REMPLI discreet event simulation system

This document presents the design choices on the simulation mechanism used to test the Tansport Layer implementation in the REMPLI project [www.rempli.org].

Children and sand play: screening of potential harmful microorganisms in sandboxes, parks, and beaches

Sand serves as a reservoir for potentially pathogenic microorganisms. Children, a high-risk group, can acquire infections from sand in sandboxes, recreational areas, and beaches. This paper reviews the microbes in sands, with an emphasis on fungi. Recreational areas and beach sands have been found to harbor many types of fungi and microbes. A newly emerging group of fungi of concern include the black yeast-like fungi. After establishing that sand is a reservoir for fungi, clinical manifestations of fungal infections are described with an emphasis on ocular and ear infections. Overall, we recommend environmental studies to develop monitoring strategies for sand and studies to evaluate the link between fungi exposure in sand and human health impacts.

Beach sand and the potential for infectious disease transmission: observations and recommendations

Recent studies suggest that sand can serve as a vehicle for exposure of humans to pathogens at beach sites, resulting in increased health risks. Sampling for microorganisms in sand should therefore be considered for inclusion in regulatory programmes aimed at protecting recreational beach users from infectious disease. Here, we review the literature on pathogen levels in beach sand, and their potential for affecting human health. In an effort to provide specific recommendations for sand sampling programmes, we outline published guidelines for beach monitoring programmes, which are currently focused exclusively on measuring microbial levels in water. We also provide background on spatial distribution and temporal characteristics of microbes in sand, as these factors influence sampling programmes. First steps toward establishing a sand sampling programme include identifying appropriate beach sites and use of initial sanitary assessments to refine site selection. A tiered approach is recommended for monitoring. This approach would include the analysis of samples from many sites for faecal indicator organisms and other conventional analytes, while testing for specific pathogens and unconventional indicators is reserved for high-risk sites. Given the diversity of microbes found in sand, studies are urgently needed to identify the most significant aetiological agent of disease and to relate microbial measurements in sand to human health risk.

The 1531 Lisbon Earthquake: A Tsunami In the Tagus Estuary?

On 26 January 1531, a strong-magnitude earthquake heavily impacted Lisbon downtown. Immediately after the earthquake, the eyewitnesses reported large waves in the Tagus estuary, mainly north of the city and along the northern bank of the river. Descriptions include large impacts on ships anchored in the estuary and even morphological changes in the riverbed. We present a synthesis of the available information concerning both the earthquake and the water disturbance as a basis for the discussion of the probable tectonic source and the magnitude of the associated river oscillations. We hypothesize that the initial disturbance of the water can be attributed to the coseismic deformation of the estuary riverbed, and we use a nonlinear shallow water model to simulate the tsunami propagation and inundation. We show that the Vila Franca de Xira fault is the most probable source of the 1531 event. The largest inundation effects of the model correlate well with the historical descriptions: the impact is relevant in the inner Tagus estuary, but inundation in downtown Lisbon is small.

Abelian realization of phenomenological two-zero neutrino textures

In an attempt at explaining the observed neutrino mass-squared differences and leptonic mixing, lepton mass matrices with zero textures have been widely studied. In the weak basis where the charged lepton mass matrix is diagonal, various neutrino mass matrices with two zeros have been shown to be consistent with the current experimental data. Using the canonical and Smith normal form methods, we construct the minimal Abelian symmetry realizations of these phenomenological two-zero neutrino textures. The implementation of these symmetries in the context of the seesaw mechanism for Majorana neutrino masses is also discussed. (C) 2014 The Authors. Published by Elsevier B.V.

The impact of Sinogram-Affirmed Iterative Reconstruction on patient dose and image quality compared to filtered back projection: a narrative review

Objective: Summarize all relevant findings in published literature regarding the potential dose reduction related to image quality using Sinogram-Affirmed Iterative Reconstruction (SAFIRE) compared to Filtered Back Projection (FBP). Background: Computed Tomography (CT) is one of the most used radiographic modalities in clinical practice providing high spatial and contrast resolution. However it also delivers a relatively high radiation dose to the patient. Reconstructing raw-data using Iterative Reconstruction (IR) algorithms has the potential to iteratively reduce image noise while maintaining or improving image quality of low dose standard FBP reconstructions. Nevertheless, long reconstruction times made IR unpractical for clinical use until recently. Siemens Medical developed a new IR algorithm called SAFIRE, which uses up to 5 different strength levels, and poses an alternative to the conventional IR with a significant reconstruction time reduction. Methods: MEDLINE, ScienceDirect and CINAHL databases were used for gathering literature. Eleven articles were included in this review (from 2012 to July 2014). Discussion: This narrative review summarizes the results of eleven articles (using studies on both patients and phantoms) and describes SAFIRE strengths for noise reduction in low dose acquisitions while providing acceptable image quality. Conclusion: Even though the results differ slightly, the literature gathered for this review suggests that the dose in current CT protocols can be reduced at least 50% while maintaining or improving image quality. There is however a lack of literature concerning paediatric population (with increased radiation sensitivity). Further studies should also assess the impact of SAFIRE on diagnostic accuracy.

A comparison of Sinogram Affirmed Iterative Reconstruction and filtered back projection on image quality and dose reduction in paediatric head CT: a phantom study

Background: Computed tomography (CT) is one of the most used modalities for diagnostics in paediatric populations, which is a concern as it also delivers a high patient dose. Research has focused on developing computer algorithms that provide better image quality at lower dose. The iterative reconstruction algorithm Sinogram-Affirmed Iterative Reconstruction (SAFIRE) was introduced as a new technique that reduces noise to increase image quality. Purpose: The aim of this study is to compare SAFIRE with the current gold standard, Filtered Back Projection (FBP), and assess whether SAFIRE alone permits a reduction in dose while maintaining image quality in paediatric head CT. Methods: Images were collected using a paediatric head phantom using a SIEMENS SOMATOM PERSPECTIVE 128 modulated acquisition. 54 images were reconstructed using FBP and 5 different strengths of SAFIRE. Objective measures of image quality were determined by measuring SNR and CNR. Visual measures of image quality were determined by 17 observers with different radiographic experiences. Images were randomized and displayed using 2AFC; observers scored the images answering 5 questions using a Likert scale. Results: At different dose levels, SAFIRE significantly increased SNR (up to 54%) in the acquired images compared to FBP at 80kVp (5.2-8.4), 110kVp (8.2-12.3), 130kVp (8.8-13.1). Visual image quality was higher with increasing SAFIRE strength. The highest image quality was scored with SAFIRE level 3 and higher. Conclusion: The SAFIRE algorithm is suitable for image noise reduction in paediatric head CT. Our data demonstrates that SAFIRE enhances SNR while reducing noise with a possible reduction of dose of 68%.

Influence of reconstruction parameters for FBP in semiquantification of brain studies with 123I-FPCIT

Brain dopamine transporters imaging by Single Photon Emission Tomography (SPECT) with 123I-FP-CIT has become an important tool in the diagnosis and evaluation of parkinsonian syndromes, since this radiopharmaceutical exhibits high affinity for membrane transporters responsible for cellular reabsorption of dopamine on the striatum. However, Ordered Subset Expectation Maximization (OSEM) is the method recommended in the literature for imaging reconstruction. Filtered Back Projection (FBP) is still used due to its fast processing, even if it presents some disadvantages. The aim of this work is to investigate the influence of reconstruction parameters for FBP in semiquantification of Brain Studies with 123I-FPCIT compared with those obtained with OSEM recommended reconstruction.

Transient Spaces: unsettling boundaries and norms at the cultural event Noc Noc, Guimarães, Portugal

Cities are increasingly expected to be creative, inventive and to exhibit intense expressivity. In the past decades many cities have experienced growing pressure to produce and stage cultural events of different sorts and to develop new strategies that optimize competitive advantages, in order to promote themselves and to boost and sell their image. Often these actions have relied on heavy public investment and major private corporation sponsoring, but it is not always clear or measured how successful and reproductive these investments have been. In the context of strained public finances and profound economic crisis of European peripheral countries, events that emerge from local communities and have low budgets, which manage to create significant fluxes of visitors and visibility, assume an increased interest. In order to reflect and sketch possible answers, we look to an emerging body of literature concerning creative cities, and we focus on the organisation of a particular cultural event and its impact and assimilation into a medium size Portuguese city. This paper looks at the two editions (2011 and 2012) of one of such events – Noc Noc – organized by a local association in the city of Guimarães, Portugal. Inspired by similar events, Noc Noc is based on creating transient spaces of culture which are explored by artists and audiences, by transforming numerous homes into ephemeral convivial and playful social ‘public’ environments. The event is based on a number of cultural venues/homes scattered around the old and newer city, which allows for an informal urban exploration and an autonomous rambling and getting lost along streets. This strategy not only disrupts the cleavages between public and private space permitting for various transgressions, but it also disorders normative urban experiences and unsettles the dominant role of the city council as the culture patron of the large majority of events. Guimarães, an UNESCO World Heritage City was the European Capital of Culture in 2012, with a public investment of roughly 73 million euro. By interviewing a sample of people who have hosted these transitory art performances and exhibitions, sometimes doubling as artists, the events’ organizers and by experience both editions of the event, this paper illustrates how urban citizens’ engagement and motivations in a low budget cultural event can strengthen community ties. Furthermore, it also questions the advantages of large scale high budget events, and how this event may be seen as unconscious counter movement against a commodification of cultural events and everyday urban experience at large, engaging with the concepts of staging and authenticity.

Perspectives of the Internal Public in a Cultural Event: the Case of Noc Noc, Guimarães - Portugal

Given the significant impact that cultural events may have in local communities and the inherent organization complexity, it is important to understand their specificities. Most of the times cultural events disregard marketing and often marketing is distant from art. Thus an analysis of an inside perspective might bring significant returns to the organization of such an event. This paper considers the three editions (2011, 2012 and 2013) of a cultural event – Noc Noc – organized by a local association in the city of Guimarães, Portugal. Its format is based in analogous events, as Noc Noc intends to convert everyday spaces (homes, commercial outlets and a number of other buildings) into cultural spaces, processed and transformed by artists, hosts and audiences. By interviewing a sample of people (20) who have hosted this cultural event, sometimes doubling as artists, and by experiencing the three editions of the event, this paper illustrates how the internal public understands this particular cultural event, analyzing specifically their motivations, ways of acting and participating, as well as their relationship with the public, with the organization of the event and with art in general. Results support that artists and hosts motivations must be identified in a timely and appropriate moment, as well as their views of this particular cultural event, in order to keep them participating, since low budget cultural events such as this one may have a key role in small scale cities.

The Cristo Rei section (Lower Miocene). Distal fluviatile environments in a marine series, plants, vertebrates and other evidence, age

The section at Cristo Rei shows sandy beds with intercalated clayey lenses (IVb division from the Lisbon Miocene series) that correspond to a major regression event dated from between ca. 17.6 and 17 Ma. They also correspond to a distal position (relatively to the typical fluviatile facies in Lisbon), nearer the basin's axis. Geologic data and paleontological analysis (plant fossils, fishes, crocodilians, land mammals) allow the reconstruction of environments that were represented in the concerned area: estuary with channels and ox-bows; upstream, areas occupied by brackish waters where Gryphaea griphoides banks developped; still farther upstream, freshwaters sided by humid forests and low mountain subtropical forests under warm temperate and rainy conditions, as well as not far away, seasonally dry environments (low density tree or shrub cover, or steppe).

A comprehensive high-throughput FTIR spectroscopy-based method for evaluating the transfection event: estimating the transfection efficiency and extracting associated metabolic responses

Reporter genes are routinely used in every laboratory for molecular and cellular biology for studying heterologous gene expression and general cellular biological mechanisms, such as transfection processes. Although well characterized and broadly implemented, reporter genes present serious limitations, either by involving time-consuming procedures or by presenting possible side effects on the expression of the heterologous gene or even in the general cellular metabolism. Fourier transform mid-infrared (FT-MIR) spectroscopy was evaluated to simultaneously analyze in a rapid (minutes) and high-throughput mode (using 96-wells microplates), the transfection efficiency, and the effect of the transfection process on the host cell biochemical composition and metabolism. Semi-adherent HEK and adherent AGS cell lines, transfected with the plasmid pVAX-GFP using Lipofectamine, were used as model systems. Good partial least squares (PLS) models were built to estimate the transfection efficiency, either considering each cell line independently (R 2 ≥ 0.92; RMSECV ≤ 2 %) or simultaneously considering both cell lines (R 2 = 0.90; RMSECV = 2 %). Additionally, the effect of the transfection process on the HEK cell biochemical and metabolic features could be evaluated directly from the FT-IR spectra. Due to the high sensitivity of the technique, it was also possible to discriminate the effect of the transfection process from the transfection reagent on KEK cells, e.g., by the analysis of spectral biomarkers and biochemical and metabolic features. The present results are far beyond what any reporter gene assay or other specific probe can offer for these purposes.

Auditory event-related potentials in children with benign epilepsy with centro-temporal spikes

Benign focal epilepsy in childhood with centro-temporal spikes (BECTS) is one of the most common forms of idiopathic epilepsy, with onset from age 3 to 14 years. Although the prognosis for children with BECTS is excellent, some studies have revealed neuropsychological deficits in many domains, including language. Auditory event-related potentials (AERPs) reflect activation of different neuronal populations and are suggested to contribute to the evaluation of auditory discrimination (N1), attention allocation and phonological categorization (N2), and echoic memory (mismatch negativity – MMN). The scarce existing literature about this theme motivated the present study, which aims to investigate and document the existing AERP changes in a group of children with BECTS. AERPs were recorded, during the day, to pure and vocal tones and in a conventional auditory oddball paradigm in five children with BECTS (aged 8–12; mean = 10 years; male = 5) and in six gender and age-matched controls. Results revealed high amplitude of AERPs for the group of children with BECTS with a slight latency delay more pronounced in fronto-central electrodes. Children with BECTS may have abnormal central auditory processing, reflected by electrophysiological measures such as AERPs. In advance, AERPs seem a good tool to detect and reliably reveal cortical excitability in children with typical BECTS.

Assessing the balance between biodiversity conservation and coastal and estuarine management of the Sado Estuary Natural Reserve, Portugal, using BIO-SAFE

Dissertação apresentada na Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa para obtenção do grau de Mestre em Engenharia do Ambiente, perfil de Engenharia Ecológica

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.