Outcome of the Public Consultation on the Draft Opinion of the Scientific Panel on Dietetic Products, Nutrition, and Allergies (NDA) on Dietary Reference Values for Fats, Including Saturated Fatty Acids, Polyunsaturated Fatty Acids, Monounsaturated Fatty Acids, Trans Fatty Acids, and Cholesterol

On 2 July 2009, the EFSA Panel on Dietetic products, Nutrition and Allergies (NDA) endorsed a draft Opinion on Dietary Reference Values for fats to be released for public consultation. This Scientific Report summarises the comments received through the public consultation and outlines how these were taken into account in the final opinion. EFSA had received contributions from 40 interested parties (individuals, non-governmental organisations, industry organisations, academia and national assessment bodies). The main comments which were received during the public consultation related to: the availability of more recent data, the nomenclature used, the use of a non-European food composition data base, the impact of genetic factors in modulating the absorption, metabolism and health effects of different fatty acids, the definition of “nutritionally adequate diet”, the use of Dietary Reference Values in the labelling of foods, the translation of advice into food-based dietary guidelines, nutrient goals and recommendations, certain risk management issues, and to Dietary Reference Values of fats, individual fatty acids, and cholesterol. All the public comments received that related to the remit of EFSA were assessed and the Opinion on Dietary Reference Values for fats has been revised taking relevant comments into consideration.

Evaluation of Tottenham Thinking Space Pilot: Final Report. Research Report 11.

This reports summarises research that began in March 2014 and was completed in October 2015 by an experienced inter-disciplinary research team from the Centre for Social Justice and Change and Psycho-Social Research Group, School of Social Sciences, the University of East London (UEL) and included Dr Yang Li from the Centre for Geo-Information Studies, UEL, for the first phase of the study. Tottenham ‘Thinking Space’ (TTS) was a pilot therapeutic initiative based in local communities and delivered by the Tavistock & Portman NHS Foundation Trust and funded by the London Borough of Haringey Directorate of Public Health. TTS aimed to improve mental health and enable and empower local communities. TTS was situated within a mental health agenda that was integral to Haringey’s Health and Wellbeing Strategy 2012-2015 and aimed to encourage people to help themselves and each other and develop confident communities. On the one hand TTS was well-suited to this agenda, but, on the other, participants were resistant to, and were trying to free themselves from labelling that implied ‘mental health difficulties’. A total of 243 meetings were held and 351 people attended 1,716 times. The majority of participants attended four times or less, and 33 people attended between 5 and 10 times and 39 people attended over 10 times. Attending a small number of times does not necessarily mean that the attendee was not helped. Attendees reflected the ethnic diversity of Tottenham; 29 different ethnic groups attended. The opportunity to meet with people from different cultural backgrounds in a safe space was highly valued by attendees. Similarly, participants valued the wide age range represented and felt that they benefited from listening to inter-generational experiences. The majority of participants were women (72%) and they were instrumental in initiating further Thinking Spaces, topic specific meetings, the summer programme of activities for mothers and young children and training to meet their needs. The community development worker had a key role in implementing the initiative and sustaining its growth throughout the pilot period. We observed that TTS attracted those whose life experiences were marked by personal struggle and trauma. Many participants felt safe enough to disclose mental health difficulties (85% of those who completed a questionnaire). Participants also came seeking a stronger sense of community in their local area. Key features of the meetings are that they are democratic, non-judgemental, respectful, and focussed on encouraging everyone to listen and to try to understand. We found that the therapeutic method was put in place by high quality facilitators and health and personal outcomes for participants were consistent with those predicted by the underpinning psychoanalytical and systemic theories. Outcomes included a reduction in anxieties and improved personal and social functioning; approximately two thirds of those who completed a questionnaire felt better understood, felt more motivated and more hopeful for the future. The overwhelming majority of survey respondents also felt good about contributing to their community, said that they were more able to cooperate with others and accepting of other cultures, and had made new friends. Participants typically had a better understanding of their current situation and how to take positive action; of those who completed a questionnaire, over half felt more confident to seek support for a personal issue and to contact services. Members of TTS supported each other and instilled hope and build community-mindedness that reduced social isolation.

Efficient delivery of Cre-recombinase to neurons in vivo and stable transduction of neurons using adeno-associated and lentiviral vectors

BACKGROUND: Inactivating genes in vivo is an important technique for establishing their function in the adult nervous system. Unfortunately, conventional knockout mice may suffer from several limitations including embryonic or perinatal lethality and the compensatory regulation of other genes. One approach to producing conditional activation or inactivation of genes involves the use of Cre recombinase to remove loxP-flanked segments of DNA. We have studied the effects of delivering Cre to the hippocampus and neocortex of adult mice by injecting replication-deficient adeno-associated virus (AAV) and lentiviral (LV) vectors into discrete regions of the forebrain. RESULTS: Recombinant AAV-Cre, AAV-GFP (green fluorescent protein) and LV-Cre-EGFP (enhanced GFP) were made with the transgene controlled by the cytomegalovirus promoter. Infecting 293T cells in vitro with AAV-Cre and LV-Cre-EGFP resulted in transduction of most cells as shown by GFP fluorescence and Cre immunoreactivity. Injections of submicrolitre quantities of LV-Cre-EGFP and mixtures of AAV-Cre with AAV-GFP into the neocortex and hippocampus of adult Rosa26 reporter mice resulted in strong Cre and GFP expression in the dentate gyrus and moderate to strong labelling in specific regions of the hippocampus and in the neocortex, mainly in neurons. The pattern of expression of Cre and GFP obtained with AAV and LV vectors was very similar. X-gal staining showed that Cre-mediated recombination had occurred in neurons in the same regions of the brain, starting at 3 days post-injection. No obvious toxic effects of Cre expression were detected even after four weeks post-injection. CONCLUSION: AAV and LV vectors are capable of delivering Cre to neurons in discrete regions of the adult mouse brain and producing recombination

Between Bacchus and Dionysus: European Union policies on rural development: the cases of Nemea and Basto wine regions

A actividade vitivinícola possui um conjunto diverso de características presentes no solo, território e comunidade que fazem parte do património cultural de uma determinada região. Quando a tradição se traduz num conceito como terroir que é formado por características territoriais, sociais e culturais de uma região rural, o vinho apresenta uma “assinatura” que se escreve “naturalmente” no paladar regionalmente identificado. Os vinhos da Região de Nemea, na Grécia e de Basto (Região dos Vinhos Verdes) em Portugal, estão ambos sob a proteção dos regulamentos das Denominações de Origem. No entanto, apesar de ambos serem regulados por sistemas institucionais de certificação e controlo de qualidade, afigura-se a necessidade de questionar se o património cultural e a identidade territorial específica, “impressa” em ambos os terroirs, pode ser protegida num sentido mais abrangente do que apenas origem e qualidade. Em Nemea, a discussão entre os produtores diz respeito ao estabelecimento de sub-zonas, isto é incluir na regulação PDO uma diferente categorização territorial com base no terroir. Ou seja, para além de estar presente no rótulo a designação PDO, as garrafas incluirão ainda informação certificada sobre a área específica (dentro do mesmo terroir) onde o vinho foi produzido. A acontecer resultaria em diferentes status de qualidade de acordo com as diferentes aldeias de Nemea onde as vinhas estão localizadas. O que teria possíveis impactos no valor das propriedades e no uso dos solos. Para além disso, a não participação da Cooperativa de Nemea na SON (a associação local de produtores de vinho) e como tal na discussão principal sobre as mudanças e os desafios sobre o terroir de Nemea constitui um problema no sector vitivinícola de Nemea. Em primeiro lugar estabelece uma relação de não-comunicação entre os dois mais importantes agentes desse sector – as companhias vinícolas e a Cooperativa. Em segundo lugar porque constituiu uma possibilidade real, não só para os viticultores ficarem arredados dessa discussão, como também (porque não representados pela cooperativa) ficar impossibilitado um consenso sobre as mudanças discutidas. Isto poderá criar um ‘clima’ de desconfiança levando a discussão para ‘arenas’ deslocalizadas e como tal para decisões ‘desterritorializadas’ Em Basto, há vários produtores que começaram a vender a sua produção para distribuidoras localizadas externamente à sub-região de Basto, mas dentro da Região dos Vinhos Verdes, uma vez que essas companhias tem um melhor estatuto nacional e internacional e uma melhor rede de exportações. Isto está ainda relacionado com uma competição por uma melhor rede de contactos e status mais forte, tornando as discussões sobre estratégias comuns para o desenvolvimento rural e regional de Basto mais difícil de acontecer (sobre isto a palavra impossível foi constantemente usada durante as entrevistas com os produtores de vinho). A relação predominante entre produtores é caracterizada por relações individualistas. Contudo foi observado que essas posições são ainda caracterizadas por uma desconfiança no interior da rede interprofissional local: conflitos para conseguir os mesmos potenciais clientes; comprar uvas a viticultores com melhor rácio qualidade/preço; estratégias individuais para conseguir um melhor status político na relação com a Comissão dos Vinhos Verdes. Para além disso a inexistência de uma activa intermediação institucional (autoridades municipais e a Comissão de Vinho Verde), a inexistência entre os produtores de Basto de uma associação ou mesmo a inexistência de uma cooperativa local tem levado a região de Basto a uma posição de subpromoção nas estratégias de promoção do Vinho Verde em comparação com outras sub-regiões. É também evidente pelos resultados que as mudanças no sector vitivinícolas na região de Basto têm sido estimuladas de fora da região (em resposta também às necessidades dos mercados internacionais) e raramente de dentro – mais uma vez, ‘arenas’ não localizadas e como tal decisões desterritorializadas. Nesse sentido, toda essa discussão e planeamento estratégico, terão um papel vital na preservação da identidade localizada do terroir perante os riscos de descaracterização e desterritorialização. Em suma, para ambos os casos, um dos maiores desafios parece ser como preservar o terroir vitivinícola e como tal o seu carácter e identidade local, quando a rede interprofissional em ambas as regiões se caracteriza, tanto por relações não-consensuais em Nemea como pelo modus operandi de isolamento sem comunicação em Basto. Como tal há uma necessidade de envolvimento entre os diversos agentes e as autoridades locais no sentido de uma rede localizada de governança. Assim sendo, em ambas as regiões, a existência dessa rede é essencial para prevenir os efeitos negativos na identidade do produto e na sua produção. Uma estratégia de planeamento integrado para o sector será vital para preservar essa identidade, prevenindo a sua desterritorialização através de uma restruturação do conhecimento tradicional em simultâneo com a democratização do acesso ao conhecimento das técnicas modernas de produção vitivinícola.

Nutrition and health claims in products directed at children via television in Spain in 2012

Objective: To describe the use of nutrition and health claims in products directed at children via television in Spain and to analyse their nutrient profile. Methods: A cross-sectional study of television food advertisements over 7 days in five Spanish television channels popular among children. The products were classified as core, non-core or miscellaneous, and as either healthy or less healthy, according to the United Kingdom Nutrient Profile Model. We registered all claims contained on the product (packaging and labelling) and its advertisement. We calculated the frequency distributions of health and nutrition claims. Results: During the 420 hours of broadcasting, 169 food products were identified, 28.5% in the dairy group and 60.9% in the non-core category. A total of 53.3% of products contained nutrition claims and 26.6% contained health claims; 62.2% of the products with claims were less healthy. Low-fat dairy products were the food category containing the highest percentage of health and nutrition claims. Conclusion: Over half of all food products marketed to children via television in Spain made some type of nutrition or health claim. Most of these products were less healthy, which could mislead Spanish consumers.

Hierarchically grouped 2D local features applied to edge contour localisation

One of the most significant research topics in computer vision is object detection. Most of the reported object detection results localise the detected object within a bounding box, but do not explicitly label the edge contours of the object. Since object contours provide a fundamental diagnostic of object shape, some researchers have initiated work on linear contour feature representations for object detection and localisation. However, linear contour feature-based localisation is highly dependent on the performance of linear contour detection within natural images, and this can be perturbed significantly by a cluttered background. In addition, the conventional approach to achieving rotation-invariant features is to rotate the feature receptive field to align with the local dominant orientation before computing the feature representation. Grid resampling after rotation adds extra computational cost and increases the total time consumption for computing the feature descriptor. Though it is not an expensive process if using current computers, it is appreciated that if each step of the implementation is faster to compute especially when the number of local features is increasing and the application is implemented on resource limited ”smart devices”, such as mobile phones, in real-time. Motivated by the above issues, a 2D object localisation system is proposed in this thesis that matches features of edge contour points, which is an alternative method that takes advantage of the shape information for object localisation. This is inspired by edge contour points comprising the basic components of shape contours. In addition, edge point detection is usually simpler to achieve than linear edge contour detection. Therefore, the proposed localization system could avoid the need for linear contour detection and reduce the pathological disruption from the image background. Moreover, since natural images usually comprise many more edge contour points than interest points (i.e. corner points), we also propose new methods to generate rotation-invariant local feature descriptors without pre-rotating the feature receptive field to improve the computational efficiency of the whole system. In detail, the 2D object localisation system is achieved by matching edge contour points features in a constrained search area based on the initial pose-estimate produced by a prior object detection process. The local feature descriptor obtains rotation invariance by making use of rotational symmetry of the hexagonal structure. Therefore, a set of local feature descriptors is proposed based on the hierarchically hexagonal grouping structure. Ultimately, the 2D object localisation system achieves a very promising performance based on matching the proposed features of edge contour points with the mean correct labelling rate of the edge contour points 0.8654 and the mean false labelling rate 0.0314 applied on the data from Amsterdam Library of Object Images (ALOI). Furthermore, the proposed descriptors are evaluated by comparing to the state-of-the-art descriptors and achieve competitive performances in terms of pose estimate with around half-pixel pose error.

Comparison of the modes of action of Apremilast and Roflumilast

The phosphodiesterase 4 (PDE4) family are cAMP specific phosphodiesterases that play an important role in the inflammatory response and is the major PDE type found in inflammatory cells. A significant number of PDE4 specific inhibitors have been developed and are currently being investigated for use as therapeutic agents. Apremilast, a small molecule inhibitor of PDE 4 is in development for chronic inflammatory disorders and has shown promise for the treatment of psoriasis, psoriatic arthritis as well as other inflammatory diseases. It has been found to be safe and well tolerated in humans and in March 2014 it was approved by the US food and drug administration for the treatment of adult patients with active psoriatic arthritis. The only other PDE4 inhibitor on the market is Roflumilast and it is used for treatment of respiratory disease. Roflumilast is approved in the EU for the treatment of COPD and was recently approved in the US for treatment to reduce the risk of COPD exacerbations. Roflumilast is also a selective PDE4 inhibitor, administered as an oral tablet once daily, and is thought to act by increasing cAMP within lung cells. As both (Apremilast and Roflumilast) compounds selectively inhibit PDE4 but are targeted at different diseases, there is a need for a clear understanding of their mechanism of action (MOA). Differences and similarity of MOA should be defined for the purposes of labelling, for communication to the scientific community, physicians, and patients, and for an extension of utility to other diseases and therapeutic areas. In order to obtain a complete comparative picture of the MOA of both inhibitors, additional molecular and cellular biology studies are required to more fully elucidate the signalling mediators downstream of PDE4 inhibition which result in alterations in pro- and anti-inflammatory gene expression. My studies were conducted to directly compare Apremilast with Roflumilast, in order to substantiate the differences observed in the molecular and cellular effects of these compounds, and to search for other possible differentiating effects. Therefore the main aim of this thesis was to utilise cutting-edge biochemical techniques to discover whether Apremilast and Roflumilast work with different modes of action. In the first part of my thesis I used novel genetically encoded FRET based cAMP sensors targeted to different intracellular compartments, in order to monitor cAMP levels within specific microdomains of cells as a consequence of challenge with Apremilast and Roflumilast, which revealed that Apremilast and Roflumilast do regulate different pools of cAMP in cells. In the second part of my thesis I focussed on assessing whether Apremilast and Roflumilast cause differential effects on the PKA phosphorylation state of proteins in cells. I used various biochemical techniques (Western blotting, Substrate kinase arrays and Reverse Phase Protein array and found that Apremilast and Roflumilast do lead to differential PKA substrate phosphorylation. For example I found that Apremilast increases the phosphorylation of Ribosomal Protein S6 at Ser240/244 and Fyn Y530 in the S6 Ribosomal pathway of Rheumatoid Arthritis Synovial fibroblast and HEK293 cells, whereas Roflumilast does not. This data suggests that Apremilast has distinct biological effects from that of Roflumilast and could represent a new therapeutic role for Apremilast in other diseases. In the final part of my thesis, Phage display technology was employed in order to identify any novel binding motifs that associate with PDE4 and to identify sequences that were differentially regulated by the inhibitors in an attempt to find binding motifs that may exist in previously characterised signalling proteins. Petide array technology was then used to confirm binding of specific peptide sequences or motifs. Results showed that Apremilast and Roflumilast can either enhance or decrease the binding of PDE4A4 to specific peptide sequences or motifs that are found in a variety of proteins in the human proteome, most interestingly Ubiquitin-related proteins. The data from this chapter is preliminary but may be used in the discovery of novel binding partners for PDE4 or to provide a new role for PDE inhibition in disease. Therefore the work in this thesis provides a unique snapshot of the complexity of the cAMP signalling system and is the first to directly compare action of the two approved PDE4 inhibitors in a detailed way.

Deep convolutional neural networks for semantic video object segmentation

In this thesis, we propose to infer pixel-level labelling in video by utilising only object category information, exploiting the intrinsic structure of video data. Our motivation is the observation that image-level labels are much more easily to be acquired than pixel-level labels, and it is natural to find a link between the image level recognition and pixel level classification in video data, which would transfer learned recognition models from one domain to the other one. To this end, this thesis proposes two domain adaptation approaches to adapt the deep convolutional neural network (CNN) image recognition model trained from labelled image data to the target domain exploiting both semantic evidence learned from CNN, and the intrinsic structures of unlabelled video data. Our proposed approaches explicitly model and compensate for the domain adaptation from the source domain to the target domain which in turn underpins a robust semantic object segmentation method for natural videos. We demonstrate the superior performance of our methods by presenting extensive evaluations on challenging datasets comparing with the state-of-the-art methods.

The pathophysiology of CADASIL: studies in a Scottish cohort

Since identification that mutations in NOTCH3 are responsible for cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the early 1990s, there has been extensive characterisation of the clinical and radiological features of the disease. However therapeutic interventions remain elusive, partly due to a limited understanding of the vascular pathophysiology and how it leads to the development of strokes, cognitive decline and disability. The apparent rarity and heterogenous natural history of CADASIL potentially make conducting any longitudinal or therapeutic trials difficult. The role of disease biomarkers is therefore of some interest. This thesis focuses on vascular function in CADASIL and how it may relate to clinical and radiological markers of disease. Establishing the prevalence of CADASIL in the West of Scotland was important to assess the impact of the disease, and how feasible a trial would be. A mutation prevalence of 10.7 per 100,000 was demonstrated, suggesting significant under diagnosis of the disease across much of Scotland. Cerebral hypoperfusion is thought to be important in CADASIL, and it has been shown that vascular abnormalities precede the development of brain pathology in mouse models. Investigation of vascular function in patients, both in the brain and systemically, requires less invasive measures. Arterial spin labelling magnetic resonance imaging (MRI) and transcranial Doppler ultrasound (TCD) can both be used to obtain non-invasive and quantifiable indices of vascular function. Monitoring patients with MRI whilst they receive different concentrations of inspired oxygen and carbon dioxide can provide information on brain function, and I reviewed the practicalities of this technique in order to guide the design of the studies in this thesis. 22 CADASIL patients were recruited to a longitudinal study. Testing included peripheral vascular assessment, assessment of disability, neurological dysfunction, mood and cognition. A CO2 reactivity challenge during both TCD and arterial spin labelling MRI, and detailed MRI sequences were obtained. I was able to demonstrate that vasoreactivity was associated with the number of lacunes and brain atrophy, as were carotid intima-media thickness, vessel stiffness, and age. Patients with greater disability, higher depressive symptoms and poorer processing speed showed a tendency to worse cerebral vasoreactivity but numbers were small. This observation suggests vasoreactivity may have potential as a therapeutic target, or a biomarker. I then wished to establish if arterial spin labelling MRI was useful for assessing change in cerebral blood flow in CADASIL patients. Cortical grey matter showed the highest blood flow, mean (SD), 55 (10) ml/100g/min and blood flow was significantly lower within hyperintensities (19 (4) ml/100g/min; p <0.001). Over one year, blood flow in both grey matter (mean -7 (10) %; p = 0.028) and deep white matter (-8 (13) %; p = 0.036) declined significantly. Cerebrovascular reactivity did not change over one year. I then investigated whether baseline vascular markers were able to predict change in radiological or neuropsychological measures of disease. Changes in brain volume, lacunes, microbleeds and normalised subcortical hyperintensity volume (increase of 0.8%) were shown over one year. Baseline vascular parameters were not able to predict these changes, or those in neuropsychological testing. NOTCH3 is found throughout the body and a systemic vasculopathy has been seen particularly affecting resistance vessels. Gluteal biopsies were obtained from 20 CADASIL patients, and ex vivo myography investigated the response to vasoactive agents. Evidence of impairment in both vasodilation and vasoconstriction was shown. The addition of antioxidants improved endothelium-dependent relaxation, indicating a role for oxidative stress in CADASIL pathology. Myography measures were not related to in vivo measures in the sub-group of patients who had taken part in both studies. The small vessels affected in CADASIL are unable to be imaged by conventional MR imaging so I aimed to establish which vessels might be responsible for lacunes with use of a microangiographic template overlaid onto brain images registered to a standard brain template. This showed most lacunes are small and associated with tertiary arterioles. On the basis of this thesis, it is concluded that vascular dysfunction plays an important role in the pathophysiology of CADASIL, and further assessment of vascular measures in longitudinal studies is needed. Arterial spin labelling MRI should be used as it is a reliable, non-invasive modality that can measure change over one year. Furthermore conventional cardiovascular risk factor prevention should be undertaken in CADASIL patients to delay the deleterious effects of the disease.

Denominações de origem e indicações geográficas na tradução vitivinícola: problemas terminológicos

O objetivo desta dissertação é examinar problemas terminológicos e a importância da preparação e pesquisa terminológica na tradução especializada. O tema escolhido é a tradução de documentação sobre as Denominações de Origem e Indicações Geográficas dos vinhos portugueses, nomeadamente dos vinhos da Região do Dão. Começa-se por apresentar no Capítulo I uma introdução às Denominações de Origem e as classificações utilizadas para vinhos portugueses. No Capítulo II estudamos os problemas mais comuns dos recursos tradutológicos, contemplando a preparação e a pesquisa terminológica que devem anteceder o processo de tradução, discutindo a bibliografia relevante e caraterizando o corpus de análise. No Capítulo III discutimos os recursos para a tradução vitivinícola. No Capítulo IV contemplamos os problemas de tradução nos documentos escolhidos para a tradução e as suas soluções. Finalmente, apresentamos as conclusões e sugerimos vias para investigações posteriores; Designations of Origin and Geographical Indications in Translating Wine- Related Documents: Terminological Problems ABSTRACT: The purpose of this dissertation is to examine terminological problems and the importance of preparation and terminology work in the field of specialized translation. The chosen topic is the translation of documents containing terminology about Designations of Origin and Geographical Indications of Portuguese wines, namely wines from the Dão region. Chapter I provides an introduction to Designations of Origin in general and then specifically for Portuguese wines. Chapter II examines common translation resource problems and the importance of documentation and terminology work prior to the translation process; then, it discusses the relevant bibliography. Chapter III provides a translation of two documents about Designations of Origin, namely Labelling Regulations and Guide for Technical Procedures of Management and Control for the wines of the Dão. Chapter IV discusses the difficulties and solutions for the translation problems encountered during the process. Finally, the conclusions are shown and suggestions for future research are given.

Oxidative stress and its haemodynamic consequences in chronic kidney disease

Chronic kidney disease (CKD) is associated with increased cardiovascular risk in comparison with the general population. This can be observed even in the early stages of CKD, and rises in proportion to the degree of renal impairment. Not only is cardiovascular disease (CVD) more prevalent in CKD, but its nature differs too, with an excess of morbidity and mortality associated with congestive cardiac failure, arrhythmia and sudden death, as well as the accelerated atherosclerosis which is also observed. Conventional cardiovascular risk factors such as hypertension, dyslipidaemia, obesity, glycaemia and smoking, are highly prevalent amongst patients with CKD, although in many of these examples the interaction between risk factor and disease differs from that which exists in normal renal function. Nevertheless, the extent of CVD cannot be fully explained by these conventional risk factors, and non-conventional factors specific to CKD are now recognised to contribute to the burden of CVD. Oxidative stress is a state characterised by excessive production of reactive oxygen species (ROS) and other radical species, a reduction in the capacity of antioxidant systems, and disturbance in normal redox homeostasis with depletion of protective vascular signalling molecules such as nitric oxide (NO). This results in oxidative damage to macromolecules such as lipids, proteins and DNA which can alter their functionality. Moreover, many enzymes are sensitive to redox regulation such that oxidative modification to cysteine thiol groups results in activation of signalling cascades which result in adverse cardiovascular effects such as vascular and endothelial dysfunction. Endothelial dysfunction and oxidative stress are present in association with many conventional cardiovascular risk factors, and can be observed even prior to the development of overt, clinical, vascular pathology, suggesting that these phenomena represent the earliest stages of CVD. In the presence of CKD, there is increased ROS production due to upregulated NADPH oxidase (NOX), increase in a circulating asymmetric dimethylarginine (ADMA), uncoupling of endothelial nitric oxide synthase (eNOS) as well as other mechanisms. There is also depletion in exogenous antioxidants such as ascorbic acid and tocopherol, and a reduction in activity of endogenous antioxidant systems regulated by the master gene regulator Nrf-2. In previous studies, circulating markers of oxidative stress have been shown to be increased in CKD, together with a reduction in endothelial function in a stepwise fashion relating to the severity of renal impairment. Not only is CVD linked to oxidative stress, but the progression of CKD itself is also in part dependent on redox sensitive mechanisms. For example, administration of the ROS scavenger tempol attenuates renal injury and reduces renal fibrosis seen on biopsy in a mouse model of CKD, whilst conversely, supplementation with the NOS inhibitor L-NAME causes proteinuria and renal impairment. Previous human studies examining the effect of antioxidant administration on vascular and renal function have been conflicting however. The work contained in this thesis therefore examines the effect of antioxidant administration on vascular and endothelial function in CKD. Firstly, 30 patients with CKD stages 3 – 5, and 20 matched hypertensive controls were recruited. Participants with CKD had lower ascorbic acid, higher TAP and ADMA, together with higher augmentation index and pulse wave velocity. There was no difference in baseline flow mediated dilatation (FMD) between groups. Intravenous ascorbic acid increased TAP and O2-, and reduced central BP and augmentation index in both groups, and lowered ADMA in the CKD group only. No effect on FMD was observed. The effects of ascorbic acid on kidney function was then investigated, however this was hindered by the inherent drawbacks of existing methods of non-invasively measuring kidney function. Arterial spin labelling MRI is an emerging imaging technique which allows measurement of renal perfusion without administration of an exogenous contrast agent. The technique relies upon application of an inversion pulse to blood within the vasculature proximal to the kidneys, which magnetically labels protons allowing measurement upon transit to the kidney. At the outset of this project local experience using ASL MRI was limited and there ensued a prolonged pre-clinical phase of testing with the aim of optimising imaging strategy. A study was then designed to investigate the repeatability of ASL MRI in a group of 12 healthy volunteers with normal renal function. The measured T1 longitudinal relaxation times and ASL MRI perfusion values were in keeping with those found in the literature; T1 time was 1376 ms in the cortex and 1491 ms in the whole kidney ROI, whilst perfusion was 321 mL/min/100g in the cortex, and 228 mL/min/100g in the whole kidney ROI. There was good reproducibility demonstrated on Bland Altman analysis, with a CVws was 9.2% for cortical perfusion and 7.1% for whole kidney perfusion. Subsequently, in a study of 17 patients with CKD and 24 healthy volunteers, the effects of ascorbic acid on renal perfusion was investigated. Although no change in renal perfusion was found following ascorbic acid, it was found that ASL MRI demonstrated significant differences between those with normal renal function and participants with CKD stages 3 – 5, with increased cortical and whole kidney T1, and reduced cortical and whole kidney perfusion. Interestingly, absolute perfusion showed a weak but significant correlation with progression of kidney disease over the preceding year. Ascorbic acid was therefore shown to have a significant effect on vascular biology both in CKD and in those with normal renal function, and to reduce ADMA only in patients with CKD. ASL MRI has shown promise as a non-invasive investigation of renal function and as a biomarker to identify individuals at high risk of progressive renal impairment.

Vivre avec un statut « dangereux » : l’expérience pénale d’hommes déclarés « délinquants dangereux » ou « délinquants à contrôler »

Cette recherche qualitative a comme objectif de comprendre et d’analyser l’expérience pénale d’individus ayant été déclarés « délinquants dangereux » ou « délinquants à contrôler », en vertu des dispositions légales prévues à la Partie XXIV (articles 752 et suivantes) du Code criminel canadien. Plus spécifiquement, nous avons voulu mettre en lumière comment se vit l’apposition de ce statut « dangereux » au plan personnel et social au moment des procédures judiciaires, lors de l’exécution de leur peine d’incarcération et dans le cadre de leur liberté surveillée, le cas échéant. Pour ce faire, nous avons rencontré dix-neuf hommes visés par ces dispositions légales afin de restituer en profondeur leur expérience pénale par rapport à ce « statut » légalement imposé, et ce, à partir de leur point de vue. Il en ressort que les individus faisant l’objet d’une déclaration spéciale traversent un grand bouleversement émotif, d’une part, en lien avec les délits qu’ils ont commis et d’autre part, relativement à la peine leur ayant été imposée. Ces sentiments complexes semblent se positionner en paradoxe entre un sentiment de culpabilité pour les gestes commis et l’impression d’avoir été traités injustement. Les hommes rencontrés partagent également un parcours pénal difficile marqué par de l’exclusion, du rejet ainsi que des mauvais traitements physiques ou psychologiques. Ils rapportent beaucoup d’impuissance à pouvoir faire évoluer leur situation, soit de se défaire de leur statut « dangereux ». Enfin, l’analyse des propos rapportés montre que l’imposition d’une déclaration spéciale ne constitue pas une « simple » peine puisqu’elle induit un processus de stigmatisation immédiat, discréditant et permanent qui a des implications importantes au niveau social et personnel. Ces implications ont de fait, engendré une transformation à l’égard de la perception qu’ils ont d’eux-mêmes ainsi que dans leurs façons de se comporter socialement.