation is associated with intracranial aneurysm rupture, but the effects may be moderated by warfarin. INR values should, therefore, be taken into consideration when counseling patients with intracranial aneurysms.

Lipid-Lowering Agents and High HDL (High-Density Lipoprotein) Are Inversely Associated With Intracranial Aneurysm Rupture.

BACKGROUND AND PURPOSE: Growing evidence from experimental animal models and clinical studies suggests the protective effect of statin use against rupture of intracranial aneurysms; however, results from large studies detailing the relationship between intracranial aneurysm rupture and total cholesterol, HDL (high-density lipoprotein), LDL (low-density lipoprotein), and lipid-lowering agent use are lacking. METHODS: The medical records of 4701 patients with 6411 intracranial aneurysms diagnosed at the Massachusetts General Hospital and the Brigham and Women's Hospital between 1990 and 2016 were reviewed and analyzed. Patients were separated into ruptured and nonruptured groups. Univariable and multivariable logistic regression analyses were performed to determine the effects of lipids (total cholesterol, LDL, and HDL) and lipid-lowering medications on intracranial aneurysm rupture risk. Propensity score weighting was used to account for differences in baseline characteristics of the cohorts. RESULTS: Lipid-lowering agent use was significantly inversely associated with rupture status (odds ratio, 0.58; 95% confidence interval, 0.47-0.71). In a subgroup analysis of complete cases that includes both lipid-lowering agent use and lipid values, higher HDL levels (odds ratio, 0.95; 95% confidence interval, 0.93-0.98) and lipid-lowering agent use (odds ratio, 0.41; 95% confidence interval, 0.23-0.73) were both significantly and inversely associated with rupture status, whereas total cholesterol and LDL levels were not significant. A monotonic exposure-response curve between HDL levels and risk of aneurysmal rupture was obtained. CONCLUSIONS: Higher HDL values and the use of lipid-lowering agents are significantly inversely associated with ruptured intracranial aneurysms.

Antihyperglycemic Agents Are Inversely Associated With Intracranial Aneurysm Rupture.

BACKGROUND AND PURPOSE: Previous studies have suggested a protective effect of diabetes mellitus on aneurysmal subarachnoid hemorrhage risk. However, reports are inconsistent, and objective measures of hyperglycemia in these studies are lacking. Our aim was to investigate the association between aneurysmal subarachnoid hemorrhage and antihyperglycemic agent use and glycated hemoglobin levels. METHODS: The medical records of 4701 patients with 6411 intracranial aneurysms, including 1201 prospective patients, diagnosed at the Massachusetts General Hospital and Brigham and Women's Hospital between 1990 and 2016 were reviewed and analyzed. Patients were separated into ruptured and nonruptured groups. Univariate and multivariate logistic regression analyses were performed to determine the association between aneurysmal subarachnoid hemorrhage and antihyperglycemic agents and glycated hemoglobin levels. Propensity score weighting was used to account for selection bias. RESULTS: In both unweighted and weighted multivariate analysis, antihyperglycemic agent use was inversely and significantly associated with ruptured aneurysms (unweighted odds ratio, 0.58; 95% confidence interval, 0.39-0.87; weighted odds ratio, 0.57; 95% confidence interval, 0.34-0.96). In contrast, glycated hemoglobin levels were not significantly associated with rupture status. CONCLUSIONS: Antihyperglycemic agent use rather than hyperglycemia is associated with decreased risk of aneurysmal subarachnoid hemorrhage, suggesting a possible protective effect of glucose-lowering agents in the pathogenesis of aneurysm rupture.

Biomarkers from circulating neutrophil transcriptomes have potential to detect unruptured intracranial aneurysms.

BACKGROUND: Intracranial aneurysms (IAs) are dangerous because of their potential to rupture and cause deadly subarachnoid hemorrhages. Previously, we found significant RNA expression differences in circulating neutrophils between patients with unruptured IAs and aneurysm-free controls. Searching for circulating biomarkers for unruptured IAs, we tested the feasibility of developing classification algorithms that use neutrophil RNA expression levels from blood samples to predict the presence of an IA. METHODS: Neutrophil RNA extracted from blood samples from 40 patients (20 with angiography-confirmed unruptured IA, 20 angiography-confirmed IA-free controls) was subjected to next-generation RNA sequencing to obtain neutrophil transcriptomes. In a randomly-selected training cohort of 30 of the 40 samples (15 with IA, 15 controls), we performed differential expression analysis. Significantly differentially expressed transcripts (false discovery rate < 0.05, fold change ≥ 1.5) were used to construct prediction models for IA using four well-known supervised machine-learning approaches (diagonal linear discriminant analysis, cosine nearest neighbors, nearest shrunken centroids, and support vector machines). These models were tested in a testing cohort of the remaining 10 neutrophil samples from the 40 patients (5 with IA, 5 controls), and model performance was assessed by receiver-operating-characteristic (ROC) curves. Real-time quantitative polymerase chain reaction (PCR) was used to corroborate expression differences of a subset of model transcripts in neutrophil samples from a new, separate validation cohort of 10 patients (5 with IA, 5 controls). RESULTS: The training cohort yielded 26 highly significantly differentially expressed neutrophil transcripts. Models using these transcripts identified IA patients in the testing cohort with accuracy ranging from 0.60 to 0.90. The best performing model was the diagonal linear discriminant analysis classifier (area under the ROC curve = 0.80 and accuracy = 0.90). Six of seven differentially expressed genes we tested were confirmed by quantitative PCR using isolated neutrophils from the separate validation cohort. CONCLUSIONS: Our findings demonstrate the potential of machine-learning methods to classify IA cases and create predictive models for unruptured IAs using circulating neutrophil transcriptome data. Future studies are needed to replicate these findings in larger cohorts.

In vitro analysis of platelet function in acute aneurysmal subarachnoid haemorrhage.

Platelet function might play an essential role in the pathogenesis of delayed cerebral ischemia (DCI) after aneurysmal subarachnoid haemorrhage (SAH). Thus, impaired platelet function and disturbed primary haemostasis induced by intake of acetylsalicylic acid (ASA) might influence the rate of DCI. Primary haemostasis and platelet function can be measured with in vitro diagnosis (platelet function analyser test, PFA 100). The aim of this study is to evaluate the rate of DCI, haemorrhagic complications and the neurological outcome. Two groups were compared (patients with regular platelet function versus patients with impaired platelet function). This is a retrospective observational study. An initial cohort of 787 patients with SAH has been treated from January 2005 to September 2012. Seventy-nine patients (10%) with aneurysmal SAH, a history of ASA medication and PFA testing within the first 24 h after aneurysm rupture have been included. The overall rate of DCI in the present study was 43%. In vitro platelet function testing showed pathological primary haemostasis in 69.6%. The DCI rate was higher in patients with regular tested primary haemostasis (p = 0.02, OR = 3.16, 95%CI = [1.19; 8.83]). However, outcome assessment by mGOS did not show a significant difference between the groups. Patients with impaired primary haemostasis did not display a higher rate of haemorrhagic complications. Impairment of primary haemostasis resulting from an impairment of platelet function at an early stage after SAH might lead to a lower rate of DCI. In vitro testing of platelet function might be useful to predict the occurrence of DCI in the course.

Screening of Critical Genes and MicroRNAs in Blood Samples of Patients with Ruptured Intracranial Aneurysms by Bioinformatic Analysis of Gene Expression Data.

BACKGROUND This study aimed to identify more potential genes and miRNAs associated with the pathogenesis of intracranial aneurysms (IAs). MATERIAL AND METHODS The dataset of GSE36791 (accession number) was downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) were screened for in the blood samples from patients with ruptured IAs and controls, followed by functional and pathway enrichment analyses. In addition, gene co-expression network was constructed and significant modules were extracted from the network by WGCNA R package. Screening for miRNAs that could regulate DEGs in the modules was performed and an analysis of regulatory relationships was conducted. RESULTS A total of 304 DEGs (167 up-regulated and 137 down-regulated genes) were screened for in blood samples from patients with ruptured IAs compared with those from controls. Functional enrichment analysis showed that the up-regulated genes were mainly associated with immune response and the down-regulated DEGs were mainly concerned with the structure of ribosome and translation. Besides, six functional modules were significantly identified, including four modules enriched by up-regulated genes and two modules enriched by down-regulated genes. Thereinto, the blue, yellow, and turquoise modules of up-regulated genes were all linked with immune response. Additionally, 16 miRNAs were predicted to regulate DEGs in the three modules associated with immune response, such as hsa-miR-1304, hsa-miR-33b, hsa-miR-125b, and hsa-miR-125a-5p. CONCLUSIONS Several genes and miRNAs (such as miR-1304, miR-33b, IRS2 and KCNJ2) may take part in the pathogenesis of IAs.

Myeloperoxidase is increased in human cerebral aneurysms and increases formation and rupture of cerebral aneurysms in mice.

BACKGROUND AND PURPOSE: Cerebral aneurysm (CA) affects 3% of the population and is associated with hemodynamic stress and inflammation. Myeloperoxidase, a major oxidative enzyme associated with inflammation, is increased in patients with CA, but whether myeloperoxidase contributes to CA is not known. We tested the hypotheses that myeloperoxidase is increased within human CA and is critical for formation and rupture of CA in mice. METHODS: Blood was drawn from the lumen of CAs and femoral arteries of 25 patients who underwent endovascular coiling of CA, and plasma myeloperoxidase concentrations were measured with ELISA. Effects of endogenous myeloperoxidase on CA formation and rupture were studied in myeloperoxidase knockout mice and wild-type (WT) mice using an angiotensin II-elastase induction model of CA. In addition, effects of myeloperoxidase on inflammatory gene expression in endothelial cells were analyzed. RESULTS: Plasma concentrations of myeloperoxidase were 2.7-fold higher within CA than in femoral arterial blood in patients with CA. myeloperoxidase-positive cells were increased in aneurysm tissue compared with superficial temporal artery of patients with CA. Incidence of aneurysms and subarachnoid hemorrhage was significantly lower in myeloperoxidase knockout than in WT mice. In cerebral arteries, proinflammatory molecules, including tumor necrosis factor-α, cyclooxygenase-2 (COX2), chemokine (C-X-C motif) ligand 1 (CXCL1), chemokine (C motif) ligand (XCL1), matrix metalloproteinase (MMP) 8, cluster of differentiation 68 (CD68), and matrix metalloproteinase 13, and leukocytes were increased, and α-smooth muscle actin was decreased, in WT but not in myeloperoxidase knockout mice after induction of CA. Myeloperoxidase per se increased expression of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 in endothelial cells. CONCLUSIONS: These findings suggest that myeloperoxidase may contribute importantly to formation and rupture of CA.

In-hospital C-reactive protein predicts outcome after aneurysmal subarachnoid haemorrhage treated by endovascular coiling.

BACKGROUND: This study aimed to examine prospectively whether the inflammatory marker C-reactive protein (CRP) increases in patients with aneurysmal subarachnoid haemorrhage (aSAH) treated by endovascular coiling and investigate whether CRP could be used as prognostic factor for long-term neurological outcome. METHODS: This single-hospital study comprised 98 consecutive patients with confirmed aSAH treated by endovascular coiling. Admission status was classified according to the World Federation of Neurosurgical Societies (WFNS) Scale and initial cerebral computed tomography according to Fisher scale. CRP was analysed on days 0, 1, 2, 3, 4, 6 and 8 after the initial bleed. A neurological follow up was performed 1 year later according to the Extended Glasgow Outcome Scale (GOSE) for overall outcome and National Institute of Health Stroke Scale (NIHSS) for focal deficit. RESULTS: CRP values increased from normal to peak at 53 mg/l at day 3-4 and then declined, without normalising, at day 8. Patients with a higher increase in CRP had a poorer neurological outcome after 1 year. CRP during the first week had a stronger correlation to outcome (r = 0.417) and NIHSS (r = 0.449) than initial clinical status (WFNS; r = 0.280 and 0.274) and radiology (Fisher scale; r = 0.137 and 0.158). CRP increase indicated a risk of poor outcome (GOSE) (P < 0.001) and permanent loss of neurological function (NIHSS) (P < 0.001). Logistic regression analysis suggested that elevated CRP already on day 2 is an independent prognostic marker for outcome. CONCLUSION: Early CRP values can perhaps be used as a prognostic factor for long-term neurological outcome prediction after endovascular treatment of aSAH.

[Content of C-reactive protein in patients in an acute period of a ruptured intracranial aneurysm].

A content of C-reactive protein (CRP) in the blood serum was determined in 36 patients in acute period of a ruptured intracranial arterial aneurysm (AA). It was significantly more, than in a control group, and have exceeded 10 mg/I in 1 - 4th day of the disease. The level of CRP have had differ, depending on severity of cerebral vasospasm (CVS), determined in accordance to the ultrasound investigation data. In a pronounced CVS in majority of patients the level of CRP in the blood serum have had exceed 10 mg/l, and have secured elevated in a spinal liquor on the 7 - 10th day of the disease, differing from this index in patients with moderately pronounced CVS or without it. In patients with severe invalidization or those, who have died, the level of CRP was trust-worthy higher.

Surgical treatment of giant aneurysm of hepatic artery: report of three cases.

BACKGROUND/AIMS: To explore the surgical way of treating giant hepatic artery aneurysm(HAA). METHODOLOGY: Three hepatic artery aneurysm patients who were performed aneurysm resection without revascularization of the hepatic artery were reviewed. After surgery, the values of liver function and enhanced CT scan of the patients were followed. RESULTS: All the three patients were recovered well postoperatively and only several values of biochemistry marks of liver function as ALT, AST, TBIL and DB in one case with liver cirrhosis were elevated and decreased to normal ranges in a few days postoperatively. The values of biochemistry marks of liver function in other two cases were within normal limits. The enhanced CT scan also showed arteries in the liver after hepatic artery aneurysm resection. CONCLUSIONS: Giant HAA may be safely removed without revascularization of the hepatic artery.

Clinical relevance of critical plasma homocysteine levels in predicting rupture risk for small and medium-sized intracranial aneurysms.

Plasma homocysteine (Hcy) has been globally recognized as an independent risk factor for various neurovascular diseases. In this study, the authors investigated the relationship between critical Hcy concentration and the risk of rupture in intracranial aneurysms (IAs). This study collected data from 423 patients with both ruptured and unruptured IAs. We compared demographic data, vascular rupture risk factors, and laboratory test results between the two groups. Multivariable logistic regression analysis was employed to determine the correlation between critical plasma Hcy levels and the risk of rupture in small to medium-sized IAs. A total of 330 cases of ruptured intracranial aneurysms (RIA) and 93 cases of unruptured intracranial aneurysms (UIA) were included. Univariate analysis revealed statistically significant differences between the ruptured and unruptured groups in terms of hypertension, hyperlipidemia, plasma Hcy levels, and IA morphology (all P < 0.05). Multivariable logistic regression analysis indicated that hypertension (odds ratio [OR] 0.504; 95% confidence interval [CI] 0.279-0.911; P = 0.023), hyperlipidemia (OR 1.924; 95% CI 1.079-3.429; P = 0.027), and plasma Hcy levels (OR 1.420; 95% CI 1.277-1.578; P < 0.001) were independently associated with the rupture of small to medium-sized IAs, all with statistical significance (P < 0.05). Our study suggests that critical plasma Hcy levels are an independent risk factor for increased rupture risk in small to medium-sized intracranial aneurysms. Therefore, reducing plasma Hcy levels may be considered a valuable strategy to mitigate the risk of intracranial vascular abnormalities rupture and improve patient prognosis.

Plasma proteomics analysis reveals potential biomarkers for intracranial aneurysm formation and rupture.

The aim of this study was to investigate the plasma proteome in individuals with intracranial aneurysms (IAs) and identify biomarkers associated with the formation and rupture of IAs. Proteomic profiles (N = 1069 proteins) were assayed in plasma (N = 120) collected from patients with ruptured and unruptured intracranial aneurysms (RIA and UIA), traumatic subarachnoid hemorrhage (tSAH), and healthy controls (HC) using tandem mass tag (TMT) labeling quantitative proteomics analysis. Gene ontology (GO) and pathway analysis revealed that these relevant proteins were involved in immune response and extracellular matrix organization pathways. Seven candidate biomarkers were verified by ELISA in a completely separate cohort for validation (N = 90). Among them, FN1, PON1, and SERPINA1 can be utilized as diagnosis biomarkers of IA, with a combined area under the ROC curve of 0.891. The sensitivity was 93.33%, specificity was 75.86%, and accuracy was 87.64%. PFN1, ApoA-1, and SERPINA1 can serve as independent risk factors for predicting aneurysm rupture. The combined prediction of aneurysm rupture yielded an area under the ROC curve of 0.954 with a sensitivity of 96.15%, specificity of 81.48%, and accuracy of 88.68%. This prediction model was more effective than PHASES score. In conclusion, high-throughput proteomics analysis with population validation was performed to assess blood-based protein expression characteristics. This revealed the potential mechanism of IA formation and rupture, facilitating the discovery of biomarkers. SIGNIFICANCE: Although the annual rupture rate of small unruptured aneurysms is believed to be minimal, studies have indicated that ruptured aneurysms typically have an average size of 6.28 mm, with 71.8% of them being <7 mm in diameter. Hence, evaluating the possibility of rupture in UIA and making a choice between aggressive treatment and conservative observation emerges as a significant challenge in the management of UIA. No biomarker or scoring system has been able to satisfactorily address this issue to date. It would be significant to develop biomarkers that could be used for early diagnosis of IA as well as for prediction of IA rupture. After TMT proteomics analysis and ELISA validation in independent populations, we found that FN1, PON1, and SERPINA1 can be utilized as diagnostic biomarkers for IA, and PFN1, ApoA-1, and SERPINA1 can serve as independent risk factors for predicting aneurysm rupture. Especially, when combined with ApoA-1, SERPINA1, and PFN1 for predicting IA rupture, the area under the curve (AUC) was 0.954 with a sensitivity of 96.15%, specificity of 81.48%, and accuracy of 88.68%. This prediction model was more effective than PHASES score.

Low plasma arginine:asymmetric dimethyl arginine ratios predict mortality after intracranial aneurysm rupture.

BACKGROUND: Asymmetrical dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthases, predicts mortality in cardiovascular disease and has been linked to cerebral vasospasm after aneurysmal subarachnoid hemorrhage (SAH). In this prospective study, we assessed whether circulating ADMA, arginine:ADMA ratio, and nitrite/nitrate levels were associated with survival and cerebral vasospasm in SAH patients. METHODS: One hundred and eleven patients were observed day 1 to 15 after SAH, with serial measurements of transcranial Doppler flow velocities (VMCA) and plasma biomarkers. Clinical status was assessed by the World Federation of Neurosurgical Societies grading scale. RESULTS: Overall 30-day mortality was 18%, but differed between patients grouped by low, midrange, and high arginine:ADMA ratio in the first week after SAH. Mortality rates were 14/37, 1/37, and 5/37 in the 3 groups, respectively (P-logrank=0.0003). Cox regression showed that low versus midrange or high arginine:ADMA was associated with a hazard ratio of 4.1 independent of World Federation of Neurosurgical Societies grade (95% confidence interval, 1.5-10.9; P=0.006). ADMA or arginine:ADMA had no association to VMCA, but there was an inverse relationship between VMCA and nitrite/nitrate levels (P<0.0001). The NOS3 894G/G genotype was associated with 15% lower VMCA (P=0.01). ATbG-NOS3 haplotype homozygosity was associated with up to 64% higher nitrite/nitrate levels (P=0.003). CONCLUSIONS: This study suggests that plasma arginine:ADMA ratios predict mortality after SAH. Both clinical and physiological measures of changes in cerebral hemodynamics are coupled to the nitric oxide system.

Localized increase of chemokines in the lumen of human cerebral aneurysms.

BACKGROUND AND PURPOSE: Inflammation may play an important role in the formation and rupture of cerebral aneurysms. Chemokines act as chemoattractants for leukocytes directing them toward sites of tissue inflammation. The purpose of this study was to determine whether chemokines and chemoattractant cytokines were increased in the lumen of human cerebral aneurysms. METHODS: The concentrations of chemokines and other inflammatory molecules in blood samples drawn from the lumen of human cerebral aneurysms of 16 consecutive patients (harboring 18 aneurysms) were compared with blood samples from the femoral arteries of the same patients. Three aneurysms had ruptured. RESULTS: The mean plasma concentration of regulated on activation, normal T cell expressed and secreted (RANTES), monokine-induced-by-γ-interferon (MIG), interferon-γ-induced protein-10 (IP-10), eotaxin, interleukin (IL) 8, and IL17 was significantly higher in samples taken from cerebral aneurysms compared with femoral arteries. In contrast, plasma concentrations of all remaining inflammatory molecules (except IL6) that were tested did not differ between cerebral aneurysms and femoral arteries. For unruptured aneurysms, there was a significantly higher mean plasma concentration of monocyte chemoattractant protein-1 as well as RANTES, MIG, IP-10, eotaxin, IL8, and IL17 in samples obtained from cerebral aneurysms. CONCLUSIONS: High plasma concentrations of chemokines (monocyte chemoattractant protein-1, RANTES, MIG, IP-10, and eotaxin) and chemoattractant cytokines (IL8 and IL17) were found in the lumen of human cerebral aneurysms. These findings suggest that there may be an active recruitment of inflammatory cells into the aneurysm wall that may be exploited therapeutically.

Effect of insular injury on autonomic functions in patients with ruptured middle cerebral artery aneurysms.

BACKGROUND AND PURPOSE: Insular injuries are known to cause autonomic derangements. Patients with ruptured middle cerebral artery aneurysms frequently develop temporal hematomas (THs) in addition to subarachnoid hemorrhages, and those with TH may sustain autonomic derangements more frequently than those without TH. Hemispheric lateralization in autonomic derangements has been reported in patients with insular ischemic stroke, and this study was conducted to clarify whether such lateralization was also observed in patients with TH resulting from middle cerebral artery aneurysm rupture. METHODS: A retrospective analysis on the medical records of 79 patients with ruptured middle cerebral artery aneurysms was performed on the basis of lateralization and presence of TH. They were quadrichotomized as left TH+ (LTH+; n=17), right TH+ (n=25), left TH- (n=15), and right TH- (n=22). Comparisons, mainly between LTH+ and right TH+, were made on demographic variables, autonomic/cardiac parameters, plasma catecholamine and glucose levels, and outcomes. RESULTS: There were no significant differences in demographic or cardiac parameters between the 2 groups. Systolic blood pressures were lower in LTH+ (139±34 versus 174±47 mm Hg; P=0.05). The LTH+ group also tended to be more bradycardiac (80±19 versus 101±22 bpm; P=0.13). The LTH+ group exhibited significantly lower plasma norepinephrine (1008±975 versus 2549±2133 pg/mL; P=0.03) and glucose levels (9.3±1.8 versus 12.2±4.5 mmol/L; P=0.04). However, in-hospital mortality did not differ significantly (41% versus 44%; P=1.00). CONCLUSIONS: Lateralization of autonomic derangements observed might not have had a significant effect on the outcomes. Nevertheless, autonomic derangements associated with insular injury should be considered in the management of subarachnoid hemorrhage patients with TH.

A Computational Model of Blood D-Dimer, Cystatin C, and CRP Levels Predicts the Risk of Intracranial Aneurysms and their Rupture.

Objective: The aim of this study is to construct a computational model of blood D-dimer, cystatin C, and CRP levels and to predict the risk of intracranial aneurysms and their rupture. Methods: A total of 69 intracranial aneurysms patients were selected as the case group, including 28 cases in the ruptured group and 41 cases in the unruptured group. Another 64 non-intracranial aneurysm patients were selected as the control group. The detection results of serum D-dimer, cystatin C, and CRP were collected. The logistic regression computational model was used to analyze the occurrence and risk factors of intracranial aneurysms. The receiver operating curves (ROC) of serum D-dimer, cystatin C, and C reactive protein (CRP) levels for predicting intracranial aneurysms and their rupture were drawn, and the area under the curve (AUC), sensitivity, and specificity were calculated. Results: The serum levels of D-dimer, cystatin C, and CRP in patients with intracranial aneurysms were significantly higher than those in the control group and the differences were statistically significant (P < 0.05). The serum levels of D-dimer, cystatin C, and CRP in patients with ruptured intracranial aneurysms were higher than those in patients with unruptured intracranial aneurysms, and the differences were also statistically significant (P < 0.05). The combined detection of serum D-dimer, cystatin C, and CRP levels has a higher AUC (0.9014) for predicting intracranial aneurysms and higher AUC (0.9412) for predicting ruptured intracranial aneurysms than D-dimer (0.7118 and 0.8750, respectively), cystatin C (0.6489 and 0.6180, respectively), and CRP (0.7764 and 0.6551, respectively) independent detection; the combined detection had a sensitivity of 93.75% and 87.80 for predicting the occurrence and rupture of intracranial aneurysms, and the specificity was 68.12% and 92.86%, respectively. Conclusion: The combined detection of serum D-dimer, cystatin C, and CRP levels is a very valuable indicator for predicting the occurrence and rupture of intracranial aneurysms, and combined detection can provide scientific evidence-based guidance for clinical prediction of the occurrence and rupture of intracranial aneurysms.

Identifying critical genes associated with aneurysmal subarachnoid hemorrhage by weighted gene co-expression network analysis.

Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening medical condition with a high mortality and disability rate. aSAH has an unclear pathogenesis, and limited treatment options are available. Here, we aimed to identify critical genes involved in aSAH pathogenesis using peripheral blood gene expression data of 43 patients with aSAH due to ruptured intracranial aneurysms and 18 controls with headache, downloaded from Gene Expression Omnibus. These data were used to construct a co-expression network using weighted gene co-expression network analysis (WGCNA). The biological functions of the hub genes were explored, and critical genes were selected by combining with differentially expressed genes analysis. Fourteen modules were identified by WGCNA. Among those modules, red, blue, brown and cyan modules were closely associated with aSAH. Moreover, 364 hub genes in the significant modules were found to play important roles in aSAH. Biological function analysis suggested that protein biosynthesis-related processes and inflammatory responses-related processes were involved in the pathology of aSAH pathology. Combined with differentially expressed genes analysis and validation in 35 clinical samples, seven gene (CD27, ANXA3, ACSL1, PGLYRP1, ALPL, ARG1, and TPST1) were identified as potential biomarkers for aSAH, and three genes (ANXA3, ALPL, and ARG1) were changed with disease development, that may provide new insights into potential molecular mechanisms for aSAH.