"Vascular Memory” as a predictive factor for endothelium function-associated conditions : Comparative study of 3 clinical models – Raynaud’s Disease, Systemic Sclerosis and Diabetes Mellitus
Autor(a) principal: | |
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Data de Publicação: | 2024 |
Idioma: | eng |
Título da fonte: | Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
Texto Completo: | http://hdl.handle.net/10362/170196 |
Resumo: | Abstract Introduction: Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by small vessel vasculopathy, autoantibody production and collagen deposition in the skin and internal organs. Although SSc is considered a fibrosing disease, vascular involvement together with immune activation, inflammatory response and oxidative stress seem to play major roles in the pathogenesis of organ dysfunction. There is some evidence that endothelial dysfunction may precede the typical perivascular abnormalities present in the disease, with the microvasculature becoming aberrant and exhibiting dilations, tortuosities and microhaemorrages, with extense avascular areas, resulting in tissular hypoxia, but the published data are still controversial. Despite the phenotypic variety, almost all patients with systemic sclerosis have Raynaud's phenomenon (RP), an episodic vasospastic ischaemic disorder. Raynaud's phenomenon can precede other symptoms and signs of systemic sclerosis by up to 30 years, but its presence alone is not sufficient for the development of SSc. Therefore, it has been particularly difficult to understand what mechanisms come first in the pre-clinical phase of systemic sclerosis, as it is a rare disease with a small direct genetic impact. Nevertheless, studying the offspring of these patients could be the closest to a control group for genetics and early in life (at least) environmental factors. This thesis was developed from the hypothesis that a ‘vascular memory’ characterized by anatomical microcirculatory changes, could be the earliest manifestation and the influencing factor for endothelial dysfunction. Methods: The study included patients with systemic sclerosis, n=124, two different endothelium dysfunction-associated diseases (disease control groups): Raynaud’s disease (RD), n=158, and type 2 diabetes mellitus (T2DM), n=98, and their respective healthy offspring (SSc offspring, n=55, RD offspring, n=11, T2DM offspring, n=50), and healthy controls (n=59). All the groups were studied concerning the demographic, clinical and general biochemical features. Circulatory anatomy was studied using Nailfold VideoCapillaroscopy (NVC) and the characterisation of the inflammation, immune activation and oxidative stress was addressed by the quantification of VCAM-1, ICAM-1, VEGF-A, 3-NT and TAC. Main findings: The healthy offspring of patients with SSc showed significant changes in NVC when compared to controls [number of capillaries per field inferior to eight (p=0.003), enlarged capillaries (p=0.003), major morphologic abnormalities (p=0.027), oedema (0.031), avascular areas (p<0.001), neoangiogenesis (p=0.041), reduced velocity of blood flow (p<0.001), sludge (p<0.001)], despite having normal levels of VCAM-1, ICAM-1, VEGF and 3-NT, with a high level of TAC. When compared to the patients with SSc, their offspring had similar changes regarding major morphologic abnormalities (p=0.6), “sludge” (p=0.06) and avascular areas (p=0.78). This two groups showed differences only in capillaries per field (p<0.001), enlarged (p<0.001) and giant (p<0.001) capillaries, minor dysmorphias (p<0.001), haemorrhages (p<0.001) and interstitial oedema (p<0.001). Capillary rarefaction and “sludge” were even more pronounced in the offspring of SSc when compared to patients with RD (p<0.001 for both parameters). Patients with RD differed from controls only in the number of enlarged capillaries (p=0.02), blood flow (p=0.002) and neoangiogenesis (p=0.04); their offspring had a practically normal NVC. Regarding the biologic products, none were higher in the RD and respective offspring group compared to controls. The offspring of patients with T2DM also showed significant differences from controls in NVC [edema (p=0.009), avascular areas (p<0.001), neoangiogenesis p=0.001, and reduced blood flow (p=0.046)]. There was only difference in haemorrhages (p=0.002) between patients with T2DM and their offspring. The T2DM offspring group had serum levels of 3-NT higher than controls (p=0.027). Conclusions: The anatomy of microvasculature in the offspring of patients with SSc appears to change before the immune system and inflammation markers get activated. This may be due to the fact that the microcirculatory structure is genetically driven whilst the disease onset may need further “hits” to develop. RD might have a different physiopathology from RP in the context of SSc, highlighting the different nature of the two conditions regarding their early (pre-clinical) mechanisms. The offspring of patients with T2DM showed the same phenomena that the SSc group, (despite the differences in the terminal vessels morphology), suggesting the presence of a genetic-based background which may develop into the metabolic disease after exposure to other stimuli. Therefore, we may postulate the existence of a ‘vascular anatomical memory’ in systemic sclerosis. |
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"Vascular Memory” as a predictive factor for endothelium function-associated conditions : Comparative study of 3 clinical models – Raynaud’s Disease, Systemic Sclerosis and Diabetes MellitusVascular MemoryRaynaud’s DiseaseSystemic SclerosisDiabetes MellitusCiências MédicasAbstract Introduction: Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by small vessel vasculopathy, autoantibody production and collagen deposition in the skin and internal organs. Although SSc is considered a fibrosing disease, vascular involvement together with immune activation, inflammatory response and oxidative stress seem to play major roles in the pathogenesis of organ dysfunction. There is some evidence that endothelial dysfunction may precede the typical perivascular abnormalities present in the disease, with the microvasculature becoming aberrant and exhibiting dilations, tortuosities and microhaemorrages, with extense avascular areas, resulting in tissular hypoxia, but the published data are still controversial. Despite the phenotypic variety, almost all patients with systemic sclerosis have Raynaud's phenomenon (RP), an episodic vasospastic ischaemic disorder. Raynaud's phenomenon can precede other symptoms and signs of systemic sclerosis by up to 30 years, but its presence alone is not sufficient for the development of SSc. Therefore, it has been particularly difficult to understand what mechanisms come first in the pre-clinical phase of systemic sclerosis, as it is a rare disease with a small direct genetic impact. Nevertheless, studying the offspring of these patients could be the closest to a control group for genetics and early in life (at least) environmental factors. This thesis was developed from the hypothesis that a ‘vascular memory’ characterized by anatomical microcirculatory changes, could be the earliest manifestation and the influencing factor for endothelial dysfunction. Methods: The study included patients with systemic sclerosis, n=124, two different endothelium dysfunction-associated diseases (disease control groups): Raynaud’s disease (RD), n=158, and type 2 diabetes mellitus (T2DM), n=98, and their respective healthy offspring (SSc offspring, n=55, RD offspring, n=11, T2DM offspring, n=50), and healthy controls (n=59). All the groups were studied concerning the demographic, clinical and general biochemical features. Circulatory anatomy was studied using Nailfold VideoCapillaroscopy (NVC) and the characterisation of the inflammation, immune activation and oxidative stress was addressed by the quantification of VCAM-1, ICAM-1, VEGF-A, 3-NT and TAC. Main findings: The healthy offspring of patients with SSc showed significant changes in NVC when compared to controls [number of capillaries per field inferior to eight (p=0.003), enlarged capillaries (p=0.003), major morphologic abnormalities (p=0.027), oedema (0.031), avascular areas (p<0.001), neoangiogenesis (p=0.041), reduced velocity of blood flow (p<0.001), sludge (p<0.001)], despite having normal levels of VCAM-1, ICAM-1, VEGF and 3-NT, with a high level of TAC. When compared to the patients with SSc, their offspring had similar changes regarding major morphologic abnormalities (p=0.6), “sludge” (p=0.06) and avascular areas (p=0.78). This two groups showed differences only in capillaries per field (p<0.001), enlarged (p<0.001) and giant (p<0.001) capillaries, minor dysmorphias (p<0.001), haemorrhages (p<0.001) and interstitial oedema (p<0.001). Capillary rarefaction and “sludge” were even more pronounced in the offspring of SSc when compared to patients with RD (p<0.001 for both parameters). Patients with RD differed from controls only in the number of enlarged capillaries (p=0.02), blood flow (p=0.002) and neoangiogenesis (p=0.04); their offspring had a practically normal NVC. Regarding the biologic products, none were higher in the RD and respective offspring group compared to controls. The offspring of patients with T2DM also showed significant differences from controls in NVC [edema (p=0.009), avascular areas (p<0.001), neoangiogenesis p=0.001, and reduced blood flow (p=0.046)]. There was only difference in haemorrhages (p=0.002) between patients with T2DM and their offspring. The T2DM offspring group had serum levels of 3-NT higher than controls (p=0.027). Conclusions: The anatomy of microvasculature in the offspring of patients with SSc appears to change before the immune system and inflammation markers get activated. This may be due to the fact that the microcirculatory structure is genetically driven whilst the disease onset may need further “hits” to develop. RD might have a different physiopathology from RP in the context of SSc, highlighting the different nature of the two conditions regarding their early (pre-clinical) mechanisms. The offspring of patients with T2DM showed the same phenomena that the SSc group, (despite the differences in the terminal vessels morphology), suggesting the presence of a genetic-based background which may develop into the metabolic disease after exposure to other stimuli. Therefore, we may postulate the existence of a ‘vascular anatomical memory’ in systemic sclerosis.Resumo Introdução: A esclerose sistémica (ES) é uma doença autoimune do tecido conjuntivo caracterizada por vasculopatia de pequenos vasos, produção de autoanticorpos e deposição de colagénio na pele e órgãos internos. Embora seja considerada uma doença fibrosante, o envolvimento vascular, em conjunto com a activação imunológica, a resposta inflamatória e o stress oxidativo, parecem desempenhar um papel importante na patogénese da disfunção de órgão. Há alguma evidência de que a disfunção endotelial poderá preceder as alterações perivasculares típicas presentes na doença, com a microvasculatura a tornar-se aberrante e a exibir dilatações, tortuosidades e micro-hemorragias, com extensas áreas avasculares, resultado em hipoxia tissular, mas os dados publicados são ainda controversos. Apesar da variabilidade fenotípica, quase todos os doentes com esclerose sistémica apresentam fenómeno de Raynaud (FR), um distúrbio isquémico vaso-espástico episódico. O fenómeno de Raynaud pode preceder em 30 anos os outros sintomas e sinais da esclerose sistémica, mas a sua presença por si só não é suficiente para o desenvolvimento da ES. Tem sido particularmente difícil compreender quais os mecanismos que surgem primeiro na fase pré-clínica da esclerose sistémica, por se tratar de uma doença rara com um pequeno impacto genético direto. No entanto, estudar a descendência destes doentes pode ser o mais próximo que conseguimos como grupo controlo para fatores genéticos e ambientais em início de vida. Esta tese foi desenvolvida a partir da hipótese de que uma “memória vascular”, caracterizada por alterações anatómicas micro-circulatórias, poderia ser a manifestação mais precoce e o factor influenciador da disfunção endotelial. Métodos: O estudo incluiu doentes com esclerose sistémica , n=124, e outras duas doenças associadas à disfunção endotelial (grupos controlo da doença): doença de Raynaud (DR, n=158) e diabetes mellitus tipo 2 (DM2, n=98); e os seus respectivos descendentes saudáveis (descendentes de ES, n=55, descendentes de DR, n=11, descendentes de DM2, n=50) e controlos (n=59). Estes grupos foram estudados quanto às características demográficas, clínicas e bioquímicas gerais. A anatomia circulatória foi estudada por vídeo-capilaroscopia peri-ungueal (VCP) e a caracterização da inflamação, ativação imunológica e stress oxidativo, foi abordada pela quantificação de VCAM-1, ICAM-1 , VEGF-A, 3-NT e TAC. Resultados principais: A descendência saudável dos doentes com ES apresentou alterações significativas na VCP quando comparada aos controlos [número de capilares por campo inferior a oito (p=0,003), capilares dilatados (p=0,003), dismorfias major (p=0,027), edema (p=0,031), áreas avasculares (p<0,001), neoangiogénese (p=0,041), redução da velocidade do fluxo sanguíneo (p<0,001), e estase eritrocitária (p<0,001)], apesar de apresentar níveis normais de VCAM-1, ICAM- 1, VEGF e 3-NT, com níveis elevados de TAC. Quando comparados aos doentes com ES, os seus descendentes tiveram alterações semelhantes em relação a dismorfias major (p=0.6), “sludge” (p=0.06) e áreas avasculares (p=0.78). Estes dois grupos apresentaram diferenças apenas no número de capilares por campo (p<0,001), nos capilares dilatados (p<0,001) e megacapilares (p<0,001), nas dismorfias minor (p<0,001), nas hemorragias (p <0,001) e no edema intersticial (p<0,001). A rarefação capilar e a estase eritrocitária foram ainda mais pronunciadas nos descendentes de ES quando comparados com doentes com DR (p<0.001 para os dois parâmetros). Os doentes com DR diferiram dos controlos apenas nos capilares dilatados (p=0.02), na velocidade reduzida de fluxo circulatório (p=0.002) e na neoangiogénese (p=0.04); a descendência de doentes com DR apresentou uma VCP quase normal. Em relação aos biomarcadores, nenhum foi maior nos descendentes de DR em comparação com os controlos. A descendência dos doentes com diabetes mellitus tipo 2 também apresentou diferenças significativas na VCP em relação aos controlos [edema (p=0,009), áreas avasculares (p<0,001), neoangiogénese (p=0,001) e redução da velocidade do fluxo sanguíneo (p=0,046)]. Houve diferença apenas nas hemorragias (p=0,002) entre os doentes com DM2 e os filhos de doentes com DM2. O grupo de descendentes apresentou níveis séricos de 3-NT superiores aos controlos (p=0.027). Conclusões: A anatomia da microvasculatura presente nos descendentes dos doentes com ES parece mudar antes do sistema imunológico e os marcadores de inflamação serem ativados. Isto pode dever-se ao facto da estrutura microcirculatória ser determinada geneticamente, enquanto que o início da doença pode necessitar de mais “eventos” para se desenvolver. A DR pode ter uma fisiopatologia diferente do FR no contexto da ES, destacando-se a natureza diferente das duas condições quanto aos seus mecanismos precoces (pré-clínicos). A descendência de doentes com DM2 apresentou os mesmos fenómenos do grupo da ES (apesar das diferenças na morfologia da circulação terminal), sugerindo a presença de uma base genética, que pode evoluir para a doença metabólica após exposição a outros estímulos. Desta forma, podemos postular a existência de uma memória anatómica vascular na esclerose sistémica.Alves, José DelgadoAmes, Paul R.J.RUNAmaral, Marta Sofia Carapeto2024-07-31T15:24:48Z2024-07-122024-07-12T00:00:00Zdoctoral thesisinfo:eu-repo/semantics/publishedVersionapplication/pdfhttp://hdl.handle.net/10362/170196TID:101593805enginfo:eu-repo/semantics/openAccessreponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãoinstacron:RCAAP2024-08-05T01:36:04Zoai:run.unl.pt:10362/170196Portal AgregadorONGhttps://www.rcaap.pt/oai/openairemluisa.alvim@gmail.comopendoar:71602024-08-05T01:36:04Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informaçãofalse |
dc.title.none.fl_str_mv |
"Vascular Memory” as a predictive factor for endothelium function-associated conditions : Comparative study of 3 clinical models – Raynaud’s Disease, Systemic Sclerosis and Diabetes Mellitus |
title |
"Vascular Memory” as a predictive factor for endothelium function-associated conditions : Comparative study of 3 clinical models – Raynaud’s Disease, Systemic Sclerosis and Diabetes Mellitus |
spellingShingle |
"Vascular Memory” as a predictive factor for endothelium function-associated conditions : Comparative study of 3 clinical models – Raynaud’s Disease, Systemic Sclerosis and Diabetes Mellitus Amaral, Marta Sofia Carapeto Vascular Memory Raynaud’s Disease Systemic Sclerosis Diabetes Mellitus Ciências Médicas |
title_short |
"Vascular Memory” as a predictive factor for endothelium function-associated conditions : Comparative study of 3 clinical models – Raynaud’s Disease, Systemic Sclerosis and Diabetes Mellitus |
title_full |
"Vascular Memory” as a predictive factor for endothelium function-associated conditions : Comparative study of 3 clinical models – Raynaud’s Disease, Systemic Sclerosis and Diabetes Mellitus |
title_fullStr |
"Vascular Memory” as a predictive factor for endothelium function-associated conditions : Comparative study of 3 clinical models – Raynaud’s Disease, Systemic Sclerosis and Diabetes Mellitus |
title_full_unstemmed |
"Vascular Memory” as a predictive factor for endothelium function-associated conditions : Comparative study of 3 clinical models – Raynaud’s Disease, Systemic Sclerosis and Diabetes Mellitus |
title_sort |
"Vascular Memory” as a predictive factor for endothelium function-associated conditions : Comparative study of 3 clinical models – Raynaud’s Disease, Systemic Sclerosis and Diabetes Mellitus |
author |
Amaral, Marta Sofia Carapeto |
author_facet |
Amaral, Marta Sofia Carapeto |
author_role |
author |
dc.contributor.none.fl_str_mv |
Alves, José Delgado Ames, Paul R.J. RUN |
dc.contributor.author.fl_str_mv |
Amaral, Marta Sofia Carapeto |
dc.subject.por.fl_str_mv |
Vascular Memory Raynaud’s Disease Systemic Sclerosis Diabetes Mellitus Ciências Médicas |
topic |
Vascular Memory Raynaud’s Disease Systemic Sclerosis Diabetes Mellitus Ciências Médicas |
description |
Abstract Introduction: Systemic sclerosis (SSc) is an autoimmune connective tissue disease characterized by small vessel vasculopathy, autoantibody production and collagen deposition in the skin and internal organs. Although SSc is considered a fibrosing disease, vascular involvement together with immune activation, inflammatory response and oxidative stress seem to play major roles in the pathogenesis of organ dysfunction. There is some evidence that endothelial dysfunction may precede the typical perivascular abnormalities present in the disease, with the microvasculature becoming aberrant and exhibiting dilations, tortuosities and microhaemorrages, with extense avascular areas, resulting in tissular hypoxia, but the published data are still controversial. Despite the phenotypic variety, almost all patients with systemic sclerosis have Raynaud's phenomenon (RP), an episodic vasospastic ischaemic disorder. Raynaud's phenomenon can precede other symptoms and signs of systemic sclerosis by up to 30 years, but its presence alone is not sufficient for the development of SSc. Therefore, it has been particularly difficult to understand what mechanisms come first in the pre-clinical phase of systemic sclerosis, as it is a rare disease with a small direct genetic impact. Nevertheless, studying the offspring of these patients could be the closest to a control group for genetics and early in life (at least) environmental factors. This thesis was developed from the hypothesis that a ‘vascular memory’ characterized by anatomical microcirculatory changes, could be the earliest manifestation and the influencing factor for endothelial dysfunction. Methods: The study included patients with systemic sclerosis, n=124, two different endothelium dysfunction-associated diseases (disease control groups): Raynaud’s disease (RD), n=158, and type 2 diabetes mellitus (T2DM), n=98, and their respective healthy offspring (SSc offspring, n=55, RD offspring, n=11, T2DM offspring, n=50), and healthy controls (n=59). All the groups were studied concerning the demographic, clinical and general biochemical features. Circulatory anatomy was studied using Nailfold VideoCapillaroscopy (NVC) and the characterisation of the inflammation, immune activation and oxidative stress was addressed by the quantification of VCAM-1, ICAM-1, VEGF-A, 3-NT and TAC. Main findings: The healthy offspring of patients with SSc showed significant changes in NVC when compared to controls [number of capillaries per field inferior to eight (p=0.003), enlarged capillaries (p=0.003), major morphologic abnormalities (p=0.027), oedema (0.031), avascular areas (p<0.001), neoangiogenesis (p=0.041), reduced velocity of blood flow (p<0.001), sludge (p<0.001)], despite having normal levels of VCAM-1, ICAM-1, VEGF and 3-NT, with a high level of TAC. When compared to the patients with SSc, their offspring had similar changes regarding major morphologic abnormalities (p=0.6), “sludge” (p=0.06) and avascular areas (p=0.78). This two groups showed differences only in capillaries per field (p<0.001), enlarged (p<0.001) and giant (p<0.001) capillaries, minor dysmorphias (p<0.001), haemorrhages (p<0.001) and interstitial oedema (p<0.001). Capillary rarefaction and “sludge” were even more pronounced in the offspring of SSc when compared to patients with RD (p<0.001 for both parameters). Patients with RD differed from controls only in the number of enlarged capillaries (p=0.02), blood flow (p=0.002) and neoangiogenesis (p=0.04); their offspring had a practically normal NVC. Regarding the biologic products, none were higher in the RD and respective offspring group compared to controls. The offspring of patients with T2DM also showed significant differences from controls in NVC [edema (p=0.009), avascular areas (p<0.001), neoangiogenesis p=0.001, and reduced blood flow (p=0.046)]. There was only difference in haemorrhages (p=0.002) between patients with T2DM and their offspring. The T2DM offspring group had serum levels of 3-NT higher than controls (p=0.027). Conclusions: The anatomy of microvasculature in the offspring of patients with SSc appears to change before the immune system and inflammation markers get activated. This may be due to the fact that the microcirculatory structure is genetically driven whilst the disease onset may need further “hits” to develop. RD might have a different physiopathology from RP in the context of SSc, highlighting the different nature of the two conditions regarding their early (pre-clinical) mechanisms. The offspring of patients with T2DM showed the same phenomena that the SSc group, (despite the differences in the terminal vessels morphology), suggesting the presence of a genetic-based background which may develop into the metabolic disease after exposure to other stimuli. Therefore, we may postulate the existence of a ‘vascular anatomical memory’ in systemic sclerosis. |
publishDate |
2024 |
dc.date.none.fl_str_mv |
2024-07-31T15:24:48Z 2024-07-12 2024-07-12T00:00:00Z |
dc.type.driver.fl_str_mv |
doctoral thesis |
dc.type.status.fl_str_mv |
info:eu-repo/semantics/publishedVersion |
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publishedVersion |
dc.identifier.uri.fl_str_mv |
http://hdl.handle.net/10362/170196 TID:101593805 |
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http://hdl.handle.net/10362/170196 |
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TID:101593805 |
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eng |
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eng |
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info:eu-repo/semantics/openAccess |
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openAccess |
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application/pdf |
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reponame:Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) instname:Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação instacron:RCAAP |
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Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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RCAAP |
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RCAAP |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) |
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Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos) - Agência para a Sociedade do Conhecimento (UMIC) - FCT - Sociedade da Informação |
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mluisa.alvim@gmail.com |
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1817546686914887680 |