Subarachnoid hemorrhage (SAH) causes 5% of all strokes and is responsible for about 18,000 deaths per year in the United States (Aneurysmal Subarachnoid Hemorrhage, 2008). The incidence of SAH has been estimated at 6 to 8 per 100,000 persons per year (Linn, Rinkel, Algra, & van Gijn, 1996). In nearly 15% (range 5–34%) of patients with SAH, no source of hemorrhage can be identified via four-vessel cerebral angiography (Alen et al., 2003; Gupta et al., 2009), resulting in two major types of SAH: aneurysmal (ASAH) and nonaneurysmal (NASAH). Anecdotal evidence and contradictory research suggest that patients with NASAH experience some of the same health-related quality of life (HRQOL) issues as patients with ASAH. The purpose of this quantitative survey design study was to compare health-related quality of life (HRQOL) 1 to 3 years post-hemorrhage in patients who have experienced a NASAH to those who have experienced an ASAH. This is the first US study to specifically investigate HRQOL in NASAH and the second study comparing HRQOL outcomes between aneurysmal and nonaneurysmal subarachnoid hemorrhage patients. Our results are comparable to the first study by Hutter and Gilsbach, (1995), which also found that the two groups are much more similar than different. There were no significant differences between 28 of the 36 demographic and clinical characteristics examined in this study. Our study confirms previous findings that there is a significant impact on employment for both hemorrhage groups and an even greater inability to return to work for the NASAH patients. The nonaneurysmal group had more physical symptom complaints while the aneurysmal group had more emotional symptoms. Lastly, both groups had low levels of PTSD, and these levels did not differ significantly between groups. However, PTSD and social support were shown by regression analysis to impact HRQOL for both groups. We recommend that clinicians assess for PTSD in all subarachnoid hemorrhage patients and institute treatment early, which will decrease the negative effects on HRQOL. This may include offering psychological services or social work early in the hospital course to all SAH patients. Further research and policy changes are needed to assist in interventions that improve vocational reintegration after SAH. NASAH patients should no longer be referred to as having suffered a “benign hemorrhage.” They have had a life changing hemorrhage that may forever change their lives and impact their HRQOL.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24785号 / 医博第4977号 / 新制||医||1066(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 金子 新, 教授 YOUSSEFIAN Shohab, 教授 阪上 優 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

BACKGROUND A subarachnoid hemorrhage (SAH) is a bleed into the subarachnoid space surrounding the brain. This disease affects roughly 30,000 Americans each year and approximately one in six affected individuals die at the time of the ictal event. Individuals that do survive suffer from many complications including delayed cerebral vasospasm (DCV), cerebral edema, fever, and increased intracranial pressure (ICP) amongst others. These patients often suffer from brain damage due to neuronal apoptosis as a consequence of excess neuroinflammation. Microglia, the resident macrophage of the central nervous system, and Toll-like Receptor-4 (TLR4), a pro-inflammatory transmembrane receptor, have both been shown to play a role in the neuroinflammation seen in SAH. RBC components have been shown to activate microglial TLR4, and this event is suggested to trigger downstream mechanisms leading to neuronal apoptosis. The presented research takes a closer look at the role of microglial TLR4 in early neuronal apoptosis seen in an SAH model. METHODS All mice used were 10- to 12-week-old males on a C57BL/6 background: TLR4−/−, MyD88−/−, TRIF−/− and wild type (WT). To induce an SAH, a total of 60 ul of arterial blood from a donor WT mouse was injected for over 30 seconds into another mouse. For in vitro experiments, either primary microglia (PMG) or murine microglial BV2 cells were used. Microglia were separated from murine neuronal HT22 cells by 3um cell culture inserts or transwells, before being stimulated with lipopolysaccharide (LPS), red blood cells (RBCs), or RBC components including hemin (structurally similar to heme) and hemoglobin. In vivo samples were studied using either immunohistochemistry (IHC) or Fluorescence Activated Cell Sorting (FACS), and in vitro cells were studied using IHC and Light Microscopy. Neuronal cell death was measured using TUNEL and/or FloroJade C (FJC) assays. Cognitive function after SAH was measured using the Barnes Maze protocol. RESULTS In a 24-hour time course, more death occurred in the HT22 cells associated with BV2s treated with RBCs for 12-hour and 24-hour incubation time points as compared to 1-hour and 3-hour time points. Similar results were seen in the WT PMGs, as HT22 apoptosis increased in the RBC treated WT groups as the incubation time points increased. The WT PMG and MyD88−/− RBC treated PMGs showed significant death as compared to a WT untreated control (p<0.05) using a FJC assay, and both showed more death in a TUNEL assay as compared to an untreated control. WT mice treated with whole blood and hemoglobin had significantly more apoptosis as compared with a normal saline (NS)-treated control mouse (p<0.05). WT PMGs treated with whole blood and hemoglobin had more apoptosis as compared with an untreated control. MyD88-/- treated with RBC, hemoglobin, and hemin had more HT22 cell death compared with other genotypes treated with the same component. For the Barnes Maze, TLR4−/− mice performed significantly less total errors than WT mice on POD5 and 6 (p<0.01), and took significantly less time to reach the goal chamber on POD4, POD5 (p<0.05), and POD6 (p<0.01). CONCLUSION Our experimental results suggest that a microglial TLR4-dependent, MyD88-independent pathway is involved in neuronal apoptosis very early in an SAH model via RBC and hemoglobin activation, and that neuronal cell apoptosis due to TLR4 expression may be related to SAH-related cognitive and behavioral deficits. Our results suggest that TRIF may be the intracellular adaptor that is involved in this mechanism, but further experiments are needed to confirm this.

Diss. (sammanfattning) Stockholm : Karol. inst., 2003. / Härtill 6 uppsatser.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2004. / Härtill 5 uppsatser.

Thesis (Ph. D.)--West Virginia University, 2010. / Title from document title page. Document formatted into pages; contains x, 102 p. : ill. (some col.). Includes abstract. Includes bibliographical references.

The trace elements zinc and copper are essential components of many enzymes, some of which are of importance for the development and function of the central nervous system. Deficiency of the metals has been shown to lead to malformations and to the loss of myelin in animals. Earlier reports of zinc concentrations in the cerebrospinal fluid are few and the results variable. In multiple sclerosis and in epilepsy therapy with phenytoin there are varying reports of changes in serum concentrations of zinc and copper. A method was developed for the determination of zinc in cerebrospinal fluid by flame atomic absorption spectrophotometry utilizing a pulse nebulizer technique. Zinc and copper in serum were determined by flame atomic absorption spectrophotometry with conti nous aspiration. The normal concentrations of zinc in cerebrospi nal fluid was 0.16_+0.03 micromoles per litre (mean +_ S.D.). The zinc concentrations were correlated with protein and albumin concentrations in the cerebrospinal fluid but not with the serum zinc levels. In the patients with increased protein concentrations in the cerebrospinal fluid or with subarachnoid haemorrhage increased zinc levels were found. In 50 patients with multiple sclerosis lower serum concentrations of zinc were found compared to age and sex matched controls. In younger patients low serum levels of copper were also observed. There was no correlation between zinc and protein parameters in the cerebrospinal fluid of multiple sclerosis patients. In untreated epileptic males low serum zinc concentrations were observed. During the first 72 hours of phenytoin therapy increased serum concentrations of zinc and copper were found. during long-term therapy with phenytoin alone or in combination with other antiepileptic drugs there was an increased serum concentration of copper and ceruloplasmin but no change in zinc concentration compared with controls. / <p>Diss. Umeå, Umeå universitet, 1982, härtill 4 uppsatser</p> / digitalisering@umu

Introduction. The glial cell water channel aquaporin-4 (AQP4) plays an important ro le in brain oedema, astrocyte migration and neuronal excitability. Current theories of AQP4 function are based largely on experiments using AQP4 -1- mice. These mice have only been partially characterized. I therefore undertook a detailed investigation of baseline brain properties in AQP4 -1- mice. In the second part of my experiments I investigated the role of AQP4 in brain oedema in a mouse model of subarachnoid haemorrhage. Method. Gross anatomical measurements included estimates of brain and ventricle size. Neurons, astrocytes and oligodendrocytes were assessed using the neuronal nuclear marker NeuN, the astrocyte marker GFAP, and the myelin stain Luxol Fast Blue. The blood brain barrier was studied by electron microscopy and the horseradish peroxidase extravasation technique. A mouse model in which 30~1 of autologous blood was injected into the basal cisterns was used to reproduce subarachnoid haemorrhage. Brain water content, intracranial pressure and neurological score were compared in wildtype and AQP4 -/- mice. I also measured blood brain barrier permeability and the osmotic permeability of the glia lim itans, one of the routes of oedema elimination.

There is conflicting data on the effects of statins on cerebral vasospasm and clinical outcomes in aneurysmal subarachnoid hemorrhage (aSAH) patients. In this retrospective cohort study, patients were divided into those who received pravastatin (PRAV group) 40mg/d and those who did not (NP group). Data were analyzed using multivariate logistic regression. Eighty-one patients met inclusion criteria. There was a statistically significant decreased in the incidence of vasospasm in the PRAV group; however, this association did not retain significance after adjusting for WFNS, race, elevated WBC, and clipping (59% PRAV vs. 88% NP, p=0.08). There was no statistically significant difference in proportion of severe radiological vasospasm or mortality between groups. However, there was a trend towards a decreased mean length of stay (P=0.06) and a significantly higher proportion of survivors discharged to home in the PRAV group (P<0.0001). In conclusion, there was a trend towards a decrease in the incidence of vasospasm in the aSAH receiving pravastatin, but this trend did not achieve statistical significance after adjusting for potential confounders. Pravastatin was associated with other favorable clinical outcomes.

Esta pesquisa analisa experimentalmente as diferenças de comportamento entre a versão clássica e a modificada da craniotomia subtemporal quanto à retração do lobo temporal. A retração é medida pelo ângulo de visão, através do microscópio, obtido ao mirar-se estruturas previamente estabelecidas. Estudou-se a correlação estatística entre a retração cerebral e os diâmetros transversos do crânio, a profundidade da fossa temporal e a altura da bifurcação medida em relação à tenda do cerebelo e à clinóide posterior. É considerada a relação entre estes achados e os aspectos pertinentes à opção entre as craniotomias pterional e subtemporal para o tratamento cirúrgico dos aneurismas da porção superior da artéria basilar. / This paper is an experimental analysis between the classic and the modified subtemporal procedures, regarding the cerebral retraction required to approach the interpeduncular cistern and the basilar artery bifurcation. The retraction is assumed to be proportional to the angle of sight, through the microscope, required to observe the basilar bifurcation and other structures. The statistical correlations between the degree of brain retraction and the transverse diameters of the skull, the vertical length of the temporal fossa and the position of the basilar bifurcation in relation to the posterior clinoid and the tentorium are analysed. Considerations are made regarding these findings and the many aspects involved in the options between the pterional and the subtemporal approaches in the surgical treatment of the basilar bifurcation aneurysms