Role of the protective gene Heme Oxygenase-1 in the control of T cell mediated responses

Tese de doutoramento em Ciências Biomédicas, (Ciências Biopatológicas), apresentada à Universidade de Lisboa através da Faculdade de Medicina, 2008As reacções inflamatórias, geralmente desencadeadas por infeccões e/ou lesões a nível dos tecidos, desempenham um papel fundamental na iniciação de respostas imunes adaptativas e conduzem, em última análise, à eliminação do evento instigador. São vários os mecanismos intrínsecos a esta resposta complexa que asseguram, após a remoção do estímulo nocivo, a correcta reparação quer a nível estrutural quer funcional do tecido afectado, ou seja, o regresso à homeostase. A importância destes mecanismos pode ser comprovada pelo facto de a não resolução das reacções inflamatórias ser uma etapa crítica para o estabelecimento e/ou progressão de um número crescente de patologias. Um dos mecanismos envolvidos na resolução da inflamação consiste na expressão do enzima Heme Oxygenase-1 (HO-1). Em condições inflamatórias, a HO-1 torna-se o enzima limitante no catabolismo dos grupos hémicos livres dando origem a quantidades equimolares de monoxido de carbono (CO), ferro (Fe) e biliverdina (BV). Estes produtos reduzem a reacção inflamatória e evitam o desenvolvimento de doenças inflamatórias. Esta Tese teve como objectivo examinar o papel da HO-1 na regulação do estabelecimento e progressão de condições neuroinflamatórias mediadas por linfócitos T. O trabalho agora apresentado sugere que a HO-1 dita o resultado patológico associado com processos neuroinflamatórios em ratinho, tais como a encefalomielite autoimune experimental (EAE), um modelo de esclerose múltipla (EM), ou a malária cerebral experimental (MCE) resultante da infecção com Plasmodium spp.Inflammatory reactions, elicited in most cases upon infection and/or injury, are critical for the initiation of adaptive immunity and ultimately lead to the removal of the inciting stimuli. Intrinsic to this complex response, there are several mechanisms that operate to ensure that, once the inciting stimulus is dealt with, structural and functional repair of the injured site is attained, i.e. return to homeostasis. However, failure to resolve inflammatory reactions is thought to contribute in a critical manner to the establishment and/or progression of a growing list of pathologic conditions. One of the mechanisms involved in the resolution of inflammation relies in the expression of Heme Oxygenase (HO)-1. Under inflammatory conditions, HO-1 becomes the rate-limiting enzyme in the catabolism of heme, yielding equimolar amounts of carbon monoxide (CO), free iron (Fe) and biliverdin (BV). These heme degradation products dampen inflammation and prevent the development of inflammatory diseases. The focus of this Thesis was to address whether HO-1 regulates the establishment and progression of T cell-mediated neuroinflammatory conditions. The body of work presented herewith suggests that HO-1 can dictate the pathologic outcome of neuroinflammation in mice, as it occurs either during autoimmunity-driven experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS), or during experimental cerebral malaria (ECM) triggered upon infection with Plasmodium spp. Induction of EAE in HO-1-deficient (Hmox-1-/-) mice led to enhanced central nervous system (CNS) demyelination, paralysis and mortality, as compared to wild-type (Hmox-1+/+) mice. Pharmacological induction of HO-1 expression after EAE onset improved the clinical course of the disease, an effect associated with inhibition of T helper (TH) and CD8+ T cell accumulation, proliferation and effector function within the CNS. HO-1 did not act via modulation of the suppressor activity of naturally occurring regulatory T cells (Treg), known to ensure peripheral tolerance to self-antigens and immune homeostasis. Furthermore, under homeostatic conditions Treg development, maintenance and function were found to be independent of HO-1, as assessed in Hmox-1-/- mice. Instead, the mechanism underlying the protective effect of HO-1 is shown to rely on its ability to inhibit major histocompatibility complex (MHC) class II expression by antigen presenting cells, including dendritic cells, microglia and macrophages. Likewise, Hmox-1 deletion or pharmacological inhibition of its activity resulted in increased ECM incidence in otherwise resistant mouse strains whereas pharmacological induction of HO-1 greatly reduced ECM incidence in susceptible mouse strains. The protection afforded by pharmacological induction of HO-1 expression was associated with decreased CD8+ T cell sequestration in the CNS, a critical event in the development of neurological damage associated with ECM. In both pathologies, i.e. EAE and ECM, exogenous CO mimicked these protective effects, suggesting that CO is the main contributor to the protective action of HO-1. Finally, we present evidence of a novel mechanism by which CO counters the development of one of these pathologies, ECM, based on its ability to bind hemoglobin, prevent its oxidation and subsequently the generation of free heme, a central effector molecule in the pathogenesis of ECM. Overall, the findings presented in this Thesis suggest that, during the establishment and/or progression of neuroinflammation, HO-1 and/or CO limit the deleterious effects associated with neuroinflammatory responses, possibly by modulating antigen presenting cells activity, in a manner that prevents the pathologic outcome of these conditions. Further, these results support the notion that pharmacological modulation of HO-1 or CO administration might be potential therapeutic strategies to counter neuroinflammatory diseases

Analysis of proteins from marine molluscs

Application of the two-dimensional gel electrophoresis (2DE) protocols which were developed for samples of mammalian origin gives unsatisfactory results when used in samples from marine molluscs. This chapter describes a detailed protocol of 2DE that can be applied to these organisms, especially for Ruditapes decussatus and Bathymodiolus azoricus.info:eu-repo/semantics/publishedVersio

Marketing approaches between Millennials and Gen-Zs in the fashion and beauty industries

This Honors College Undergraduate Senior Thesis analyzes the marketing practices with respect to Gen-Zs and Millennials’ behavior in regard to the beauty and fashion industries. In order to do so, a survey among Gen-Z and Millennial adults from diverse backgrounds was conducted to gather important data. The survey consists of twenty-three questions, some focusing on the participant demographics and cultural backgrounds and the rest focusing on behaviors they have had with various forms of paid advertising through social- media practices. Additionally, this thesis includes insights regarding some of the literature review topics and includes results that enforce some of the analysis. Some of the remarkable results from the research conducted resulted in average Gen-Z and Millennial respondents feeling neutral about the influence of fashion and beauty paid advertisements. Overall, Gen-Z respondents showed to have more influence and pressure in regard to how they look from the exposure to trendy fashion or beauty brands’ advertisements

SATISFACCIÓN PROFESIONAL DE LOS ENFERMEROS: ESTUDIO COMPARATIVO DE LOS CENTROS HOSPITALARIOS Y DE SALUD EN LA REGIÓN DE ÉVORA, PORTUGAL

Objective: to define if the job satisfaction dimensions can vary according the category and the workplace. Method: this is about a descriptive and exploratory study from quantitative approach using a questionnaire with a Lickert scale, in order to collect data. The questionnaire was prepared, pretested and redrafted to cover several dimensions. The sample was nursing professionals who perform in the fourteen health centers and on twenty one care units of the Évora Espírito Santo’s Hospital. We elaborated a share sampling distributed by the four professional categories. Results: the results show a significant and positive correlation between some categories. Conclusion: it is noted that the health centers professionals are more satisfied in the relationship nurse / patient dimension. The health centers professionals also show great satisfaction with the "working relationship and social support" and "job security" dimensions. Hospital professionals have greater satisfaction in the "autonomy and power" dimension. The Health Centers and Hospital professionals are more dissatisfied in the “remuneration” dimension. Descriptors: satisfaction; motivation; nurses

An investigation on automatic systems for fault diagnosis in chemical processes

Plant safety is the most important concern of chemical industries. Process faults can cause economic loses as well as human and environmental damages. Most of the operational faults are normally considered in the process design phase by applying methodologies such as Hazard and Operability Analysis (HAZOP). However, it should be expected that failures may occur in an operating plant. For this reason, it is of paramount importance that plant operators can promptly detect and diagnose such faults in order to take the appropriate corrective actions. In addition, preventive maintenance needs to be considered in order to increase plant safety. Fault diagnosis has been faced with both analytic and data-based models and using several techniques and algorithms. However, there is not yet a general fault diagnosis framework that joins detection and diagnosis of faults, either registered or non-registered in records. Even more, less efforts have been focused to automate and implement the reported approaches in real practice. According to this background, this thesis proposes a general framework for data-driven Fault Detection and Diagnosis (FDD), applicable and susceptible to be automated in any industrial scenario in order to hold the plant safety. Thus, the main requirement for constructing this system is the existence of historical process data. In this sense, promising methods imported from the Machine Learning field are introduced as fault diagnosis methods. The learning algorithms, used as diagnosis methods, have proved to be capable to diagnose not only the modeled faults, but also novel faults. Furthermore, Risk-Based Maintenance (RBM) techniques, widely used in petrochemical industry, are proposed to be applied as part of the preventive maintenance in all industry sectors. The proposed FDD system together with an appropriate preventive maintenance program would represent a potential plant safety program to be implemented. Thus, chapter one presents a general introduction to the thesis topic, as well as the motivation and scope. Then, chapter two reviews the state of the art of the related fields. Fault detection and diagnosis methods found in literature are reviewed. In this sense a taxonomy that joins both Artificial Intelligence (AI) and Process Systems Engineering (PSE) classifications is proposed. The fault diagnosis assessment with performance indices is also reviewed. Moreover, it is exposed the state of the art corresponding to Risk Analysis (RA) as a tool for taking corrective actions to faults and the Maintenance Management for the preventive actions. Finally, the benchmark case studies against which FDD research is commonly validated are examined in this chapter. The second part of the thesis, integrated by chapters three to six, addresses the methods applied during the research work. Chapter three deals with the data pre-processing, chapter four with the feature processing stage and chapter five with the diagnosis algorithms. On the other hand, chapter six introduces the Risk-Based Maintenance techniques for addressing the plant preventive maintenance. The third part includes chapter seven, which constitutes the core of the thesis. In this chapter the proposed general FD system is outlined, divided in three steps: diagnosis model construction, model validation and on-line application. This scheme includes a fault detection module and an Anomaly Detection (AD) methodology for the detection of novel faults. Furthermore, several approaches are derived from this general scheme for continuous and batch processes. The fourth part of the thesis presents the validation of the approaches. Specifically, chapter eight presents the validation of the proposed approaches in continuous processes and chapter nine the validation of batch process approaches. Chapter ten raises the AD methodology in real scaled batch processes. First, the methodology is applied to a lab heat exchanger and then it is applied to a Photo-Fenton pilot plant, which corroborates its potential and success in real practice. Finally, the fifth part, including chapter eleven, is dedicated to stress the final conclusions and the main contributions of the thesis. Also, the scientific production achieved during the research period is listed and prospects on further work are envisaged.La seguridad de planta es el problema más inquietante para las industrias químicas. Un fallo en planta puede causar pérdidas económicas y daños humanos y al medio ambiente. La mayoría de los fallos operacionales son previstos en la etapa de diseño de un proceso mediante la aplicación de técnicas de Análisis de Riesgos y de Operabilidad (HAZOP). Sin embargo, existe la probabilidad de que pueda originarse un fallo en una planta en operación. Por esta razón, es de suma importancia que una planta pueda detectar y diagnosticar fallos en el proceso y tomar las medidas correctoras adecuadas para mitigar los efectos del fallo y evitar lamentables consecuencias. Es entonces también importante el mantenimiento preventivo para aumentar la seguridad y prevenir la ocurrencia de fallos. La diagnosis de fallos ha sido abordada tanto con modelos analíticos como con modelos basados en datos y usando varios tipos de técnicas y algoritmos. Sin embargo, hasta ahora no existe la propuesta de un sistema general de seguridad en planta que combine detección y diagnosis de fallos ya sea registrados o no registrados anteriormente. Menos aún se han reportado metodologías que puedan ser automatizadas e implementadas en la práctica real. Con la finalidad de abordar el problema de la seguridad en plantas químicas, esta tesis propone un sistema general para la detección y diagnosis de fallos capaz de implementarse de forma automatizada en cualquier industria. El principal requerimiento para la construcción de este sistema es la existencia de datos históricos de planta sin previo filtrado. En este sentido, diferentes métodos basados en datos son aplicados como métodos de diagnosis de fallos, principalmente aquellos importados del campo de “Aprendizaje Automático”. Estas técnicas de aprendizaje han resultado ser capaces de detectar y diagnosticar no sólo los fallos modelados o “aprendidos”, sino también nuevos fallos no incluidos en los modelos de diagnosis. Aunado a esto, algunas técnicas de mantenimiento basadas en riesgo (RBM) que son ampliamente usadas en la industria petroquímica, son también propuestas para su aplicación en el resto de sectores industriales como parte del mantenimiento preventivo. En conclusión, se propone implementar en un futuro no lejano un programa general de seguridad de planta que incluya el sistema de detección y diagnosis de fallos propuesto junto con un adecuado programa de mantenimiento preventivo. Desglosando el contenido de la tesis, el capítulo uno presenta una introducción general al tema de esta tesis, así como también la motivación generada para su desarrollo y el alcance delimitado. El capítulo dos expone el estado del arte de las áreas relacionadas al tema de tesis. De esta forma, los métodos de detección y diagnosis de fallos encontrados en la literatura son examinados en este capítulo. Asimismo, se propone una taxonomía de los métodos de diagnosis que unifica las clasificaciones propuestas en el área de Inteligencia Artificial y de Ingeniería de procesos. En consecuencia, se examina también la evaluación del performance de los métodos de diagnosis en la literatura. Además, en este capítulo se revisa y reporta el estado del arte correspondiente al “Análisis de Riesgos” y a la “Gestión del Mantenimiento” como técnicas complementarias para la toma de medidas correctoras y preventivas. Por último se abordan los casos de estudio considerados como puntos de referencia en el campo de investigación para la aplicación del sistema propuesto. La tercera parte incluye el capítulo siete, el cual constituye el corazón de la tesis. En este capítulo se presenta el esquema o sistema general de diagnosis de fallos propuesto. El sistema es dividido en tres partes: construcción de los modelos de diagnosis, validación de los modelos y aplicación on-line. Además incluye un modulo de detección de fallos previo a la diagnosis y una metodología de detección de anomalías para la detección de nuevos fallos. Por último, de este sistema se desglosan varias metodologías para procesos continuos y por lote. La cuarta parte de esta tesis presenta la validación de las metodologías propuestas. Específicamente, el capítulo ocho presenta la validación de las metodologías propuestas para su aplicación en procesos continuos y el capítulo nueve presenta la validación de las metodologías correspondientes a los procesos por lote. El capítulo diez valida la metodología de detección de anomalías en procesos por lote reales. Primero es aplicada a un intercambiador de calor escala laboratorio y después su aplicación es escalada a un proceso Foto-Fenton de planta piloto, lo cual corrobora el potencial y éxito de la metodología en la práctica real. Finalmente, la quinta parte de esta tesis, compuesta por el capítulo once, es dedicada a presentar y reafirmar las conclusiones finales y las principales contribuciones de la tesis. Además, se plantean las líneas de investigación futuras y se lista el trabajo desarrollado y presentado durante el periodo de investigación

Adolescents sexual practices

Introduction: If teens options are experimenting sexualized practices, we should facilitate their knowledge, make them aware of their choices and help them living their sexuality in a safer mode. Objectives: To identify adolescents sexual practices; characterize the attitudes of teenagers against the use of contraception. Methods: quantitative research with exploratory nature. We studied a convenience sample of 301 adolescents of both sexes whitch attend the 9th grade. Sexual practices and attitudes towards the use of contraception were assessed by "Contraceptive Attitude Scale" (CAS) Kyes (sd). Statistical analysis using SPSS-19, we used measures of central tendency, measures of dispersion, mean difference tests One-way ANOVA. Results: The presence of young people with sexual experience. The petting is used by the majority (62.2%), the practice of coitus are at 19.6% and auto-eroticism is denied by the majority (56.8%), while 43.2% report that their practice. For the petting and considering the sex of the subjects, there are some significant differences : (U (299) = 8004, Z = -4.14, p <.05) and the same occurs in the autoeroticism (U (299) = 1899 Z = -13.56, p <.05), in the intercourse in sexually active, there are no significant differences (U (299) = 10650.5, Z = - .233, p = .816). The consistent use of contraception is approximately (50.8%) to the inconsistent use (49.2%), with no differences according to the gender of the subjects (U (59) = 325.5, Z = -1523, p = .128) Conclusions: Alentejo region is considered as problematic in what concerns to our sample of adolescent motherhood and the risky practices coitu

Pharmacogenetics of hypercholesterolemia drugs

Doentes com dislipidemia grave necessitam de tomar medicação antidislipidémica para diminuir as concentrações elevadas de colesterol de forma a reduzirem o seu elevado risco cardiovascular. Distintos tipos e/ou doses de estatinas levam a diferentes níveis de redução dos níveis de LDL-C, mas existe uma grande variação interpessoal na resposta, que se pensa estar associada a variantes nos genes envolvidos na farmacodinâmica e farmacocinética desta classe de fármacos. Este trabalho tem como objetivo determinar a prevalência de genótipos associados a uma menor eficácia ou a um maior risco de efeitos secundários adversos no tratamento com estatinas na população portuguesa. Foram genotipados vários SNPs envolvidos no metabolismo, absorção, transporte e/ou excreção dos vários tipos de estatinas numa amostra de adultos da população portuguesa proveniente das diferentes regiões do país. A variante SLCO1B1*5, associada com um maior risco de desenvolver miopatia com o tratamento com sinvastatina, tem uma frequência 2 vezes superior na nossa amostra do que o descrito nas bases de dados populacionais. Este fato, aliado ao grande aumento de consumo nacional de estatinas, principalmente de sinvastatina, é um fator importante que deve ser considerado na tomada de decisão da prescrição de antidislipidémicos.Patients with severe dyslipidaemia need to take antidislipidemic medication to lower the high cholesterol concentrations to decrease their increased cardiovascular risk. Different types and/or dose of statins lead to different levels of LDL-C reduction, but there is a large interpersonal variation in the response, which is thought to be associated with variants in genes involved in pharmacodynamics and pharmacokinetics of this class of drugs. This work aims to determine the prevalence of genotypes associated with a lower efficacy or a higher risk of adverse side effects in the treatment with statins in the Portuguese population. Several SNPs involved in the metabolism, absorption, transport and/or excretion of the various types of statins were genotyped in a sample of adults from the Portuguese population from different regions of the country. The SLCO1B1*5 variant, associated with an increased risk of developing myopathy on simvastatin treatment, has a frequency 2 times higher in our sample than described in the population databases. This fact, coupled with the large increase in national consumption of statins, mainly simvastatin, is an important factor that should be considered in the decision-making of the prescription of antidislipidemics.info:eu-repo/semantics/publishedVersio

Os Alvos Aéreos na Artilharia Antiaérea do Exército Português

O presente Trabalho de Investigação Aplicada tem como finalidade investigar se os alvos aéreos que o Exército Português possui são os mais indicados para os nossos sistemas de armas de Artilharia Antiaérea efetuarem o seu treino, bem como analisar, face às novas ameaças aéreas, se os alvos aéreos que possuímos e utilizamos atualmente têm as capacidades para simular uma ameaça aérea atual. A elaboração deste trabalho teve lugar no Regimento de Artilharia Antiaérea Nº 1, tendo por base a consulta e análise de documentos, realização de entrevistas e relatos de experiências pessoais de diferentes militares com créditos neste domínio. Este trabalho inicia-se com o estudo do ambiente contemporâneo em que se desenrolam as operações militares e as novas ameaças aéreas que fazem parte dos fatores operacionais militares. Evidencia, também o importante papel que a defesa aérea assume, nos nossos dias, e demonstra a importância do treino operacional das unidades de Artilharia Antiaérea que culminam obrigatoriamente com o treino das suas guarnições. No decorrer da investigação identificam-se as principais características que um alvo aéreo deve possuir para garantir o treino operacional das nossas forças de Artilharia Antiaérea, bem como, as limitações que surgiram com os alvos aéreos utilizados anteriormente pelo Exército Português, de modo a que numa futura aquisição essas limitações sejam colmatadas ou reduzidas. Numa fase posterior da investigação são identificados os sistemas de alvos aéreos mais desenvolvidos da atualidade e investiga-se se esses são adequados aos nossos sistemas de armas de Artilharia Antiaérea do Exército Português. Na parte final da investigação são apresentadas as respetivas conclusões que procuram responder à pergunta de partida bem como às perguntas derivadas, concluindo que os alvos aéreos existentes atualmente não têm capacidade de simular as características necessárias de todas as ameaças aéreas, evidenciando que a Artilharia Antiaérea não está totalmente preparada para fazer face às novas ameaças aéreas.Abstract This applied research paper aims to investigate if the aerial targets that the Portuguese Army owns are the best suited to train the Air Defence Artillery weapons systems, as well as to analyse, taking into account the new aerial threats, if the aerial targets we currently possess and use have the capacity to simulate a present-day aerial threat. The making of this paper took place in the 1st Air Defence Artillery Regiment, and it was based upon the inquiry and analysis of documents, interviews and reports of personal experiences by different military members with relevant knowledge in this domain environment. This paper begins with a study of the contemporaneous setting where the military operations and new aerial threats take place, which are part of the military operational factors. It also points out the significant role that air defence plays nowadays, and the relevance of the operational training of Air Defence units, which mandatorily culminate with the training of its garrisons. During this research, are identified the main characteristics that an aerial target must have to allow the operational training of Air Defence Artillery forces, as well as the limitations that emerged with the aerial targets previously used by the Portuguese Army, so that in a future acquisition those limitations can be reduced or eliminated. On a subsequent phase of this research, we identify the most developed aerial target systems nowadays, and we find out if they are suitable to our weapons systems of Air Defence Artillery. On the last part of this research, we present the conclusions that seek to answer the initial and derived questions, concluding that the aerial targets are unable to simulate the necessary characteristics of all aerial threats. This shows that the Portuguese Artillery is not completely prepared to face new aerial threats