Campanhas publicitárias de prevenção rodoviária em Portugal

Dissertação de Mestrado apresentada à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências da Comunicação, com especialização em Marketing e Comunicação Estratégica.

Estudo do comportamento no âmbito da radioprotecção de uma população trabalhadora na área da medicina dentária

Monografia apresentada à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Licenciada em Medicina Dentária

O Impacto das Alergias Alimentares no dia-a-dia

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

Infeções Herpéticas

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

Farmacologia e terapêutica do fármaco Benfluorex

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

Avaliação dos efeitos positivos do consumo moderado de álcool

Projeto de Pós-Graduação/Dissertação apresentado à Universidade Fernando Pessoa como parte dos requisitos para obtenção do grau de Mestre em Ciências Farmacêuticas

Hazard and early warning analysis based on domain specific modeling technologies

An aim of proactive risk management strategies is the timely identification of safety related risks. One way to achieve this is by deploying early warning systems. Early warning systems aim to provide useful information on the presence of potential threats to the system, the level of vulnerability of a system, or both of these, in a timely manner. This information can then be used to take proactive safety measures. The United Nation’s has recommended that any early warning system need to have four essential elements, which are the risk knowledge element, a monitoring and warning service, dissemination and communication and a response capability. This research deals with the risk knowledge element of an early warning system. The risk knowledge element of an early warning system contains models of possible accident scenarios. These accident scenarios are created by using hazard analysis techniques, which are categorised as traditional and contemporary. The assumption in traditional hazard analysis techniques is that accidents are occurred due to a sequence of events, whereas, the assumption of contemporary hazard analysis techniques is that safety is an emergent property of complex systems. The problem is that there is no availability of a software editor which can be used by analysts to create models of accident scenarios based on contemporary hazard analysis techniques and generate computer code that represent the models at the same time. This research aims to enhance the process of generating computer code based on graphical models that associate early warning signs and causal factors to a hazard, based on contemporary hazard analyses techniques. For this purpose, the thesis investigates the use of Domain Specific Modeling (DSM) technologies. The contributions of this thesis is the design and development of a set of three graphical Domain Specific Modeling languages (DSML)s, that when combined together, provide all of the necessary constructs that will enable safety experts and practitioners to conduct hazard and early warning analysis based on a contemporary hazard analysis approach. The languages represent those elements and relations necessary to define accident scenarios and their associated early warning signs. The three DSMLs were incorporated in to a prototype software editor that enables safety scientists and practitioners to create and edit hazard and early warning analysis models in a usable manner and as a result to generate executable code automatically. This research proves that the DSM technologies can be used to develop a set of three DSMLs which can allow user to conduct hazard and early warning analysis in more usable manner. Furthermore, the three DSMLs and their dedicated editor, which are presented in this thesis, may provide a significant enhancement to the process of creating the risk knowledge element of computer based early warning systems.

Optimisation of immune effector function within the tumour microenvironment

Cancer represents a leading of cause of death in the developed world, inflicting tremendous suffering and plundering billions from health budgets. The traditional treatment approaches of surgery, radiotherapy and chemotherapy have achieved little in terms of cure for this deadly disease. Instead, life is prolonged for many, with dubious quality of life, only for disease to reappear with the inevitable fatal outcome. “Blue sky” thinking is required to tackle this disease and improve outcomes. The realisation and acceptance of the intrinsic role of the immune system in cancer pathogenesis, pathophysiology and treatment represented such a “blue sky” thought. Moreover, the embracement of immunotherapy, the concept of targeting immune cells rather than the tumour cells themselves, represents a paradigm shift in the approach to cancer therapy. The harnessing of immunotherapy demands radical and innovative therapeutic endeavours – endeavours such as gene and cell therapies and RNA interference, which two decades ago existed as mere concepts. This thesis straddles the frontiers of fundamental tumour immunobiology and novel therapeutic discovery, design and delivery. The work undertaken focused on two distinct immune cell populations known to undermine the immune response to cancer – suppressive T cells and macrophages. Novel RNAi mediators were designed, validated and incorporated into clinically relevant gene therapy vectors – involving a traditional lentiviral vector approach, and a novel bacterial vector strategy. Chapter 2 deals with the design of novel RNAi mediators against FOXP3 – a crucial regulator of the immunosuppressive regulatory T cell population. Two mediators were tested and validated. The superior mediator was taken forward as part of work in chapter 3. Chapter 3 deals with transposing the RNA sequence from chapter 2 into a DNA-based construct and subsequent incorporation into a lentiviral-based vector system. The lentiviral vector was shown to mediate gene delivery in vitro and functional RNAi was achieved against FOXP3. Proof of gene delivery was further confirmed in vivo in tumour-bearing animals. Chapter 4 focuses on a different immune cell population – tumour-associated macrophages. Non-invasive bacteria were explored as a specific means of delivering gene therapy to this phagocytic cell type. Proof of delivery was shown in vitro and in vivo. Moreover, in vivo delivery of a gene by this method achieved the desired immune response in terms of cytokine profile. Overall, the data presented here advance exploration within the field of cancer immunotherapy, introduce novel delivery and therapeutic strategies, and demonstrate pre-clinically the potential for such novel anti-cancer therapies.

Digital signal processing and artificial intelligence for the automated classification of food allergy

As a by-product of the ‘information revolution’ which is currently unfolding, lifetimes of man (and indeed computer) hours are being allocated for the automated and intelligent interpretation of data. This is particularly true in medical and clinical settings, where research into machine-assisted diagnosis of physiological conditions gains momentum daily. Of the conditions which have been addressed, however, automated classification of allergy has not been investigated, even though the numbers of allergic persons are rising, and undiagnosed allergies are most likely to elicit fatal consequences. On the basis of the observations of allergists who conduct oral food challenges (OFCs), activity-based analyses of allergy tests were performed. Algorithms were investigated and validated by a pilot study which verified that accelerometer-based inquiry of human movements is particularly well-suited for objective appraisal of activity. However, when these analyses were applied to OFCs, accelerometer-based investigations were found to provide very poor separation between allergic and non-allergic persons, and it was concluded that the avenues explored in this thesis are inadequate for the classification of allergy. Heart rate variability (HRV) analysis is known to provide very significant diagnostic information for many conditions. Owing to this, electrocardiograms (ECGs) were recorded during OFCs for the purpose of assessing the effect that allergy induces on HRV features. It was found that with appropriate analysis, excellent separation between allergic and nonallergic subjects can be obtained. These results were, however, obtained with manual QRS annotations, and these are not a viable methodology for real-time diagnostic applications. Even so, this was the first work which has categorically correlated changes in HRV features to the onset of allergic events, and manual annotations yield undeniable affirmation of this. Fostered by the successful results which were obtained with manual classifications, automatic QRS detection algorithms were investigated to facilitate the fully automated classification of allergy. The results which were obtained by this process are very promising. Most importantly, the work that is presented in this thesis did not obtain any false positive classifications. This is a most desirable result for OFC classification, as it allows complete confidence to be attributed to classifications of allergy. Furthermore, these results could be particularly advantageous in clinical settings, as machine-based classification can detect the onset of allergy which can allow for early termination of OFCs. Consequently, machine-based monitoring of OFCs has in this work been shown to possess the capacity to significantly and safely advance the current state of clinical art of allergy diagnosis

Early warning sign attributes for the safety of drinking water treatment works

A proactive risk management strategy seeks to prevent accidents from taking place and maintain the safety of a system. In this context, the task of identifying and disseminating early warning signs and signals is among the most important. The problem is that warning signs that are present before an accident takes place are often being overlooked and not picked up or identified as warning signs. If these warning signs were responded to, then an accident may be averted. Accidents occuring in the critical domain of a drinking water treatments works can have serious implications for the public health of consumers of the water supplied. Realising and comprehending early warning signs is a major challenge for the domain of systems safety and especially in the domain of a water treatment works. The approaches that are typically used to enhance the realisation, comprehension and dissemination of early warning signs in the water treatment domain in Ireland mainly involves the creation of accident scenarios, the use of monitoring data and procedures for the dissemination of warnings. While all of these approaches are all useful to inform the mental or process models of possible accident scenarios, nevertheless, accidents are still occurring in this domain. Therefore, a new approach to enhance the comprehension of and effective dissemination of early warning signs is required in order to improve safety and proactive risk management strategies. The contributions of this thesis is the provision of a set of attributes associated with the early warning sign concept that provides meaningful data on the early warning signs and allows recipients to better comprehend them. The values of these attributes were customised for application in the water treatment domain. This research proves that early warning signs at a water treatment works received with information on their attributes are comprehended and communicated more effectively and efficiently than the usual pragmatic approach and thereby improves the safety and proactive risk management strategies.

Immune and stress factors in the pathophysiology of the mdx mouse model of Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy (DMD) is a fatal multi-system neuromuscular disease caused by loss of dystrophin. The loss of dystrophin from membranes of contractile muscle cells and the dysregulation of the DAPC, induces chronic inflammation due to tissue necrosis and eventual replacement with collagen which weakens muscular force and strength. Dystrophin deficiency may cause under-diagnosed features of DMD include mood disorders such as depression and anxiety and dysfunction of the gastrointestinal tract. The first study in the thesis examined mood in the dystrophin-deficient mdx mouse model of DMD and examined the effects of the tri-cyclic antidepressant, amitriptyline on behaviours. Amitriptyline had anti-depressant and anxiolytic effects in the mdx mice possibly through effects on stress factors such as corticotrophin-releasing factor (CRF). This antidepressant also reduced skeletal muscle inflammation and caused a reduction in circulating interleukin (IL)-6 levels. In the second and third studies, we specifically blocked IL-6 signalling and used Urocortin 2, CRFR2 agonist to investigate their potential as therapeutic targets in mdx mice pathophysiology. Isometric and isotonic contractile properties of the diaphragm, were compared in mdx mice treated with anti IL-6 receptor antibodies (anti IL-6R) and/or Urocortin 2. Deficits in force production, work and power detected in mdx mice were improved with treatment. In study three I investigated contractile properties in gastrointestinal smooth muscle. As compared to wild type mice, mdx mice had slower faecal transit times, shorter colons with thickened muscle layers and increased contractile activity in response to recombinant IL-6. Blocking IL-6 signalling resulted in an increase in colon length, normalised faecal output times and a reduction in IL-6-evoked contractile activity. The findings from these studies indicate that for both diaphragm and gastrointestinal function in a dystrophin-deficient model, targeting of IL-6 and CRFR2 signalling has beneficial therapeutic effects.

The ecology of the Irish stoat

The Irish stoat, Mustela erminea hibernica (Thomas and Barrett-Hamilton), has been regarded as an intermediate between the British stoat and the weasel. In this study Irish stoats, mainly from road casualties, were collected and studied. A small number were also live-trapped and radio-tracked. Thus information was gathered on the stoat’s ecology, in particular its form (size and coat colours), reproduction, food habits, parasites, habitat utilisation mortality and predation. The Irish stoats studied were clearly not intermediate in size between British stoats and weasels. They showed considerable size overlap with British stoats, and marked size variation within Ireland. It is argued that size of stoats is determined by food supply early in life. The ventral coat pattern of Irish stoats is apparently unique in the Palaearctic, being similar to that of some stoats found on the west coast of North America. It is argued that this is an example of parallel evolution resulting from adaptation to similar climatic conditions. The stoats were reproductively active in spring and summer. Food consisted mainly of rabbits, but rats, birds, shrews mice and voles were also consumed. Mites were the most numerous ectoparasites, followed by lice, ticks and fleas. Damage by the parasitic nematode Skrjabingylus nasicola was found more frequently in female stoat skulls. Stoats were frequently found in a variety of habitats, both open and wooded. Some of the radio-tracked stoats climbed trees. Dens used were often rat holes. Only one home range, that of a breeding female, was considered to have been accurately measured. It was 22 ha. in size. Mortality is known to have been caused by road accidents and domestic carnivores. It is argued that predation by raptorial birds is important to stoat populations. Results of this study are compared with information available from elsewhere.

Study on street children in four selected towns of Ethiopia

The child is the most precious asset and the focal point of development for any country. However, unless children are brought up in a stimulating and conducive environment getting the best possible care and protection, their physical, mental, emotional and social development is susceptible to permanent damage. Ethiopia, being one of the least developed countries of the world due to interrelated and complex socio-economic factors including man-made and natural calamities, a large portion of our population - especially children - are victimized by social evils like famine, disease, poverty, mass displacement, lack of education and family instability. Owing to the fact that children are the most vulnerable group among the whole society and also because they constitute half of the population it is evident that a considerable number of Ethiopian children are living under difficult circumstances. Therefore, as in a number of other third world countries there are many poor, displaced, unaccompanied and orphaned children in our country. A considerable proportion of these children work on the street with some even totally living on the street without any adult care and protection. These children are forced to the streets in their tight for survival. They supplement their parents meagre income or support themselves with the small incomes they earn doing menial jobs. In doing this, street children face the danger of getting into accidents and violence, they get exploited and abused, many are forced to drop out of school or never get the chance to be enroled at all and some drift into begging or petty crime. This study is undertaken mainly for updating the findings of previous studies, monitoring changing trends, examining new facts of the problem and getting a better understanding of the phenomenon in the country by covering at least some of the major centres where the problem is acute. Thus, the outcome of this research can be useful in the formation of the social welfare programme of the country. Finally, in recognition of the urgency of the problem and the limited resources available, the Ministry of Labour and Social Affairs expresses appreciation to all agencies engaged in the rehabilitation of street children and prevention of the problem. The Ministry also calls for more co-operation and support between concerned governmental and non-governmental organizations in their efforts for improving the situation of street children and in curbing the overwhelming nature of the problem.

VERSATILITY IN THE MODERN PERFORMER: THREE DIVERSE OPERA ROLES

This dissertation project consisted of performances of three diverse operatic roles. The goal was to examine the challenges and benefits of performing diverse repertoire (baroque, classical, and romantic opera, in this case) and to observe how vocal and acting techniques might adjust to different styles and voice classifications. On December 3, 5, 11, and 13,2003, I performed a composite role in Fatal Song, directed by Leon Major, in the Robert & Arlene Kogod Theatre. This opera pastiche, premiered in 1996, contains spoken dialogue, and the music originates from famous eighteenth and nineteenth-century operas. I explored the challenges and benefits of playing three different, well-known opera characters within the same opera, performing four different languages within the same opera, and performing spoken dialogue in an opera. My roles in this pastiche of famous opera included Lucia from Lucia di Lammermoor by Gaetano Donizetti, Manon from Manon by Jules Massenet, and Pamina from Die ZauberJlote by W.A. Mozart. On January 28 and 29, 2005, I performed the role of Nice in Eurilla e Alcindo, a serenata by Antonio Vivaldi, in Homer Ulrich Recital Hall; musical direction by Joseph Gascho and stage direction by Kate Vetter Cain. I explored the challenges and benefits of preparing baroque ornamentation, singing without a conductor, performing an unknown work, staging a work that is not traditionally staged, singing with minimal sets and costumes, and singing with period instruments. On April 16,20, and 24,2005, I performed the role of Musetta in Giacomo Puccini's La BohBme, directed by Pat Diamond and conducted by Jeffrey Rink, in the Ina & Jack Kay Theatre. I examined the challenges and benefits of singing with a large orchestra of modem instruments, singing Puccini rubato and coordinating this with the conductor, and singing a role in one of the most well-known operas in today's repertoire. As a result of this investigation, I concluded that singing different styles, and singing outside one's voice classification, within reason, is beneficial. The knowledge, skill, confidence and insight I acquired by becoming more versatile benefited me as a performer and as a teacher.

Mutations in NGLY1 cause an inherited disorder of the endoplasmic reticulum-associated degradation pathway.

PURPOSE: The endoplasmic reticulum-associated degradation pathway is responsible for the translocation of misfolded proteins across the endoplasmic reticulum membrane into the cytosol for subsequent degradation by the proteasome. To define the phenotype associated with a novel inherited disorder of cytosolic endoplasmic reticulum-associated degradation pathway dysfunction, we studied a series of eight patients with deficiency of N-glycanase 1. METHODS: Whole-genome, whole-exome, or standard Sanger sequencing techniques were employed. Retrospective chart reviews were performed in order to obtain clinical data. RESULTS: All patients had global developmental delay, a movement disorder, and hypotonia. Other common findings included hypolacrima or alacrima (7/8), elevated liver transaminases (6/7), microcephaly (6/8), diminished reflexes (6/8), hepatocyte cytoplasmic storage material or vacuolization (5/6), and seizures (4/8). The nonsense mutation c.1201A>T (p.R401X) was the most common deleterious allele. CONCLUSION: NGLY1 deficiency is a novel autosomal recessive disorder of the endoplasmic reticulum-associated degradation pathway associated with neurological dysfunction, abnormal tear production, and liver disease. The majority of patients detected to date carry a specific nonsense mutation that appears to be associated with severe disease. The phenotypic spectrum is likely to enlarge as cases with a broader range of mutations are detected.