Using genomics for drug discovery in medulloblastoma

Tese de doutoramento, Medicina (Neurocirurgia), Universidade de Lisboa, Faculdade de Medicina, 2014

Brain-derived neurotrophic factor and adenosine signalling on amyloid-β peptide induced toxicity : impact on hippocampal function

Tese de doutoramento, Ciências Biomédicas (Neurociências), Universidade de Lisboa, Faculdade de Medicina, 2014

Cataloguing Kays: Body Image in the Catalogues of Kay & Co Ltd of Worcester, 1920 - 2000. JISC Final Report

Cataloguing Kays is a university-run project intended to create a community web-archive to celebrate the history and public memory of Kay & Co Ltd of Worcester, a noted mailorder catalogue company which was, until 2006, the largest employer in Worcester. The Kays Archive, housed at UoW, is one of the most comprehensive archive collections of 20th century mail-order catalogues in the UK and has a strong local elevance. The catalogues provide a window into over 100 years of body image, social history, consumable goods, fashion and design. The Project Team created www.WorldofKays.org, an online, fully-searchable archive containing 1500 digitised images from the catalogues, 1920-2000. The website is intended to form a seed bed for international research, focussing in particular on the representation of body image and the way the catalogues represent the developing tropes of consumer lifestyle and aspiration. The images are enhanced by blog postings from or film and audio interviews with local residents and former Kays staff members, who recall how the goods were selected and presented; as well as the impact the mail-order industry had on shaping 20th century lifestyle and consumption. These interviews and blogs have been sourced through the Cataloguing Kays team’s outreach activity in the local, academic and online communities. From the outset, we, the Cataloguing Kays team, engaged with online communities through social media sites, Facebook and Twitter, and through specialist blogs and online forums, inviting comment and contributions. Through events for the general public and a programme of targeted community outreach work with Kays Heritage Group and support groups for Worcestershire’s young and adult carers, we have also collected filmed and audio reminiscence material as well as community art and poetry content for the website. Our academic conference, the Catalogue of Dreams, showcased both the website and the physical archive to the wider academic, cultural and heritage sectors, provoking lively debateand much interest from international scholars.

Cuidados paliativos ao doente em fim de vida num serviço de urgência básico

Tese de mestrado, Cuidados Paliativos, Faculdade de Medicina, Universidade de Lisboa, 2015

Localism as restorative politics; social capital and anti-politics in the London Borough of Burgundia

ABSTRACT The purpose of this paper is to explore the political implications of policies and measures designed to promote “localism”. That is to say, the devolution of power down to a neighbourhood level, as enacted under the 2011 Localism Act. The implementation of localism in London boroughs will be examined. The context is the current concern over disengagement in an era of “anti-politics”, so it is intended to gain an understanding of how localism is interpreted and implemented on the ground. A tentative thesis, of a “restorative politics”, is proposed, such that localism is dynamic and is generating healthy political activity which counters anti-politics in the local community. This could have profound implications for the political parties locally and at Westminster. The extant theories about localism include constructivist interpretations suggesting that a neo-liberal localism is anti-political. This is contested. An emerging narrative heralding a new dawn of empowerment, and related themes concerning social capital, subsidiarity and anti-politics are reviewed. A necessarily empirical approach is adopted in an essentially functionalist frame of reference. There is a review of both academic and policy literature, combined with interviews of professionals involved in localism. This paper is designed to scope a future more substantial piece of research. The conference brief asks; “what scales or levels are appropriate for organising politics in this century”. In a century so far characterised by disillusionment, democratic deficits and abstention, the answer may be; local. The Good Life is lived locally in shared experience and familiar surroundings, hitherto not much amenable to local change. Burgundia is a reference to the film “Passport to Pimlico” (1949), when ABSTRACT The purpose of this paper is to explore the political implications of policies and measures designed to promote “localism”. That is to say, the devolution of power down to a neighbourhood level, as enacted under the 2011 Localism Act. The implementation of localism in London boroughs will be examined. The context is the current concern over disengagement in an era of “anti-politics”, so it is intended to gain an understanding of how localism is interpreted and implemented on the ground. A tentative thesis, of a “restorative politics”, is proposed, such that localism is dynamic and is generating healthy political activity which counters anti-politics in the local community. This could have profound implications for the political parties locally and at Westminster. The extant theories about localism include constructivist interpretations suggesting that a neo-liberal localism is anti-political. This is contested. An emerging narrative heralding a new dawn of empowerment, and related themes concerning social capital, subsidiarity and anti-politics are reviewed. A necessarily empirical approach is adopted in an essentially functionalist frame of reference. There is a review of both academic and policy literature, combined with interviews of professionals involved in localism. This paper is designed to scope a future more substantial piece of research. The conference brief asks; “what scales or levels are appropriate for organising politics in this century”. In a century so far characterised by disillusionment, democratic deficits and abstention, the answer may be; local. The Good Life is lived locally in shared experience and familiar surroundings, hitherto not much amenable to local change. Burgundia is a reference to the film “Passport to Pimlico” (1949), when a London neighbourhood declared independence and its citizens temporarily created the Good Life for themselves. Is the 21st century localism generating a restorative politics?

Crianças com défices no controlo motor: contributo para a elaboração do core set da Classificação Internacional de Funcionalidade, Incapacidade e Saúde (CIF)

A CIF é um sistema de classificação adotado pela OMS, que serve de referência universal para descrever, avaliar e medir saúde e incapacidade, a nível individual e ao nível da população. Contudo, apesar do interesse internacional gerado em torno da CIF, esta é considerada uma classificação complexa e extensa, fato que despoletou a criação de core sets – listas de itens da CIF especificamente selecionados pela sua relevância na descrição e qualificação de uma determinada condição de saúde – como resposta a esta problemática. Até à data, foram desenvolvidos core sets para várias patologias comuns. Contudo, apesar do controlo motor ser uma área de investigação muito reconhecida nos últimos 20 anos, ainda não possui um core set próprio. Assim, o objetivo deste estudo é contribuir para o desenvolvimento de um core set, com base na CIF-CJ, dirigido para uma descrição abrangente das competências inerentes a crianças, dos 6 aos 18 anos de idade, com défices no controlo motor. Deste modo, recorreu-se a uma revisão da literatura sobre a temática em estudo, de modo a reunir informação para a construção de uma proposta a core set, posteriormente sujeita ao escrutínio de peritos, através do recurso ao método de Delphi. Após várias rondas, foi alcançado um consenso acerca da lista final de códigos CIF que constituem o core set final.

Influência da crioterapia no tendão quadricipital na força máxima, na sensação de força produzida e na funcionalidade do membro inferior

Enquadramento: A aplicação de crioterapia utiliza-se como coadjuvante na reeducação neuromuscular e tem como objetivo atingir o mais rápido possível a capacidade funcional, devido aos seus efeitos analgésicos e anti- inflamatórios, contudo, o seu efeito negativo ao nível da propriocepção tem vindo a ser questionado. Objetivo: Verificar se a aplicação de crioterapia no tendão quadricipital tem influência na força máxima, na sensação de força produzida e na funcionalidade do membro inferior. Metodologia: Tratou-se de um estudo experimental, do tipo laboratorial e com um desenho cruzado. Quarenta sujeitos foram distribuídos inicialmente e de forma aleatória em um grupo experimental e um grupo controlo, sendo que, após uma semana os elementos que pertenceram ao grupo experimental passaram para grupo controlo e vice-versa. O grupo experimental foi submetido a um programa com gelo dinâmico durante 10 minutos, avaliando-se a força máxima, sensação de força produzida e funcionalidade do membro, enquanto grupo controlo esteve em repouso o mesmo período de tempo. Resultados: Verificaram-se que não houve diferenças estatisticamente significativas relativas a todas variáveis estudadas (p>0,05). Conclusão: O uso da crioterapia na região mio-tendinosa do quadrícipete não provoca défices significativos ao nível das respostas sensório-motoras do joelho, e que à luz destes resultados, esta pode ser utilizada antes da realização de outras técnicas terapêuticas, sem qualquer risco adicional a nível motor.

Metacognitive and social cognition training (MSCT) in schizophrenia: a preliminary efficacy study

Psychosocial interventions have proven to be effective in treating social cognition in people with psychotic disorders. The current study aimed to determine the effects of a metacognitive and social cognition training (MSCT) program, designed to both remediate deficits and correct biases in social cognition. Thirty-five clinically stable outpatients were recruited and assigned to the MSCT program (n = 19) for 10 weeks (18 sessions) or to the TAU group (n = 16), and they all completed pre- and post-treatment assessments of social cognition, cognitive biases, functioning and symptoms. The MSCT group demonstrated a significant improvement in theory of mind, social perception, emotion recognition and social functioning. Additionally, the tendency to jump to conclusions was significantly reduced among the MSCT group after training. There were no differential benefits regarding clinical symptoms except for one trend group effect for general psychopathology. The results support the efficacy of the MSCT format, but further development of the training program is required to increase the benefits related to attributional style.

Effects of early life permethrin exposure on spatial working memory and on monoamine levels in different brain areas of pre-senescent rats

Pesticide exposure during brain development could represent an important risk factor for the onset of neurodegenerative diseases. Previous studies investigated the effect of permethrin (PERM) administered at 34 mg/kg, a dose close to the no observable adverse effect level (NOAEL) from post natal day (PND) 6 to PND 21 in rats. Despite the PERM dose did not elicited overt signs of toxicity (i.e. normal body weight gain curve), it was able to induce striatal neurodegeneration (dopamine and Nurr1 reduction, and lipid peroxidation increase). The present study was designed to characterize the cognitive deficits in the current animal model. When during late adulthood PERM treated rats were tested for spatial working memory performances in a T-maze-rewarded alternation task they took longer to choose for the correct arm in comparison to age matched controls. No differences between groups were found in anxiety-like state, locomotor activity, feeding behavior and spatial orientation task. Our findings showing a selective effect of PERM treatment on the T-maze task point to an involvement of frontal cortico-striatal circuitry rather than to a role for the hippocampus. The predominant disturbances concern the dopamine (DA) depletion in the striatum and, the serotonin (5-HT) and noradrenaline (NE) unbalance together with a hypometabolic state in the medial prefrontal cortex area. In the hippocampus, an increase of NE and a decrease of DA were observed in PERM treated rats as compared to controls. The concentration of the most representative marker for pyrethroid exposure (3-phenoxybenzoic acid) measured in the urine of rodents 12 h after the last treatment was 41.50 µ/L and it was completely eliminated after 96 h.

Ajustes Posturais dos músculos da tibiotársica em indivíduos com Doença de Parkinson durante o sit-to-stand

Introdução: Os ajustes posturais antecipatórios (APAs) são essenciais para o movimento típico, estando alterados nas doenças neuro degenerativas como a doença de Parkinson (DP) Objectivo(s): Estudar os early postural adjustments e os APAs em indivíduos com DP durante o sentar para levantar (STS), com e sem dupla tarefa. Métodos: Foi recolhida a atividade eletromiográfica (EMG) dos músculos tibial anterior, solear e gastrocnémio medial, em indivíduos com e sem DP (9 em cada grupo), durante o STS. Este foi determinado pelo deslocamento antero posterior do centro de pressão através da plataforma de forças, sendo a tarefa cognitiva dada pelo stroop colour word interference test. Os ajustes posturais foram avaliados pelo tempo de ativação e pela atividade EMG relativa, bem como pela análise da co ativação agonista/antagonista. Resultados: Não foram encontradas diferenças estatisticamente significativas entre o grupo de controlo e o grupo com DP em nenhuma das variáveis analisadas Há uma tendência para o grupo com DP apresentar APAs mais cedo na tarefa simples, mantendo atividade muscular durante mais tempo e com maior atividade EMG relativa que o grupo controlo. Na dupla tarefa mantém-se essa tendência, exceto o tempo de ativação ser mais próximo do levante. Conclusão: Os défices posturais decorrentes da doença de Parkinson parecem não ser evidenciados na primeira fase do sit-to-stand.

Avaliação dos ajustes posturais em indivíduos com instabilidade funcional do tornozelo

Introdução:O Controlo Postural é um processo neural complexo envolvido na organização da estabilidade e orientação da posição do corpo no espaço. A Instabilidade Funcional (IF) do tornozelo é descrita como uma perceção subjetiva de instabilidade articular, que afeta o controlo postural. Apesar de vários estudos terem investigado os fatores inerentes à IF ainda existe inconsistência nos resultados da literatura sobre os mecanismos envolvidos nesta. Objetivo (s):avaliar os ajustes posturais envolvidos na resposta a uma perturbação externa realizada de forma previsível e imprevisível em indivíduos com IF. Métodos:Estudo observacional analítico transversal, teve uma amostra de 20 indivíduos, que foram divididos em grupo com IF e grupo de controlo. Foi recolhida atividade eletromiográfica bilateral dos músculos longo e curto peroneal (PL e PC), tibial anterior (TA) e solear (SOL) associado a uma perturbação externa aplicada de forma previsível e imprevisível. Os ajustes posturais foram avaliados através da análise do início da atividade muscular, da magnitude global dos ajustes posturais compensatórios e antecipatórios e magnitude das respostas de curta e média latência Resultados: Na perturbação imprevisível não se verificaram diferenças significativas no início da atividade muscular (p>0,05). Enquanto na magnitude das respostas de curta e média latência verificou-se diferenças nos músculos TA (Ia,p=0,000; II, p=0,011), CP (Ia,p=0,029; II, p=0,001) e LP (Ia, p=0,030) entre o membro com IF e o controlo e no LP (II, p=0,011) entre o membro sem IF do grupo com IF e o controlo. Na perturbação previsível observaram-se diferenças nos ajustes posturais antecipatórios (APA) dos músculos TA (p=0,006) e LP (p=0,020) entre o membro sem IF do grupo com IF e o controlo. Conclusão: Os indivíduos com IF apresentam défices na magnitude das respostas de média e curta latência numa perturbação imprevisível e nos APA na perturbação previsível.

Desempenho Manual do Membro Superior Ipsilesional em Indivíduos com Acidente Vascular Encefálico

Introdução: nos pacientes que sofreram um Acidente Vascular Encefálico são incididos programas de reabilitação que visam principalmente o hemicorpo contralesional, negligenciando o lado ipsilesional. Porém, estão descritas alterações sensitivas e motoras do membro superior ipsilesional neste grupo populacional. Objetivo: avaliar os défices de sensibilidade, destreza grossa e fina e força de preensão da mão ipsilesional em indivíduos com diagnóstico de Acidente Vascular Encefálico, comparando o sexo, o hemisfério cerebral onde se localiza a lesão, a fase aguda e crónica, tendo como referência um grupo controlo. Metodologia: este estudo observacional de carácter analítico transversal foi constituído por 34 indivíduos em que 18 deles tem diagnóstico de Acidente Vascular Encefálico e 16 sem défices neurológicos. A avaliação foi iniciada com um questionário para recolha de informações dos participantes e de seguida foram aplicados instrumentos de avaliação num só momento com o mesmo examinador. Para avaliar a sensibilidade foi usado o Moving Touch-Pressure Test, para a força o Dinamómetro Baseline®, na avaliação da destreza grossa o Teste Caixa e Blocos e por fim a destreza fina com o Purdue Pegboard Test. Estatisticamente recorreu-se ao teste T-student para amostras independentes com nível de significância de 0,05. Resultados: verificou-se que o membro superior ipsilesional dos indivíduos que sofreram um AVE apresenta um défice na força de preensão manual com nível se significância de p=0,001, e de p=0,000 para a destreza fina e grossa e sensibilidade, quando comparados com um grupo controlo. Constatou-se também que no grupo de indivíduos com diagnóstico de Acidente Vascular Encefálico, o sexo masculino obteve melhores resultados em todos os parâmetros avaliados. Observou-se ainda que tanto os homens como as mulheres após sofrerem um Acidente Vascular Encefálico apresentam défices funcionais na mão ipsilesional, mas no entanto os homens apresentam apenas alterações na destreza grossa (p=0,017) e na força (p=0,001). Na comparação dos hemisférios cerebrais lesados e das fases aguda e crónica do AVE verificou-se que não houve diferenças significativas. Conclusão: Existem défices no membro superior ipsilesional após Acidente Vascular Encefálico, sendo então pertinente a sua inclusão em programas de reabilitação, podendo assim melhorar a qualidade de vida dos indivíduos com esta patologia.

Descending pain modulation in a Kaolin-induced hydrocephalus rat model

Pain transmission at the spinal cord is modulated by descending actions that arise from supraspinal areas which collectively form the endogenous pain control system. Two key areas involved of the endogenous pain control system have a circunventricular location, namely the periaqueductal grey (PAG) and the locus coeruleus (LC). The PAG plays a crucial role in descending pain modulation as it conveys the input from higher brain centers to the spinal cord. As to the LC, it is involved in descending pain inhibition by direct noradrenergic projections to the spinal cord. In the context of neurological defects, several diseases may affect the structure and function of the brain. Hydrocephalus is a congenital or acquired disease characterized by an enlargement of the ventricles which leads to a distortion of the adjacent tissues, including the PAG and LC. Usually, patients suffering from hydrocephalus present dysfunctions in learning and memory and also motor deficits. It remains to be evaluated if lesions of the periventricular brain areas involved in pain control during hydrocephalus may affect descending pain control and, herein, affect pain responses. The studies included in the present thesis used an experimental model of hydrocephalus (the rat injected in the cisterna magna with kaolin) to study descending modulation of pain, focusing on the two circumventricular regions referred above (the PAG and the LC). In order to evaluate the effects of kaolin injection into the cisterna magna, we measured the degree of ventricular dilatation in sections encompassing the PAG by standard cytoarquitectonic stanings (thionin staining). For the LC, immunodetection of the noradrenaline-synthetizing enzyme tyrosine hydroxylase (TH) was performed, due to the noradrenergic nature of the LC neurons. In general, rats with kaolin-induced hydrocephalus presented a higher dilatation of the 4th ventricle, along with a tendency to a higher area of the PAG. Due to the validated role of detection the c-fos protooncogene as a marker of neuronal activation, we also studied neuronal activation in the several subnuclei which compose the PAG, namely the dorsomedial, dorsolateral, lateral and ventrolateral (VLPAG) parts. A decrease in the numbers of neurons immunoreactive for Fos protein (the product of activation of the c-fos protooncogene) was detected in rats injected with kaolin, whereas the remaining PAG subnuclei did not present changes in Fos-immunoreactive nuclei. Increases in the levels of TH in the LC, namely at the rostral parts of the nucleus, were detected in hydrocephalic animals. The following pain-related parameters were measured, namely 1) pain behavioural responses in a validated pain inflammatory test (the formalin test) and 2) the nociceptive activation of spinal cord neurons. A decrease in behavioral responses was detected in rats with kaolin-induced hydrocephalus was detected, namely in the second phase of the test (inflammatory phase). This is the phase of the formalin test in which the motor behaviour is less important, which is important since a semi-quantitative analysis of the motor performance of rats injected with kaolin indicates that these animals may present some motor impairments. Collectively, the results of the behavioral studies indicate that rats with kaolin-induced hydrocephalus exhibit hypoalgesia. A decrease in Fos expression was detected at the superficial dorsal layers of the spinal cord in rats with kaolin-induced hydrocephalus, further indicating that hydrocephalus decreases nociceptive responses. It remains to be ascertained if this is due to alterations in the PAG and LC in the rats with kaolin-induced hydrocephalus, which may affect descending pain modulation. It remains to be evaluated what are the mechanisms underlying the increased pain inhibition at the spinal dorsal horn in the hydrocephalus rats. Regarding the VLPAG, the decrease in neuronal activity may impair descending modulation. Since the LC has higher levels of TH in rats with kaolininduced hydrocephalus, which also appears to increase the noradrenergic innervation in the spinal dorsal horn, it is possible that an increase in the release of noradrenaline at the spinal cord accounts for pain inhibition. Our studies also determine the need to study in detail patients with hydrocephalus namely in what concerns their thresholds to pain and to perform imaging studies focused on the structure and function of pain control areas in the brain.

Influence of dual-task on sit-to-stand-to-sit postural control in Parkinson's disease

Postural control deficits are the most disabling aspects of Parkinson's disease (PD), resulting in decreased mobility and functional independence. The aim of this study was to assess the postural control stability, revealed by variables based on the centre of pressure (CoP), in individuals with PD while performing a sit-to-stand-to-sit sequence under single- and dual-task conditions. An observational, analytical and cross-sectional study was performed. The sample consisted of 9 individuals with PD and 9 healthy controls. A force platform was used to measure the CoP displacement and velocity during the sit-to-stand-to-sit sequence. The results were statistically analysed. Individuals with PD required greater durations for the sit-to-stand-to-sit sequence than the controls (p < 0.05). The anteroposterior and mediolateral CoP displacement were higher in the individuals with PD (p < 0.05). However, only the anteroposterior CoP velocity in the stand-to-sit phase (p = 0.006) was lower in the same individuals. Comparing the single- and dual-task conditions in both groups, the duration, the anteroposterior CoP displacement and velocity were higher in the dual-task condition (p < 0.05). The individuals with PD presented reduced postural control stability during the sit-to-stand-to-sit sequence, especially when under the dual-task condition. These individuals have deficits not only in motor performance, but also in cognitive performance when performing the sit-to-stand-to-sit sequence in their daily life tasks. Moreover, both deficits tend to be intensified when two tasks are performed simultaneously.

Do Spirituality and Faith Make a Difference? Report from the Southern European Psycho-Oncology Study Group

OBJECTIVE: In the last decade, some attention has been given to spirituality and faith and their role in cancer patients' coping. Few data are available about spirituality among cancer patients in Southern European countries, which have a big tradition of spirituality, namely, the Catholic religion. As part of a more general investigation (Southern European Psycho-Oncology Study--SEPOS), the aim of this study was to examine the effect of spirituality in molding psychosocial implications in Southern European cancer patients. METHOD: A convenience sample of 323 outpatients with a diagnosis of cancer between 6 to 18 months, a good performance status (Karnofsky Performance Status > 80), and no cognitive deficits or central nervous system (CNS) involvement by disease were approached in university and affiliated cancer centers in Italy, Spain, Portugal, and Switzerland (Italian speaking area). Each patient was evaluated for spirituality (Visual Analog Scale 0-10), psychological morbidity (Hospital Anxiety and Depression Scale--HADS), coping strategies (Mini-Mental Adjustment to Cancer--Mini-MAC) and concerns about illness (Cancer Worries Inventory--CWI). RESULTS. The majority of patients (79.3%) referred to being supported by their spirituality/faith throughout their illness. Significant differences were found between the spirituality and non-spirituality groups (p ≤ 0.01) in terms of education, coping styles, and psychological morbidity. Spirituality was significantly correlated with fighting spirit (r = -0.27), fatalism (r = 0.50), and avoidance (r = 0.23) coping styles and negatively correlated with education (r = -0.25), depression (r = -0.22) and HAD total (r = -0.17). SIGNIFICANCE OF RESULTS: Spirituality is frequent among Southern European cancer patients with lower education and seems to play some protective role towards psychological morbidity, specifically depression. Further studies should examine this trend in Southern European cancer patients.