La dépression est une maladie psychiatrique qui atteint environ 20% de la population. En 2006 notre équipe a montré l’implication du canal potassique TREK-1 dans cette pathologie, et, en 2010, elle a identifié un bloqueur de TREK-1, la spadine, ayant des propriétés antidépressives. La spadine a la même efficacité après quatre jours de traitement que les antidépresseurs classiques qui en nécessitent vingt-et-un. Lors de mon doctorat, nous avons démontré la spécificité de la spadine pour les canaux TREK-1 et l’absence d’effet secondaire notamment au niveau cardiaque et sur les fonctions où l’activation du canal TREK-1 a des effets bénéfiques (ischémie, épilepsie, douleur). Nous avons pour cela utilisé des techniques d’électrophysiologiques et différents tests comportementaux adaptés à ces différentes pathologies. J’ai également démontré les effets antidépressifs de la spadine sur deux modèles animaux, un modèle génétique, les souris Rouen, et un modèle induit par un traitement à la coticostérone. La dernière partie de ma thèse a porté sur l’identification d’analogues de la spadine ayant une meilleure affinité et une meilleure efficacité in vivo, et ne présentant pas d’effet secondaire. Deux peptides synthétisés par la technique de retro-inverso ont présenté ces propriétés. Parallèlement, nous avons également recherché, en collaboration avec la société MedinCell, une formulation de polymère permettant la libération constante et prolongée de l’analogue sélectionné. Cette formulation a pour but de résoudre les problèmes engendrés par le non-respect de la prise de médicaments par les patients en administrant en une seule injection le traitement pour trois voire quatre semaines. / Depression is a devastating psychiatric disorder which affects about 20% of the population. In 2006 our team demonstrated the involvement of TREK-1, a potassium channel, in this pathology, and that its inhibition has led to a depression’s resistant phenotype. The search of TREK-1 inhibitors, a potential antidepressant, has led to the discovery of spadin. Spadin has, after only a four day treatment, similar efficacy than classical antidepressants which require about three weeks of treatment to produce their therapeutic effects. My work was firstly focused on the potential side effects of spadin. Indeed, TREK- 1’s activation has beneficial effects in many pathophysiologies (ischemia, epilepsy, pain). Its inhibition by spadin could generate significant adverse effects. The use of animal models has allowed us to confirm that spadin has no side effects related to TREK-1 channel’s inhibition. The specificity of spadin has been demonstrated since it has no effect on other potassium channels belonging to the K2P family. My work was also to study the effects of spadin in two mice models of depression, a genetic model and an induced model. In both cases, spadin shows a specific antidepressant effect in different behavioral tests of depression. The last part of my work was focused on the development of spadin’s analogs in order to improve the affinity and in vivo efficiency. We also developed, in collaboration with the MedinCell society, a polymer formulation for the constant and prolonged release of the selected analog. This formulation will be administered as a single injection treatment for three to four weeks, solving the problems caused by non respected medication by patients.

Master of Agribusiness / Department of Agricultural Economics / Jeffery R. Williams / Economically optimized ration formulations were used to test whether California dairy producers who implemented price risk management strategies on both the input and output sides achieved significantly higher net returns as measured by milk income minus feed costs compared to producers who bought feed and sold milk on the spot market. Two ration formulation models were developed, a least cost and a profit-maximization. The least cost method formulates a ration that meets the nutritional requirements of a lactating cow at the lowest possible cost for a given level of milk production. The profit maximization model incorporates into its algorithm a production function between net energy intake and milk production that increases at a decreasing rate. For today's high producing cows, after being supplied with enough energy to meet maintenance requirements, all additional energy is partitioned for milk production. Up to a certain point, depending on the price of milk and the price of feed, the cost of providing additional feed units is more than offset by the revenues derived by the extra milk produced from the larger quantities of feed consumed. The profit-maximization model used formulates a ration using both feed and milk prices where the cost of the last unit of feed provided is equal to the revenues of the last unit of milk produced. To compare returns, a ration program was designed that could either use spot or forward values for feed costs and milk price to economically optimize the ration on a weekly basis in the cow’s milk production cycle. To better gauge the impact of price volatility on both the input and output sides and to account for the extended nature of the forward contracts, the 305-day lactation cycle of a high producing cow over six successive cycles was used. The federal order Class III milk price was used for milk values and it was assumed that unless the producer engaged in some sort of forward contract, the milk price received was the monthly Class III value. To account for forward sales, the Class III futures contract traded at the Chicago Mercantile Exchange was used. For the feed prices, the ration model had a library of 16 different ingredients, 11 of which had forward and spot values. Similar to the output side, it was assumed that unless the producer engaged in some sort of forward contract the feed price used was the spot value averaged for each month. Most California dairy operators use some version of the least-cost method when formulating their rations. A large number also forward contract a significant portion of their feed as the concept of forward contracting feed is much more common in the western U.S. as compared to other regions in the country. Conversely, there has been little interest in locking in future milk prices as the tools for forward contracting are relatively new and many producers are not familiar with the mechanics. This helps explain the limited use of the profit-maximization model since milk prices are an integral part of this process. Results of this study show that producers who formulate using the profit-maximization model attain higher milk production and derive higher milk revenues, albeit with higher feed costs. Nonetheless, across every situation, that is whether one forward contracts feed, milk, or some combination thereof the profit-maximization model returned anywhere from $0.14 to $0.19 of milk revenues in excess of feed costs per hundredweight of milk as opposed to the least-cost method. For a producer milking 1,000 cows this represents another $50,000 to $70,000 of income per year. The results also show that whether least-cost or the profit-maximization method is employed, feed costs were lower when producers forward contract at least a portion of their needs. Milk prices, on the other hand, were lower relying on the spot market as opposed to either of the two forward milk contracting models that were developed. Finally, the variability of returns as measured by the coefficient of variability show less volatility in revenues when producers forward contract milk and less variability with input costs when producers forward contract feed.

L'objet de cette thèse est d'étudier un problème de la magnétostatique tridimensionnel. On propose trois formulations mixtes couplant une méthode d'éléments finis pour tenir compte du milieu hétérogène et une méthode éléments de frontière pour le milieu extérieur homogène. Pour la méthode intégrale on a utilisé les équations de Calderon, l'opérateur de Neumann-Dirichlet ou d'autres opérateurs intégraux. L'utilisation des éléments d'arête de Nédélec pour le champ magnétique, et les éléments de face de Raviart pour l'induction magnétique permet d'utiliser des méthodes éléments finis conformes. Des résultats numériques ont permis de valider ces méthodes. La deuxième partie a porté sur la comparaison de diverses discrétisations pour l'opérateur de Poincaré-Steklov. Ces méthodes ont été comparées sur une formulation de la magnétostatique. Enfin, on propose des formulations discontinues du problème de la magnétostatique avec des conditions aux limites. On montre que ces formulations sont consistantes et des estimations d'erreur sont obtenues.

Most individuals are influenced by pain at some stage in their lives. It can either be of acute or chronic nature. An acute pain condition initiates and is treated within a time span of 12 weeks. Chronic pain can, however, take substantially longer to treat. Chronic pain may last up to 6 months after the original injury was sustained. The after effects of chronic pain can, however, take years to heal, but physical and emotional scars may even last much longer than the initial chronic ailment. In this study the skin was chosen as an area for delivery of non-steroidal anti-inflammatory drugs for the treatment of pain at the joint and muscle tissue regions. The stratum corneum (the topmost horny layer of the skin), however bars the effective movement of chemical substances across the skin as it forms part of the skin's function to protect the superficial tissue of the body against the external environment. It furthermore plays an important role in regulation of the movement of chemicals across the skin. Sweat pores and hair follicles can be utilised as pathways for the movement of chemical substances through the stratum corneum. Physical deformation ie, hydration of the top layer of the skin, may also enhance the movement of chemicals The non-steroidal anti-inflammatory drug, diclofenac, has been evaluated for transdermal diffusion. Three different diclofenac salts were evaluated, namely diclofenac diethylamine, diclofenac hydroxyethyl pyrrolidine and diclofenac sodium. These salts have the potential to relieve systemic pain conditions. Diclofenac salts, however, possess physicochemical characteristics that are unfavourable for transdermal diffusion. Pheroid™ delivery technology, as patented by the Northwest-University, was implemented as a method to enhance transdermal delivery of the diclofenac salts. During the study each of the diclofenac salts was formulated in a Pheroid™ and non-Pheroid™ formulation. All the formulations as well as corresponding retail products containing similar diclofenac salts were evaluated in order to determine which preparation had the most effective transdermal diffusion. High performance liquid chromatograhphy was implemented in order to determine the concentration of each salt in their various preparations. The Pheroid™ and non-Pheroid™ formulations were also compared to retail products currently available. An active ingredient flux was determined by means of Franz cell diffusion studies. Membrane diffusion studies were utilised in order to determine whether the active ingredients were effectively released from the formulated preparations and market products. Membrane diffusion studies determined that Arthruderm (the retail product containing diclofenac sodium) had the most potential to effectively release the active ingredient from the formulation (median flux 28.36 ± 0.26 ug/cm2.h"1). Franz cell diffusion studies showed no flux values for any of the evaluated preparations, including the retail products. Concentrations obtained within the epidermis and dermis were determined through tape stripping of these areas. The largest concentration of active ingredient within the epidermis was obtained from the studies done on Voltaren® (the retail product containing diclofenac diethylamine) which was 7.27 |ig/cm2.h"1 the largest value in the dermis was obtained from a non-Pheroid™ formulation containing diclofenac sodium (4.47 ug/ml). Confocal laser scanning microscopy was utilised and the micrographs where evaluated to ensure that the diclofenac salts were effectively entrapped in the Pheroid™ delivery system. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

Most individuals are influenced by pain at some stage in their lives. It can either be of acute or chronic nature. An acute pain condition initiates and is treated within a time span of 12 weeks. Chronic pain can, however, take substantially longer to treat. Chronic pain may last up to 6 months after the original injury was sustained. The after effects of chronic pain can, however, take years to heal, but physical and emotional scars may even last much longer than the initial chronic ailment. In this study the skin was chosen as an area for delivery of non-steroidal anti-inflammatory drugs for the treatment of pain at the joint and muscle tissue regions. The stratum corneum (the topmost horny layer of the skin), however bars the effective movement of chemical substances across the skin as it forms part of the skin's function to protect the superficial tissue of the body against the external environment. It furthermore plays an important role in regulation of the movement of chemicals across the skin. Sweat pores and hair follicles can be utilised as pathways for the movement of chemical substances through the stratum corneum. Physical deformation ie, hydration of the top layer of the skin, may also enhance the movement of chemicals The non-steroidal anti-inflammatory drug, diclofenac, has been evaluated for transdermal diffusion. Three different diclofenac salts were evaluated, namely diclofenac diethylamine, diclofenac hydroxyethyl pyrrolidine and diclofenac sodium. These salts have the potential to relieve systemic pain conditions. Diclofenac salts, however, possess physicochemical characteristics that are unfavourable for transdermal diffusion. Pheroid™ delivery technology, as patented by the Northwest-University, was implemented as a method to enhance transdermal delivery of the diclofenac salts. During the study each of the diclofenac salts was formulated in a Pheroid™ and non-Pheroid™ formulation. All the formulations as well as corresponding retail products containing similar diclofenac salts were evaluated in order to determine which preparation had the most effective transdermal diffusion. High performance liquid chromatograhphy was implemented in order to determine the concentration of each salt in their various preparations. The Pheroid™ and non-Pheroid™ formulations were also compared to retail products currently available. An active ingredient flux was determined by means of Franz cell diffusion studies. Membrane diffusion studies were utilised in order to determine whether the active ingredients were effectively released from the formulated preparations and market products. Membrane diffusion studies determined that Arthruderm (the retail product containing diclofenac sodium) had the most potential to effectively release the active ingredient from the formulation (median flux 28.36 ± 0.26 ug/cm2.h"1). Franz cell diffusion studies showed no flux values for any of the evaluated preparations, including the retail products. Concentrations obtained within the epidermis and dermis were determined through tape stripping of these areas. The largest concentration of active ingredient within the epidermis was obtained from the studies done on Voltaren® (the retail product containing diclofenac diethylamine) which was 7.27 |ig/cm2.h"1 the largest value in the dermis was obtained from a non-Pheroid™ formulation containing diclofenac sodium (4.47 ug/ml). Confocal laser scanning microscopy was utilised and the micrographs where evaluated to ensure that the diclofenac salts were effectively entrapped in the Pheroid™ delivery system. / Thesis (M.Sc. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

Ce travail de thèse a pour objectif une meilleure connaissance des formulations filmogènes développées par les Laboratoires URGO. Deux aspects ont été développés.Il a tout d’abord été recherché un système d’encapsulation afin de protéger des molécules d’intérêt dans des solutions filmogènes. Des polymersomes en phase aqueuses et en phase organique ont été développés à base de copolymères amphiphiles m-PEG-PCL synthétisés et caractérisés au laboratoire. Ces auto-assemblages des copolymères possèdent des tailles variables (40 nm à 800 nm) avec une membrane en bicouche. Leur caractérisation a été réalisée en phase aqueuse et organique par différentes techniques : DLS, NTA, microscopie biphotonique et AFM. Puis des techniques de caractérisation ont été mises au point pour évaluer une formulation filmogène à base de nitrocellulose contenant de l’urée libre ou encapsulée dans des polymersomes. Cette formulation a été suivie au cours d’essais de stabilité à 25°C et à 40°C pendant 6 mois. Il a été observé une chute de viscosité, surtout à 40°C, attribuée à une coupure des chaînes macromoléculaires de la nitrocellulose (par CES). Les films formés ont un module de Young stable dans le temps avec apparition d’un jaunissement (paramètre b en colorimétrie). La quantité d’urée reste stable dans le temps mais elle accélère les phénomènes de vieillissement. Le jaunissement est dû à la décomposition de l’huile de ricin. L’encapsulation de l’urée au sein des polymersomes n’a pas amélioré la stabilité de la formulation prouvant ainsi le rôle catalyseur de l’urée. / This work aims at a better understanding of film-forming formulations developed by Laboratoires Urgo. Two parts have been developed. First, an encapsulation system to protect a model drug in film forming solutions was investigated. Polymersomes in aqueous and organic media have been developed based on amphiphilic copolymers m-PEG-PCL which were synthesized and characterized in the laboratory. Auto-assemblies of copolymers display variable sizes (40 nm to 800 nm) with a bilayer membrane. Their characterization was carried out in aqueous and organic phase by various techniques: DLS, NTA, bi-photonic microscopy and AFM. In a second part, characterization techniques have been developed to assess a film forming solution based on nitrocellulose, containing free or encapsulated urea in polymersomes. This formulation was investigated during stability studies at 25°C and 40°C up to 6 months. A drop in viscosity was observed, especially at 40°C, due to cleavage of the macromolecular chains of nitrocellulose (SEC). The formed films have a stable Young's modulus over time with an appearance of yellowing (parameter b in colorimetry). The urea quantity remains stable in time, but accelerates the aging of the solution. Yellowing is caused by the decomposition of castor oil. The encapsulation of the urea within polymersomes did not improve the stability of the formulation thus proving the catalytic role of urea.

Title: Nonconvex stochastic programming problems - formulations, sample approximations and stability Author: RNDr. Martin Branda Author's e-mail address: branda@karlin.mff.cuni.cz Supervisor: Doc. RNDr. Petr Lachout, CSc. Supervisor's e-mail address: lachout@karlin.mff.cuni.cz Abstract: We deal with problems where integer variables may appear, hence no assumptions on convexity are made throughout this thesis. The goal of Chapter 2 is to introduce stochastic programming problems and to outline the most important tasks connected with solving the problems. In Chapter 3, we compare basic formulations of static stochastic programming problems with chance constraints, with integrated chance constraints and with penalties in the objective function. We show that the problems are asymptotically equivalent under mild conditions. We discuss solving the problems using sample approximation techniques and extend some results on rates of convergence. All the formulations and corresponding sample approximations are compared on an investment problem with real features with Value at Risk constraint, integer allocations and transaction costs. Then, stability of financial decision models where two-stage mixed-integer value function appears as a loss variable is studied. In Chapter 4, we study qualitative properties of the...

Submitted by Marcele Costal de Castro (costalcastro@gmail.com) on 2017-10-04T17:13:38Z No. of bitstreams: 1 PAULO AUGUSTO BERQUÓ DE SAMPAIO D.pdf: 6576641 bytes, checksum: 71355f6eedcf668b2236d4c10f1a2551 (MD5) / Made available in DSpace on 2017-10-04T17:13:38Z (GMT). No. of bitstreams: 1 PAULO AUGUSTO BERQUÓ DE SAMPAIO D.pdf: 6576641 bytes, checksum: 71355f6eedcf668b2236d4c10f1a2551 (MD5) Previous issue date: 1991-09 / The basic difficulties associated with the numerical solution of the incompressible Navier-Stokes equations in primitive variables are identified and analysed. These difficulties, namely the lack of self-adjointness of the flow equations and the requirement of choosing compatible interpolations for velocity and pressure, are addressed with the development of consistent Petrov-Galerkin formulations. In particular, the solution of incompressible viscous flow problems using simple equal order interpolation for all variables becomes possible .

The primary purpose of this study is to identify the 'universal' rate formulations with scaled-dependent parameters for the biological reduction of hematite. Three possible rate formulations were proposed to describe the bioreduction rate of hematite, and two kinds of simulation were conducted to validate the formulations and parameters with both batch and column experimental data: a reaction-based biogeochemical (batch) modeling with BIOGEOCHEM 1.0 and a reactive biogeochemical transport (column) modeling via HYDROGEOCHEM 4.0. Based on the results of simulations, only the dual Monod kinetic with inhibition rate formulation with respect to the concentrations of lactate, ßFeOOH, and Fe2+ under certain initial concentration of dissimilatory metal-reducing bacterium could fit the experimental data well. Our results also revealed that the equilibrium reaction rate for the surface hydration of hematite may have to be substituted with the kinetic rate formulation.

Dans ce document, nous étudions deux problèmes de sectorisation et proposons plusieurs méthodes de résolution exactes basées sur la décomposition de Dantzig-Wolfe et la génération de colonnes. Nous proposons deux modélisations en fonction de la manière d’appréhender l’objectif du problème qui consiste à obtenir des secteurs compacts. Pour chacune des modélisations, nous comparons des approches de résolution exactes basées sur des formulations compactes ou sur des formulations étendues obtenues par la décomposition de Dantzig-Wolfe. Le premier type de modèles proposé définit la fonction objectif à la manière d’un problème de p-median. Concernant les méthodes de résolution pour ce type de modèle, l’accent est mis sur l’accélération de la convergence de l’algorithme de génération de colonnes en mettant en place des techniques d’agrégation de contraintes afin de réduire la dégénérescence de l’algorithme du simplexe. Les expérimentations numériques montrent que la méthode d’agrégation de contraintes proposée permet effectivement de réduire le nombre d’itérations dégénérées. Cependant, elle ne suffit pas à accélérer l’algorithme de branch-and-price. Le choix d’utilisation de la formulation compacte ou de la formulation étendue dépend du type d’instances résolu. Le second type de modèles formule l’objectif d’une manière assez proche de celui des problèmes de p-centre. L’utilisation d’un tel objectif complexifie la résolution des sous-problèmes de génération de colonnes. L’accent est donc mis sur la conception d’algorithmes de branch-and-bound et de programmation dynamique pour les résoudre efficacement. Les expériences montrent que l’algorithme de branch-and-price surpasse les approches de résolution utilisant une formulation compacte du problème. / In this document, we study two districting problems and propose several exact methods, based on Dantzig-Wolfe decomposition and column generation, to solve them. For each model, we compare exact approaches based either on compact formulations or on extended formulations obtained using Dantzig-Wolfe decomposition. The first type of model that we propose defines the objective function in a p-median problem fashion. Regarding the methods used to solve that kind of model, we emphasize accelerating the convergence of the column generation algorithm by designing constraint aggregation techniques in order to reduce the degeneracy in the simplex algorithm. Numerical experiments show that this constraint aggregation method indeed reduces the proportion of degenerated iterations. However, it is not enough to speed up the branch-and-price algorithm. Choosing to tackle the problem through either a compact formulation or an extended formulation depends on the structure of the instances to solve. The second type of model formulates the objective function in a way quite similar to that of p-centre problems. Using such an objective function induces complex column generation subproblems. We focus on designing branch-and-bound and dynamic programming algorithms in order to solve them efficiently. Experiments show that the branch-and-price approach surpasses any proposed method based on compact formulations of the problem.