Os praguicidas organofosforados (OPs) são amplamente utilizados na indústria química e na agricultura em todo o mundo. Muitos deles são potenciais causadores da \"Neuropatia Retardada Induzida por Organofosforados\" (NRIOP), caracterizada pela degeneração distal de axônios do sistema nervoso central e periférico (degeneração do tipo Walleriana). O praguicida triclorfom (dimetil 2,2,2-tricloro-1-hidroxietil fosfonato) tem sido utilizado em larga escala na produção agrícola e também no controle de vetores transmissores de várias doenças. Há relatos de efeitos neuropáticos em seres humanos expostos ao triclorfom, mas apesar disso, o seu potencial neuropático e seus mecanismos de neurotoxicidade ainda não foram elucidados. Assim, no presente estudo foram avaliados os mecanismos de toxicidade do praguicida OP triclorfom utilizando linhagem SH-SY5Y de neuroblastoma humano como modelo, e também foram avaliados possíveis agentes neuroprotetores em células tratadas com o bem estabelecido indutor da neuropatia mipafox. Foram utilizados como possíveis neuroprotetores: a amilorida e nimodipino (bloqueadores de canais de cálcio tipo T e L respectivamente), MDL 28170 (inibidor (III) de calpaína) e liraglutida (um agonista do \"glucagon like peptide\" -GLP-1). Foram usados o mipafox, como modelo de indução da NRIOP e o paraoxon, como modelo não indutor da NRIOP. Os ensaios de inibição e reativação da esterase susceptível à neuropatia (ESNp) e de citotoxicidade mostraram que somente o mipafox e o triclorfom apresentaram inibição e envelhecimento da ESNp superiores a 70% em concentrações com baixa toxicidade, condição compatível com a indução da NRIOP. A ativação das calpaínas foi observada apenas no tratamento com mipafox, efeito este inibido pela nimodipina, amilorida e pelo MDL 28170. Triclorfom e o mipafox causaram elevação significativa nos níveis de cálcio intracelular e da caspase-3, além de inibir significativamente o crescimento de neuritos. Os três OPs avaliados foram capazes de diminuir a captação da glicose, que foi aumentada nos grupos tratados com mipafox associado com neuroprotetores. As quatro substâncias utilizadas como possíveis neuroprotetoras reduziram significativamente o dano causado pelo mipafox sobre os neuritos. O modelo usado no estudo mostrou-se apropriado para a caracterização dos OP neuropáticos, pois permitiu a diferenciação dos efeitos do mipafox (neuropático) e do paraoxon (não-neuropático). Os dados obtidos indicam que o triclorfom tem potencial indutor de NRIOP, e a amilorida, nimodipino liraglutida e MDL apresentaram potencial neuroprotetor / Organophosphorus (OP) pesticides are widely used in the chemical industry and agriculture around the world. \"Organophosphate Induced Delayed Neuropathy\" (OPIDN) is characterized by distal degeneration of axons of the central and peripheral nervous system (Wallerian-type degeneration). The OP trichlorfom (dimethyl 2,2,2-trichloro-1-hydroxyethyl phosphonate) has been used in large scale in agricultural production and also for the control of vectors that are transmitter of diseases. There are reports of neuropathic effects in humans exposed to trichlorfon, but despite this, its neuropathic potential and mechanisms of neurotoxicity have not yet been elucidated. Thus, in the present study we evaluated the mechanisms of toxicity of trichlorfom and possible neuroprotective agents in SH-SY5Y human neuroblastoma cells treated with the well-established neuropathy inducer mipafox. The following neuroprotective agents were used: amyloride and nimodipine (T and L-type calcium channel blockers, respectively), MDL 28170 (calpain inhibitor (III) and liraglutide (a \"glucagon-like peptide\" - GLP-1 agonist). Mipafox was used as neuropathic OP and paraoxon was used as a non-neuropathic OP. Inhibition and reactivation assays of neurpathy target esterase (NTE) and cytotoxicity showed that only mipafox and trichlorfon showed inhibition and aging of 70% of the NTE in concentrations that presented low toxicity, consistent with development of OPIDN. Activation of calpain was observed only in the treatment with mipafox, an effect inhibited by nimodipine, amyloride and MDL 28170. Triclorfom and mipafox caused significant increase in the levels of intracellular calcium, caspase-3 and significantly inhibiting neurite growth. All three OPs assessed in this work caused a decrease in glucose uptake, which was increased in groups treated whith mipafox plus neuroprotectors. Substances used as possible neuroprotective agents significantly reduced the inhibitory effect of mipafox on neurite outgrowth. The model used in the study proved to be appropriate for characterizing neuropathic OPs, because it allowed a differentiation of the effects of mipafox (neuropathic) and paraoxon (non-neuropathic). The data obtained indicate that trichlorfonm has potential in cause OPIDN. Amiloride, nimodipine, MDL and liraglutide have presented potential neuroprotective effects

Esta tese de doutorado é devotada a problemas de campos fortes em eletrodinâmica e teoria quântica de campos. Alguns sistemas físicos bem conhecidos são estudados sob o formalismo da eletrodinâmica quântica (QED) com campos externos e eletrodinâmica não-linear. Primeiramente estudamos propriedades estatísticas de estados quânticos de Dirac e Klein-Gordon massivos que interagem com campos elétricos dependentes do tempo que viola a estabilidade do vácuo, primeiro em termos gerais e em seguida para um campo de fundo específico. Como ponto de partida, derivamos uma expressão não-perturbativa de tais campos. Construímos operadores de densidade reduzidos para subsistemas de elétrons e pósitrons e discutimos o efeito de decoerência que pode ocorrer no curso de evolução devido à uma medição intermediária. Calculamos a perda de informação em estados em QED devido a reduções parciais e uma possível decoerência por meio da entropia de von Neumann. Em seguida consideramos um campo elétrico específico, denominado por campo T-constante, como campo de fundo forte. Este modelo exatamente solúvel nos permite calcular, explicitamente, todas propriedades estatísticas de vários estados quânticos de campos massivos e carregados em consideração. Utilizamos uma abordagem não-perturbativa para a QED com X-degraus elétricos críticos e consideramos dois exemplos de configuração de campo de tipo exponencial (campo simétrico que varia lentamente e campo do tipo pico). Os números médios de partículas criadas por essas configurações de campo são calculados. As condições quando espaços \"in\" e \"out\" de QED com campos em consideração são unitariamente equivalentes são obtidos. Então construímos um operador de densidade geral, cuja condição inicial é o vácuo. Tal operador descreve a deformação de um estado de vácuo inicial por X-degraus elétricos críticos. Encontramos as reduções do estado deformado para subsistemas de elétrons e pósitrons e calculamos a perda de informação destas reduções. A consideração geral é ilustrada por meio de um estudo de estados de vácuo quântico entre duas placas de capacitor. Calculamos as medidas de emaranhamento destes estados reduzidos como entropias de von Neumann. Por fim, determinamos o campo de uma partícula puntiforme em movimento em eletrodinâmica local não-linear. Utilizamos como um modelo a lagrangiana de Euler-Heisenberg truncada no seu termo de ordem principal em uma expansão, em série de potências, do primeiro invariante de campo eletromagnético. Calculamos a energia total do campo produzido por uma partícula pontual e mostramos que a mesma é finita; portanto tornando sua configuração de campo como um sóliton. Definimos o tensor de energia-momento finito para esta configuração e demonstramos que suas componentes satisfazem a relação mecânica padrão de uma partícula massiva livre que se move. / This thesis is devoted to strong field problems in electrodynamics and quantum field theory. Some well known physical systems are studied in a framework of quantum electrodynamics with external field and nonlinear electrodynamics. First, the statistical properties of states of quantized charged massive Dirac and Klein-Gordon fields interacting with a time-dependent background that violates the vacuum stability, first in general terms and then for a special electromagnetic background. As a starting point, a nonperturbative expression for the density operators of such fields. The reduced density operators for electron and positron subsystems are constructed and a decoherence that may occur in course of the evolution due to an intermediate measurement is discussed. The loss of the information in QED states due to partial reductions and a possible decoherence is studied by calculating the von Neumann entropy. Next, the so-called T-constant external electric field as an external background is considered. This exactly solvable example allows the explicit calculation of all statistical properties for various quantum states of the massive charged fields under consideration. Next, a nonperturbative approach to QED with x-electric critical potential steps is used. The general consideration is illustrated by the example of so-called exponential in two different configurations (slowly varying field and sharp peak field); differential and full mean numbers of particles created by these field configurations are calculated. The conditions when in- and out- spaces of the QED under consideration are unitarily equivalent are found. Then, a general density operator with the vacuum initial condition is constructed. Such an operator describes a deformation of the initial vacuum state by x-electric critical potential steps. The reductions of the deformed state to electron and positron subsystems are found, and the loss of the information in these reductions is calculated. The general consideration is illustrated by studying the deformation of the quantum vacuum between two capacitor plates. The entanglement measures of these reduced states are calculated as von Neumann entropies. Third, the field of a moving pointlike charge is determined in nonlinear local electrodynamics. The Euler-Heisenberg Lagrangian of quantum electrodynamics truncated at the leading term of its expansion in powers of the first field invariant is used as a model Lagrangian. The total energy of the field produced by a point charge is calculated and shown to be finite; thereby making its field configuration a soliton. A finite energy-momentum vector of this field configuration is defined to demonstrate that its components satisfy the standard mechanical relation characteristic of a freely moving massive particle

Ein vielversprechendes Design für organische lichtemittierende Dioden (OLEDs) verwendet eine Wirt-Gast-Strategie durch Dispergieren einer kleinen Menge eines hocheffizienten Emitters (der Gast) in eine passende Transportmatrix (der Wirt). Die Aufgabe des Wirts ist den Exzitonentranport zum Emitter sicherzustellen und den Zerfall von Triplet-Exzitonen zu verhindern, und damit eine hohe Bauteilperformance zu erreichen. Die vorliegende Arbeit konzentriert sich auf die Beziehung zwischen Molekülstruktur und optoelektrischer Eigenschaften von Carbazol/Dibenzothiophen-Derivaten. Die Untersuchung umfasst sieben dieser Derivate für den Wirt, bei denen die Carbazoleinheit als Donator und die Dibenzothiopheneinheit als Akzeptor fungiert, wobei beide durch einen oder mehrere Phenylabstandshalter verbunden sind. Diese Wahl der Wirtsmaterialien erlaubt es den Einfluss der erweiterten Phenylabstandshalter und der unterschiedlichen molaren Verhältnisse von Akzeptor zu Donator zu untersuchen. Es ergab sich, dass eine kürzere Phenylabstandshalterlänge die Bauteilperformance durch eine größere Löcher- und Elektronendichte in der Emitterschicht verbessert; und ein 1:1 Carbazol-zu-Dibenzothiophen-Verhältnis der Bauteilperformance zuträglich ist, da es zu einem Ladungsträgergleichgewicht in der Emitterschicht führt. Diese Arbeit zeigt, unter Verwendung dieser Wirtsmaterialien, blaue FIrpic-basierte phosphoreszierende OLEDs (PhOLEDs) und grüne 4CzIPN-basierte thermisch aktivierte verzögerte Phosphoreszenz (TADF) OLEDs. Die blauen PhOLEDs und grünen TADF OLEDs mit mDCP zeigten Effizienzen von 43 cd/A (18.6%) beziehungsweise 66 cd/A (21%). / A particularly interesting organic light-emitting diodes (OLEDs) design adopts a host-guest strategy by dispersing a small amount of highly efficient emitter (the guest) into an appropriate transport matrix (the host). The host is utilized to transfer excitons to the emitter and to prevent triplet exciton quenching, thus high device performance can be achieved. The present thesis focuses on the relationship between the molecular structure and opto-electrical properties of carbazole/dibenzothiophene derivatives. The investigation encompasses seven of these derivatives for the host, in which the carbazole unit acts as a donor and the dibenzothiophene as an acceptor while they are linked through phenyl spacer(s). This choice of host materials enables to assess the impact of extended phenyl spacers and different acceptor to donor molar ratios. It was found that decreasing the phenyl spacer length enhances the device performance due to the larger both hole and electron densities in the emitting layer; and a 1:1 carbazole to dibenzothiophene ratio is favorable for device performance, since it balances the charge carriers in the emitting layer. Using these host materials, the work presented in this thesis demonstrates high-performance blue FIrpic-based phosphorescent OLEDs (PhOLEDs) and green 4CzIPN-based thermally activated delayed fluorescence (TADF) OLEDs. The blue PhOLEDs and green TADF OLEDs with mDCP showed efficiencies of 43 cd/A (18.6%) and 66 cd/A (21%), respectively.

Ce travail est motivé par la spectroscopie de photoélectrons et l'étude de la cinématique des galaxies où les données correspondent respectivement à une séquence temporelle de spectres et à une image multispectrale. L'objectif est d'estimer les caractéristiques (amplitude, position spectrale et paramètre de forme) des raies présentes dans les spectres, ainsi que leur évolution au sein des données. Dans les applications considérées, cette évolution est lente puisque deux spectres voisins sont souvent très similaires : c'est une connaissance a priori qui sera prise en compte dans les méthodes développées. Ce problème inverse est abordé sous l'angle de la séparation de sources retardées, où les spectres et les raies sont attribués respectivement aux mélanges et aux sources. Les méthodes de l'état de l'art sont inadéquates car elles supposent la décorrélation ou l'indépendance des sources, ce qui n'est pas le cas. Nous tirons parti de la connaissance des sources pour les modéliser par une fonction paramétrique. Nous proposons une première méthode de moindres carrés alternés : les paramètres de formes sont estimés avec l'algorithme de Levenberg-Marquardt, tandis que les amplitudes et les positions sont estimées avec un algorithme inspiré d'Orthogonal Matching Pursuit. Une deuxième méthode introduit un terme de régularisation pour prendre en compte l'évolution lente des positions; un nouvel algorithme d'approximation parcimonieuse conjointe est alors proposée. Enfin, une troisième méthode contraint l'évolution des amplitudes, positions et paramètres de forme par des fonctions B-splines afin de garantir une évolution lente conforme au physique des phénomènes observés. Les points de contrôle des B-splines sont estimés par un algorithme de moindre carrés non-linéaires. Les résultats sur des données synthétiques et réelles montrent que les méthodes proposées sont plus efficaces que les méthodes de l'état de l'art et aussi efficaces qu'une méthode bayésienne adaptée au problème mais avec un temps de calcul sensiblement réduit. / This work is motivated by photoelectron spectroscopy and the study of galaxy kinematics where data respectively correspond to a temporal sequence of spectra and a multispectral image. The objective is to estimate the characteristics (amplitude, spectral position and shape) of peaks embedded in the spectra, but also their evolution within the data. In the considered applications, this evolution is slow since two neighbor spectra are often very similar: this a priori knowledge that will be taken into account in the developed methods. This inverse problem is approached as a delayed source separation problem where spectra and peaks are respectively associated with mixtures and sources. The state-of-the-art methods are inadequate because they suppose the source decorrelation and independence, which is not the case. We take advantage of the source knowledge in order to model them by a parameterized function. We first propose an alternating least squares method: the shape parameters are estimated with the Levenberg-Marquardt algorithm, whilst the amplitudes and positions are estimated with an algorithm inspired from Orthogonal Matching Pursuit. A second method introduces a regularization term to consider the delay slow evolution; a new joint sparse approximation algorithm is thus proposed. Finally, a third method constrains the evolution of the amplitudes, positions and shape parameters by B-spline functions to guarantee their slow evolution. The B-spline control points are estimated with a non-linear least squares algorithm. The results on synthetic and real data show that the proposed methods are more effective than state-of-the-art methods and as effective as a Bayesian method which is adapted to the problem. Moreover, the proposed methods are significantly faster.

Esta tese de doutorado é devotada a problemas de campos fortes em eletrodinâmica e teoria quântica de campos. Alguns sistemas físicos bem conhecidos são estudados sob o formalismo da eletrodinâmica quântica (QED) com campos externos e eletrodinâmica não-linear. Primeiramente estudamos propriedades estatísticas de estados quânticos de Dirac e Klein-Gordon massivos que interagem com campos elétricos dependentes do tempo que viola a estabilidade do vácuo, primeiro em termos gerais e em seguida para um campo de fundo específico. Como ponto de partida, derivamos uma expressão não-perturbativa de tais campos. Construímos operadores de densidade reduzidos para subsistemas de elétrons e pósitrons e discutimos o efeito de decoerência que pode ocorrer no curso de evolução devido à uma medição intermediária. Calculamos a perda de informação em estados em QED devido a reduções parciais e uma possível decoerência por meio da entropia de von Neumann. Em seguida consideramos um campo elétrico específico, denominado por campo T-constante, como campo de fundo forte. Este modelo exatamente solúvel nos permite calcular, explicitamente, todas propriedades estatísticas de vários estados quânticos de campos massivos e carregados em consideração. Utilizamos uma abordagem não-perturbativa para a QED com X-degraus elétricos críticos e consideramos dois exemplos de configuração de campo de tipo exponencial (campo simétrico que varia lentamente e campo do tipo pico). Os números médios de partículas criadas por essas configurações de campo são calculados. As condições quando espaços \"in\" e \"out\" de QED com campos em consideração são unitariamente equivalentes são obtidos. Então construímos um operador de densidade geral, cuja condição inicial é o vácuo. Tal operador descreve a deformação de um estado de vácuo inicial por X-degraus elétricos críticos. Encontramos as reduções do estado deformado para subsistemas de elétrons e pósitrons e calculamos a perda de informação destas reduções. A consideração geral é ilustrada por meio de um estudo de estados de vácuo quântico entre duas placas de capacitor. Calculamos as medidas de emaranhamento destes estados reduzidos como entropias de von Neumann. Por fim, determinamos o campo de uma partícula puntiforme em movimento em eletrodinâmica local não-linear. Utilizamos como um modelo a lagrangiana de Euler-Heisenberg truncada no seu termo de ordem principal em uma expansão, em série de potências, do primeiro invariante de campo eletromagnético. Calculamos a energia total do campo produzido por uma partícula pontual e mostramos que a mesma é finita; portanto tornando sua configuração de campo como um sóliton. Definimos o tensor de energia-momento finito para esta configuração e demonstramos que suas componentes satisfazem a relação mecânica padrão de uma partícula massiva livre que se move. / This thesis is devoted to strong field problems in electrodynamics and quantum field theory. Some well known physical systems are studied in a framework of quantum electrodynamics with external field and nonlinear electrodynamics. First, the statistical properties of states of quantized charged massive Dirac and Klein-Gordon fields interacting with a time-dependent background that violates the vacuum stability, first in general terms and then for a special electromagnetic background. As a starting point, a nonperturbative expression for the density operators of such fields. The reduced density operators for electron and positron subsystems are constructed and a decoherence that may occur in course of the evolution due to an intermediate measurement is discussed. The loss of the information in QED states due to partial reductions and a possible decoherence is studied by calculating the von Neumann entropy. Next, the so-called T-constant external electric field as an external background is considered. This exactly solvable example allows the explicit calculation of all statistical properties for various quantum states of the massive charged fields under consideration. Next, a nonperturbative approach to QED with x-electric critical potential steps is used. The general consideration is illustrated by the example of so-called exponential in two different configurations (slowly varying field and sharp peak field); differential and full mean numbers of particles created by these field configurations are calculated. The conditions when in- and out- spaces of the QED under consideration are unitarily equivalent are found. Then, a general density operator with the vacuum initial condition is constructed. Such an operator describes a deformation of the initial vacuum state by x-electric critical potential steps. The reductions of the deformed state to electron and positron subsystems are found, and the loss of the information in these reductions is calculated. The general consideration is illustrated by studying the deformation of the quantum vacuum between two capacitor plates. The entanglement measures of these reduced states are calculated as von Neumann entropies. Third, the field of a moving pointlike charge is determined in nonlinear local electrodynamics. The Euler-Heisenberg Lagrangian of quantum electrodynamics truncated at the leading term of its expansion in powers of the first field invariant is used as a model Lagrangian. The total energy of the field produced by a point charge is calculated and shown to be finite; thereby making its field configuration a soliton. A finite energy-momentum vector of this field configuration is defined to demonstrate that its components satisfy the standard mechanical relation characteristic of a freely moving massive particle

Made available in DSpace on 2016-04-29T13:18:17Z (GMT). No. of bitstreams: 1 Monica Milharezi Mendonca.pdf: 1227656 bytes, checksum: e4408bd029458b28b9a5b7d2bf8dbf72 (MD5) Previous issue date: 2010-05-18 / Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Variables that influence rule control are important to be known because the control by rules seems to be a distinctive characteristic of humans. Some of these variables are the specification of deadlines and consequences in rules that also state immediate (OIR) or delayed (OAR) opportunity to respond, investigated by Bram & Malott (1990), Mistr & Glenn (1992) e Hupp & Reitman (1999) and replicated in this experiment. Two experiments have been conducted; the first one, due to unpredictable variables interference, it was used as a preparatory for the second one. Four children, between 3 years and 11 months and 5 years and 6 months old participated in the experiment and were divided in 2 groups. The 2 children in Group I were exposed to conditions PI (in which rules specified an immediate deadline), CA (rules specified delayed consequence) and CA-PI (rules specified delayed consequence and immediate deadline) with OIR, and children in Group II, to the same conditions, but with OAR. Results suggested that the specification of immediate deadline or delayed consequence could be enough to evoke the response specified by the rule in OIR, however, the variables manipulated could have had their effect modulated by the presence of the variable history of rule following, and therefore, the interaction between them is still to be investigated. In conditions with OAR, the variable specification of delayed consequence and immediate deadline had a subtle effect and Mistr & Glenn (1992)‟s suggestion that the declaration of immediate consequence could be critical in OAR condition, couldn‟t be discarded. The variable type of opportunity to respond showed to be critical, although could have also been in interaction with the history of rule following to produce some of the results. It was also found verbalizations of the participants, which we called rule related responses, which seemed to differ between groups and thus deserve a greater investigation. The long-lasting function-altering effect of rules was observed in the preparatory experiment / Variáveis que influenciam o controle por regras são importantes de serem conhecidas, pois o controle por regras parece ser uma característica distintiva de humanos. Algumas destas variáveis são as especificações de prazos e consequências em regras que declaram oportunidade imediata (OIR) e atrasada para responder (OAR), investigadas por Bram & Malott (1990), Mistr & Glenn (1992) e Hupp & Reitman (1999) e replicadas no presente experimento. Foram realizados 2 experimentos, o 1°, devido à interferência de variáveis não previstas, serviu como preparatório para o 2° experimento (experimento principal). Do experimento principal participaram 4 crianças, com idades entre 3 anos e 11 meses e 5 anos e 6 meses, divididas em 2 grupos. As 2 crianças do Grupo I passaram pelas condições PI (em que regras especificavam prazo imediato), CA (especificavam consequência atrasada) e CA-PI (consequência atrasada e prazo imediato) em OIR e as 2 crianças do Grupo II, pelas mesmas condições, porém em OAR. Os resultaram sugeriram que a especificação de prazo imediato ou de consequência atrasada poderia ser suficiente para evocar a resposta especificada pela regra em OIR, entretanto, as variáveis manipuladas podem ter tido seu efeito modulado pela presença da variável história de seguimento de regras e, portanto, a interação entre elas ainda deve ser investigada. Nas condições em OAR, a variável especificação de consequência atrasada e prazo imediato teve um efeito sutil, e a hipótese de Mistr & Glenn (1992) de que a declaração de consequência imediata seria crítica em OAR não pôde ser descartada. A variável tipo de oportunidade para responder se mostrou crítica, embora também possa ter estado em interação com a história de seguimento de regras para produzir alguns dos resultados. Foram encontradas também verbalizações dos participantes, a que chamamos respostas relacionadas à regra, que pareceram diferir entre os grupos e merecem, portanto, maior investigação. O efeito duradouro da função alteradora de função das regras pôde ser observado no experimento preparatório

Dans le domaine pharmaceutique, la voie orale demeure la voie d’administration de prédilection, car plus simple et mieux acceptée par les patients. Cependant, ce mode d’administration pose problème pour de nombreux principes actifs (PA) présentant une faible solubilité, une faible perméabilité et/ou une instabilité dans l’environnement gastro-intestinal. Leur micro-encapsulation dans des matrices polymériques peut permettre d’y répondre, notamment si les microparticules générées résistent aux environnements rencontrés lors du tractus gastro-intestinal et jouent alors un rôle protecteur, tant pour le principe actif que pour les muqueuses rencontrées. La recherche de nouveaux excipients, issus des agro-ressources tels que les polymères naturels, est en plein essor. Les protéines végétales, grâce à leurs propriétés fonctionnelles telles qu’une bonne solubilité, une viscosité relativement basse, et des propriétés émulsifiantes et filmogènes, représentent des candidats privilégiés. De plus, la grande diversité de leurs groupements fonctionnels permet d’envisager des modifications chimiques ou enzymatiques variées. L’objectif de ce travail était d’étudier l’intérêt de la protéine de soja en tant que matériau enrobant de principes actifs pharmaceutiques destinés à la voie orale, et plus particulièrement en tant que candidat pour l’élaboration de formes gastro-résistantes. Un isolat protéique de soja (SPI) été utilisé comme matière enrobante et l’atomisation comme procédé. L’ibuprofène, anti-inflammatoire non stéroïdien, a été choisi comme molécule modèle du fait de sa faible solubilité nécessitant une amélioration de sa biodisponibilité, et de ses effets indésirables gastriques nécessitant une mise en forme entérique. Deux modifications chimiques des protéines (l’acylation et la succinylation) ont été étudiées dans le but de modifier la solubilité de la protéine de soja. Ces modifications ont été effectuées dans le respect des principes de la Chimie Verte, notamment en absence de solvant organique. Les microcapsules obtenues par atomisation ont été caractérisées en termes de taux et efficacité d'encapsulation, morphologie et distribution de tailles des particules, état physique du PA encapsulé et capacité de libération en milieu gastrique et intestinal simulé. Les résultats obtenus ont permis de valider l’intérêt des modifications chimiques de la protéine de soja pour moduler les cinétiques de libération d’actif. Les modifications chimiques sont apparues particulièrement adaptées pour l’encapsulation de principes actifs hydrophobes, et ont permis de l’obtention de cinétiques de libération d’ibuprofène ralenties à pH acide (gastrique). La dernière partie de ce travail a permis de valider cette dernière hypothèse par la réalisation de formes gastro-résistantes sur le modèle des comprimés MUPS (multiple unit pellet system). Les résultats de ce travail exploratoire démontrent que les protéines de soja, associées à un procédé de mise en forme multi-particulaire couplé à de la compression directe, peuvent constituer une alternative biosourcée, respectueuse de l’environnement (manipulation en solvant aqueux, temps de séchage et étapes de compression réduits) et sûre à l’enrobage utilisé dans les formes gastro-résistantes traditionnelles. / In the pharmaceutical field, the oral route remains the preferred route of administration because it is simpler and better accepted by patients. However, this mode of administration is problematic for many active pharmaceutical ingredients (API) with low solubility, low permeability and/or instability in the gastrointestinal environment. Their microencapsulation in polymeric matrices can make them able to respond to these factors, especially if the microparticles generated resist the environments encountered during the gastrointestinal tract and then play a protective role, both for the API and for the mucous membranes encountered. The search for new excipients, from agroresources such as natural polymers, is booming. Vegetable proteins, thanks to their functional properties such as good solubility, relatively low viscosity, and emulsifying and film-forming properties, are preferred candidates. In addition, the great diversity of their functional groups makes it possible to envisage various chemical or enzymatic modifications. The aim of this work was to study the interest of soy protein as a coating material for API intended for the oral route, and more particularly as a candidate for the development of gastro-resistant forms. A soy protein isolate (SPI) was used as a coating material and the atomization as a process. Ibuprofen, a nonsteroidal anti-inflammatory drug, was chosen as a model molecule because of its low solubility requiring an improvement in its bioavailability, and its gastric side effects requiring an enteric shaping. Two chemical modifications of proteins (acylation and succinylation) have been studied in order to modify the solubility of the soy protein. These modifications were carried out in accordance with the principles of Green Chemistry, especially in the absence of organic solvent. The microcapsules obtained by spray-drying were characterized in terms of rate and encapsulation efficiency, morphology and size distribution of the particles, physical state of the encapsulated API and capacity of release in simulated gastric and intestinal medium. The results obtained validated the interest of the chemical modifications of the soy protein to modulate the release kinetics of API. The chemical modifications appeared particularly suitable for the encapsulation of hydrophobic active ingredients, and allowed to obtain ibuprofen release kinetics decreased to acidic pH (gastric). The last part of this work allowed to validate this last hypothesis by the realization of gastro-resistant forms on the model of MUPS tablets (multiple unit pellet system). The results of this exploratory work demonstrate that soy protein, combined with a multiparticle shaping process coupled with direct compression, can be a biosourced, environmentally friendly alternative (aqueous solvent handling, drying and compression steps reduced) and confident to the coating used in traditional gastroresistant forms.

Deux populations de tortues d’Hermann (Testudo hermanni, une espèce à maturité tardive ~10 ans) ont été étudiées sur le continent et sur une île dans la région du lac Prespa en Macédoine. Avant la maturité, la croissance des tortues est lente, puis accélère, entrainant une augmentation des taux de survie annuelle (de 0.30 à 0.70) et des variations de taille. Un potentiel pour une croissance continue, le durcissement de la carapace et un plateau de survie à cinq ans (0.90) induisent de fortes variations interindividuelles des trajectoires de croissance, et donnent une gamme étendue des tailles asymptotiques. Nos données questionnent la notion d’une taille unique à maturité puisqu‘une augmentation progressive des taux de testostérone suggère que la maturité s’établit pour des tailles entre 115 et 140 mm. Dans le genre Testudo les femelles sont plus grandes que les mâles ; les estimations des tailles asymptotiques observées le confirment. Mais sur l’île les plus grandes tortues sont des mâles. Avec ~100 individus/ha et un sexe ratio opérationnel (OSR ♂/♀) de ~11, la coercition exercée par les mâles entraine des blessures cloacales chez les femelles et dégrade leur condition corporelle, augmentant les coûts des accouplements. La survie des mâles (0.97) surpasse celle des femelles (0.84). Les femelles insulaires ne vivent pas longtemps, sont détournées de la reproduction et le faible recrutement biaise encore le sexe ratio, poussant la population vers l’extinction. Les rares femelles souffrent tandis que les mâles frustrés exhibent des comportements homosexuels fréquents, voire exubérants. Ces résultats sont discutés dans un contexte de conservation. / Two populations, island and mainland, of promiscuous sexually coercive Hermann tortoises (Testudo hermanni, a species with delayed maturity ~10 years) from the Prespa Region in Macedonia were scrutinized. Prior maturity, tortoises first grow slowly, thereafter gradually increase growth speed, variation in body size and survival probability (mean annual survival rate: 0.30 to 0.70). Potential for indeterminate growth, progressive hardening of the carapace and a survival plateau at the age of five (0.90) promote inter-individual variations in growth trajectories and a wide range of adult asymptotic sizes. Our data question the classical notion of a given size at maturity; instead progressive raise of testosterone levels suggests that maturity is established in growing males ranging from 115 to 140mm in body length. In the Testudo genus females are larger than males; asymptotic estimates of body size show that the studied populations make no exception. Yet, the largest island tortoises are males. With ~100 individuals/ha and an operational sex ratio (OSR ♂/♀) of ~11, male sexual coercion provokes cloacal injuries to females and reduces their body-condition, increasing female mating costs. Male adult survival (0.97) is greater compared to female survival (0.84). Island females do not live long, are discouraged from reproduction and low recruitment further exacerbates OSR-bias, eventually leading to population extinction. Where females suffer and are underrepresented, frustrated males exhibit frequent same-sex sexual behaviours along with extravagant sexual behaviours. The results are discussed in a conservation framework.

L'exploitation des champs de pétrole et de gaz sous haute pression (HP) et haute température (HT) a augmenté ces dernières années, nécessitant de réévaluer les risques de corrosion dans ces milieux de plus en plus sévères. Afin de contribuer à une meilleure évaluation des risques de rupture différée des aciers en présence d'H2S (SSC, Sulfide Stress Cracking) dans ces conditions, trois axes de recherche ont été suivis. Nous avons d'abord identifié un besoin d'amélioration de prédiction des conditions corrosives sous haute pression et haute température, et en particulier pour le calcul du pH in situ. Un modèle a été développé ; il prend en compte le comportement non-idéal des phases en équilibre, et permet un calcul plus précis du pH et de la fugacité des gaz acides à haute pression et haute température. Dans un deuxième temps, nous avons étudié l'effet de la pression partielle de CO2 (PCO2) sur les réactions de surface et sur les risques de SSC. Cette étude, réalisée à l'aide de mesures électrochimiques en l’absence d’un film de sulfure de fer, a permis de montrer que la présence de CO2 augmente sensiblement les cinétiques des réactions cathodiques à la surface de l'acier ainsi que le chargement en hydrogène, en particulier lorsque la pression partielle en H2S (PH2S) est faible. Enfin, des essais SSC ont été mis en œuvre dans des conditions fixes de pH et de PH2S, en faisant varier PCO2 entre zéro et 100 bar. L'objectif était de vérifier que la présence de CO2 sous forte pression augmentait bien les risques de fissuration, comme prévu par les résultats des essais électrochimiques. Les difficultés liées à la mise en œuvre d'essais en autoclave sous pression n'ont pas permis d'apporter une conclusion définitive. Néanmoins, ces travaux montrent qu'il peut exister un risque de sous-estimation de la sévérité des milieux dans les pratiques conventionnelles, lorsque PCO2 est significativement plus élevée que PH2S. Dans ces conditions spécifiques, les résultats de ce travail peuvent servir à améliorer les critères de choix de matériaux pour les milieux HP/HT. / The production of high pressure (HP) and high temperature (HT) wells has considerably increased in the last decade. It is therefore needed to reassess the risks of corrosion in always more severe environments. This work was three fold to better assess the risk of Sulfide Stress Cracking (SSC) in these environments. Firstly, there was a need to improve prediction methods for the evaluation of HP/HT environments severity, especially the in situ pH calculation. A model was which taking into account the non-ideal behaviour of gas and liquid phases in equilibrium. The determination of the in situ pH and the acid gas fugacity at high pressure and high temperature is more accurate. In a second part of the work, the impact of CO2 partial pressure (PCO2) on surface reactions and hence on the risk of SSC was examined. Electrochemical and hydrogen permeation measurements in the absence of an iron sulphide film showed that CO2 induces an increase of both cathodic reactions kinetics and hydrogen charging in the steel, especially at low H2S partial pressure (PH2S). In the last part of this work, SSC tests were performed at constant pH and constant PH2S, with various PCO2 from 0 to 100 bar. The objective was to experimentally confirm that increasing PCO2 increases the SSC risk, as inferred from the electrochemical study. Unfortunately, experimental artefacts linked with autoclave test conditions did not lead to clear conclusions on this point. However, this work shows that conventional tools might lead to underestimate SSC risks at high PCO2 and low PH2S. In these specific conditions, the new results presented in this report may contribute to improve materials selection criteria for high pressure and high temperature conditions.

This is a prospective study of a cohort sample of injured Kuwaiti First Gulf War survivors designed to investigate the prevalence of psychiatric morbidity due to combat and exposures to traumatic events. The study included two main phases. The first phase conducted in 1998, and in 2003 the second phase was executed. This study was designed to investigate the contribution of combat physical injury to the neurobiology of posttraumatic stress disorder (PTSD), prevalence rates of PTSD, depression, anxiety and other psychological morbidity, and predictors of chronic PTSD. The first assessment was in 1998 and the second assessment in 2003 that involved biological investigations. Beside the clinical interview and the physical examination of the site of injury, multiple psychological scales and questionnaires were used. Based on DSM-IV criteria of PTSD, after the second assessment the population of this study were classified to: Chronic PTSD(have PTSD at both assessments), Delayed PTSD (have PTSD only on the second assessment), Recovered (have PTSD only in the first assessment), and Never PTSD (have no PTSD in both assessments). The biological assessment include: blood investigations, BMI, and visual analogue. The data of the study were analyzed based on the four PTSD subgroups. In the first chapter an introduction to the First Gulf War was presented followed by the second chapter that discussed literature review. The third chapter tackled the methods used in this study. The fourth to the sixth chapters discussed the results of this study regarding prevalence of Chronic PTSD, Cortisol and PTSD and Thyroid hormones and PTSD respectively. The last chapter presented the limitations and strengths of the study. There were three main hypotheses. First: combat injured survivors with chronic PTSD have cluster of symptoms severity similar to delayed PTSD after 13 years of the trauma and the prevalence of chronic PTSD is constant over time. Second: low cortisol levels observed in chronic PTSD are constant with chronicity, normalize with recovery, unrelated to degree of disability, and are influenced by comorbid disorders. Third: there is minor role for thyroid hormones in chronic PTSD. All of registered Kuwaiti combat injured survivors at the Social Development Office in Kuwait, were approached to voluntary participate in this study. Of 234 individuals 212 participate in the first stage, and out of these 123 participate in the second stage with the addition of 33 new cases that were not examined in 1998 but were registered in SDO after 1998. An informed consent was taken from the participants at both phases. The participants were assessed using General Health Questionnaire, Trauma Questionnaire, Clinician Administered PTSD Scale, Eysenck Personality Questionnaire, Symptom Checklist-90 Revised, and Life Event Scale. Questionnaires and scales applied in the first stage were applied in the second stage with the addition of Impact of Event Scale, Composite International Diagnostic Interview and Scale of Gulf War Syndrome. Biochemical assessment comprised cortisol level, thyroxine (fT4), free triiodothyronine (fT3) and thyroid stimulating hormone (TSH). The blood samples were taken before starting the interview. Physical assessment involved measurements of: pulse rate, systolic and diastolic blood pressure, waist-hip circumference, body mass index and visual analogue before and after the interview. Data entry program using Statistical Package for Social Scientists was used to enter data and analysis. The prevalence rate of delayed onset PTSD (14.6%), chronic PTSD (15.4) recovered from PTSD (22.8%) and never had PTSD (47.2%). With chronic PTSD there are higher cluster of PTSD symptoms severity, not related to severity of physical injury, has more prevalence of PTSD associated symptoms, higher comorbid psychiatric disorders. Intrusions, avoidance and arousal are PTSD cluster of symptoms more predictive of future development of PTSD after the injury. There was a low baseline cortisol level with chronic PTSD, and it was significantly lower in participants with delayed PTSD. Furthermore trauma itself rather than PTSD diagnosis may have an impact on cortisol level. Other psychiatric comorbidity has an enhancing effect on cortisol level. The levels of thyroid hormones were within the normal range. The trend of thyroid function in delayed and chronic PTSD is lower fT3, and TSH and higher fT4 levels, with higher fT3 levels in delayed PTSD compared to chronic PTSD. It was found that the higher severity of trauma score with PTSD the higher fT3 mean values. / Thesis (Ph.D.) - University of Adelaide, School of Medicine, 2008