Metabolism of primary astrocytes studied by NMR: metabolic trafficking and neuroprotection

Dissertation presented to obtain a Ph. D. degree in Biochemistry by Universidade Nova de Lisboa, Instituto de Tecnologia Qu��mica e Biol��gica.

Metabolic flux analysis of neural cell metabolism in primary cultures

Dissertation presented to obtain the Ph.D degree in Biochemistry, Neuroscience

A conversa e o relato enquanto possibilidades do comum, apartir de we aim to be amateurs (Art & Language, 1997)

Disserta����o apresentada para cumprimento dos requisitos necess��rios �� obten����o do grau de Mestre em Filosofia-Est��tica

Writing skills at secondary level. Developing an English language writing syllabus - a case study

Trabalho de projecto apresentado para o cumprimento dos requisitos necess��rios �� obten����o do grau de mestre em Did��tica do Ingl��s

Interculturality in the Primary EFL Classroom: Increasing Tolerance through (Inter) Cultural Awareness

Disserta����o apresentada para cumprimento dos requisitos necess��rios �� obten����o do grau de Mestre em Did��ctica do Ingl��s,

Psicopatologia obsessivo-compulsiva na distonia focal prim��ria : aspectos neuropsiqui��tricos de uma doen��a do movimento

RESUMO: pela contrac����o involunt��ria de grupos musculares de extens��o vari��vel, originando movimentos involunt��rios e posturas an��malas, por vezes dolorosas. O tratamento convencional consiste em injec����es localizadas de toxina botul��nica, podendo, em casos refract��rios, estar indicado o tratamento por estimula����o cerebral profunda. A neurobiologia da distonia focal prim��ria permanece incompletamente compreendida. Os estudos de neuro-imagem estrutural e funcional revelam altera����es subtis da anatomia e funcionamento do estriado e das vias cortico-basais, com destaque para o aumento do volume, da actividade metab��lica e da neuroplasticidade do putamen e de ��reas corticais motoras, pr��-motoras e sensitivas. O conjunto destas altera����es aponta para uma disrup����o da regula����o inibit��ria de programas motores autom��ticos sustentados pelo estriado e pelas vias ortico-subcorticais. Nos ��ltimos anos tem crescido o interesse pelas manifesta����es psiqui��tricas e cognitivas da distonia (estas ��ltimas muito pouco estudadas). Tem despertado particular interesse a poss��vel associa����o entre distonia focal prim��ria e perturba����o obsessivo-compulsiva (POC), cuja neurobiologia parece notavelmente sobrepon��vel �� da distonia prim��ria. Com efeito, os estudos de neuro-imagem estrutural e funcional na POC revelam consistentemente aumento do volume e actividade do estriado e do c��rtex ��rbito-frontal, apontando mais uma vez para uma disfun����o do controlo inibit��rio, no estriado, de programas comportamentais e cognitivos autom��ticos. Objectivos: 1. Explorar a preval��ncia e intensidade de psicopatologia em geral, e de psicopatologia obsessivo-compulsiva em particular, numa amostra de indiv��duos com distonia focal prim��ria; 2. Explorar a ocorr��ncia, natureza e intensidade de altera����es do funcionamento cognitivo numa amostra de indiv��duos com distonia focal prim��ria; 3. Investigar a associa����o entre a gravidade da distonia focal, a intensidade da psicopatologia, e a intensidade das altera����es cognitivas. Metodologia: Estudo de tipo transversal, caso-controlo, observacional e descritivo, com objectivos puramente explorat��rios. Casos: 45 indiv��duos com distonia focal prim��ria (15 casos de blefaroespasmo, 15 de c��ibra do escriv��o, 15 de distonia cervical espasm��dica), recrutados atrav��s da Associa����o Portuguesa de Distonia. Crit��rios de inclus��o: idade = 18; distonia focal prim��ria pura (excluindo casos de distonia psicog��nica poss��vel ou prov��vel de acordo com os crit��rios de Fahn e Williams); Metabolismo do cobre e Resson��ncia Magn��tica Nuclear sem altera����es. Controlos doentes: 46 casos consecutivos recrutados a partir da consulta externa do Hospital Egas Moniz: 15 doentes com espasmo hemifacial, 14 com espondilartropatia cervical, 17 com s��ndrome do canal c��rpico. Controlos saud��veis: 30 volunt��rios. Crit��rios de exclus��o para todos os grupos: Mini-Mental State Examination patol��gico, tratamento actual com anti-colin��rgicos, antipsic��ticos, inibidores selectivos da recapta����o da serotonina, antidepressivos tri- ou tetrac��clicos. Avalia����o: Avalia����o neurol��gica: hist��ria e exame m��dico e neurol��gico completos. Cota����o da gravidade da distonia com a Unified Dystonia Rating Scale. Avalia����o psicopatol��gica: Symptom Check-List-90-Revised; entrevista psiqui��trica de 60 minutos incluindo a Mini-International Neuropsychiatric Interview (MINI), vers��o 4.4 (validada em Portugu��s), complementada com os m��dulos da MINI Plus vers��o 5.0.0 para depress��o ao longo da vida e depend��ncia/ abuso do ��lcool e outras subst��ncias ao longo da vida; Yale-Brown Obsessive-Compulsive Symptom Checklist e a Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Avalia����o neuropsicol��gica: Wisconsin Card Sorting Test (WCST; flexibilidade cognitiva); Teste de Stroop (inibi����o de resposta); Block Assembly Test (capacidade visuo-construtiva); Teste de Reten����o Visual de Benton (mem��ria de trabalho visuo-espacial). An��lise estat��stica:os dados foram analisados com a aplica����o inform��tica SPSS for Windows, vers��o 13. Para a compara����o de propor����es utilizaram-se o teste do Chi-quadrado e o teste de Fisher. Para a compara����o de vari��veis quantitativas entre dois grupos utilizou-se o teste t de Student ou o teste U de Mann-Whitney (teste de Wilcoxon no caso de amostras emparelhadas). Para compara����es de m��dias entre tr��s grupos recorreu-se �� An��lise de Vari��ncia a um factor (vari��veis de intervalo e de r��cio), ou ao teste de Kruskal-Wallis (vari��veis ordinais). Para o estudo da associa����o entre vari��veis foram utilizados os coeficientes de correla����o de Pearson ou de Spearman, a an��lise de correla����es can��nicas, a an��lise de traject��rias e a regress��o log��stica. Adoptou-se um Alpha de 0.05. Resultados: Os doentes com distonia focal prim��ria apresentaram uma pontua����o m��dia na Y- -BOCS significativamente superior �� dos dois grupos de controlo. Em 24.4% dos doentes com distonia a pontua����o na Y-BOCS foi superior a 16. Estes doentes eram predominantemente mulheres, tinham uma maior dura����o m��dia da doen��a e referiam predominantemente sintomas obsessivo-compulsivos (SOC) de contamina����o e lavagem. Os dois grupos com doen��a cr��nica apresentaram pontua����es m��dias superiores ��s dos indiv��duos saud��veis nas escalas de ansiedade, somatiza����o e psicopatologia geral. Os doentes com distonia tratados com toxina botul��nica apresentaram pontua����es inferiores ��s dos doentes n��o tratados nas escalas de ansiedade generalizada, fobia, somatiza����o e depress��o, mas n��o na Y-BOCS. Sessenta por cento dos doentes com distonia apresentavam pelo menos um diagn��stico psiqui��trico actual ou pregresso. O risco de apresentar um diagn��stico psiqui��trico actual era menor nos doentes tratados com toxina botul��nica, aumentando com a gravidade da doen��a. A preval��ncia de POC foi 8,3% e a de depress��o major 37,7%. No WCST e na Prova de Benton, os doentes com distonia focal prim��ria demonstraram um desempenho inferior ao de ambos os grupos de controlo, cometendo sobretudo erros perseverativos. Os doentes com distonia e pontua����o na Y-BOCS > 16 cometeram mais erros e respostas perseverativas no WCST do que os restantes doentes com distonia. As an��lises de correla����es e de traject��rias revelaram que nos doentes com distonia a gravidade da distonia foi, juntamente com a idade e a escolaridade, o factor que mais interagiu com o desempenho cognitivo. Discuss��o: o nosso estudo �� o primeiro a descrever, nos mesmos doentes com distonia focal prim��ria, SOC significativos e altera����es cognitivas. Os nossos resultados confirmam a hip��tese de uma associa����o cl��nica espec��fica entre distonia focal prim��ria e psicopatologia obsessivo-compulsiva. Confirmam igualmente que a distonia focal prim��ria est�� associada a um maior risco de desenvolver morbilidade psiqui��trica ansiosa e depressiva. O tratamento com toxina botul��nica reduz este risco, mas n��o influencia os SOC. Entre os doentes com distonia, os que t��m SOC significativos poder��o diconstituir um grupo particular com maior dura����o da doen��a (mas n��o uma maior gravidade), predom��nio do sexo feminino e predom��nio de SOC de contamina����o e limpeza. Em termos cognitivos, os indiv��duos com distonia focal prim��ria apresentam d��fices significativos de flexibilidade cognitiva (particularmente acentuados nos doentes com SOC significativos) e de mem��ria de trabalho visuo-espacial. Estes ��ltimos devem-se essencialmente a um d��fice executivo e n��o a uma incapacidade visuo-construtiva ou visuo-perceptiva. A disfun����o cognitiva n��o �� explic��vel pela psicopatologia depressiva nem pela incapacidade motora, j�� que os controlos com doen��a perif��rica cr��nica tiveram um desempenho superior ao dos doentes com distonia. No seu conjunto os nossos resultados sugerem que os SOC que ocorrem na distonia focal prim��ria constituem uma das manifesta����es cl��nicas da neurobiologia desta doen��a do movimento. O predom��nio de sintomas relacionados com higiene e o perfil disexecutivo de altera����es cognitivas���persevera����o e dificuldades executivas de mem��ria de trabalho visuo-espacial ��� apontam para a via cortico-basal dorso-lateral e para as ��reas corticais que lhe est��o associadas como estando implicadas na tripla associa����o entre sintomas motores, obsessivo-compulsivos e cognitivos. Conclus��es: A distonia focal prim��ria �� um s��ndrome neuropsiqui��trico complexo com importantes manifesta����es n��o motoras, nomeadamente compromisso cognitivo do tipo disexecutivo e sintomas obsessivo-compulsivos. Clinicamente estas manifesta����es representam necessidades de tratamento que v��o muito para al��m da simples incapacidade motora, devendo ser activamente exploradas e tratadas.-------------- ABSTRACT: Introduction: primary focal dystonia is an idiopathic movement disorder that manifests as involuntary, sustained contraction of muscular groups, leading to abnormal and often painful postures of the affected body part. Treatment is symptomatic, usually with local intramuscular injections of botulinum toxin. The neurobiology of primary focal dystonia remains unclear. Structural and functional neuroimaging studies have revealed subtle changes in striatal and cortical-basal pathway anatomy and function. The most consistent findings involve increased volume and metabolic activity of the putamen and of motor, pre-motor and somato-sensitive cortical areas. As a whole, these changes have been interpreted as reflecting a failure of striatal inhibitory control over automatic motor programs sustained by cortical-basal pathways. The last years have witnessed an increasing interest for the possible non-motor ��� mainly psychiatric and cognitive ��� manifestations of primary focal dystonia. The possible association of primary focal dystonia with obsessive-compulsive disorder (OCD) has raised particular interest. The neurobiology of the two disorders has indeed remarkable similarities: structural and functional neuroimaging studies in OCD have revealed increased volume and metabolic activity of the striatum and orbital-frontal cortex, again pointing to a disruption of inhibitory control of automatic cognitive and behavioural programs by the striatum. Objectives: 1. To explore the prevalence and severity of psychopathology ��� with a special emphasis on obsessive-compulsive symptoms (OCS) ��� in a sample of patients with primary focal dystonia;2. To explore the nature and severity of possible cognitive dysfunction in a sample of patients with primary focal dystonia; 3. To explore the possible association between dystonia severity, psychiatric symptom severity, and cognitive performance, in a sample of patients with primary focal dystonia. Methods: cross-sectional, case-control, descriptive study. Cases: forty-five consecutive, primary pure focal dystonia patients recruited from the Portuguese Dystonia Association case register (fifteen patients with blepharospasm, 15 with cervical dystonia and 15 with writer���s cramp). Inclusion criteria were: age = 18; primary pure focal, late-onset dystonia (excluding possible or probable psychogenic dystonia according to the Fahn & Williams criteria); normal copper metabolism and Magnetic Resonance Imaging. Diseased controls: forty-six consecutive subjects from our hospital case register (15 patients with hemi-facial spasm; 14 with cervical spondilarthropathy and cervical spinal root compression; 17 with carpal tunnel syndrome). Healthy controls were 30 volunteers.Exclusion criteria for all groups: Mini-Mental State Examination score below the validated cut-off for the Portuguese population (<23 for education between 1 and 11 years; <28 for education >11 years); use of anti-cholinergics, neuroleptics, selective serotonin reuptake inhibitors, triciclic or tetraciclic antidepressants. Assessment: neurological assessment: complete medical and neurological history and physical examination; dystonia severity scoring with the Unified Dystonia Rating Scale. Psychiatric assessment:Symptom Check-List-90-Revised; 60 minute-long psychiatric interview, including Mini-International Neuropsychiatric Interview (MINI), version 4.4 (validated Portuguese version), extended with the sections for life-time major depressive disorder and life-time alcohol and substance abuse disorder from MINI-Plus version 5.0.0; Yale-Brown Obsessive-Compulsive Symptom Checklist and Yale-Brown Obsessive-Compulsive Scale (Y-BOCS). Cognitive assessment: Wisconsin Card Sorting Test (WCST; cognitive set-shifting ability); Stroop Test (response inhibition); Block Assembly Test(visual-constructive ability); Benton���s Visual Retention Test (visual-spatial working memory). Statistic analysis: Data were analyzed with SPSS for Windows version 13. Proportions were compared using Chi-Square test, or Fisher���s exact test when appropriate. Student���s t-test or Mann-Whitney���s U test (or Wilcoxon���s teste in the case of matched samples) were used for two-group comparisons. P-values were corrected for multiple comparisons. One-way ANOVA with Bonferroni post-hoc analysis (interval data), or the Kruskal-Wallis Test (ordinal data), were used for three-group comparisons. Associations were analysed with Pearson���s or Spearman���s correlation coefficients, canonical correlations, path analysis and logistic regression analysis. Alpha was set at 0.05. Results: Dystonia patients had higher Yale-Brown Obsessive-Compulsive Symptom scores than both control groups. 24.4% of primary dystonia patients had a Y-BOCS score > 16. These patients were predominantly women; they had longer disease duration, and showed a predominance of hygiene-related OCS. The two groups with chronic disease had higher anxiety, somatization and global psychopathology scores than healthy subjects. Primary dystonia patients undergoing treatment with botulinum toxin had lower anxiety, phobia, somatization and depression scores than their untreated counterparts, but similar Y-BOCS scores. Sixty percent of primary dystonia patients had at least one lifetime psychiatric diagnosis. The odds of having a currently active psychiatric diagnosis were lower in botulinum toxin treated patients, and increased with dystonia severity. The prevalence of OCD was 6.7%, and the lifetime prevalence of major depression was 37.7%. Primary dystonia patients had a lower performance than the two control groups in both the WCST and Benton���s Visual Retention Test, mainly due to an excess of perseveration errors. Primary dystonia patients with Y-BOCS score > 16 had much higher perseveration error and perseveration response scores than dystonia patients with Y-BOCS = 16. Correlation and path analysis showed that, in the primary dystonia group, dystonia severity, along with age and education, was the main factor influencing cognitive performance. Discussion: our study is the first description ever of concomitant significant OCS and cognitive impairment in primary dystonia patients. Our results confirm that primary dystonia is specifically associated with obsessive-compulsive psychopathology. They also confirm that primary focal dystonia patients are at a higher risk of developing anxious and depressive psychiatric morbidity. Treatment with botulinum toxin decreases this risk, but does not influence OCS. Primary focal dystonia patients with significant OCS may constitute a particular subgroup. They are predominantly women, with higher disease duration (but not severity) and a predominance of hygiene related OCS.In terms of cognitive performance, primary focal dystonia patients have significant deficits involving set-shifting ability and visual-spatial working memory. The latter result from an essentially executive deficit, rather than from a primary visual-constructive apraxia or perceptual deficit. Furthermore, cognitive flexibility difficulties were more prominent in the subset of primary dystonia patients with significant OCS. The cognitive dysfunction found in dystonia patients is not attributable to depressive psychopathology or motor disability, as their performance was significantly lower than that of similarly impaired diseased controls. Our results suggest that OCS in primary focal dystonia are a direct, primary manifestation of the motor disorder���s neurobiology. The predominance of hygiene-related symptoms and the disexecutive pattern of cognitive impairment ��� set-shifting and visual-spatial working memory deficits ��� suggest that the dorsal-lateral cortical-basal pathway may play a decisive role in the triple association of motor dysfunction, OCS and cognitive impairment. Conclusions: primary focal dystonia is a complex neuropsychiatric syndrome with significant non- -motor manifestations, namely cognitive executive deficits and obsessive-compulsive symptoms.Clinically, our results show that PFD patients may have needs for care that extend far beyond a merely motor disability and must be actively searched for and treated.

Estimating demand for primary health care services

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Economics from the NOVA ��� School of Business and Economics

Primary public health care and socioeconomic asymmetries in Portugal

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Economics from the NOVA ��� School of Business and Economics

Primary and hospitalar health care: Building a happy marriage

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Management from the NOVA ��� School of Business and Economics

Impairment in the mortagage loan portfolio: The example of Banco Popular portugal

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Finance from the NOVA ��� School of Business and Economics

Health care needs and resources distribution: How to allocate financial resources in primary care trust?

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Economics from the NOVA ��� School of Business and Economics

Benchmarking in primary health care: An application of the stochasticd frontier analysis and the grades of membership approach to Portuguese family health units

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Economics from the NOVA ��� School of Business and Economics

The use of corpora to the teach english as a foreign language in secondary education in Portugal

Trabalho de Projecto apresentado para cumprimento dos requisitos necess��rios �� obten����o do grau de Mestre em Did��ctica Do Ingl��s

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 F2�� (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.

Impairment of tangible fixed assets in the Portuguese listed companies: Disclosures

A Work Project, presented as part of the requirements for the Award of a Masters Degree in Management from the NOVA ��� School of Business and Economics