Atherogenesis and atherosclerosis in primary antiphospholipid syndrome

ABSTRACT: In the late seventies the term “Haematological Stress Syndrome” defined some haematological abnormalities appearing in the course of acute and chronic disorders, such as raised plasma levels of fibrinogen (FNG) and factor VIII, reduced fibrinolytic activity and hyperviscosity. In the early nineties the “Membrane stress syndrome hypothesis” proposed the unification of the concepts of haematological stress syndrome with those of oxidation, inflammation and immune activation to explain the pathogenesis of the antiphospholipid syndrome (APS) Antiphospholipid antibodies, coagulation, fibrinolysis and thrombosis. This chapter investigated the occurrence of the “Haematological Stress Syndrome” and thrombosis in 144 participants positive for aPL detected by clotting and immune tests. Among the clotting assays for the detection of lupus anticoagulant, dilute Russell's viper venom time better correlated with a history of venous thrombosis than activated partial thromboplastin time (p<0.0002 vs p<0.009) and was the only test correlated with a history of arterial thrombosis (p<0.01). By regression analysis, serum levels of IgG anticardiolipin antibodies (aCL) associated with the number of venous occlusions (p<0.001). With regards to FNG and von Willebrand factor (vWF), the former rose by 36% (95% CI; 21%, 53%) and the latter by 50% (95% CI; 29%, 75%) at the first venous occlusion and remained unchanged after subsequent occlusions. At variance FNG rose by 45% (95% CI; 31%, 60%) per arterial occlusion and vWF by 27% (95% CI; 10%, 47%) per arterial occlusion throughout. The coagulation/fibrinolytic balance was cross-sectionally evaluated on 18 thrombotic PAPS patients, 18 subjects with persistence of idiopathic aPL and in healthy controls. Markers of thrombin generation prothrombin fragment 1+2 (F1+2), thrombin-antithrombin complex (TAT) and of fibrin turnover D-Dimer (D-D) were higher in thrombotic (p=0.006)and non-thrombotic subjects (p=0.0001) than in controls as were those of D-D (p<0.0001 and p=0.003 respectively). TAT levels did not differ. Gender analysed data revealed blunted tPA release (hence a negative venous occlusion test) in thrombotic females but neither in thrombotic males (p=0.01) nor in asymptomatic subjects of either sex. Also, in both patient groups females had higher mean PAI than males (p<0.0002) and control females (p<0.02). The activity of factor XIII (FXIIIa) was evaluated was evaluated in 29 patients with PAPS, 14 persistent carriers of aPL without thrombosis, 24 thrombotic patients with inherited thrombophilia, 28 healthy controls and 32 patients with mitral and aortic valve prosthesis as controls for FXIII only. FXIIIa was highest in PAPS (p=0.001), particularly in patients with multiple (n=12) than single occlusion (p=0.02) and in correlation with PAI (p=0.003) and FNG (p=0.005). Moreover FXIIIa was strongly associated with IgG aCL and IgG anti-2GPI (p=0.005 for both) in the PAPS group and to a lesser degree in the aPL group (FXIIIa with IgG aCL, p=0.02, with IgG anti-2GPI, p=0.04). Altogether these results indicate: 1) a differential relationship of aPL, vWF and FNG with venous and arterial thrombosis; 2) heightened thrombin generation, accelerated fibrin turnover and fibrinolysis abnormalities also in asymptomatic carriers of aPLs; 3) enhanced FXIIIa that may contribute to atherothrombosis via increased fibrin/fibrinogen cross-linking. Lipid profile, lipid peroxidation and anti-lipoprotein antibodies in thrombotic primary antiphospholipid syndrome. Given the atherogenic lipid profile of SLE, the same possibility was explored in PAPS by comparing high-density lipoprotein (HDL), low-density lipoprotein (LDL), total cholesterol (CHO), apolipoprotein AI (ApoAI), apolipoprotein B (ApoB), triglycerides (TG), anti-lipoprotein antibodies, beta-2-glycoprotein I complexed to oxidized low-density lipoprotein (oxLDL-2GPI) and C-reactive protein (CRP) in 34 thrombotic PAPS patients compared to 36 thrombotic patients with inherited thrombophilia (IT), to 18 subjects persistently positive for antiphospholipid antibodies (aPL) with no underlying autoimmune or non-autoimmune disorders and to 28 healthy controls. Average concentrations of HDL (p<0.0001), LDL (p<0.0001), CHO (p=0.0002), ApoAI (p=0.002) were lower in PAPS whereas average TRY was higher (p=0.01) than other groups. Moreover PAPS showed higher IgG anti-HDL (p=0.01) and IgG anti-ApoAI (p<0.0001) as well as greater average oxLDL-2GPI (p=0.001) and CRP (p=0.003). Within PAPS, IgG anti-HDL correlated negatively to HDL (p=0.004) and was an independent predictor of oxLDL-2GPI (p=0.009). HDL and ApoAI correlated negatively with CRP (p=0.001 and p=0.007, respectively). IgG anti-HDL may hamper the antioxidant and anti-inflammatory effect of HDL favouring low-grade inflammation and enhanced oxidation in thrombotic PAPS. Indeed plasma 8-epi-prostaglandin F2α (a very specific marker of lipid peroxidation) was significantly higher in 10 patients with PAPS than 10 age and sex matched healthy subjects (p=0.0002) and strongly related to the titre of plasma IgG aCL (r=0.89, p=0.0004). Hence oxidative stress, a major player in atherogenesis, also characterises PAPS. Nitric oxide and nitrative stress in thrombotic primary antiphosholipid syndrome. Oxidative stress goes hand in hand with nitrative stress and to address the latter plasma nitrotyrosine (NT, marker of nitrative stress), nitrite (NO2-) and nitrate (NO3-) were measured in 46 thrombotic PAPS patients, 21 asymptomatic but persistent carriers of antiphospholipid antibodies (PCaPL), 38 patients with inherited thrombophilia (IT), 33 patients with systemic lupus erythematosus (SLE) and 29 healthy controls (CTR). Average crude NT was higher in PAPS and SLE (p=0.01) whereas average plasma NO2- was lower in PAPS and average NO3- highest in SLE (p<0.0001). In PAPS, IgG aCL titer and number of vascular occlusions negatively predicted NO2-, (p=0.03 and p=0.001, respectively) whereas arterial occlusions and smoking positively predicted NO3- (p=0.05 and p=0.005). Moreover CRP (an inflammatory marker) positively predicted NT (p=0.004). Nitric oxide metabolites relates to type and number of vascular occlusions and to aPL titers, whereas nitrative stress relates to low grade marker) positively predicted NT (p=0.004). Nitric oxide metabolites relates to type and number of vascular occlusions and to aPL titers, whereas nitrative stress relates to low grade inflammation and both phenomena may have implications for thrombosis and atherosclerosis in PAPS Inflammation and immune activation in thrombotic primary antiphospholipid syndrome. To investigate inflammation and immune activation in thrombotic PAPS high-sensitivity CRP (hs-CRP), serum amyloid A (SAA), oxLDL-2GPI, CRP bound to oxLDL-2GPI (CRP-oxLDL-2GPI) (as inflammatory markers) neopterin (NPT) and soluble CD14 (sCD14) (as immune activation markers) were measured by ELISA in 41 PAPS patients, in 44 patients with inherited thrombophilia (IT) and 39 controls (CTR). Compared to other groups, PAPS presented with higher plasma concentrations of inflammatory, hs-CRP (p=0.0004), SAA (p<0.01), CRP-oxLDL-2GPI (p=0.0004) and immune activation markers, NPT (p<0.0001) and sCD14 (p=0.007). By regression analysis SAA independently predicted thrombosis number (p=0.003) and NPT independently predicted thrombosis type (arterial, p=0.03) and number (p=0.04). These data confirm that low-grade inflammation and immune activation occur and relate to vascular features of PAPS. Antiphosholipid antibodies, haemostatic variables and atherosclerosis in thrombotic primary antiphospholipid syndrome To evaluate whether IgG aCL titre, haemostatic variables and the lipid profile bore any relationship to the intima media thickness (IMT) of carotid arteries high-resolution sonography was applied to the common carotid (CC), carotid bifurcation (CB) and internal carotid (IC) of 42 aPL subjects, 29 with primary thrombotic antiphospholipid syndrome and 13 with persistence of aPL in the absence of any underlying disorder. The following were measured: plasma FNG, vWF, PAI, homocysteine (HC), CHO, TG, HDL, LDL, platelet numbers and aCL of IgG and IgM isotype. By multiple regression analysis, IgG aCL titre independently predicted IMT at all carotid segments examined (p always <0.005). Plasma FNG and HC independently predicted IMT at the CB (p=0.001 and p<0.0001, respectively) and IC (p=0.03 and p<0.0001, respectively). These data strongly support an atherogenic role for IgG aCL in patients with aPL in addition to traditional risk factors. The atherosclerosis hypothesis was investigated in an age and sex-matched case-double-control study including 49 thrombotic PAPS patients (18 M, 31 F, mean age 37 ± 11), 49 thrombotic patients for IT and 49 healthy subjects. Average IMT was always greater in PAPS than control patients (CC: p=0.004, CB: p=0.013, IC: p=0.001). By dividing participants into age tertiles the IMT was greater in the second (CC: p=0.003, CB: p=0.023, IC: p=0.003) and third tertiles (CC: p=0.03, CB: p=0.004, IC: p=0.007). Conclusion: Coagulation activation, fibrinolysis depression, hightened fibrin turnover, oxidative and nitrative stress in parallel with low grade inflammation and immune activation characterise thrombotic PAPS: all these are early atherogenic processes and contribute to the demonstrated premature atherosclerosis that should be considered a clinical feature of PAPS.

Multipath policy routing in packet switched networks

Dissertação apresentada para obtenção do Grau de Mestre em Engenharia Electrotécnica e de Computadores, pela Universidade Nova de Lisboa, Faculdade de Ciências e Tecnologia

Maintaining the correctness of transactional memory programs

Dissertação para obtenção do Grau de Doutor em Engenharia Informática

Planning and verification of multipath routing protocols

Conventionally the problem of the best path in a network refers to the shortest path problem. However, for the vast majority of networks present nowadays this solution has some limitations which directly affect their proper functioning, as well as an inefficient use of their potentialities. Problems at the level of large networks where graphs of high complexity are commonly present as well as the appearing of new services and their respective requirements, are intrinsically related to the inability of this solution. In order to overcome the needs present in these networks, a new approach to the problem of the best path must be explored. One solution that has aroused more interest in the scientific community considers the use of multiple paths between two network nodes, where they can all now be considered as the best path between those nodes. Therefore, the routing will be discontinued only by minimizing one metric, where only one path between nodes is chosen, and shall be made by the selection of one of many paths, thereby allowing the use of a greater diversity of the present paths (obviously, if the network consents). The establishment of multi-path routing in a given network has several advantages for its operation. Its use may well improve the distribution of network traffic, improve recovery time to failure, or it can still offer a greater control of the network by its administrator. These factors still have greater relevance when networks have large dimensions, as well as when their constitution is of high complexity, such as the Internet, where multiple networks managed by different entities are interconnected. A large part of the growing need to use multipath protocols is associated to the routing made based on policies. Therefore, paths with different characteristics can be considered with equal level of preference, and thus be part of the solution for the best way problem. To perform multi-path routing using protocols based only on the destination address has some limitations but it is possible. Concepts of graph theory of algebraic structures can be used to describe how the routes are calculated and classified, enabling to model the routing problem. This thesis studies and analyzes multi-path routing protocols from the known literature and derives a new algebraic condition which allows the correct operation of these protocols without any network restriction. It also develops a range of software tools that allows the planning and the respective verification/validation of new protocols models according to the study made.

Prevalence of Chagas disease in blood donors at the Uberaba Regional Blood Center, Brazil, from 1995 to 2009

INTRODUCTION: A retrospective study was conducted to assess the occurrence of blood donations that were ineligible due to Chagas disease infection from 1995 to 2009 at the Uberaba Regional Blood Center (HRU), Brazil, verify the tendency of this ineligibility, and describe the epidemiologic profile of the donors. METHODS: Retrospective studies of serological ineligibility due to Chagas disease, statistical analysis by means of the chi-square test and odds ratio, study of the tendencies using a dispersion graph and the linear correlation coefficient (r) were performed. RESULTS: In the period under study, a 0.2% serum prevalence of ineligibility due to Chagas disease was found, with a significant drop in ineligible donations from 2001 to 2009. Among the serum positive-donors, there was a significant predominance among those aged 30 years or above and non-single individuals. CONCLUSIONS: The results show a rate of occurrence that is lower than that described in literature, as well as a progressive drop during the 15 years under assessment. Such results are a consequence of systematic combat of the vector since the 70s and the progressive and consistent increase of returning donors, resulting in a drop of the contamination risk factor by means of blood transfusion and in the improvement of the quality of hemotherapy practices in the HRU.

NAV Portugal's performance within the single European Sky Initiative

NAV Portugal is the Air Navigation Service Provider in Portugal, providing air traffic control services in the airspace under the country’s responsibility. Recently, the company has been included in an initiative launched by the European Commission, called the Single European Sky. This aims for a unification of the European airspace, improving it in four main pillars: safety, capacity, environment, and cost-efficiency. To each of them, Key Performance Indicators need to be computed and monitored, all having pre-defined targets. The presented work project will be analyzing how NAV Portugal is doing in the pillar of capacity, proving suggestions if needed.

Sistema de segurança interna : a unificação do sistema em Portugal

A aceleração do ritmo de mudança verificado nas sociedades atuais, tem sido impulsionado pela globalização, fenómeno decorrente da evolução das tecnologias da informação, das telecomunicações, das comunicações e transportes e do desaparecimento de fronteiras. Viver na “aldeia global” ou à escala global como o previu Marshall McLuhan (1964) no livro Understanding Media, é hoje uma realidade inquestionável. As consequências desta transformação foram múltiplas quer do ponto de vista dos benefícios, quer do ponto de vista dos problemas gerados. No plano da segurança, face ao multiculturalismo envolvido e ao aumento crescente do crime transfronteiriço, tornou-se essencial a partilha de informação a nível internacional tendo em vista o seu combate não só olhando a situação dos cidadãos como a defesa dos princípios democráticos. Realça-se que os progressos tecnológicos e as facilidades que criam aos seus utilizadores, neste caso os criminosos, fazem com que as ações por estes praticadas sejam cada vez mais meticulosas, imprevisíveis, sofisticadas e complexas o que impõe uma resposta correspondente e adequada. Por essa razão, as políticas de segurança existentes mostraram-se insuficientes e esgotadas requerendo novas respostas capazes de produzir os efeitos desejáveis para uma efetiva prevenção da criminalidade. Pelas dimensões que tem vindo a tomar, a criminalidade tornou-se uma preocupação que ultrapassou o domínio da segurança interna de cada país para ser encarada a nível internacional ou mesmo mundial. Para o efeito urge concertar processos e procedimentos securitários agregando vontades que convirjam e defendam a unificação dos sistemas dos países a nível mundial. A verificar-se tal intento, daí resultariam significativas melhorias da segurança a todos os níveis (nacional, internacional e mundial). Além disso também resultariam ganhos em termos de tempo, redução de custos, impacto na qualidade dos serviços prestados, na gestão das pessoas e na eficiência das organizações. Realça-se que a democracia ao promover a dignidade do homem densificando os seus direitos, liberdades e garantias, criou indiretamente condições para que fosse gerada instabilidade e o desenvolvimento de comportamentos criminosos. Importa, portanto, face à situação existente e à previsível complexidade do crime no futuro, estudar profundamente a nova realidade neste domínio, para tomar as medidas preventivas tendentes a reporem a estabilidade e a promoverem a paz social. Foi neste contexto que a presente investigação, desenvolvida no âmbito académico, mas também suportado na realidade profissional, pretendeu refletir sobre o estado da segurança global e dar o seu contributo nesta matéria.

Para um (novo) modelo de intervenção penal na União Europeia: uma reflexão a partir do princípio de legalidade como limite material de atuação da Procuradoria Europeia

Tese de Doutoramento em Ciências Jurídicas (área de especialização em Ciências Jurídicas - Públicas)

Concurrency detection on finish-to-start activity precedence networks

We explore the finish-to-start precedence relations of project activities used in scheduling problems. From these relations, we devise a method to identify groups of activities that could execute concurrently, i.e. activities in the same group can all execute in parallel. The method derives a new set of relations to describe the concurrency. Then, it is represented by an undirected graph and the maximal cliques problem identifies the groups. We provide a running example with a project from our previous studies in resource constrained project cost minimization together with an example application on the concurrency detection method: the evaluation of the resource stress.

Palinologia holocênica do testemunho Bom Jesus, margem leste da ilha do Marajó, Pará, Amazônia

A porção superior (1,25m) do testemunho de sondagem Bom Jesus (TBJ), coletado no limite campo-mangue da Fazenda Bom Jesus, município de Soure, ilha do Marajó, Pará, Brasil, foi estudada através de análise palinológica de alta resolução objetivando a determinação da composição, abundância e diversidade de tipos polínicos bioindicadores de modificações na paleovegetação durante o Holoceno. 16 amostras sedimentares de 2cm³ foram tratadas de acordo com metodologia padrão em palinologia. Os programas Tilia e Tilia Graph foram utilizados para a construção dos diagramas palinológicos de abundância e concentração. A base do testemunho foi datada por 14C em 2730 ± 40 anos A.P. Foram definidas três zonas palinológicas. A presença de pólen de Rhizophora com abundância máxima de 88% apontou dominância de mangue ao longo de todo o testemunho sedimentar. Variações recorrentes na hidrodinâmica da baía do Marajó, caracterizadas por pulsos erosivos de curto período, parecem ter provocado redução na dominância de mangue. O incremento na abundância de tipos polínicos bioindicadores de campo inundável associados a elementos de restinga e floresta, evidenciam a migração do campo inundável sobre o manguezal. Os dados indicam correlação com outros registros polínicos holocênicos de transgressão marinha para a costa norte amazônica no Holoceno Superior.

Column-based databases: estudo exploratório no âmbito das bases de dados NoSQL

Dissertação de mestrado integrado em Engenharia e Gestão de Sistemas de Informação

Document-based databases: estudo comparativo no âmbito das bases de dados NoSql

Dissertação de mestrado integrado em Engenharia e Gestão de Sistemas de Informação

From software extensions to product lines of dataflow programs

Abstract Dataflow programs are widely used. Each program is a directed graph where nodes are computations and edges indicate the flow of data. In prior work, we reverse-engineered legacy dataflow programs by deriving their optimized implementations from a simple specification graph using graph transformations called refinements and optimizations. In MDE-speak, our derivations were PIM-to-PSM mappings. In this paper, we show how extensions complement refinements, optimizations, and PIM-to-PSM derivations to make the process of reverse engineering complex legacy dataflow programs tractable. We explain how optional functionality in transformations can be encoded, thereby enabling us to encode product lines of transformations as well as product lines of dataflow programs. We describe the implementation of extensions in the ReFlO tool and present two non-trivial case studies as evidence of our work’s generality

A insolvência no contexto dos grupos de sociedades

Dissertação de mestrado em Direito dos Contratos e da Empresa

BIOMedical search engine framework: lightweight and customized implementation of domain-specific biomedical search engines

The Smart Drug Search is publicly accessible at http://sing.ei.uvigo.es/sds/. The BIOMedical Search Engine Framework is freely available for non-commercial use at https://github.com/agjacome/biomsef