Amyloid is a form of abnormal protein aggregation within the living body. Massive deposits can lead to organ failure. There is also increasing evidence that smaller pre-amyloid aggregates exert direct toxic effects to cells. To date 25 different proteins are known to occur as amyloid deposition in human tissues, although not all of these conditions are known to be associated with clinical diseases. This thesis deals with the very common form of amyloid localized to the arterial media. The fibril protein called ‘medin’ was identified in 1999. Medin is a 50 amino acid residue internal fragment of the precursor protein lactadherin. Lactadherin, first found in human milk, is expressed in various tissues such as breast epithelium (including carcinomas), macrophages and aorta. The function of the protein is not known but it has several functional domains. There is an EFG like domain, including an RGD-sequence, in the N-terminal part of the molecule. The C-terminal part consists of C1 and C2 coagulation factor V and VIII like domains. Medin is from within the C2 domain. This region is suggested to be involved in phosphatidyl serine binding, important in phagocytosis of apoptotic cells. Medin amyloid was originally described from studies of the aorta. It is shown here that deposits are more widely spread and can be found in many large arteries, particularly within the upper part of the body. The prevalence of medin amyloid increases with age and deposits are found, to a certain degree, in virtually everyone above the age of 60 years. The amyloid is not only found extracellularly but intracellular deposits may also occur. Amyloid is usually associated with elastic lamina or lamellae which often show signs of fragmentation. Given the localization of amyloid to elastic structures of the arterial media, three different vascular diseases were studied: temporal (giant cell) arteritis, thoracic aortic aneurysm and thoracic aortic dissection. Medin amyloid was found in temporal arteries with and without inflammation. In inflamed arteries, amyloid was mainly located along the broken internal elastic lamina. Medin was also demonstrated within giant cells. It is suggested that medin may be an antigen triggering autoimmune giant cell arteritis. In the study of thoracic aortic aneurysms and dissections, we found significant less medin amyloid in diseased aortic tissues compared with a control material. On the other hand, immunoreactive medin, probably in the state of oligomeric aggregates, was regularly found in association with aneurysms and dissections but not in the control material. It is suggested that medin oligomers exert toxic effects on smooth muscle cells which may lead to weakening of the arterial wall with aneurysm or dissection as a consequence.

By applying a segmentation procedure to two different sets of computed tomography scans, two geometrical models of the abdominal aorta, containing one inlet and two outlets have been constructed. One of these depicts a healthy blood vessel while the other displays one afflicted with a Abdominal Aortic Aneurysm. After inputting these geometries into the computational dynamics software FLUENT, six simulations of laminar, stationary flow of a fluid that was assumed to be Newtonian were performed. The mass flow rate across the model outlet boundaries was varied for the different simulations to produce a basis for a parameter analysis study. The segmentation data was also used as input data to a surface description procedure which produced not only the surface itself, but also the first and second directional derivatives in every one of its defining spatial data points. These sets of derivatives were followingly applied in an additional procedure that calculated values of Gaussian curvature. A parameter variance analysis was carried out to evaluate the performance of the surface generation procedure. An array of resultant surfaces and surface directional derivatives were obtained. Values of Gaussian curvature were calculated in the defining spatial data points of a few selected surfaces. The curvature values of a selected data set were visualized through a contour plot as well as through a surface map. Comparisons between the curvature surface map and one wall shear stress surface map were made.

Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease with no available pharmacological treatment. AAA formation reduces the structural integrity of the vessel and increases the susceptibility to rupture. The inflammatory response within human aneurysmal tissue is characterized by increased expression of cyclooxygenase-2 (COX-2). Similarly, in a mouse model of the disease induced by chronic Angiotensin II (AngII) infusion, we have shown that COX-2 expression in the abdominal aortic smooth muscle layer increases early in the development of the disease. Furthermore, genetic or pharmacological inactivation of COX-2 prior to disease initiation reduces AAA incidence. The current study utilized nonhyperlipidemic mice to determine the effectiveness of COX-2 inhibition initiated after AAA formation. COX-2 inhibitor treatment was initiated 5 days after beginning the AngII infusion, a time-point where significant aneurysmal pathology is observed. COX-2 inhibition with celecoxib significantly reduced the incidence as well as severity of AAAs as compared to the control group. Celecoxib treatment also protected the mice from aortic rupture and death. AAA development is characterized by degradation of the aortic smooth muscle layer with loss of the contractile phenotype. We found that the effectiveness of celecoxib was associated with significantly increased mRNA expression of alpha-actin, SM22alpha and desmin, all of which are markers of a differentiated smooth muscle cell phenotype. Celecoxib treatment also decreased mRNA expression of a marker of dedifferentiated smooth muscle (hyaluronic acid synthase 2). We also examined the role of altered expression of COX-2 in the increased susceptibility of the abdominal segment to AAA formation. We found a prolonged and greater induction of COX-2 in the abdominal aortic smooth muscle layer in contrast to a transient induction of COX-2 in the other regions of the aorta throughout disease progression. Overall, these findings suggest that COX-2 plays an important role in AAA development in mice, and COX-2 inhibition with celecoxib attenuates progression of aneurysm development by maintaining a differentiated phenotype in abdominal aortic smooth muscle cells.

Abdominal aortic aneurysm (AAA) is a disease of the aorta characterized by pathological remodeling and progressive weakening of the vessel resulting in the increased risk of rupture and sudden death. In a mouse model of the disease induced by chronic Angiotensin II (AngII) infusion, progression of AAAs is associated with reduced differentiation of smooth muscle cells (SMCs) at the site of lesion development. In the mouse model, the effectiveness of cyclooxygenase-2 (COX-2) inhibition for attenuating AAA progression is associated with maintenance of a differentiated SMC phenotype. However, the safety of COX-2 inhibitors is currently in question due to the increased risk of adverse cardiovascular events. Thus, it is crucial to identify mediators downstream of COX-2 that may provide new targets for treatment of this disease. Recent studies in humans and mouse models have suggested that the microsomal prostaglandin E synthase (mPGES-1) enzyme, which acts downstream of COX-2, may also be involved in the pathogenesis of the disease. We hypothesized that increased prostaglandin E2 (PGE2) synthesis resulting from the induction of both COX-2 and mPGES-1 may result in reduced differentiation of SMCs, and that disruption of this pathway would preserve the differentiated phenotype. To test this hypothesis, human aortic smooth muscle cells (hASMCs) were utilized to examine the effects of a variety of agents involved in AAA development and the COX-2 pathway. My findings suggest that one of the effects of exposing hASMCs to AngII involves a specific induction of mPGES-1 expression. Furthermore, although different COX-2-derived products may have opposing effects, mPGES-1-derived PGE2 may be the primary prostanoid synthesized by SMCs which functions to attenuate differentiation. Therefore, mPGES-1 inhibition may provide inhibition of PGE2 that is more specific than COX-2 inhibitor treatment and may serve as a therapeutic target for attenuating AAA progression by maintaining a differentiated SMC phenotype.

Diss. (sammanfattning) Linköping : Linköpings universitet, 2007. / Härtill 5 uppsatser.

A rupturing abdominal aortic aneurysm (AAA) has a mortality rate of 50% while an elective repair has a mortality rate of 3-8%. Screening programmes with ultrasound are used in some countries to detect AAA at an early stage. Ultrasound is however very observer bias and dependent on the observer's experience. The study was performed in Vietnam, a country that have experienced exceptional economic growth with increasing risk factors for cardiovascular diseases but has no national screening programme. The aim of this study was to examine the interobserver variability when measuring the abdominal aorta with ultrasound on young adults in Vietnam. The abdominal aorta was measured in the longitudinal and the transverse axis by two different observers using the leading edge to leading edge method. Participants in this study were 31 voluntary students, 16 men and 15 women in the ages 18-26 years, from the Da Nang university of medical technology and pharmacy and the design was a cross-sectional study with a quantitative approach. The study showed a significant difference between the longitudinal measurements but not between the transverse measurements. Despite this statistical significance, the observers' differences were within the recommended limit of 5 mm. / Ett rupturerande bukaortaaneurysm har en dödlighet på 50% medan förebyggande vaskulär kirurgi har en dödlighet på 3-8%. Screeingprogram med ultraljud används i vissa länder för att upptäcka bukaortaaneurysm i ett tidigt skede innan de rupterar. Ultraljudsundersökningen är dock väldigt beroende på utövarens erfarenhet och utbildning. Studien genomfördes i Vietnam, ett land som genomgått stor ekonomisk tillväxt men även en ökning av riskfaktorer för kardiovaskulära sjukdomar. Vietnam har dock inget nationellt screeningprogram för bukaortaaneurysm. Syftet med studien var att undersöka observatörsvariationen vid mätning av bukaortan med ultraljud på unga vuxna i Vietnam. Populationen var ung för att minska patologiska fynd. Bukaortan mättes med metoden leading edge to leading edge, både i det longitudinella och i det transversella snittet av två olika utövare. Observatörerna var två studenter från Biomedicinska analytikerprogrammet med inriktning klinisk fysiologi, Jönköpings Universitet. Deltagare i studien var 31 frivilliga studenter, 16 män och 15 kvinnor i åldrarna 18-26 år, från Da Nang University of medical technology and pharmacy och designen var en tvärsnittsstudie med kvantitativ ansats. Studien visade en signifikant skillnad i de longitudinella mätningarna men inte i de transversella mätningarna. Trots denna statistiska signifikans var observatörernas differenser inom den rekommenderade gränsen på 5 mm.

BACKGROUND: Posterior inferior cerebellar artery (PICA) aneurysms are an uncommon, heterogeneous group of aneurysms with poorer neurological outcomes compared to other intracranial aneurysms. At first, as part A, we conducted a systematic review of the literature to evaluate the safety and efficacy of treatment strategies for PICA-aneurysms. Subsequently, as part B, we performed a multicenter retrospective study to analyze the outcome in a large series of patients treated with contemporary microsurgical and endovascular techniques. METHODS: For the meta-analysis, a systematic search of Medline, EMBASE, Scopus and Web of Science was done for studies published through November 2015. We included studies that described treatment of PICA-aneurysms with ≥10 patients. Random-effects meta-analysis was used to pool the following outcomes: complete occlusion, technical success, periprocedural morbidity/mortality, stroke rates, aneurysm recurrence/rebleed, CN-palsies rates, and long-term neurological morbidity/mortality. As the second part, aiming to report the current trends and results in treatment strategies for PICA-aneurysms, records of 94 patients treated for PICA-aneurysms between 2000 and 2015 at 3 large referral neurovascular centers were retrospectively reviewed. RESULTS: In the meta-analysis, we...

Orientador: Antonio Guilherme Borges Neto / Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas / Made available in DSpace on 2018-08-10T13:43:01Z (GMT). No. of bitstreams: 1 Loureiro_AndersonBarbosa_M.pdf: 1654963 bytes, checksum: d49b2312387926f779b4d3c3fec27cfe (MD5) Previous issue date: 2007 / Resumo: A hemorragia subaracnóide (HSA) aneurismática é causada mais comumente pela ruptura de aneurismas saculares, o que leva a um déficit motor e cognitivo importante afetando as atividades funcionais dos pacientes. A mensuração da função é importante na otimização do tratamento fisioterapêutico e alta hospitalar destes pacientes. Este estudo teve como objetivo descrever os resultados da reabilitação em pacientes submetidos a tratamento cirúrgico de clipagem aneurismática admitidos no Hospital das Clínicas da Universidade Estadual de Campinas. Os pacientes foram avaliados por meio dos seguintes instrumentos: escala clínica de Hunt ¿ Hess (na internação hospitalar), que avalia o estado clínico do paciente; a escala neurorradiográfica de Fisher (na internação hospitalar), que avalia a quantidade de sangue no espaço subaracnóide; medida de independência funcional (MIF) (no pós-operatório e alta hospitalar) e escala de prognóstico de Glasgow (na alta hospitalar). Os pacientes foram submetidos ao tratamento fisioterapêutico durante todo o período de internação (dois atendimentos diários). Para comparar os valores da MIF entre admissão e alta foi realizado o teste de Wilcoxon, para verificar a correlação entre os instrumentos de avaliação foi utilizado o coeficiente de correlação de Spearman. Foram avaliados 13 pacientes, 12 (92.31%) mulheres e um homem, com predomínio de aneurismas na artéria cerebral média (53.85%). A idade média foi de 51.62 (DP 13.04) anos. Ocorreu diferença estatística significativa entre as avaliações da MIF (admissão 56.92 ± 23.42; alta 91.77 ± 20.32; p < 0.001). Não foi encontrada correlação significativa entre a MIF e a escala clínica de Hunt-Hess (r = - 0.16282; p = 0.5951), escala neurorradiografica de Fisher (r = 0.06935; p = 0.8219) e a escala de prognóstico de Glasgow (r = 0.24972; p = 0.4106). Os pacientes apresentaram melhoras funcionais após o procedimento cirúrgico e tratamento fisioterapêutico demonstradas de forma quantitativa por meio da MIF e não foi encontrada relação das medidas clínicas com os resultados funcionais / Abstract: Subarachnoid hemorrhage results in critical motor and cognitive impairment which leads to dysfunctions causing a negative impact in quality of life. The functional independence measure (FIM) scale is the most widely accepted functional assessment measure in use in the rehabilitation community. The aim of this study was to describe the rehabilitation outcome after a surgical aneurysm occlusion realized in patients admitted in the Clinical Hospital of Campinas State University ¿ UNICAMP. Patients were submitted to the Hunt-Hess and Fisher assessment scales after admission in to the hospital; to the FIM after surgery; and to FIM and Glasgow Outcome Scale (GOS) after hospital discharge. The days in the hospital were counted, patients had physical therapy twice a day and the injured arteries were identified. Thirteen patients, 12 woman¿s (92,31%) with aneurysm predominant in middle cerebral artery (53,85%) were evaluated. The mean age was 51, 62 (DP 13,04) years old. The mean FIM rate, between the admission and the discharge period, was 34,85 (DP 20,85), with average of 5-69 points (p<0,001). There was non significant correlation between the FIM, Hunt-Hess, Fisher and GOS. The subarachnoid hemorrhage is a catastrophic neurologic event that results in motor and cognitive impairment. The FIM could have an important role in predict the neurorehabilitation outcome in acute aneurysmal subarachnoid hemorrhage / Mestrado / Ciencias Biomedicas / Mestre em Ciências Médicas

Introdução: A alta incidência de oclusão incompleta e recanalização dos aneurismas intracranianos de colo largo tratados por via endovascular levaram ao desenvolvimento de novas técnicas, entre elas o uso do Onyx ®. Objetivos: avaliar a eficiência do agente embólico líquido Onyx® em produzir oclusão completa dos aneurismas intracranianos de colo largo e avaliar a estabilidade do tratamento aos 6 meses e aos 18 meses, por meio de controles angiográficos. Casuística e métodos: Esta tese foi realizada na Seção de Neuroradiologia Intervencionista da Med Imagem, do Hospital São Joaquim da Real e Benemérita Associação Portuguesa de Beneficência de São Paulo, através da revisão de dados clínicos e radiológicos de 69 pacientes tratados pelo autor, com 84 aneurismas intracranianos de colo largo no período de julho de 2002 a fevereiro de 2006. Dez pacientes eram do sexo masculino e 59 do sexo feminino, com idade variando de 24 anos a 86 anos (mediana de 52 anos). Todos os aneurismas tinham origem lateral à artéria e apresentavam pelo menos um dos critérios usados para definir colo largo - colo maior que 4 mm de diâmetro e relação saco/colo menor que 1,5. Cinqüenta aneurismas eram pequenos, 30 grandes e quatro gigantes (diâmetro máximo menor que 12mm, de 12mm a 25mm e maiores que 25mm, respectivamente). As apresentações clínicas mais comuns foram: achado incidental em 34 pacientes, pós-hemorragia sub aracnóide e recanalização após tratamento com espirais destacáveis em 10. A maioria dos aneurismas era da artéria carótida interna (76 aneurismas). Controles angiográficos foram feitos ao final, aos seis meses e aos 18 meses do tratamento (controles I, II e III respectivamente), sendo analisados principalmente o grau de oclusão (completa ou incompleta), incidência de recanalização e complicações clínicas. Avaliação estatística foi feita pelo método de Kaplan-Meier para o percentual cumulativo de oclusão completa e percentual de recanalização e análise univariada e multivariada dos fatores preditivos de oclusão total imediata e tardia através de regressão logística. Resultados: O índice de oclusão completa foi de 65,5%, 84,6% e de 90,3% para todos os aneurismas, nos controles I, II e III respectivamente. Estes índices foram de 74%, 95,1% e de 95,2% para os aneurismas pequenos e de 53,3%, 70% e de 80% para os aneurismas grandes nos controles I, II e III respectivamente. Oclusão completa ocorreu em 50% dos aneurismas gigantes nos controles I e II, sem haver controle III neste grupo. Recanalização ocorreu em 3 aneurismas (4,6%). O porcentual cumulativo de oclusão completa foi de 97,63% (IC de 95% variando de 95,27 a 100) para os aneurismas pequenos aos 9 meses e de 83,86% (IC de 95% variando de 67,73 a 100) para os aneurismas grandes aos 21 meses. Três pacientes faleceram (4,3%), havendo relação com o procedimento em dois (2,9%). Morbidade permanente ocorreu em cinco pacientes (7,2%), sendo incapacitante em um (1,4%). Conclusões: 1. O uso do Onyx® foi eficiente na oclusão completa dos aneurismas intracranianos de colo largo. 2. O tratamento foi estável nos controles angiográficos aos 6 meses e aos 18 meses. / Introduction: The high rate of incomplete occlusion and intracranial large neck aneurysms recanalization lead to the development of new techniques, including the use of Onyx®. Purpose: to evaluate the efficacy of the liquid embolic system Onyx ® to produce completes occlusion of the intracranial large neck aneurysms and evaluates the stability of the treatment at 6 month and 18 month angiographic control. Materials and Methods: this thesis has been performed at Section of Interventional Neuroradiology of Med Imagem, at the Hospital São Joaquim da Real e Benemérita Associação Portuguesa de Beneficência de São Paulo, based on a review of clinical and radiological records of 69 patients treated by the author, harboring 84 large neck intracranial aneurysms between July 2002 and February 2006. Ten patients were male and 59 female, with age ranging from 24 to 86 years old. All aneurysms were lateral to the parent vessel and were wide neck (neck > 4 mm and/or domus to neck ratio < 1.5). Fifty aneurysms were small (<12 mm), 30 were large (12 to 25 mm) and 4 were giant (> 25 mm). Thirty four aneurysms were incidental, 10 were ruptured and 10 were recanalized after coil treatment and the majority was located in the internal carotid artery (76). Angiographic follow-up was done at the end of the procedure, at six month and at 18 month (controls I, II and III respectively), analyzing the rate of complete occlusion, recanalization and clinical complication. Statically analysis were done by Kaplan-Meier method for cumulative percentage of complete aneurysm occlusion and for recanalization, and univariate and multivariate analysis of predictive factors of immediate and late complete occlusion through logistic regression. Results: Complete aneurysm occlusion was achieved in 65.5% on immediate control, in 84.6% at 6 month, and in 90.3% at 18 month follow-up periods for all aneurysms. This rate was 74%, 95.1% and 95.2% for small and 53.3%, 70% and 80% for large aneurysms at the same follow-up periods. In the giant aneurysm group, two had complete and stable occlusion at six month follow-up angiography. Recanalization was seen in three aneurysms (4,6%). Kaplan Meyer\'s cumulative percentage of complete aneurysm occlusion was 97.63% (CI 95% ranging from 95,27 to 100) for small aneurysms at 9 months and 83.86% (CI 95% ranging from 67,73 to 100) for large aneurysms at 21 months. There were three deaths (4,3%), two procedure-related (2.9%). Overall morbidity was 7.2%, being disabling in one (1,4%). Conclusions: 1. The use of Onyx was efficient in the complete occlusion of wide neck intracranial aneurysms. 2. The treatment was stable at 6 month and 18 month angiographic controls.

Introdução. As artérias perfurantes comumente são evidenciadas durante a dissecção microcirúrgica para clipagem de aneurismas intracranianos. A oclusão de artérias perfurantes pode ser responsável por infarto encefálico isquêmico e resultados clínicos indesejáveis. O presente estudo objetiva descrever a utilidade da vídeo-angiografia intra-operatória com indocianina verde (VAIICG) na avaliação do fluxo sanguíneo em artérias perfurantes visibilizadas no campo microcirúrgico, durante a clipagem de aneurismas intracranianos. Secundariamente, foi analisada a incidência de artérias perfurantes envolvidas durante a cirurgia de aneurismas intracranianos, e a ocorrência de infarto encefálico isquêmico causado pelo comprometimento das artérias perfurantes. Método. Sessenta pacientes, com 64 aneurismas intracranianos foram tratados cirurgicamente, e prospectivamente incluídos neste estudo. A VAIICG intra-operatória foi realizada com o uso de microscópio neurocirúrgico (Carl Zeiss Co. Oberkochen, Germany) com a tecnologia VAIICG integrada. A presença e o envolvimento de artérias perfurantes foram analisados no campo microcirúrgico durante a dissecção cirúrgica, e durante a clipagem do aneurisma. A patência vascular após a clipagem também foi investigada. Apenas artérias pequenas que não foram visibilizadas nas imagens pré-operatórias de angiografia digital com subtração (ADS) foram consideradas para análise. Resultados. A VAIICG permitiu a visibilização do fluxo sanguíneo em todos os casos que apresentaram artérias perfurantes no campo microcirúrgico. Dentre 36 casos cujas artérias perfurantes estavam visíveis à VAIICG, 11 casos (30,5%) apresentaram relação próxima entre o aneurisma e artérias perfurantes. Em um paciente (9,0%), dentre os 11 casos com relação próxima, a VAIICG evidenciou oclusão de uma artéria perfurante de P1 após a aplicação do clipe, cujo reposicionamento correto restabeleceu imediatamente o fluxo sanguíneo, o qual foi visibilizado com a VAIICG, sem conseqüências clínicas. Quatro pacientes (6,7%) apresentaram infarto pós-operatório em território de artérias perfurantes, sendo que em três deles, as artérias perfurantes estavam ausentes ou distantes do aneurisma clipado. Conclusão. O envolvimento de artérias perfurantes durante a clipagem microcirúrgica de aneurismas intracranianos é comum. A VAIICG intra-operatória fornece informação visual do fluxo sanguíneo em artérias de calibre milimétrico, e seu uso possibilita evitar a oclusão de artérias perfurantes e subseqüente infarto encefálico. / Background. Perforating arteries are commonly involved during the surgical dissection and clipping of intracranial aneurysms. Occlusion of perforating arteries may be responsible for ischemic infarction and poor outcome. The goal of this study was to describe the usefulness of near-infrared indocyanine green videoangiography (ICGA) for the intraoperative assessment of blood flow in perforating arteries that are visible in the surgical field during clipping of intracranial aneurysms. In addition we analyzed the incidence of perforating vessels involved during the aneurysms surgery and the incidence of ischemic infarct caused by compromising of these small arteries. Method. Sixty patients harboring 64 aneurysms were surgically treated and prospectively included in this study. Intraoperative ICGA was performed using a surgical microscope (Carl Zeiss Co. Oberkochen, Germany) with integrated ICGA technology. The presence and involvement of perforating arteries was analyzed in the microsurgical field, during surgical dissection, and during the clip application. Assessment of vascular patency after clipping was also investigated. Only those small arteries that were not visible on preoperative digital subtraction angiography (DSA) were considered for analysis. Results. In all cases in which perforating vessels were found in the microscope field, the ICGA was able to visualize flow. Among 36 cases whose perforating vessels were visible on ICGA, 11 cases (30,5%) presented a close relation between the aneurysm and perforating arteries. In one patient (9,0%), among these 11 cases with close relation, ICGA showed occlusion of a P1 perforating artery after clip application, which led to immediate correction of the clip confirmed by immediate re-establishment of flow visible with ICGA without clinical consequences. Four patients (6,7%) presented with postoperative perforating artery infarct of whom in 3 patients the perforating arteries were either not visible or distant from the aneurysm. Conclusion. The involvement of perforating arteries during clip application for aneurysm occlusion is a usual finding. Intraoperative ICGA provide visual information with regard to patency of these milimetric vessels, which may avoid their occlusion and further ischemic infarction.