Experimental design methodologies for the identification of Michaelis-Menten type kinetics

The main objective of this work was to investigate the application of experimental design techniques for the identification of Michaelis-Menten kinetic parameters. More specifically, this study attempts to elucidate the relative advantages/disadvantages of employing complex experimental design techniques in relation to equidistant sampling when applied to different reactor operation modes. All studies were supported by simulation data of a generic enzymatic process that obeys to the Michaelis-Menten kinetic equation. Different aspects were investigated, such as the influence of the reactor operation mode (batch, fed-batch with pulse wise feeding and fed-batch with continuous feeding) and the experimental design optimality criteria on the effectiveness of kinetic parameters identification. The following experimental design optimality criteria were investigated: 1) minimization of the sum of the diagonal of the Fisher information matrix (FIM) inverse (A-criterion), 2) maximization of the determinant of the FIM (D-criterion), 3) maximization of the smallest eigenvalue of the FIM (E-criterion) and 4) minimization of the quotient between the largest and the smallest eigenvalue (modified E-criterion). The comparison and assessment of the different methodologies was made on the basis of the Cramér-Rao lower bounds (CRLB) error in respect to the parameters vmax and Km of the Michaelis-Menten kinetic equation. In what concerns the reactor operation mode, it was concluded that fed-batch (pulses) is better than batch operation for parameter identification. When the former operation mode is adopted, the vmax CRLB error is lowered by 18.6 % while the Km CRLB error is lowered by 26.4 % when compared to the batch operation mode. Regarding the optimality criteria, the best method was the A-criterion, with an average vmax CRLB of 6.34 % and 5.27 %, for batch and fed-batch (pulses), respectively, while presenting a Km’s CRLB of 25.1 % and 18.1 %, for batch and fed-batch (pulses), respectively. As a general conclusion of the present study, it can be stated that experimental design is justified if the starting parameters CRLB errors are inferior to 19.5 % (vmax) and 45% (Km), for batch processes, and inferior to 42 % and to 50% for fed-batch (pulses) process. Otherwise equidistant sampling is a more rational decision. This conclusion clearly supports that, for fed-batch operation, the use of experimental design is likely to largely improve the identification of Michaelis-Menten kinetic parameters.

Vulnerability of mediterranean watersheds to climate change

Desertification is a critical issue for Mediterranean drylands. Climate change is expected to aggravate its extension and severity by reinforcing the biophysical driving forces behind desertification processes: hydrology, vegetation cover and soil erosion. The main objective of this thesis is to assess the vulnerability of Mediterranean watersheds to climate change, by estimating impacts on desertification drivers and the watersheds’ resilience to them. To achieve this objective, a modeling framework capable of analyzing the processes linking climate and the main drivers is developed. The framework couples different models adapted to different spatial and temporal scales. A new model for the event scale is developed, the MEFIDIS model, with a focus on the particular processes governing Mediterranean watersheds. Model results are compared with desertification thresholds to estimate resilience. This methodology is applied to two contrasting study areas: the Guadiana and the Tejo, which currently present a semi-arid and humid climate. The main conclusions taken from this work can be summarized as follows: • hydrological processes show a high sensitivity to climate change, leading to a significant decrease in runoff and an increase in temporal variability; • vegetation processes appear to be less sensitive, with negative impacts for agricultural species and forests, and positive impacts for Mediterranean species; • changes to soil erosion processes appear to depend on the balance between changes to surface runoff and vegetation cover, itself governed by relationship between changes to temperature and rainfall; • as the magnitude of changes to climate increases, desertification thresholds are surpassed in a sequential way, starting with the watersheds’ ability to sustain current water demands and followed by the vegetation support capacity; • the most important thresholds appear to be a temperature increase of +3.5 to +4.5 ºC and a rainfall decrease of -10 to -20 %; • rainfall changes beyond this threshold could lead to severe water stress occurring even if current water uses are moderated, with droughts occurring in 1 out of 4 years; • temperature changes beyond this threshold could lead to a decrease in agricultural yield accompanied by an increase in soil erosion for croplands; • combined changes of temperature and rainfall beyond the thresholds could shift both systems towards a more arid state, leading to severe water stresses and significant changes to the support capacity for current agriculture and natural vegetation in both study areas.

Matching CO2 large point sources and potential geological storage sites in mainland Portugal

Dissertação apresentada na Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa para obtenção do grau de Mestre em Engenharia do Ambiente, Perfil Gestão e Sistemas Ambientais

A coherent approach to non-integer order derivatives

Signal Processing, vol. 86, nº 10

Biodiversity of cyanobacteria and green algae on monuments in the Mediterranean Basin: an overview

Microbiology (2009), 155, 3476–3490

Controlo da tuberculose em Portugal : papel e qualidade da detecção de casos

RESUMO - A impressionante evolução da incidência notificada desde 1950 evidencia o quanto o sistema de informação é sensível ao esforço de notificação, reflectindo ainda o impacte das medidas de controlo que foram sendo introduzidas, bem como alguma melhoria nas condições sociais com efeito favorável sobre a doença (Briz, 2005). Sendo a tuberculose uma doença de notificação obrigatória, nos termos da Portaria n.º 766/86, de 26 de Dezembro, os casos deverão ser sempre comunicados à Autoridade de Saúde, em impresso aprovado. O facto de a tuberculose ter um sistema de informação próprio tem permitido um conhecimento relativamente completo da situação epidemiológica. (DGS, 1995) Pretende-se caracterizar o perfil de distribuição da incidência notificada da tuberculose pulmonar, em Portugal Continental, nomeadamente a nível distrital, no período compreendido entre 2000 e 2008, inclusive, partindo-se depois para um estudo mais pormenorizado, relacionado com a sensibilidade do sistema de notificação da tuberculose, no sentido de se quantificarem os problemas de subnotificação. Para validação da notificação, serão utilizados os dados de 2007 e 2008. Procurar-se-á depois obter o perfil da incidência ajustada para a detecção em cada um desses anos, avançando-se de seguida para a identificação e caracterização de parâmetros complementares e de acesso fácil que contribuam para interpretar a distribuição geográfica da incidência notificada, em função da sua provável validade. Perante o eventual confronto com o problema da subnotificação, a identificação das razões da menor adesão à notificação de casos de tuberculose pulmonar apresenta-se quase como inevitável, sendo feita através do recurso a entrevistas a informadores-chave. --------------------------------------ABSTRACT - The impressive development of the incidence reported since 1950 shows how the system is sensitive to the effort of notification, still reflects the impact of control measures have been introduced, and some improvement in social conditions with favorable effect on the disease ( Briz, 2005). As tuberculosis a notifiable disease, according to Ordinance No. 766/86, December 26, cases should be reported to the Health Authority, approved in print. The fact that tuberculosis have an information system itself has allowed a relatively complete knowledge of the epidemiological situation. (DGS, 1995) The aim is to characterize the distribution profile of the reported incidence of pulmonary tuberculosis, in Portugal, particularly at district level in the period between 2000 and 2008, starting from then to a more detailed study, related to the sensitivity of the system notification of tuberculosis, in order to quantify the problems of underreporting. For validation of the notification, we used the data from 2007 and 2008. Search will then obtain the profile of the adjusted incidence for detection in each of those years, advancing is then for the identification and characterization of additional parameters and easy access to contribute to interpret the geographical distribution of reported incidence in according to their likely validity. Given the eventual confrontation with the problem of underreporting, the identification of reasons for the lower adherence to reporting cases of pulmonary tuberculosis has become almost as inevitable, being made through the use of interviews with key informants.

Meta-analysis of gender and science research - Country report - Portugal

In Portugal, especially starting in the 1970s, women’s studies had implications on the emergency of the concept of gender and the feminist criticism to the prevailing models about differences between sexes. Until then, women had been absent from scientific research both as subject and as object. Feminism brought more reflexivity to the scientific thinking. After the 25th of April 1974, because of the consequent political openness, several innovating themes of research emerged, together with new concepts and fields of study. However, as far as gender and science relationship is concerned, such studies especially concentrate on higher education institutions. The feminist thinking seems to have two main objectives: to give women visibility, on the one hand, and to denunciate men’s domain in the several fields of knowledge. In 1977, the “Feminine Commission” is created and since then it has been publishing studies on women’s condition and contributing to the enhancement of the reflection of female condition at all levels. In the 1980s, the growing feminisation of tertiary education (both of students and academics), favoured the development of women’s studies, especially on their condition within universities with a special focus on the glass ceiling, despite the lack of statistical data by gender, thus making difficult the analysis of women integration in several sectors, namely in educational and scientific research activities. Other agglutinating themes are family, social and legal condition, work, education, and feminine intervention on political and social movements. In the 1990s, Women Studies are institutionalised in the academic context with the creation of the first Master in Women Studies in the Universidade Aberta (Open University), in Lisbon. In 1999, the first Portuguese journal of women studies is created – “Faces de Eva”. Seminars, conferences, thesis, journals, and projects on women’s studies are more and more common. However, results and publications are not so divulgated as they should be, because of lack of comprehensive and coordinated databases. 2. Analysis by topics 2.1. Horizontal and vertical segregation Research questions It is one of the main areas of research in Portugal. Essentially two issues have been considered: - The analysis of vertical gender segregation in educational and professional fields, having reflexes on women professional career progression with special attention to men’s power in control positions and the glass ceiling. - The analysis of horizontal segregation, special in higher education (teaching and research) where women have less visibility than men, and the under-representation of women in technology and technological careers. Research in this area mainly focuses on description, showing the under-representation of women in certain scientific areas and senior positions. Nevertheless, the studies that analyze horizontal segregation in the field of education adopt a more analytical approach which focuses on the analysis of the mechanisms of reproduction of gender stereotypes, especially socialisation, influencing educational and career choices. 1

The three main marine depositional cycles of the Neogene of Portugal

The present work follows a stratigraphic model for the marine Neogene of Portugal based on the definition of three main marine sedimentary cycles. Conceptually the I, II and III Neogene Cycles can be defined as 2nd order sedimentary sequences with duration ranging from 5 to 8 Ma. The I Neogene Cycle is fully represented only in the Lower Tagus Basin. Ranging from the Early Aquitanian to the Late Burdigalian the I Neogene Cycle testify a transgressive episode in the region of Lisbon and Setúbal Peninsula. Rapid lateral facies variations suggest a shallowmarine basin. This cycle ends with an important Late Burdigalian tectonic compressive event expressed by uplift of the surrounding areas and deformation affecting the Early Miocene deposits of the Arrábida Chain. The II Neogene Cycle includes thick sedimentary sequences covering Paleozoic and Mesozoic formations in the Algarve and Alvalade-Melides regions and it extends as far north as Santarém in the Lower Tagus Basin. Mainly controlled by global eustasy, it was generated by the important positive eustatic trend that characterized the Middle Miocene worldwide to which the Portuguese continental margin acted more or less passively. This cycle ended with a second and the most important compression event starting after the end of the Serravallian affecting the entire Portuguese onshore and shelf areas. This led to an important depositional hiatus of marine sediments for more than 2.5 Ma. During the Early and the Middle Tortonian occurred the clockwise rotation of the Guadalquivir Basin. The thickmarine units deposited afterwards in this basin produced a litostatic load, which seems to have induced subsidence farther west resuming the Neogene marine sedimentation in the Cacela region (Eastern Algarve), during the Late Tortonian. This marks the beginning of the III Neogene Cycle. To the north, in the Sado Basin (Alvalade-Melides region), a similar depositional sequence starts its sedimentation during the Messinian. Further north, in the Pombal-Caldas da Rainha region, marine sedimentation started during the Late Pliocene (Piacenzian). The migration in time, from south to north for the beginning of the marine sedimentation of this cycle is interpreted as reflecting a visco-elastic propagation of the deformation from the Betic chain northwards.

Static detection of anomalies in transactional memory programs

Dissertação apresentada na Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa para a obtenção do Grau de Mestre em Engenharia Informática

A regulação endócrina dos balanços de cálcio

RESUMO: As concentrações circulantes de cálcio são notavelmente constantes a despeito das variações diárias na absorção intestinal e na eliminação renal deste elemento. A regulação da calcémia é um sistema complexo que compreende vários factores controladores (a calcémia, a fosforémia, as concentrações circulantes de paratormona (PTH) e calcitriol além de muitos outros factores como hormonas esteróides em geral, outros iões como o magnésio e outros factores hormonais) e vários órgãos alvo (glândulas paratiroideias, osso, rim e intestino). As respostas dos órgãos alvo também são muito variadas. No caso mais simples, a cristalização de sais de cálcio corresponde a uma mudança de fase em que participam moléculas orgânicas que a iniciam, aceleram ou inibem. Em geral a combinação de um factor controlador com o respectivo receptor de membrana (para polipeptídeos ou iões) ou intracelular (hormonas esteróides) é apenas o primeiro passo de uma cadeia bioquímica que introduz uma enorme amplificação na resposta. A esta variedade de mecanismos de resposta correspondem grandes diferenças nos tempos de resposta que podem ser de minutos a semanas. É hoje possível “observar” (medir) com apreciável rigor nos líquidos biológicos (sangue, urina, fezes, etc.) os factores mais importantes do sistema de regulação da calcémia (cálcio, fósforo, paratormona e calcitriol) assim como administrar estes factores em experiências agudas. Esta possibilidade reflecte – se na literatura neste campo que tem vindo a crescer. O advento das técnicas da biologia molecular tem permitido a caracterização molecular de algumas das disfunções da homeostase do cálcio e é de esperar um diagnóstico fisiopatológico cada vez mais rigoroso dessas disfunções. Com o avanço dos conhecimentos nesta área que não cessa de aumentar temos cada vez maiores capacidades para fazer diagnósticos e é cada vez mais difícil interpretar com rigor os correspondentes quadros metabólicos. A análise ou síntese de sistemas complexos é a actividade mais nobre dos engenheiros que lhes permite desenhar pontes, diques, barcos, aviões ou automóveis. Com o aparecimento de computadores de médio ou grande porte foi – lhes possível utilizar descrições matemáticas não só para desenhar sistemas como ainda para interpretar eventuais falhas na sua operação. Essas descrições matemáticas consistem numa sequência de operações realizadas num computador segundo um “programa informático” que receberam a designação genérica de modelos, por analogia com as famosas leis (equações) da física que foram deduzidas a partir de um certo número de postulados e que permitem representar matematicamente processos físicos. As famosas leis de Newton são talvez os exemplos mais famosos de “modelos” de sistemas físicos. A introdução de modelos matemáticos em biologia e particularmente em medicina só se deu recentemente.MÉTODOS No trabalho que aqui se apresenta construiu - se um modelo simplificado da homeostase do cálcio destinado ao cálculo de variáveis observáveis (concentrações de cálcio, fósforo, PTH e calcitriol) de modo a poderem comparar-se valores calculados com valores observados. A escolha dos componentes do modelo foi determinada pela nossa experiência clínica e pela informação fisiopatológica e clínica publicada. Houve a preocupação de construir o modelo de forma modular de modo a ser possível a sua expansão sem grandes transformações na descrição matemática (e informática) já existente. Na sua fase actual o modelo não pode ser usado como instrumento de diagnóstico. É antes uma ferramenta destinada a esclarecer “em princípio” mecanismos fisiopatológicos. Usou – se o modelo para simular um certo número de observações publicadas e para exemplificar a sua eventual aplicação clínica na simulação de situações hipotéticas e na análise de possíveis mecanismos fisiopatológicos responsáveis por situações de hipo ou hipercalcémias. Simultaneamente fez – se uma análise dos dados acumulados relativos a doentes vistos no Serviço de Endocrinologia do Instituto Português de Oncologia de Francisco Gentil – Centro Regional Oncológico de Lisboa, S.A. CONCLUSÕES Numa população de 894 doentes com patologias variadas do Instituto Português de Oncologia de Lisboa os valores da calcémia tiveram uma distribuição normal unimodal com uma média de 9.56 mg/dl, e um erro padrão de 0.41 mg/dl. Estas observações sugerem que a calcémia está sujeita a regulação. A partir dos resultados publicados em que o metabolismo do cálcio foi perturbado por infusões de cálcio, calcitriol ou PTH, de estudos bioquímicos e fisiológicos sobre os mecanismos de acção de factores controladores da calcémia e do estudo do comportamento de órgãos alvo (paratiroideias, intestino, osso e rim) foi possível construir um modelo matemático de parâmetros concentrados do sistema de regulação da calcémia. As expressões analíticas usadas foram baseadas na cinética enzimática de modo a que os seus parâmetros tivessem um significado físico ou fisiológico simples. O modelo revelou apreciável robustez e flexibilidade. É estável quando não perturbado e transita entre estados estacionários quando perturbado. Na sua forma actual gera simulações que reproduzem satisfatoriamente um número apreciável de dados experimentais colhidos em doentes. Isto não significa que possa ser usado como instrumento de diagnóstico aplicável a doentes individuais. O desenho do modelo comporta a adição posterior de novas relações quando surgirem situações para as quais se revele insuficiente. A utilização exaustiva do modelo permitiu explicitar aspectos do metabolismo do cálcio que ou não estão contidas na sua formulação actual – o aparecimento de hipertrofia ou de adenomas das paratiroideias e as alterações na estrutura óssea , a participação de outros factores controladores – magnésio, ou estão insuficientemente descritas – alterações do metabolismo do fósforo nos hipoparatiroidismos. A análise dos dados relativos aos doentes do Serviço de Endocrinologia do IPO permitiu o início da caracterização dos tipos de patologia que representam e de possíveis mecanismos fisiopatológicos subjacentes. Estas observações são o ponto de partida para análises futuras. São exemplos das relações encontradas: a distribuição dos doentes por dois grandes grupos conforme a calcémia é determinada pelas concentrações circulantes de PTH ou estas são determinadas pela calcémia; a distribuição sazonal das concentrações de Vit. D25. no sangue; a correlação negativa entre estas e as concentrações de PTH no sangue. Também foi possível extrair a cinética do controlo da PTH sobre a síntese de calcitriol. O estudo dos níveis circulantes de PTH no pós-operatório imediato de doentes paratiroidectomizados permitiu determinar as suas taxas de degradação metabólica. O modelo permitiu simular as relações Ca/PTH no sangue, Ca/Fracção excretada da carga tubular, Ca/P no sangue para valores normais ou altos de Ca. Foram feitas simulações de situações fisiopatológicas (em “doentes virtuais”): infusões crónicas de cálcio, PTH e calcitriol; alterações no comportamento de receptores. Estas simulações correspondem a experiências que não podem ser realizadas em humanos. São exemplos da utilização do modelo na exploração de possíveis mecanismos fisiopatológicos através da observação de resultados quantitativos inacessíveis à intuição. O modelo foi útil em duas fases do trabalho: Primeiro, durante a sua síntese implicou uma escolha criticamente selectiva de informação, sua análise quantitativa e processamento, uma explicitação rigorosa (analítica) das relações funcionais entre os controladores e as variáveis e da sua integração numa estrutura global; Segundo, a simulação de situações experimentais ou clínicas (dados do Serviço de Endocrinologia do IPO) em doentes obrigou a explicitar raciocínios fisiopatológicos habitualmente formulados em bases puramente intuitivas. Esta prática revelou comportamentos óbvios após as simulações – acção reduzida das infusões PTH (simulação de hiperparatiroidismos primários) enquanto não há inibição total da respectiva secreção, necessidade de aumento da massa secretora da paratiroideia nas insuficiências renais avançadas, etc. A síntese e utilização do modelo não implicaram uma preparação matemática avançada e foram possíveis mercê da disponibilidade de “software” interactivo especificamente desenhado para a simulação de sistemas dinâmicos em que os programas se escrevem em inglês usando a simbologia simples da álgebra elementar. A função nobre de modelos desta natureza é semelhante à dos modelos usados pelos físicos desde o século XVII: permitir explicações de carácter geral funcionando como uma ferramenta intelectual para manipulação de conceitos e para a realização de “experiências pensadas” (“thought experiments”) respeitando certos princípios físicos (princípios de conservação) que estabelecem as fronteiras da realidade. -------ABSTRACT: Calcium blood levels are remarkably constant despite great variations in calcium daily intake, intestinal absorption and renal excretion. The regulation of the calcium concentration in the blood is achieved by a complex system that includes several controller factors (mainly the serum levels of calcium, phosphorus, parathyroid hormone (PTH) and calcitriol but also of steroid hormones, ions such as magnesium and other hormonal factors) and several target organs (parathyroid glands, bone, kidney and intestine). The functional response to the controlling factors obeys a variety of kinetics. The precipitation of calcium salts is a simple phase transition in which organic molecules may provide nucleation centres or inhibit the process. The combination of a controller factor with its receptor located in the cell membrane (for peptides or ions) or in the nucleus (for steroid hormones) is only the first step of a biochemical chain that introduces a huge amplification in the response. To this great variability of response we have to add the times of response that vary from minutes to weeks. It is possible to “observe” (measure) with great accuracy in biological fluids (blood, urine, faeces, etc.) the most important factors intervening in the calcium regulation (calcium, phosphorus, PTH and calcitriol). The response of the system to acute infusions of the controlling factors has also been studied. Using molecular biology techniques it has been possible to characterize some calcium homeostasis dysfunctions and better physiopathological diagnosis are expected. With the increasingly new knowledge in this area we have better capacity to diagnose but it is harder to explain correctly the underlying metabolic mechanisms. The analysis or synthesis of complex systems is the noble activity of engineers that enables them to draw bridges, dams, boats, airplanes or cars. With the availability of medium-large frame computers it was possible to use mathematical descriptions not only to draw systems but also to explain flaws in its operations. These mathematical descriptions are generally known as models by analogy with the laws (equations) of physics that allow the mathematical description of physical processes. In practice it is not possible to find general solutions for the mathematical descriptions of complex systems but (numeric) computations for specific situations can be obtained with digital computers. The introduction of mathematical models in biology and particularly in medicine is a recent event. METHODS In this thesis a simplified model of calcium homeostasis was built that enables the computation of observable variables (concentrations of calcium, phosphorus, PTH and calcitriol) and allows the comparison between the simulation values and observed values. The choice of the model’s components was made according to our clinical experience and to the published clinical and physiopathological data. The model has a modular design that allows future expansions with minor alterations in its structure. In its present form the model cannot be used for diagnosis. It is a tool designed to enlighten physiopathological processes. To exemplify its possible clinical application in the simulation of hypothetical situations and in the analysis of possible mechanisms responsible for hypo or hypercalcemias the model was used to simulate a certain number of published observations. An analysis of clinical and laboratory data from the Endocrinology Department of the Portuguese Cancer Institute (I.P.O.F.G.-C.R.O.L.,S.A.) is also presented. CONCLUSIONS In a population of 188 patients without an identifiable disease of the calcium metabolism at the Portuguese Cancer Institute the calcemia levels had a unimodal distribution with an average of 9.56 mg/dL and a S.E.M of 0.41 mg/dL. This observation confirms that serum calcium is regulated. Using published data; in which calcium metabolism was disrupted by calcium, PTH or calcitriol infusions; from biochemical and physiological studies of the action of controller factors on the calcemia; in which the response of target organs (parathyroid glands, intestine, bone, kidney) was studied it was possible to build a mathematical model of concentrated parameters of the calcium homeostasis. Analytical expressions used were based on enzymatic kinetics. The model is flexible and robust. It is stable when not disturbed and changes between steady states when disturbed. In its present form it provides simulations that reproduce closely a number of experimental clinical data. This does not mean that it can be used as a diagnostic tool for individual patients. The exhaustive utilisation of the model revealed the need of future expansions to include aspects of the calcium metabolism not included in its present form –hypertrophy or adenomas of the parathyroid glands, bone structure changes, participation of other controller factors such as magnesium – or insufficiently described – phosphate metabolism in hypoparathyroidism. The analysis of the data collected from the I.P.O.’s Endocrinology Department allowed the initial characterization of the different pathologies represented and of their possible physiopathological mechanisms. These observations are a starting point for future analysis. As examples of the relations found were: the distribution of patients in two groups according to the dependency of calcium by PTH levels or PTH levels by calcium concentration; the seasonal distribution of the serum concentrations of D25; its negative correlation with PTH concentration. It was also possible to extract the kinetics of the control of the synthesis of calcitriol by PTH. The analysis of immediate post-surgical levels of PTH in parathyroidectomized patients allowed the determination of its metabolic clearance. The model also allowed the simulation of the relations between Ca/PTH in blood, serum Ca/Fraction of tubular load excreted and Ca/P in blood for normal and high values of calcium. Simulations were made of pathological situations (in “virtual patients”): chronic infusions of calcium, PTH and calcitriol; changes in the characteristics of receptors. These simulations are not possible in real persons. They are an example of the use of this model in exploring possible mechanisms of disease through the observation of quantitative results not accessible to simple intuition. This model was useful in two phases: Firstly, its construction required a careful choice of data, its quantitative analysis and processing, an analytical description of the relations between controller factors and variables and their integration in a global structure. Secondly, the simulation of experimental or clinical (I.P.O.’s Endocrinology Department) data implied testing physiopathological explanations that previously were based on intuition. The construction and utilisation of the model didn’t demand an advanced mathematical preparation since user-friendly interactive software was used. This software was specifically designed for the simulation of dynamic systems. The programs are written in English using elementary algebra symbols. The essential function of this type of models is identical to that of those used by physicists since the XVII century which describe quantitatively natural processes and are an intellectual tool for the manipulation of concepts and the performance of “thought experiments” based in certain physical principles (conservation principles) that are the frontiers of reality.------------------RESUMÉE: Les concentrations circulantes de calcium sont constantes même pendant des variations de l’absorption intestinale et de l’élimination rénale de cet élément. La régulation de la calcémie est un système complexe qui comprend plusieurs éléments contrôleurs (la calcémie, la phosphorémie, les concentrations circulantes de l’hormone parathyroïdienne (PTH) e du calcitriol et d’autres comme les hormones stéroïdes ou des ions comme le magnésium) et plusieurs organes (glandes parathyroïdiennes, l’os, le rein et l’intestin). Les réponses de ces organes sont variées. Dans le cas plus simple, la cristallisation des sels de calcium correspond à un changement de phase dans lequel y participent des molécules organiques que la débutent, l’accélèrent ou l’inhibent. Généralement la combinaison d’un élément contrôleur avec leur récepteur de membrane (pour les peptides ou les ions) ou intracellulaire (pour les hormones stéroïdes) n’est que le premier pas d’une chaîne biochimique qu’introduit une grande amplification de la réponse. A cette variété de réponses correspondent des grandes différences des temps de réponses qu’y vont des minuits a semaines. Il est possible « observer » (mesurer) dans les fluides biologiques (sang, urine, fèces, etc.) les éléments plus importants du système de régulation de la calcémie (calcium, phosphate, PTH et le calcitriol) et les administrer en expérimentes aigus. Cette possibilité est visible dans la littérature publiée dans ce domaine qui est en croissance permanente. L’avenir des techniques de biologie moléculaire a permis caractériser des nombreuses dysfonctions de la régulation de la calcémie et on attend un diagnostique physiopathologique de ces dysfonctions chaque fois plus rigoureuses. Les connaissances dans ce domaine s’agrandissent et on a de plus de capacités pour faire des diagnostiques et il est chaque fois plus difficile les interpréter. L’analyse ou synthèse de systèmes complexes est l’activité plus noble des ingénieurs qui les permit dessiner des ponts, bateaux, avions ou automobiles. Avec des ordinateurs de médium ou grand port il les est possible utiliser descriptions mathématiques pour dessiner les systèmes et interpréter des éventuelles fautes d’opération. Ces descriptions mathématiques sont une séquence d’opérations réalisées dans un ordinateur selon « un programme informatique » qui ont reçu la désignation générique de modèles, pour analogie avec les équations de la physique qui ont été déduits d’un nombre de postulées et qu’ont permit représenter des processus physiques en équations mathématiques. Les fameuses équations de Newton sont peut-être les exemples plus connus des systèmes physiques. L’introduction des modèles mathématiques en biologie et en particulier en médecine est un évènement récent. Dans ce travaille, on a construit un modèle simplifié de l’homéostasie du calcium pour calculer les variables observables (concentrations de calcium, phosphate, PTH et calcitriol) pour les comparer. Les choix des components a été déterminés par notre expérience clinique et par l’information physiopathologique et clinique publiée. Le modèle a été construit de façon modulaire ce que permit leur postérieur expansion sans des grandes altérations dans la description mathématique et informatique déjà existante. Dans cette forme le modèle ne peut être utilisé comme un instrument de diagnostique. Il est un outil pour éclairer la physiopathologie. Le modèle a été utilisé pour simuler un certain nombre d’observations publiées et pour exemplifier leur possible utilisation clinique dans la simulation des hypothèses et de la physiopathologie des situations d’hypo ou hypercalcémie. On a fait une analyse des éléments des procès cliniques des malades observées dans le Service d’Endocrinologie de l’IPOFG-CROL, SA. Dans une population de 894 malades avec des différentes pathologies les valeurs de calcémie on une distribution uni modale avec une Médie de 9.56 mg/dL et une erreur standard de 0.41 mg/dL. Ces observations suggèrent que la calcémie soit sujette de régulation. En utilisant des résultats de travaux publiés dans lesquels le métabolisme du calcium a été changé par des infusions de calcium, calcitriol ou PTH, des études biochimiques et physiologiques sur des mécanismes d’action des éléments contrôleurs de la calcémie et de l’étude du comportement des organes cible (parathyroïdes, intestin, rein, os), il a été possible de construire un modèle mathématique de paramètres concentrés du système de régulation de la calcémie. Les expressions analytiques utilisées ont été basées sur la cinétique enzymatique de façon à que les paramètres aient eu une signification physique ou biologique. Le modèle est stable quand il n’est pas perturbé et transit entre états stationnaires quand il est sujet a des perturbations. A ce moment il fait des simulations qui reproduisent de façon satisfaisant un nombre d’observations expérimentales. La construction du modèle permit l’addiction de nouvelles relations dans les cas ou il est insuffisant. L’utilisation exhaustive du modèle a permit expliciter des aspects du métabolisme du calcium qui y ne sont pas compris – l’hyperplasie ou la formation des adénomes des parathyroïdes, les altérations de la structure des os, la participation d’outres éléments régulateurs (magnésium), ou sont insuffisamment décrites – les altérations du métabolisme des phosphates dans l’hypoparathyroidism. L’analyse de l’information des malades du Service d’Endocrinologie a permit caractériser les pathologies représentées et leurs possibles mécanismes physiopathologiques. Ces observations sont le point de départ pour les analyses futures. Sont des exemples des relations trouvées: la distribution des malades par deux groupes: ceux dans lequel la calcémie est déterminée par la PTH ou ceux dans lesquels la PTH est déterminée par la calcémie; la distribution sazonale de la concentration de la vitamine D; la corrélation négative entre la vitamine D et la PTH. On a eu la possibilité de déduire la cinétique de control de la PTH sur la synthèse du calcitriol. L’étude des niveaux circulants de PTH sur des sujets parathyroidectomisées a permit déduire leur taux de dégradation métabolique. Le modèle a permit simuler les relations Ca/PTH dans le sang, Ca/fraction éliminée par le rein, Ca/P dans le sang pour des valeurs normales ou hautes de calcium. On a fait des simulations de situations physiopathologiques (dans “malades virtuelles”): Infusions chroniques de calcium, PTH ou calcitriol; altérations des récepteurs. Ces simulations ne peuvent pas être réalisées dans les humains. Sont des exemples d’utilisation du modèle dans l’exploration des possibles mécanismes de la physiopathologie en observant des résultats quantitatifs inaccessibles à l’intuition. Le modèle a été utile pendant deux étapes des travaux: La première, dans sa construction on a choisi l’information disponible, son analyse quantitative, l’explicitation rigoureuse (analytique) des relations fonctionnelles entre les contrôleurs et les variables et sa intégration dans une structure globale. La deuxième, la simulation de situations expérimentales ou cliniques (du Service d’Endocrinologie) a obligé d’expliciter des raisonnements physiopathologiques généralement formulés utilisant l’intuition. Cette pratique a montré des comportements – action réduite des infusions de PTH (jusqu’à l’inhibition totale de leur respective sécrétion), nécessité d’augmenter la masse sécréteuse de la parathyroïde dans les insuffisants rénales, etc. La synthèse et utilisation du modèle n’ont pas besoin d’une formation avancée en mathématique et sont possibles grâce à un programme interactif qui a été conçu pour la simulation des systèmes dynamiques dans lesquels le programme se construit en anglais en utilisant la symbolique élémentaire de l’algèbre. La fonction noble de ces modèles est semblable à celles des physiques du XVII siècle: Permettre établir explications générales en fonctionnant comme un outil intellectuel pour manipuler des concepts et pour la réalisation d’expérimentes pensées en respectant certains principes de la physique (principe de la conservation) qu’établissent les frontières de la réalité.

The impact of global forces on the individual: empirical evidence from the German clothing industry

Starting from theoretical perspectives on globalisation, the following article analyses how current working conditions are affected by globalisation processes. For this purpose, recent developments in the German clothing sector are traced back to the power of economic globalisation processes. Characterising the German clothing sector as pioneer in economic globalisation, we use empirical findings to illustrate how current processes of globalisation influence the work place: At organisational level, corporate strategies aim at rationalisation, standardisation and flexibilisation of work in order to response to the economic pressure of global markets. At individual level these strategies, in turn, speed up working processes and intensify working processes for the employees. Although these developments form strong trends, we conclude that the local embeddedness of companies is still of high importance with regard to organisational and individual consequences of globalisation.

Industry level foresight: designing foresight methods for Lithuanian energy sector

Enterprise and Work Innovation Studies,6,IET, pp.9-51

O impacto económico da obesidade em Portugal : custos directos com internamento

RESUMO - A prevalência da obesidade não teve alterações significativas em Portugal. Uma vez que os recursos são escassos e é cada vez mais premente distribuí-los de forma racional, torna-se importante conhecer o impacto económico da obesidade para o país e perceber se os custos se alteraram. Objectivo: Actualizar, à luz de evidência mais recente, a estimativa dos custos directos com internamento hospitalar atribuíveis à obesidade, em Portugal, no ano 2008. Metodologia: Foi estimado o custo directo da obesidade, na componente internamento, a partir da metodologia custo da doença, utilizando uma abordagem baseada na prevalência. Os dados da prevalência advém do estudo epidemiológico mais recente em Portugal (14,4%). Os valores de risco relativo utilizados provêm da meta análise epidemiológica mais completa. Foi calculado, a partir destes dados, o risco atribuível populacional (RAP) de cada patologia. Através da base de dados nacional dos episódios de internamento, fez-se uma pesquisa de todos os episódios de internamento relativos às comorbilidades associadas à obesidade e aplicou-se o respectivo RAP. Com base na portaria n.º 839-A/2009 de 31 Julho atribuíramse os custos. Resultados: Os custos directos com a obesidade, na componente internamento, no ano 2008 foram de 85,9 milhões de euros, o que corresponde a 0,92% da despesa total em saúde. Os três maiores contribuintes para esta despesa são as patologias do sistema circulatório e cerebrovascular, a osteoartrite e os episódios relativos ao tratamento da obesidade em si. Conclusões: O impacto económico relativo ao internamento da obesidade diminuiu em Portugal. Este estudo surge então, como ponto de partida para estudar os custos totais com a obesidade e a efectividade das estratégias de prevenção.

Framework-specific DSL para sensoriamento participado

Dissertação para obtenção do Grau de Mestre em Engenharia Informática

Combining open and closed world reasoning for the semantic web

Dissertação para obtenção do Grau de Doutor em Informática