No description available.

Object Rupture of intracranial arteriovenous malformations is a leading cause of stroke in children and young adults. Treatment options include surgery and highly focused radiation (stereotactic radiosurgery). For large and deep seated lesions, the risks of surgery may be prohibitively high, while radiosurgery has a disappointingly low efficacy and long latency. Radiosurgery carries the most promise for significant advances, however the process by which radiosurgery achieves obliteration is incompletely understood. Inflammation and thrombosis are likely to be important in the radiation response and may be amenable to pharmacological manipulation to improve radiosurgical efficacy. Materials and methods Immunohistochemistry and electron microscopy were used to study normal cerebral vessels, cavernous malformations and AVMs, some of which had previously been irradiated. An attempt was made to culture AVM endothelial cells to study the immediate response of AVM endothelium to radiosurgery. The effects of radiosurgery in a rat model of AVM were studied using immunohistochemistry and the results used to determine the choice of a pharmacological strategy to enhance the thrombotic effects of radiosurgery. Results Vascular malformations have a different endothelial inflammatory phenotype than normal cerebral vessels. Radiosurgery may cause long term changes in inflammatory molecule expression and leads to endothelial loss with exposure of pro-thrombotic molecules. Ultrastructural effects of irradiation include widespread cell loss, smooth muscle cell (SMC) proliferation and thrombosis. Endothelial culture from AVMs proved difficult due to SMC predominance in initial cultures. Radiosurgery upregulated several endothelial inflammatory molecules in the animal model and may induce pro-thrombotic cell membrane alterations. The administration of lipopolysaccharide and soluble tissue factor to rats following radiosurgery led to selective thrombosis of irradiated vessels. Conclusions Inflammation and thrombosis are important in the radiosurgical response of AVMs. Lumen obliteration appears to be mediated by proliferation of cells within the vessel wall and thrombosis. Upregulation of inflammatory molecules and perhaps disruption of the normal phospholipid asymmetry of the endothelial and SMC membranes are some of the earliest responses to radiosurgery. The alterations induced by radiation may be harnessed to selectively initiate thrombus formation. Stimulation of thrombosis may improve the efficacy of radiosurgery, increasing treatable lesion size and reducing latency.

Para desenvolver e avaliar a aplicabilidade de uma escala técnica prognostica das dificuldades no tratamento microcirúrgico dos aneurismas gigantes e complexos da circulação anterior do polígono de Willis, 50 lesões foram operadas. Um valor numérico foi dado a cada uma das 8 variáveis da escala. Somando-se os valores para cada variável, uma nota (de 1 a 14) foi obtida, para cada uma das 50 cirurgias. Dois grupos, portanto, foram definidos: cirurgia difícil (nota de 1 a 8) e cirurgia extremamente difícil (nota de 9 a 14). Foi feita análise estatística comparando-se os 2 grupos em relação a diversas variáveis demográficas e clínicas. Concluiu-se que a escala proposta é útil no planejamento pré-operatório, intra-operatório e prognóstico neste tipo de aneurisma / In order to develop and verify the applicability of a technical and prognostic scale of the difficulties in the microsurgical treatment of giant and complex aneurysms of the anterior circulation of the Cicle of Willis, 50 lesions were operated. A numeric amount was given for each of 8 variants of the scale. By adding each amount for each variant a score(from 1 to 14) was achieved, for each of the 50 surgeries. Two groups, therefore, were established: difficult surgery (scores from 1 to 8) and extremely difficult surgery (scores from 9 to 14). Statistical assessment comparing both groups in relation to several demographic and clinical variants was done. It was concluded that the proposed scale is useful in preoperative, intraoperative and prognostic planning in microsurgery for this kind of aneurysms

Thesis (Ph. D.)--University of Virginia, 2008. / Title from title page. Includes bibliographical references. Also available online through Digital Dissertations.

Para desenvolver e avaliar a aplicabilidade de uma escala técnica prognostica das dificuldades no tratamento microcirúrgico dos aneurismas gigantes e complexos da circulação anterior do polígono de Willis, 50 lesões foram operadas. Um valor numérico foi dado a cada uma das 8 variáveis da escala. Somando-se os valores para cada variável, uma nota (de 1 a 14) foi obtida, para cada uma das 50 cirurgias. Dois grupos, portanto, foram definidos: cirurgia difícil (nota de 1 a 8) e cirurgia extremamente difícil (nota de 9 a 14). Foi feita análise estatística comparando-se os 2 grupos em relação a diversas variáveis demográficas e clínicas. Concluiu-se que a escala proposta é útil no planejamento pré-operatório, intra-operatório e prognóstico neste tipo de aneurisma / In order to develop and verify the applicability of a technical and prognostic scale of the difficulties in the microsurgical treatment of giant and complex aneurysms of the anterior circulation of the Cicle of Willis, 50 lesions were operated. A numeric amount was given for each of 8 variants of the scale. By adding each amount for each variant a score(from 1 to 14) was achieved, for each of the 50 surgeries. Two groups, therefore, were established: difficult surgery (scores from 1 to 8) and extremely difficult surgery (scores from 9 to 14). Statistical assessment comparing both groups in relation to several demographic and clinical variants was done. It was concluded that the proposed scale is useful in preoperative, intraoperative and prognostic planning in microsurgery for this kind of aneurysms

Foram utilizados 30 encéfalos de jacaré do papo-amarelo (Cayman latirostris), injetados com látex, corado em vermelho, com objetivo de sistematizar e descrever a distribuição e territórios das artérias carótidas internas e suas principais ramificações na superfície do encéfalo. As artérias carótidas internas apresentaram uma anastomose intercarótica e a artéria oftálmica interna. Na altura da hipófise estas se dividiram num ramo rostral e num curto ramo caudal, que continuou naturalmente como artéria cerebral caudal. O ramo rostral formou a rede da artéria cerebral média, a artéria cerebral rostral e a artéria comunicante rostral. A artéria cerebral caudal antes de penetrar na fissura transversa do cérebro emitiu o Iº ramo central, e em seu interior originou a artéria diencefálica, o IIº ramo central, ramos hemisféricos occipitais e a artéria pineal. Ao abandonar a fissura, a artéria cerebral caudal, curvou-se caudodorsalmente, emergindo no pólo occipital do hemisfério cerebral, projetou-se rostralmente, sagital a fissura longitudinal do cérebro como artéria interhemisférica. Esta lançou ramos hemisféricos convexos e hemisféricos mediais para as respectivas faces dos hemisférios cerebrais, e anastomosou-se com sua homóloga contralateral formando a artéria etmoidal comum, que se dividiu nas artérias etmoidais: direita e esquerda, as quais progrediram para as cavidades nasais, vascularizando-as. O curto ramo caudal emitiu sua porção de médio calibre, que lançou as artérias mesencefálica e cerebelar ventral rostral. Esta porção do ramo caudal anastomosou-se com seu homólogo contralateral formando a artéria basilar. A artéria basilar acompanhou a fissura mediana ventral da medula oblonga, e lançou as artérias cerebelares ventrais caudais e espinhais dorsais, e abandonou a cavidade craniana como artéria espinhal ventral. A artéria mesencefálica formou as artérias tectais, cerebelar dorsal rostral e cerebelar dorsal caudal. A artéria espinhal dorsal originou a artéria trigeminal. O círculo arterial cerebral apresentou-se fechado tanto rostral como caudalmente e o suprimento sanguíneo cerebral foi feito exclusivamente pelo sistema carótico. / It was utilized 30 brains of broad- snouted Cayman (Cayman latirostris), injected with red stained latex, aiming to systematize and describe the distribution and territories of the internal carotid arteries and their main branches on the surface of the brain. The internal carotid arteries showed an anastomosis intercarótica and internal ophthalmic artery. At the level of the hypophysis divided into a rostral branch and a short caudal branch, which continued naturally as caudal cerebral artery. The rostral branch formed a middle cerebral artery network, the rostral cerebral artery and the rostral communicating artery. The caudal cerebral artery before entering the cerebral transverse fissure gave of the Iº central branch and inside emitted the diencephalic artery, the IIº central branch, occipital hemispheric branches and the pineal artery. After leaving the cerebral transverse fissure, the caudal cerebral artery curved caudodorsalwards, emerging at the occipital pole of the cerebral hemisphere and projected rostrally sagittal to the cerebral longitudinal fissure, as interhemispheric artery. This gave off convex hemispheric branches and medial hemispheric branches of the same, and anastomosed with its contralateral homologous to form the common ethmoidal artery, which divided into the ethmoidal arteries: right and left, which progressed to the nasal cavities, vascularizing them. The short caudal branch gave off his portion of medium caliber, which originated the mesencephalic and ventral rostral cerebellar arteries. This portion of the caudal branch anastomosed with its contralateral homologous to form the basilar artery. The basilar artery accompanied the ventral median fissure of medulla oblongata, and emitted the ventral caudal cerebellar artery and dorsal spinal artery, and abandoned the cranial cavity as ventral spinal artery. The mesencephalic artery formed: the tectal, dorsal rostral cerebellar and dorsal caudal cerebellar arteries. The dorsal spinal artery originated a trigeminal artery. The cerebral arterial circle was rostral and caudally closed with cerebral blood supply provided, exclusively, by the carotid system.

Foram utilizados 30 encéfalos de nutria (Myocastor coypus), injetados com látex, corado em vermelho, com objetivo de sistematizar e descrever a distribuição e territórios das artérias cerebrais rostral, média e caudal e suas ramificações na superfície dos hemisférios cerebrais e no tronco encefálico. A artéria carótida interna apresentou-se atrofiada, sendo o encéfalo vascularizado exclusivamente pelo sistema vértebro-basilar. A artéria vertebral penetrou pelo forame magno, e seus antímeros anastomosaram-se formando uma calibrosa artéria basilar. A artéria basilar, de grande calibre, alcançou o sulco rostral da ponte, dividiu-se em dois ramos terminais, em uma divergência de aproximadamente 90°, e lançou as artérias cerebelar rostral, cerebral caudal, hipofisária, corióidea rostral e ramos centrais para o lobo piriforme. Após, os ramos terminais da artéria basilar projetaram-se rostro-lateralmente até a altura da origem aparente do nervo oculomotor (III par craniano), e curvaram-se alcançando o trato óptico, lançando a artéria cerebral média e a artéria cerebral rostral, seu ramo terminal. A artéria cerebelar rostralemitiu um ramo tectal mesencefálico caudal, para a face caudal do colículo caudal. A artéria cerebral caudal, normalmente única, de grosso calibre, projetava-se látero-dorsalmente para o interior da fissura transversa do cérebro, lançando as artérias tectal mesencefálica rostral (componente proximal) e inter-hemisférica caudal. A artéria tectal mesencefálica rostral vascularizou a maior parte do tecto mesencefálico, e os ramos terminais das artérias tectais mesencefálicas, rostral e caudal, formaram uma rede anastomótica sobre a superfície dos colículos rostrais e caudais. A artéria inter-hemisférica caudal lançou ramos centrais, artérias corióidea caudal (esta anastomosava-se com a artéria corióidea rostral, vascularizando o diencéfalo e o hipocampo), hemisféricas occipitais (para o pólo occipital do hemisfério cerebral), ramos tectais mesencefálicos rostrais (componentes distais), e então contornava o esplênio do corpo caloso anastomosando-se “em ósculo” com a artéria inter-hemisférica rostral. A artéria cerebral média, de grande calibre, projetava-se pelo interior da fossa lateral do cérebro, lançando ramos centrais caudais e rostrais para o páleo-palio da região. Ela ultrapassou o sulco rinal lateral, formando um a dois eixos principais para a face convexa do hemisfério cerebral, originando ramos hemisféricos convexos caudais e rostrais, e suas ramificações terminais anastomosavam-se “em ósculo” no lobo parietal com os ramos das artérias hemisféricas mediais rostrais, ramo da artéria cerebral rostral. A artéria cerebral rostral, de grosso calibre, projetou-se rostro-medialmente, na altura do quiasma óptico, emitindo um ramo medial, para a fissura longitudinal do cérebro. Seu eixo principal projetava-se rostralmente, acompanhando a fissura longitudinal do cérebro, até o bulbo olfatório, continuando-se para a cavidade nasal como artéria etmoidal interna. Esta emitiu ramos centrais, hemisférico medial e artérias lateral e medial do bulbo olfatório. O ramo medial anastomosava-se com seu homólogo contralateral, quando presente, fechando o círculo arterial cerebral rostralmente, formando uma artéria comunicante rostral, mediana ímpar. Esta se bifurcou nas artérias inter-hemisféricas rostrais, que vascularizavam toda face medial dos hemisférios cerebrais, até o esplênio do corpo caloso, emitindo as artérias hemisférica rostral e hemisférica medial rostral, sendo que os ramos terminais desta alcançavam a face convexa, anastomosando-se com os ramos terminais da artéria cerebral média. / Thirty nutria brains were used (Myocastor coypus), injected with latex and stained in red, in order to systematize and describe the distribution and the territories of the rostral, middle and caudal cerebral arteries and their ramifications in the surface of cerebral hemispheres and in the brain stem in nutria. The internal carotid artery was atrophied, being the encephalic vascularized exclusively by the vertebro-basilar system. The vertebral artery penetrated the magnum foramen, and their antimeres anastomosed to form a calibrous basilar artery. The basilar artery, of great caliber, reached the rostral sulcus of the pons, divided into two terminal branches, at a divergence of approximately 90°, and launched the rostral cerebellar, caudal cerebral, hypophyseal, rostral choroid arteries and central branches to the piriform lobe. Afterwards, the terminal branches of the basilar artery were projected rostrolaterally up to the apparent origin of the oculomotor nerve (III cranial nerve), and bent over reaching the optic tract, launching the middle cerebral artery and the rostral cerebral artery, its terminal branch. The rostral cerebellar artery emitted a caudal tectal mesencephalic branch, to the caudal surface of the caudal colliculus. The caudal cerebral artery, usually unique, of large caliber, projected laterally into the transverse fissure of the brain, launching the rostral tectal mesencephalic (proximal component) and caudal inter-hemispheric arteries. The rostral tectal mesencephalic artery vascularized most of the mesencephalic roof, and the terminal branches of the tectal mesencephalic arteries, rostral and caudal, formed an anastomotic network on the surface of rostral and caudal colliculus. The caudal inter-hemispheric artery emitted central branches, caudal choroid (this anastomosis with the rostral choroidal artery, vascularizing of the diencephalon and hippocampus), occipital hemispheres artery (to the occipital pole of the cerebral hemisphere), rostrais tectral mesencephalic branches (distal components), and then bypassed the splenius of the corpus callosum anastomosing "in osculum" with the rostral inter-hemispheric artery. The medium cerebral artery, of great caliber, projected through the interior of the cerebral lateral fossa, Releasing caudal and rostrais central branches to the paleopallio region. It crossed the lateral rinal groove, forming one to two main axes to the convex surface of the cerebral hemisphere, originating caudal and rostral convex hemispheric branches, and its terminal branches anastomosed "in osculum" in the parietal lobe with the branches of the mediais rostrais hemispherics arteries, branch of the rostral cerebral artery. The rostral cerebral artery, of large caliber, projected rostro-medially, at the level of optic chiasm, emitting a medial branch, for the cerebral longitudinal fissure. Its main axis was projected rostrally, accompanying the cerebral longitudinal fissure, until the olfactory bulb, continuing to the nasal cavity as internal ethmoidal artery. It emitted central branches, medial hemispheric and lateral and medial of the olfactory bulb arteries. The medial branch was anastomosed with its contralateral homologous, when present, closing the cerebral arterial circle rostrally, forming a rostral communicating artery, unique median. This bifurcated in the inter-hemispheric rostrais arteries, which vascularized the entire medial face of the cerebral hemispheres, until the splenius of the corpus callosum, emitting the rostral hemispherical and hemispherical medial rostral arteries, being that the terminal branches of this reached the convex surface, anastomosing with the terminal branches of the middle cerebral artery.

名古屋大学博士学位論文 学位の種類 : 博士(医学)(課程) 学位授与年月日:平成5年5月14日 雄山博文氏の博士論文として提出された

Stroke is the third largest cause of death, and the leading cause of disability worldwide. Treatments are sought to reduce mortality, and increase survival time following an ischaemic stroke. Hypoxia-ischaemia (HI) is the combination of cerebral ischaemia and global hypoxia that can lead to neuronal damage, particularly perinatally. The complex neurodegenerative cascade following ischaemic stroke and HI activates many stress pathways, including heme oxygenase (HO). HO metabolises free heme to release iron, carbon monoxide, and biliverdin, which is subsequently metabolised to bilirubin. This thesis aims to elucidate the role HO plays following HI, and assess any neuroprotective mechanisms using HO modulators. The 26 day old rat model of HI was used to induce the neurodegenerative cascade. All animals were sacrificed 3 days post-insult. Immunohistochemistry and Western blotting demonstrated that HO-1 was increased in the ipsilateral hemisphere of both HI (by 1.7 � 0.1 fold: p = 0.016, n = 4) and middle cerebral artery occlusion (MCAO) brains (by 1.6 � 0.1 fold: p = 0.037, n = 4), compared to controls. HO-2 was constitutively expressed throughout the control brain, but HI upregulated HO-2 expression (by 1.7 � 0.2 fold: p = 0.027, n = 4) ipsilaterally, whereas MCAO did not alter HO-2 expression. Administration of the HO inhibitor tin protoporphyrin (SnPP; 30[mu]mol/kg intraperitoneally) daily, beginning 1 day prior to HI until sacrifice, reduced infarct volume to 50% � 10 of saline-treated animals (p = 0.039, n = 6-8). The HO inducer ferriprotoporphyrin (FePP; 30[mu]mol/kg) had no effect on infarct volume. HO activity and protein expression were not significantly altered following treatment with SnPP. Therefore, the neuroprotective actions of SnPP may be through alternative mechanisms. SnPP treatment increased HI + saline-induced total nitric oxide synthase (NOS) activity by 1.5 � 0.06 fold (p < 0.001, n = 6-8). Conversely, SnPP inhibited both inducible NOS (50% � 7 of HI + saline; p = 0.045, n = 7-8) and cyclooxygenase (COX) activity (32% � 6 of HI + saline; p = 0.049, n = 4-8). SnPP treatment also increased mitochondrial complex I activity by 1.6 � 0.25 fold (p = 0.04, n = 4-8) and complex V activity by 1.7 � 0.26 fold (p = 0.046, n = 4-8) in the ipsilateral hemisphere. It appears that SnPP is acting on inflammatory and mitochondrial enzymes to produce neuroprotection. In vitro analysis of cultured RAW264.7 macrophages exposed to lipopolysaccharide (LPS; 10[mu]g/mL) treated with SnPP (dose range: 10⁻�⁰M - 10⁻⁵M) did not alter nitrite levels or cell viability. However, high dose SnPP (10⁻⁵M) in the absence of LPS increased nitrite levels from control cells by 2.7 � 0.7 fold (p = 0.043, n = 6), complementing the in vivo total NOS data. Other mechanisms such as NMDA receptor activation were not affected by 100[mu]M SnPP or 100[mu]M SnCl₂ in patch clamped cortical pyramidal neurons. Overall, the role that HO plays following HI remains unclear, but this thesis provides definitive evidence that SnPP (an established HO inhibitor) provides neuroprotection. This neuroprotection may be due to its effects on inducible pathways such as NOS and COX. Therefore, further experimentation is required to fully elucidate the role that HO plays following cerebral ischaemia, and additional in vivo evidence will be necessary to establish HO inhibitors as a putative candidate for cerebral ischaemia neuroprotection.

Stroke is the third largest cause of death, and the leading cause of disability worldwide. Treatments are sought to reduce mortality, and increase survival time following an ischaemic stroke. Hypoxia-ischaemia (HI) is the combination of cerebral ischaemia and global hypoxia that can lead to neuronal damage, particularly perinatally. The complex neurodegenerative cascade following ischaemic stroke and HI activates many stress pathways, including heme oxygenase (HO). HO metabolises free heme to release iron, carbon monoxide, and biliverdin, which is subsequently metabolised to bilirubin. This thesis aims to elucidate the role HO plays following HI, and assess any neuroprotective mechanisms using HO modulators. The 26 day old rat model of HI was used to induce the neurodegenerative cascade. All animals were sacrificed 3 days post-insult. Immunohistochemistry and Western blotting demonstrated that HO-1 was increased in the ipsilateral hemisphere of both HI (by 1.7 � 0.1 fold: p = 0.016, n = 4) and middle cerebral artery occlusion (MCAO) brains (by 1.6 � 0.1 fold: p = 0.037, n = 4), compared to controls. HO-2 was constitutively expressed throughout the control brain, but HI upregulated HO-2 expression (by 1.7 � 0.2 fold: p = 0.027, n = 4) ipsilaterally, whereas MCAO did not alter HO-2 expression. Administration of the HO inhibitor tin protoporphyrin (SnPP; 30[mu]mol/kg intraperitoneally) daily, beginning 1 day prior to HI until sacrifice, reduced infarct volume to 50% � 10 of saline-treated animals (p = 0.039, n = 6-8). The HO inducer ferriprotoporphyrin (FePP; 30[mu]mol/kg) had no effect on infarct volume. HO activity and protein expression were not significantly altered following treatment with SnPP. Therefore, the neuroprotective actions of SnPP may be through alternative mechanisms. SnPP treatment increased HI + saline-induced total nitric oxide synthase (NOS) activity by 1.5 � 0.06 fold (p < 0.001, n = 6-8). Conversely, SnPP inhibited both inducible NOS (50% � 7 of HI + saline; p = 0.045, n = 7-8) and cyclooxygenase (COX) activity (32% � 6 of HI + saline; p = 0.049, n = 4-8). SnPP treatment also increased mitochondrial complex I activity by 1.6 � 0.25 fold (p = 0.04, n = 4-8) and complex V activity by 1.7 � 0.26 fold (p = 0.046, n = 4-8) in the ipsilateral hemisphere. It appears that SnPP is acting on inflammatory and mitochondrial enzymes to produce neuroprotection. In vitro analysis of cultured RAW264.7 macrophages exposed to lipopolysaccharide (LPS; 10[mu]g/mL) treated with SnPP (dose range: 10⁻�⁰M - 10⁻⁵M) did not alter nitrite levels or cell viability. However, high dose SnPP (10⁻⁵M) in the absence of LPS increased nitrite levels from control cells by 2.7 � 0.7 fold (p = 0.043, n = 6), complementing the in vivo total NOS data. Other mechanisms such as NMDA receptor activation were not affected by 100[mu]M SnPP or 100[mu]M SnCl₂ in patch clamped cortical pyramidal neurons. Overall, the role that HO plays following HI remains unclear, but this thesis provides definitive evidence that SnPP (an established HO inhibitor) provides neuroprotection. This neuroprotection may be due to its effects on inducible pathways such as NOS and COX. Therefore, further experimentation is required to fully elucidate the role that HO plays following cerebral ischaemia, and additional in vivo evidence will be necessary to establish HO inhibitors as a putative candidate for cerebral ischaemia neuroprotection.