Anemia de células falciformes na idade pediátrica : contribuição para o estudo das suas principais complicações e indicadores de prognóstico

RESMO: Introdução: A anemia de células falciformes doença hereditária, com repercussão multi-orgânica, tem grande variabilidade na sua expressão clínica. Daí o interesse do estudo de indicadores de prognóstico. A investigação realizada foi precedida de um resumo histórico incidindo sobre a compreensão de aspectos fundamentais da doença ao longo dos tempos. Na primeira parte do estudo e após revisão bibliográfica, foram referidos dados da fisiopatologia como base para os estudos que integram a presente dissertação. Abordou-se o estado da arte relativamente às complicações, aos indicadores de prognóstico e à terapêutica utilizada. Objectivos: Constituíram objectivos deste estudo realizado numa amostra populacional representativa: identificar as lesões a nível dos sistemas cardio-respiratório e nervoso central, avaliando-se as respectivas repercussões; avaliar a presença de indicadores de prognóstico entre as variáveis seleccionadas; estudar a eficácia e toxicidade da HU nos doentes com as formas graves da ACF. Para a prossecução destes objectivos foram delineados para além do estudo global três estudos específicos: Estudo 1- repercussão no sistema cardio-respiratório; Estudo 2- repercussão no sistema nervoso central; Estudo 3- terapêutica com hidroxiureia. Doentes e métodos: Procedeu-se a um estudo prospectivo e multi-institucional durante um período de três anos tendo-se seleccionado para a amostra, e de acordo com critérios pré-definidos, 30 doentes com ACF na fase estável da doença, com idades compreendidas entre os sete e os 18 anos, todos de origem africana à excepção de um caucasiano. O diagnóstico baseou-se em técnicas de electroforese e estudo molecular que definiu o genotipo da doença e a presença da delecção da -talassémia assim como os haplotipos da amostra populacional. Foram utilizadas diferentes metodologias para avaliar a existência de lesão pulmonar e cerebral. Através do estudo estatístico foram seleccionadas diversas variáveis como hipotéticos indicadores de prognóstico. Estudo 1. Para determinar a existência de lesão a nível pulmonar usaram-se duas metodologias diferentes, a avaliação da função pulmonar com estudo da saturação da Hb em O2 no sangue arterial e a tomografia computadorizada de alta resolução. Estudou-se também a possível disfunção cardíaca como repercussão da lesão pulmonar, através do ecocardiograma, e os indicadores de prognóstico com significado estatístico para a lesão encontrada. Estudo 2. O desenho deste estudo foi sobreponível ao anterior, mas com metodologia adequada para o SNC. Procedeu-se ao estudo das lesões cerebrais por meio de exames imagiológicos, (RMN-CE e DTC) e de testes psicológicos. Correlacionaram-se as três metodologias utilizadas e a importância de cada uma para a decisão de atitudes terapêuticas preventivas. Estudo 3. Consistiu num estudo aberto prospectivo não controlado com nove crianças e adolescentes com formas graves de ACF, com o objectivo de avaliar a eficácia da terapêutica com hidroxiureia, durante um período de 24 meses. Todos os doentes completaram no mínimo 15 meses de terapêutica, com uma dose final média de 194 mg/K/dia. Resultados globais: Durante o período anterior à investigação caracterizou-se a amostra populacional estudada quanto ao fenotipo genético, clínico e hematológico de acordo com os critérios utilizados por outros investigadores. Verificou-se: predomínio do haplotipo Bantu na forma homozigótica em 53% dos doentes; número total de EVO ≥3/ano em 87,5% dos doentes; crises de sequestração em 18,75%; dactilites no primeiro ano de vida em 31,2%; quadro de sépsis grave apenas num doente; crises de hiper-hemólise em 50%; e STA em 59,38% dos doentes. Quanto ao fenotipo hematológico evidenciaram-se como factores de risco reticulocitose (13,1x103/l) e hiperbilirrubinémia (2,5 mg/dl) e como factores de bom prognóstico a presença de delecção de um gene da -talassémia em 46,9% dos doentes e valor médio de Hb 8,1 g/dl. Resultados dos estudos parcelares: Estudo 1. Deste estudo infere-se que a DPR ligeira foi diagnosticada em 70% dos doentes, uma vez que as alterações da difusão não foram estatisticamente significativas, o estudo dos gases no sangue não evidenciaram resultados anormais e a TCAR evidenciou alterações em 43,3% dos doentes. Apenas num doente se verificou doença pulmonar obstrutiva relacionada com maior número da STA.O estudo da disfunção cardíaca encontrada em 86,7% dos doentes não reflecte a repercussão da DPR a nível cardíaco, podendo estar associada às alterações fisiopatológicas da própria anemia crónica. Encontraram-se indicadores de prognóstico hematológicos e clínicos. Entre os primeiros, valores de Hb ≥8,5 g/dl e de HbF ≥13% foram considerados indicadores de bom prognóstico para a lesão pulmonar. Em relação aos parâmetros clínicos, as STA não foram consideradas indicadoras de prognóstico para a DPR ao contrário do que se verificou com o número de EVO. Pela análise dos parâmetros genéticos e socio-económicos provou-se a ausência de relação estatisticamente significativa com lesão pulmonar. Estudo 2. Pela RMN-CE foram diagnosticados ES em 33,3% com uma localização preferencial na substância branca profunda em 26,6% dos doentes. Relativamente aos parâmetros hematológicos seleccionados, o valor médio da HbF 8,6% constituíu um indicador de bom prognóstico para o aparecimento de ES, enquanto o valor médio de leucócitos 12.39x103/μl foi considerado um indicador de mau prognóstico. No estudo do DTC apenas um doente apresentou aumento da velocidade do fluxo cerebral na ACM igual a 196 cm/segundos, associado a vasculopatia grave. Os testes psicológicos alterados em 80% dos doentes mostraram ser o método mais sensível para detectar alterações do neurodesenvolvimento, mas sem correlação com os ES em 10% dos doentes. Realça-se a baixa percentagem de DTC patológicos encontrados neste estudo em relação ao número elevado de ES e de testes psicológicos alterados, não se verificando concordância entre os três exames. Dos indicadores de prognóstico estudados a -talassémia foi considerada um factor de protecção para o coeficiente de inteligência da escala de Wechsler. Em relação a parâmetros clínicos estudados os doentes com maior número de EVO, tem em média valores inferiores nos testes psicológicos. Estudo 3. Neste estudo verificou-se que o valor médio da HbF aumentou significativamente de 7,0±4% para 13,7±5,3% (p=0,028) ao fim de 15 meses de terapêutica com hidroxiureia. Clinicamente todos os doentes responderam significativamente com uma redução de 80% no número de EVO, 69% no número de internamentos, 76% no número de dias de hospitalização e 67% no número de transfusões. Deste modo comprovou-se não só a eficácia desta terapêutica neste grupo pediátrico como também a falta de efeitos secundários significativos. Considera-se a necessidade de estudos mais prolongados e em grande séries, para com segurança se usar a HU antes que a lesão orgânica se estabeleça, portanto logo nos primeiros anos de vida. Conclusão: Na amostra populacional estudada foram evidenciadas lesões pulmonares e cerebrais na grande maioria dos doentes que condicionaram a sua qualidade de vida. Foram identificados indicadores de prognóstico que poderão eventualmente ditar medidas terapêuticas precoces com o objectivo de diminuir a morbilidade e a mortalidade neste grupo etário. Demonstrou-se que a terapêutica com a HU foi eficaz e bem tolerada----------ABSTRACT: Background: Sickle cell anemia (SCA), a hereditary disease characterized by pain and lifetime multi-organic lesion, is a challenge for all that work with carriers of this disease. The clinical expression variability of SCA is a constant reality and a problem to be solved in the current world of investigation, for which the knowledge of prognostic indicators responsible for the different aspects of clinical evolution diversity wiil be an added value. The study is preceded by a historical summary of the most important factors in the evolution of SCA, which are in themselves, an incentive for future research. In the first part of the study, after an extensive bibliographical revision, physiopathology data is referred to in general and specifically regarding the target organs, that constituted the base for the studies presented in the dissertation. The state of the art for the complications to be studied, the choice of prognostic indicators and the therapeutics application, were approached for the renewed interest in the theme. Aims: In regard to the investigation, the objective was to study the lesions in the most affected organs of a chosen pediatric group, to investigate prognostic indicators for lung and cerebral lesions and to evaluate the protective effect of hydroxyurea in children with severe outcomes. Patients and methods: A prospective and multi-institutional study was carried out during a three-year period, February 1998 to March 2001, with children and adolescents followed up at a Immunohematology Outpatient Clinic of Dona Estefânia's Hospital, Lisbon. Based in predefined criteria, 30 children with SCA were selected in a stable phase of the disease, aged from seven to 18 years old, all of whom were of African origin with exception of one who was Caucasian. The diagnosis was based on electrophoresis techniques and molecular study that allowed to define the genotype, the presence of deletional alpha-thalassemia as well as haplotypes in the population. Different methodologies were used to evaluate the existence of lung and cerebral lesion. Statistical study of the different variables selected the prognostic indicators. In Study 1, to determine the existence of lung lesion two different methodologies were used: pulmonar function study with arterial blood gases determination; and high resolution computerized tomography. Heart dysfunction as a repercussion of lung lesion was also studied through echocardiography, and prognostic indicators were statistically significant for lesions found. The design of Study 2 was similar to Study 1, but with the appropriate methodology for CNS. After neurological examination, which was normal in all patients (control group), cerebral lesions were studied with imagiologic exams (MRN-CE and TCD) and psychological tests. These three methodologies were correlated and the importance of each one in the decision of the therapeutic profilactic attitudes. Study 3 consisted of a controlled prospective open study in children with severe forms of SCA, with the aim of the evaluating therapeutic effectiveness of hydroxyurea, during a period of 24 months. Results: In the global overall study preceding the Studies 1,2 and 3, there were a prevalence of haplotype Bantu (53%) and other risk factors, namely the number of VOC (87,5%), sequestration crisis (18,75%), dactilytis in first year of life(31,2%), hyperhemolysis crisis (50%) and ATC in more than half of the patients (59,38%). This group of bad prognostic indicators, associated with the population of the lower class according to the Graffar scale, demonstrates the importance of primary health care services, information provided to the children and their relatives, as well as the interest in prophylactic therapeutics, specific screening and prenatal diagnosis. Study 1. It was evident from this study that slight RPD was diagnosed in 70% of the patients, because alterations of the diffusion had no statistical significance and arterial blood gases determinations were normal. Only one patient had restrictive lung disease related with numerous ACS. However ACS was not considered a prognostic indicator for RPD, contrary to the number of EVO. HRTC revealed discreet fibrotic lines that could be related with slight RPD, but the lack of correlation of these two exams (33%) supports the value of lung function tests for precocious diagnosis of RPD. Heart dysfunction was found in 86,7% of patients, does not reflect the repercussion of RPD, but with the physiopathology of chronic anemia. Hematologic and clinical prognostic indicators were found. Good prognostic indicators for the non-evolution of RPD with average Hb values of ≥ 8,5 g/dl and average HbF values of ≥13%, respectively. The genetic and social-economic factors had no statistical significance; nevertheless, they were more prevalent among Bantu haplotype (53,3%) in patients with RPD. Study 2. RMN-CE detected SI in 33,3% of the patients, with preferential location in deep white substance in 26,6% and in front lobe in 20%. This distribution can be related to structural aspects of the brain and with the high sensibility of this organ to hypoxia. From the hematological parameters selected, average HbF value 8,6% and average leucocyte count 12.39x103/μl were prognostic indicators with different meaning to SI. The increase in the total bilirubin related to hyperhemolysis clinically explains the genesis of SI In the TCD study, only one patient had increased cerebral flow speed >196 cm/sec in CMA, which corresponded to serious vasculopathy in AngioMR. This patient never present previously neurological symptoms and had several hyperhemolysis crisis and VOC as risk factors. Low percentage of pathological TCD in this study, in relation to the high number of SI and altered tests, although without correlation among the three exams, is probably attributed to factors related to the methodology, aspects of cerebral physiopathology or perhaps a sign of good prognostic if the duration of study had not been so short. TCD should be used as a screening method in the age groups with higher risk of AVC and should never be considered separately in prophylactic therapeutics indication. Psychological tests were the most sensitive method to detect neurodevelopment impairment; in 80% of patients the neuropsychologics tests were altered, but without correlation with SI (10%). Since SI can become evident during the first two years of life and develop with time, the first psychological tests should be carried out between 3 and 5 years of age to timely be referred to special education and stimulation programs. Prognostic indicators to psychological tests were also found: alpha-thalassemia was found to be a protection factor of the IQ, just as other hematologic factors (hematocrit, MGCV and erythrocytes count). In relation to clinical parameters, although without statistical significance, patients with larger number of VOC had average lower scores versus the average in tests, except in TP. Results from different studies were conclusive as to the type of lesion found and the importance of prognostic indicators. Study 3. All the patients completed a minimum of 15 months therapeutic treatment with the final average daily dose of 19±4 mg/kg/day. The average value of the fetal hemoglobin increased significantly from 7,0±3,9% to 13,7±5,3% (p=0.028). The HbF average values increased from 6% to 15% after 15 months of therapeutic treatment. Clinically there was a reduction of 80% in the number of VOE , 69% in the number of hospitalization, 76% in the number of days of hospitalization and 67% in the number of transfusions. Once again the effectiveness of this treatment in this pediatric group, as well as the lack of any significant secondary effects, was evident. The study confirms the need for further detailed research in order to safely effect the appropriate treatment prior to the development of organic lesions, which ideally should be in the first year of life. Conclusions: These results allow us to clarify the importance of either pulmonary lesions or either nervous central system impairment among patients, children and adolescents, with sickle cell anemia. These lesions were demonstrated in most of the patients studied compromising their quality of life and the mortality. The treatment with HU is proved to be effective and having low toxicity.

Multi-objective Parallel Particle Swarm Optimization for Day-ahead Vehicle-To-Grid Scheduling

This paper presents a methodology for multi-objective day-ahead energy resource scheduling for smart grids considering intensive use of distributed generation and Vehicle- To-Grid (V2G). The main focus is the application of weighted Pareto to a multi-objective parallel particle swarm approach aiming to solve the dual-objective V2G scheduling: minimizing total operation costs and maximizing V2G income. A realistic mathematical formulation, considering the network constraints and V2G charging and discharging efficiencies is presented and parallel computing is applied to the Pareto weights. AC power flow calculation is included in the metaheuristics approach to allow taking into account the network constraints. A case study with a 33-bus distribution network and 1800 V2G resources is used to illustrate the performance of the proposed method.

Scenarios Generation for Multi-Agent simulation of Electricity Markets based on Intelligent Data Analysis

This document presents a tool able to automatically gather data provided by real energy markets and to generate scenarios, capture and improve market players’ profiles and strategies by using knowledge discovery processes in databases supported by artificial intelligence techniques, data mining algorithms and machine learning methods. It provides the means for generating scenarios with different dimensions and characteristics, ensuring the representation of real and adapted markets, and their participating entities. The scenarios generator module enhances the MASCEM (Multi-Agent Simulator of Competitive Electricity Markets) simulator, endowing a more effective tool for decision support. The achievements from the implementation of the proposed module enables researchers and electricity markets’ participating entities to analyze data, create real scenarios and make experiments with them. On the other hand, applying knowledge discovery techniques to real data also allows the improvement of MASCEM agents’ profiles and strategies resulting in a better representation of real market players’ behavior. This work aims to improve the comprehension of electricity markets and the interactions among the involved entities through adequate multi-agent simulation.

Intelligent Micro Grid Management using a Multi-Agent approach

Recent changes in electricity markets (EMs) have been potentiating the globalization of distributed generation. With distributed generation the number of players acting in the EMs and connected to the main grid has grown, increasing the market complexity. Multi-agent simulation arises as an interesting way of analysing players’ behaviour and interactions, namely coalitions of players, as well as their effects on the market. MASCEM was developed to allow studying the market operation of several different players and MASGriP is being developed to allow the simulation of the micro and smart grid concepts in very different scenarios This paper presents a methodology based on artificial intelligence techniques (AI) for the management of a micro grid. The use of fuzzy logic is proposed for the analysis of the agent consumption elasticity, while a case based reasoning, used to predict agents’ reaction to price changes, is an interesting tool for the micro grid operator.

Multi-Agent Based Smart Grid Management and Simulation: Situation Awareness and Learning in a Test Bed with Simulated and Real Installations and Players

The rising usage of distributed energy resources has been creating several problems in power systems operation. Virtual Power Players arise as a solution for the management of such resources. Additionally, approaching the main network as a series of subsystems gives birth to the concepts of smart grid and micro grid. Simulation, particularly based on multi-agent technology is suitable to model all these new and evolving concepts. MASGriP (Multi-Agent Smart Grid simulation Platform) is a system that was developed to allow deep studies of the mentioned concepts. This paper focuses on a laboratorial test bed which represents a house managed by a MASGriP player. This player is able to control a real installation, responding to requests sent by the system operators and reacting to observed events depending on the context.

Upper Ontology for Multi-Agent Energy Systems’ Applications

Energy systems worldwide are complex and challenging environments. Multi-agent based simulation platforms are increasing at a high rate, as they show to be a good option to study many issues related to these systems, as well as the involved players at act in this domain. In this scope the authors research group has developed three multi-agent systems: MASCEM, which simulates the electricity markets; ALBidS that works as a decision support system for market players; and MASGriP, which simulates the internal operations of smart grids. To take better advantage of these systems, their integration is mandatory. For this reason, is proposed the development of an upper-ontology which allows an easier cooperation and adequate communication between them. Additionally, the concepts and rules defined by this ontology can be expanded and complemented by the needs of other simulation and real systems in the same areas as the mentioned systems. Each system’s particular ontology must be extended from this top-level ontology.

Demonstration of the Multi-Agent Simulator of Competitive Electricity Markets

Electricity markets are complex environments with very particular characteristics. A critical issue concerns the constant changes they are subject to. This is a result of the electricity markets’ restructuring, performed so that the competitiveness could be increased, but with exponential implications in the increase of the complexity and unpredictability in those markets’ scope. The constant growth in markets unpredictability resulted in an amplified need for market intervenient entities in foreseeing market behavior. The need for understanding the market mechanisms and how the involved players’ interaction affects the outcomes of the markets, contributed to the growth of usage of simulation tools. Multi-agent based software is particularly well fitted to analyze dynamic and adaptive systems with complex interactions among its constituents, such as electricity markets. This paper presents the Multi-Agent System for Competitive Electricity Markets (MASCEM) – a simulator based on multi-agent technology that provides a realistic platform to simulate electricity markets, the numerous negotiation opportunities and the participating entities.

Automatic Electricity Markets Data Extraction for Realistic Multi-agent Simulations

Electricity markets worldwide suffered profound transformations. The privatization of previously nationally owned systems; the deregulation of privately owned systems that were regulated; and the strong interconnection of national systems, are some examples of such transformations [1, 2]. In general, competitive environments, as is the case of electricity markets, require good decision-support tools to assist players in their decisions. Relevant research is being undertaken in this field, namely concerning player modeling and simulation, strategic bidding and decision-support.

Histoplasmin and paracoccidioidin skin reactivity in infantile population of Northern Argentina

In order to estimate ages at which etiological agents of systemic mycoses initiate infection, histoplasmin and paracoccidioidin skin tests were performed in 344 children of both sexes, between 2 and 15 years old. They were selected from a statistically significant population sample Gral. San Martín city (Northeast Argentina). Tests were read 48h after injection and considered positive if a 5 mm on larger induration was present. Circulating antibodies were also evaluated by agar gel immunodiffusion. The overall infection rate for H. capsulatum was 9.2%, belonging to children from 4 to 14 years old, without significant differences among sexes. Five children from 2 to 14 years old were positive to paracoccidioidin (1.6%). None of the children had specific antibodies neither signs of active mycosis. Results show H. capsulatum infection can be found from age 4, while for P. brasiliensis the lower limit was two years old. These findings may contribute to better knowledge on infantile fungal infection in a geographical region where no previous references can be found.

Load Control Timescales Simulation in a Multi-Agent Smart Grid Platform

Environmental concerns and the shortage in the fossil fuel reserves have been potentiating the growth and globalization of distributed generation. Another resource that has been increasing its importance is the demand response, which is used to change consumers’ consumption profile, helping to reduce peak demand. Aiming to support small players’ participation in demand response events, the Curtailment Service Provider emerged. This player works as an aggregator for demand response events. The control of small and medium players which act in smart grid and micro grid environments is enhanced with a multi-agent system with artificial intelligence techniques – the MASGriP (Multi-Agent Smart Grid Platform). Using strategic behaviours in each player, this system simulates the profile of real players by using software agents. This paper shows the importance of modeling these behaviours for studying this type of scenarios. A case study with three examples shows the differences between each player and the best behaviour in order to achieve the higher profit in each situation.

Biomarkers in Solea Senegalensis Kaup, 1858 exposed to contaminated estuarine sediments: a multi-level approach

Thesis submitted to the Universidade Nova de Lisboa, Faculdade de Ciências e Tecnologia for the degree of Doctor of Philosophy in Environmental Sciences

Multi-scale vegetation classification using earth observation data of the Sundarban mangrove forest, Bangladesh.

Dissertation submitted in partial fulfilment of the requirements for the Degree of Master of Science in Geospatial Technologies.

Multi-agent Simulation of Bilateral Contracting in Competitive Electricity Markets

Traditional vertically integrated power utilities around the world have evolved from monopoly structures to open markets that promote competition among suppliers and provide consumers with a choice of services. Market forces drive the price of electricity and reduce the net cost through increased competition. Electricity can be traded in both organized markets or using forward bilateral contracts. This article focuses on bilateral contracts and describes some important features of an agent-based system for bilateral trading in competitive markets. Special attention is devoted to the negotiation process, demand response in bilateral contracting, and risk management. The article also presents a case study on forward bilateral contracting: a retailer agent and a customer agent negotiate a 24h-rate tariff.

Realistic Multi-Agent Simulation of Competitive Electricity Markets

The dynamism and ongoing changes that the electricity markets sector is constantly suffering, enhanced by the huge increase in competitiveness, create the need of using simulation platforms to support operators, regulators, and the involved players in understanding and dealing with this complex environment. This paper presents an enhanced electricity market simulator, based on multi-agent technology, which provides an advanced simulation framework for the study of real electricity markets operation, and the interactions between the involved players. MASCEM (Multi-Agent Simulator of Competitive Electricity Markets) uses real data for the creation of realistic simulation scenarios, which allow the study of the impacts and implications that electricity markets transformations bring to different countries. Also, the development of an upper-ontology to support the communication between participating agents, provides the means for the integration of this simulator with other frameworks, such as MAN-REM (Multi-Agent Negotiation and Risk Management in Electricity Markets). A case study using the enhanced simulation platform that results from the integration of several systems and different tools is presented, with a scenario based on real data, simulating the MIBEL electricity market environment, and comparing the simulation performance with the real electricity market results.

Data Mining Approach to support the Generation of Realistic Scenarios for Multi-Agent simulation of Electricity Markets

This paper presents the Realistic Scenarios Generator (RealScen), a tool that processes data from real electricity markets to generate realistic scenarios that enable the modeling of electricity market players’ characteristics and strategic behavior. The proposed tool provides significant advantages to the decision making process in an electricity market environment, especially when coupled with a multi-agent electricity markets simulator. The generation of realistic scenarios is performed using mechanisms for intelligent data analysis, which are based on artificial intelligence and data mining algorithms. These techniques allow the study of realistic scenarios, adapted to the existing markets, and improve the representation of market entities as software agents, enabling a detailed modeling of their profiles and strategies. This work contributes significantly to the understanding of the interactions between the entities acting in electricity markets by increasing the capability and realism of market simulations.