Construction and Validation of a New Model for the Prediction of Rupture in Patients with Intracranial Aneurysms.

BACKGROUND: Despite progress in the detection of biological molecules that contribute to intracranial aneurysm (IA) development, many pathophysiological mechanisms remain unclear, particularly with regard to predicting IA rupture. In this study, we aimed to identify hub genes and construct a new model to predict IA rupture. METHODS: Four datasets (62 ruptured IAs, 16 unruptured IAs, and 31 normal controls) were downloaded from the Gene Expression Omnibus. Differentially expressed genes (DEGs) were identified between the IAs and normal controls. All overlapping genes were analyzed using weighted gene co-expression network analysis. Functional enrichment analyses were performed using key modules. We then intersected the key module genes with DEGs. Protein-protein interaction networks were assessed to identify key hub genes. Least absolute shrinkage and selection operator logistic regression analysis was performed to construct a prediction model. A receiver operating characteristic curve was constructed to evaluate the reliability of the scoring system. RESULTS: After intersection and normalization, 433 DEGs were identified and 15,388 genes were selected for weighted gene co-expression network analysis. The black module with 1145 genes exhibited the highest correlation with IA rupture. Many potential mechanisms are involved, such as the inflammatory response, innate immune response, extracellular exosome, and extracellular space. Thirty hub genes were selected from the protein-protein interaction, and 4 independent risk genes, TNFAIP6, NCF2, OSM, and IRAK3, were identified in the least absolute shrinkage and selection operator logistic regression model. CONCLUSIONS: Our prediction model not only serves as a useful tool for assessing the risk of IA rupture, but the key genes identified herein could also serve as biomarkers and therapeutic targets.

Mast Cell Promotes the Development of Intracranial Aneurysm Rupture.

BACKGROUND AND PURPOSE: Inflammation has emerged as a key component of the pathophysiology of intracranial aneurysms. Mast cells have been detected in human intracranial aneurysm tissues, and their presence was associated with intramural microhemorrhage and wall degeneration. We hypothesized that mast cells play a critical role in the development of aneurysmal rupture, and that mast cells can be used as a therapeutic target for the prevention of aneurysm rupture. METHODS: Intracranial aneurysms were induced in adult mice using a combination of induced systemic hypertension and a single injection of elastase into the cerebrospinal fluid. Aneurysm formation and rupture were assessed over 3 weeks. Roles of mast cells were assessed using a mast cell stabilizer (cromolyn), a mast cell activator (C48/80), and mice that are genetically lacking mature mast cells (KitW-sh/W-sh mice). RESULTS: Pharmacological stabilization of mast cells with cromolyn markedly decreased the rupture rate of aneurysms (80% versus 19%, n=10 versus n =16) without affecting the aneurysm formation. The activation of mast cells with C48/80 significantly increased the rupture rate of aneurysms (25% versus 100%, n=4 versus n=5) without affecting the overall rate of aneurysm formation. Furthermore, the genetic deficiency of mast cells significantly prevented aneurysm rupture (80% versus 25%, n=10 versus n=8, wild-type versus KitW-sh/W-sh mice). CONCLUSIONS: These results suggest that mast cells play a key role in promoting aneurysm rupture but not formation. Stabilizers of mast cells may have a potential therapeutic value in preventing intracranial aneurysm rupture in patients.

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.

Characteristics of circulating monocytes at baseline and after activation in patients with intracranial aneurysm.

Intracranial aneurysm (IA) is a bulging of blood vessels around the brain that is often asymptomatic but may cause severe complications and death if ruptured. Macrophage-mediated immune responses can contribute to the development of IA. During homeostasis and inflammation, circulating monocytes can infiltrate the vasculature, where they develop into macrophages, and modulate immune responses. Based on the expression of CD14 and CD16, total circulating monocytes can be distinguished into three main subsets, including the CD14+CD16- classical monocytes, the CD14+CD16+ intermediate monocytes, and the CD14loCD16++ non-classical monocytes. In this study, we found that frequencies of CD14+CD16- classical monocytes were significantly lower in IA patients than in healthy controls, while the frequencies of CD14+CD16+ intermediate monocytes and CD14loCD16++ non-classical monocytes were significantly higher in IA patients than in healthy controls. The frequencies of CD14+CD16+ intermediate monocytes were further elevated in IA-ruptured patients compared to those in IA-unruptured patients. Compared to classical monocytes, intermediate monocytes and non-classical monocytes presented higher TNF-α and IL-1ß expression. When cocultured with autologous naive CD4 T cells, intermediate and non-classical monocytes preferentially promoted the expression of TBX21 and RORC over the expression of FOXP3 in CD4 T cells. Inhibition of TNF-α and IL-1ß slightly reduced TBX21 expression and markedly reduced RORC expression, and at the same time significantly increased FOXP3 expression in CD4 T cells. Overall, this study demonstrated that the monocytes were dysregulated in IA patients in a manner that favored the development of proinflammatory responses.

Estrogen Deficiency Promotes Cerebral Aneurysm Rupture by Upregulation of Th17 Cells and Interleukin-17A Which Downregulates E-Cadherin.

BACKGROUND: Estrogen deficiency is associated with the development of cerebral aneurysms; however, the mechanism remains unknown. We explored the pathway of cerebral aneurysm development by investigating the potential link between estrogen deficiency and inflammatory factors. METHODS AND RESULTS: First, we established the role of interleukin-17 (IL-17)A. We performed a cytokine screen demonstrating that IL-17A is significantly expressed in mouse and human aneurysms (P=0.03). Likewise, IL-17A inhibition was shown to prevent aneurysm formation by 42% (P=0.02) and rupture by 34% (P<0.05). Second, we found that estrogen deficiency upregulates T helper 17 cells and IL-17A and promotes aneurysm rupture. Estrogen-deficient mice had more ruptures than control mice (47% versus 7%; P=0.04). Estradiol supplementation or IL-17A inhibition decreased the number of ruptures in estrogen-deficient mice (estradiol 6% versus 37%; P=0.04; IL-17A inhibition 18% versus 47%; P=0.018). Third, we found that IL-17A-blockade protects against aneurysm formation and rupture by increased E-cadherin expression. IL-17-inhibited mice had increased E-cadherin expression (P=0.003). E-cadherin inhibition reversed the protective effect of IL-17A inhibition and increased the rate of aneurysm formation (65% versus 28%; P=0.04) and rupture (12% versus 0%; P=0.22). However, E-cadherin inhibition alone does not significantly increase aneurysm formation in normal mice or in estrogen-deficient mice. In cell migration assays, E-cadherin inhibition promoted macrophage infiltration across endothelial cells (P<0.05), which may be the mechanism for the estrogen deficiency/IL-17/E-cadherin aneurysm pathway. CONCLUSIONS: Our data suggest that estrogen deficiency promotes cerebral aneurysm rupture by upregulating IL-17A, which downregulates E-cadherin, encouraging macrophage infiltration in the aneurysm vessel wall.

The Quantitative and Functional Changes of Postoperative Peripheral Blood Immune Cell Subsets Relate to Prognosis of Patients with Subarachnoid Hemorrhage: A Preliminary Study.

OBJECTIVE: It has been suggested that the preoperative (PRE) and postoperative (POST) immune system alteration triggered by aneurysmal subarachnoid hemorrhage (SAH) and surgical treatment itself may affect patients' prognosis and contribute to POST complications. The mechanisms may be attributed to immune suppression-triggered infection or immune overreaction-triggered aseptic inflammation. In this study, we investigated the dynamic changes in peripheral immune cell subsets as well as the alterations of inflammatory cytokines in patients with aneurysmal SAH who received craniotomy and clipping surgery. In addition, we studied the association of those changes with POST complications and clinical prognosis. METHODS: We investigated 27 patients who received craniotomy and clipping surgery for aneurysmal SAH. The operations were all performed within 24 hours after the occurrence of aneurysm rupture. Detailed immune monitoring (peripheral blood leukocytes and lymphocyte subsets and inflammatory cytokines) was performed on PRE (on admission), day 1, day 3, and day 6 after operation. RESULTS: Our data showed that the percentage of CD3+, CD8+, natural killer T (NKT), CD4+, and regulatory T (Treg) cells significantly decreased and the level of interleukin 4 (IL-4), interferon γ, and IL-2 significantly increased 1 day after surgery compared with the data in PRE. On the contrary, natural killer (NK), NK group 2 (NKG2D), and B cells increased and the level of IL-10 in plasma decreased. In study of the relationship between POST fever and the change in immune cell subgroups, the fever group had a lower percentage of CD3+, CD4+, NKT, Tregs, and B cells on day 1, day 3, and day 6 after surgery compared with the patients who did not have fever, whereas the CD8+, NK, and NKG2D subsets showed the opposite trend. Furthermore, we analyzed the association between immune profile changes and the prognosis of those patients. The patients were divided into those with an unfavorable prognosis (n = 6) and those with a favorable prognosis (n = 21) according to Glasgow Outcome Scale score and postoperation (POST) coma. Our results showed that except for B cells, patients with a favorable prognosis had a relatively higher percentage of CD3+, CD4+, CD8+, NK, NKT, NKG2D, and Treg cells compared with the unfavorable prognosis group from PRE to day 6 POST. CONCLUSIONS: Our results indicated that patients with aneurysmal SAH undergoing craniotomy and clipping surgery had a profound transient deterioration in immune function. In addition, the changes in immune cell subgroups had a strong association with POST fever. The changes in immune cell subgroups were also directly associated with clinical prognosis of the patients. These association findings might be attributable to a better biomarker to predict patient diagnosis.

Unruptured intracranial aneurysms: development, rupture and preventive management.

Saccular unruptured intracranial aneurysms (UIAs) have a prevalence of 3% in the adult population, and are being increasingly detected because of improved quality and higher frequency of cranial imaging. Large amounts of data, providing varying levels of evidence, have been published on aneurysm development, progression and rupture, but less information is available on the risks and efficacy of preventive treatment. When deciding how to best manage UIAs, clinicians must consider the age and life expectancy of the patient, the estimated risk of rupture, the risk of complications attributed to preventive treatment, and the level of anxiety caused by the awareness of having an aneurysm. This Review highlights the latest human data on the formation, progression and rupture of intracranial aneurysms, as well as risks associated with preventive treatment. Considering these we discuss the implication for clinical management. Furthermore, we highlight pivotal questions arising from current data on intracranial aneurysms and the implications the data have for future experimental or clinical research. We also discuss data on novel radiological surrogates for rupture for those aneurysms that do not require preventive occlusion. Finally, we provide guidance for clinicians who are confronted with patients with incidentally detected UIAs.

Macrophages Mediate the Repair of Brain Vascular Rupture through Direct Physical Adhesion and Mechanical Traction.

Hemorrhagic stroke and brain microbleeds are caused by cerebrovascular ruptures. Fast repair of such ruptures is the most promising therapeutic approach. Due to a lack of high-resolution in vivo real-time studies, the dynamic cellular events involved in cerebrovascular repair remain unknown. Here, we have developed a cerebrovascular rupture system in zebrafish by using multi-photon laser, which generates a lesion with two endothelial ends. In vivo time-lapse imaging showed that a macrophage arrived at the lesion and extended filopodia or lamellipodia to physically adhere to both endothelial ends. This macrophage generated mechanical traction forces to pull the endothelial ends and facilitate their ligation, thus mediating the repair of the rupture. Both depolymerization of microfilaments and inhibition of phosphatidylinositide 3-kinase or Rac1 activity disrupted macrophage-endothelial adhesion and impaired cerebrovascular repair. Our study reveals a hitherto unexpected role for macrophages in mediating repair of cerebrovascular ruptures through direct physical adhesion and mechanical traction.

[Postoperative changes of Th17/Treg balance in patients with intracranial aneurysm rupture].

OBJECTIVE: To observe the dynamic changes of Th17/Treg balance in patients following surgical intervention for intracranial aneurysm rupture. METHODS: The percentage of Th cells and the intracellular IL-17 level, Treg cell percentage and transforming growth factor -ß1 (TGF-ß1) levels were examined in 73 patients with rupture of aneurysms before and at 24 h, 72 h and 1 week after operation, with 62 patients with unruptured aneurysms and 65 healthy volunteers as the control. The correlations among the immune cells, cytokines and clinical characteristics of the patients (NIHSS, ADL and hospitalization stay) were analyzed. RESULTS: Th17 percentage and intracellular IL-17 levels were significantly higher in the patients with ruptured and unruptured aneurysms than in the healthy volunteers, and were significantly higher in patients with ruptured aneurysms than in those with unruptured aneurysms. Treg cell percentage and TGF-ß1 level were significantly lower in patients with aneurysms than in the healthy volunteers, and were lower in patients with ruptured aneurysms than in those with uruptured aneurysms (P<0.05). Patients with intracranial aneurysm rupture showed significantly increased Th17 cell percentage and IL-17 level but significantly lowered Treg cell percentage and TGF-ß1 at 24 h following the surgery (P<0.05); these changes were reversed significantly at 72 h and 1 week after the surgery. Th17 cell percentage and IL-17 level were positively correlated with NIHSS and the length of postoperative hospital stay but inversely correlated with ADL; Treg cell percentage and TGF-ß1 were inversely correlated with NIHSS and hospital stay but positively with ADL (P<0.05). CONCLUSION: In patients with intracranial aneurysms, the systemic immune inflammatory response is highlighted by excessive Th17 cells and insufficient Treg cells, which are closely related with the outcomes of the patients following surgical intervention. Evaluation of Th17/Treg balance and the cytokine levels can help to assess the prognosis of patients with aneurysm rupture.

ApoB-100-related peptide vaccine protects against angiotensin II-induced aortic aneurysm formation and rupture.

BACKGROUND: T cells and macrophages are implicated in the pathogenesis of aortic aneurysm (AA) and atherosclerosis. We recently demonstrated that a vaccine using an apoB-100-related peptide p210 reduces atherosclerosis with favorable modulation of CD8+ T cells in apolipoprotein E-deficient (apoE-/-) mice. OBJECTIVES: This study hypothesized that a p210 vaccine could reduce AA formation in the angiotensin II (Ang II)-induced AA model. METHODS: Male apoE-/- mice were immunized with p210 vaccine and implanted with an Ang II-releasing pump for 4 weeks. Flow cytometry assessed T cell activation and phenotype. Interleukin-6 (IL-6) and monocyte chemotactic protein 1 (MCP-1) expression were assessed using reverse transcription polymerase chain reaction. We used ex vivo aortic explants to test monocyte adhesion and in vitro cocultures to evaluate CD8+ T cell function. RESULTS: The p210 vaccine activated CD8+ T cells and reduced AA formation and mortality due to AA rupture, which was attenuated by CD8+ T cell depletion. Vaccination decreased expression of IL-6 and MCP-1 and reduced macrophage infiltration in the aorta. Cytotoxic T-lymphocyte assay showed that CD8+ T cells from p210-immunized mice had higher lytic activity against Ang II-stimulated macrophages. The p210 vaccine decreased splenic Th17 cells, and in vitro coculture of CD4+ and CD8+ T cells showed that CD8+ T cells from p210-immunized mice inhibited the polarization of CD4+ T cells into Th17 cells. IL-17A-/- mice infused with a higher dose of Ang II did not develop AA rupture. CONCLUSIONS: A p210 vaccine protected against Ang II-induced AA formation and mortality by reducing macrophage infiltration in the aorta and decreasing Th17 cell polarization. Our findings provide a potentially novel immunomodulating approach against AA.

Proteomic identification of differentially expressed proteins in vascular wall of patients with ruptured intracranial aneurysms.

OBJECTIVE: Intracranial aneurysms (IA) are serious cerebral vascular abnormalities, however, little is known about the mechanisms underlying IA formation, progression and rupture. Therefore, this study aimed to assess protein expression specific to the vascular tissues of IA patients. METHODS: IA samples were intraoperatively collected from 14 patients after microneurosurgical clipping and pooled. Matched superficial temporal artery (STA) tissues collected from the same patients were used as controls. Differentially expressed proteins were identified using isobaric tags for relative and absolute quantification (iTRAQ) and two-dimensional liquid chromatography-tandem mass spectrometry (2D LC-MS/MS), validated by immunoblot. RESULTS: 816 proteins were found to be differently expressed in IA and healthy tissues. The expression level of 162 proteins differed by at least two fold. Expression of 80 proteins was up-regulated and expression of 82 was down-regulated. According to PANTHER, these proteins were involved in immune responses, cell adhesion, cellular component organization and developmental processes. Azurocidin-1 (AZU1, a known antimicrobial) and Transmembrane 9 superfamily member 1 (TM9SF1, a novel autophagy-related protein) were 8.0 and 8.6 fold up-regulated, respectively, in IA, while Sorbin and SH3 domain-containing protein 2 (SORBS2), involved in signaling complex assembly, was 12.1 fold down-regulated. CONCLUSION: These findings suggest that IA formation and rupture might be related to autophagy and immune responses, which possibly accounts for proteolytic degradation of vessel wall connective tissues and cytoskeleton components.

Immunoglobulin G4-related multiple systemic aneurysms and splenic aneurysm rupture during steroid therapy.

Immunoglobulin G4 (IgG4)-related disorders in various organs have recently been described, but multiple systemic aneurysms have not yet been reported. Here, we present a 68-year-old Japanese man with multiple systemic aneurysms and tumor-forming pericoronary arteritis who was undergoing low-dose corticosteroid therapy. Elevated serum IgG4 (2390 mg/dL) and IgG4-positive plasmacyte infiltration in the salivary glands led to a diagnosis of IgG4-related disease. High-dose corticosteroid therapy was initiated, whereupon the inflammatory lesions shrank. However, the large, well-developed common hepatic aneurysm and splenic aneurysm did not change. Our patient died of splenic aneurysm rupture in the sixth month of treatment. The autopsy revealed IgG4-positive plasmacyte infiltration in the coronary wall and a thinned splenic aneurysm wall. This case suggests that early high-dose corticosteroid therapy may be necessary for the treatment of IgG4-related cardiovascular disorders. A minor salivary gland biopsy might facilitate the early diagnosis of IgG4-related disease even if (18)F-fluorodeoxyglucose positron emission tomography provides no inflammatory findings.

Lack of complement inhibitors in the outer intracranial artery aneurysm wall associates with complement terminal pathway activation.

Inflammation and activation of the complement system predispose to intracranial artery aneurysm (IA) rupture. Because disturbances in complement regulation may lead to increased susceptibility to complement activation and inflammation, we looked for evidence for dysregulation of the complement system in 26 unruptured and 26 ruptured IAs resected intraoperatively. Immunohistochemical and immunofluorescence results of parallel IA sections showed that deposition of the complement activation end-product C5b-9 was lacking from the luminal part of the IA wall that contained complement inhibitors factor H, C4b binding protein, and protectin as well as glycosaminoglycans. In contrast, the outer, less cellular part of the IA wall lacked protectin and had enabled full complement activation and C5b-9 formation. Decay accelerating factor and membrane cofactor protein had less evident roles in complement regulation. The Factor H Y402H variant, studied in 97 IA patients, was seen as often in aneurysm patients with or without aneurysm rupture as in the control population. The regulatory capacity of the complement system thus appears disturbed in the outer part of the IA wall, allowing full proinflammatory complement activation to occur before aneurysm rupture. Insufficient complement control might be due to matrix remodeling and cell loss by mechanical hemodynamics and/or inflammatory stress. Apparently, disturbed complement regulation leads to an increased susceptibility to complement activation, inflammation, and tissue damage in the IA wall.

Complement system becomes activated by the classical pathway in intracranial aneurysm walls.

Inflammation and activation of the complement system in the intracranial aneurysm (IA) wall predispose to IA rupture. We have previously shown that increased C5b-9 accumulation correlates with IA rupture and wall degeneration. To elucidate the underlying mechanisms, we investigated initiators and the pathway of complement activation in unruptured and ruptured IAs. Unruptured and ruptured IA wall samples were studied in parallel sections by immunohistochemical and immunofluorescence stainings for the location and relations of classical and alternative pathway complement components (C1q, C3b/iC3b, C3d, C4b/iC4b; n=35 and properdin, n=10), putative complement activators IgG (n=90), IgM, CRP and OxLDL (n=10), and complement activation endproduct C5b-9. Classical pathway components were seen in all IAs, and they were located mostly in the extracellular matrix. The early pathway complement components colocalized with each other, but were present in larger areas than C5b-9. The areas positive for complement component accumulation were significantly broader in ruptured than in unruptured IAs. The potential complement activators IgG, IgM, CRP and OxLDL were found mostly in the extracellular matrix and in partial overlap with C5b-9. Lipids were seen in Oil-Red-O staining in colocalization with C5b-9. Complement becomes activated by the classical pathway in the IA wall. The activation appears to be induced by multiple factors, which, in addition to the traditional activators (immunoglobulins, CRP, OxLDL), could involve vascular pressure-induced tissue damage. Despite wide early pathway activation, the terminal pathway is focused on a distinct lipid-rich layer. The profile of the complement components and the association of C5b-9 with lipids in the extracellular matrix indicate a long-term chronic inflammatory process rather than an acute targeted inflammatory reaction. The observed pattern of complement activation may be the consequence of local stress-induced insufficiency of complement regulation in IA walls.

Network-based gene expression analysis of intracranial aneurysm tissue reveals role of antigen presenting cells.

Little is known about the pathology and pathogenesis of the rupture of intracranial aneurysms. For a better understanding of the molecular processes involved in intracranial aneurysm (IA) formation we performed a gene expression analysis comparing ruptured and unruptured aneurysm tissue to a control artery. Tissue samples of six ruptured and four unruptured aneurysms, and four cerebral arteries serving as controls, were profiled using oligonucleotide microarrays. Gene ontology classification of the differentially expressed genes was analyzed and regulatory functional networks and canonical pathways were identified with a network-based computational pathway analysis tool. Real time reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemical staining were performed as confirmation. Analysis of aneurysmal and control tissue revealed 521 differentially expressed genes. The most significantly associated gene ontology term was antigen processing (P=1.64E-16). Further network-based analysis showed the top scoring regulatory functional network to be built around overexpressed major histocompatibility class (MHC) I and II complex related genes and confirmed the canonical pathway "Antigen Presentation" to have the highest upregulation in IA tissue (P=7.3E-10). Real time RT-PCR showed significant overexpression of MHC class II genes. Immunohistochemical staining showed strong positivity for MHC II molecule specific antibody (HLA II), for CD68 (macrophages, monocytes), for CD45RO (T-cells) and HLA I antibody. Our results offer strong evidence for MHC class II gene overexpression in human IA tissue and that antigen presenting cells (macrophages, monocytes) play a key role in IA formation.

Association of fatal aneurysmal subarachnoid hemorrhage with human leukocyte antigens in the Finnish population.

Human leukocyte antigens (HLA) have been reported to associate with the risk of aneurysmal subarachnoid hemorrhage (SAH) and poor outcome after SAH. Our aim was to identify HLA antigens that associate with the risk of fatal SAH in the Finnish population. Medical records of 600 cadaveric organ donors were reviewed to find organ donors that succumbed to SAH (n = 232) or brain trauma (n = 151). HLA antigen frequencies in these groups were compared with HLA frequencies in a reference population of 10,000 bone marrow donors. Chi-Square test with Bonferroni correction and multiplicative logistic regression models were used and false positive result probabilities (FPRP) were calculated. Alpha-level was 0.01. HLA-A3 associated with fatal SAH (p = 0.0014, OR 1.3 and 95%CI 1.1-1.6) and HLA-DR7 inversely associated with fatal SAH (p = 0.0040, OR 0.3 and 95%CI 0.2-0.6). HLA-A3 but not HLA-DR7 showed also a positive trend in donors with brain trauma. FPRP was below 0.5 for HLA-A3, but clearly above 0.5 for HLA-DR7. HLA-A3 seems to associate with fatal SAH in the Finnish population. Further studies are needed to reveal the pathobiologic mechanisms for how HLA-A3 associates with the risk of fatal SAH in Finns.

Ruptured pediatric posterior cerebral artery aneurysm 9 years after the onset of Kawasaki disease: a case report.

CASE REPORT: A 12-year-old boy who had a history of Kawasaki disease 9 years ago experienced a subarachnoid hemorrhage by ruptured right posterior cerebral artery aneurysm. On day 1 operation, as the aneurysm was very fragile and bled easily, two intraoperative ruptures, including a very premature rupture, were encountered. As a result, a left hemiparesis especially severe in the left hand was caused by the right anterior thalamic infarction due to the occlusion of a thalamo-perforating artery arising near the neck of the aneurysm. DISCUSSION: The histopathological examination of the intraoperative excised aneurysmal dome disclosed the thickening of the endothelial inner due to the endothelial hypertrophy and the invasion of inflammatory cells. This finding of the aneurysm was partially mimicking the finding of the coronary artery of the patients with Kawasaki disease. The combination of cerebral aneurysm and Kawasaki disease has never been reported until now, and the etiology of the aneurysm of this patient is unclear.

Inflammation and intracranial aneurysms.

OBJECTIVE: An intracranial aneurysm is an important acquired cerebrovascular disease that can cause a catastrophic subarachnoid hemorrhage. Despite modern therapy, most patients die or are left disabled as a direct result of a severe initial hemorrhage. The development of more effective treatment strategies depends on understanding the fundamental biology of cerebral aneurysms. The purpose of the present study is to determine whether inflammation or immunological reaction occurs in cerebral aneurysms. METHODS: Aneurysm tissue was collected at the time of microsurgical repair from 23 unruptured and 2 ruptured aneurysms (25 patients) and compared with 11 control basilar arteries harvested at autopsy. Immunohistochemistry was used to localize complement (C3c, C9), immunoglobulins (IgG, IgM), vascular cell adhesion molecule-1, macrophages and monocytes (CD68), T lymphocytes (CD3), and B lymphocytes (CD20). RESULTS: Complement (C3c, P < 0.0001; C9, P = 0.0017), immunoglobulin (IgG, P = 0.0013; IgM, P = 0.031), vascular cell adhesion molecule-1 (P = 0.0022), macrophages (CD68, P = 0.004), and T lymphocytes (CD3, P = 0.0004) were all frequently present in the wall of aneurysm tissue but were rarely identified in control basilar arteries. A few B lymphocytes (CD20, P = 0.41) were found in aneurysm tissue, but none were found in the basilar arteries. CONCLUSION: Extensive inflammatory and immunological reactions are common in unruptured intracranial aneurysms and may be related to aneurysm formation and rupture.

Impaired in vitro proliferative response of suppressor lymphocytes in patients with subarachnoid haemorrhage from ruptured intracranial aneurysm.

Proliferative response to mitogens concanavalin A, phytohemagglutinin and pokeweed mitogen, and other chosen indicators of the activity of the immune system were assayed in peripheral blood mononuclear cells isolated from blood of patients with subarachnoid haemorrhage from ruptured aneurysm. Healthy blood donors served as control group. The SAH group displayed impaired response to concanavalin A, which is a mitogen specific for suppressor cells. It is suggested that the impaired activity of suppressor cells pre-existed in patients with subarachnoid haemorrhage, and after intracranial bleeding it might have contributed to the development of late neurological deficits.