Orientador: Edson Denis Leonel / Resumo: Este estudo objetiva provar que sistemas dinâmicos de dimensão N, de codimensão um e satisfazendo as condições do teorema da bifurcação de Hopf, podem ser expressos em uma forma analítica simplificada que preserva a topologia do espaço de fases da configuração original, na vizinhança do ponto de equilíbrio. A esta forma simplificada é atribuído o nome de forma normal. Para tanto, foi utilizado a teoria da variedade central, necessária para reduzir a dimensão de sistemas à sua variedade bidimensional, e o teorema das formas normais, utilizando-se como método para determinar a forma simplificada da variedade central associada aos sistemas dinâmicos, atendendo as condições do teorema da bifurcação de Hopf. A partir da análise dos resultados aqui encontrados foi possível construir a prova matemática de que sistemas de dimensão N, atendendo as condições do teorema de Hopf, podem ser reescritos em uma expressão analítica geral e simplificada. Enfim, através deste estudo foi possível resumir todos os resultados aqui obtidos em um teorema geral que, além de reduzir a custosa tarefa de obtenção de formas normais, abrange sistemas N-dimensionais com ocorrência da bifurcação de Hopf. / Abstract: In this work we prove the following: consider a N-dimensional system that is reduced to its center manifold. If it is proved the system satisfies the conditions of Hopf bifurcation theorem, then the original system of differential equations is rewritten in a simpler analytical expression that preserves the phase space topology. This last is also known as the normal form. The center manifold is used to derive a reduced order expression, and the normal form theory is applied to simplify the form of the dynamics on the center manifold. The key results here allow constructing a general mathematical proof for the normal form of N-dimensional systems reduced to its center manifold. In the class of dynamical systems under Hopf bifurcations, the present work reduces the work done to obtain normal forms. / Mestre

This thesis examines the preoccupation with the relationship between history and fiction present in the work of Leonardo Sciascia and Jorge Luis Borges. By means of different narrative strategies, both authors underscore the narrative elements that underpin any reconstruction of the past, and in this way they link the process of reconstruction of past events to the process of rewriting of a literary work. They emphasise, however, that whereas the literary work can be enriched by multiple rewritings, multiple reconstructions of the same real past event risk threatening its truthfulness. This thesis investigates the different ways in which Borges’s and Sciascia’s works intersect, across three narrative forms: the detective story, the historical essay (inchiesta or ‘enquiry’ for Sciascia) and the historical fiction. The analysis of Sciascia’s texts starts from a focus on the structural similarities with the work of Borges in the detective story, paying particular attention to Il contesto (1971), Todo modo (1974), and Il cavaliere e la morte (1988). It then moves on to Sciascia’s inclusion of fragments of Borges’s texts in two of his inchieste, L’affaire Moro (1978) and Il teatro della memoria (1981). The last chapter of the thesis proposes a metafictional reading of Sciascia’s historical novel Il Consiglio d’Egitto (1963), in the light of the comparisons with Borges’s work undertaken in the previous chapters. The two key aims of this thesis are to show (1) that studying the ways in which Sciascia integrates Borges’s texts in his own writing allows a deeper understanding of Sciascia’s texts, but also underscores traits in Borges’s which might have been downplayed by previous criticism of his work, and (2) that reconsidering in the light of this understanding a number of Sciascia’s other texts where Borges’s influence is not explicit allows us to identify a preoccupation with regards to the relationship between history and fiction shared between both authors.

Cette thèse est composée de quatre chapitres et analyse une régularité empirique très mal connue et très peu analysée : les « formes organisationnelles plurielles ». Dans le premier chapitre, j’examine les diverses tentatives de théoriser les formes plurielles et comment ce domaine a évolué au fil du temps. Cela me permet d’identifier deux variables qu’on retrouve au cœur des idées exprimées dans ces tentatives pour expliquer l’existence et la stabilité des formes plurielles : la spécificité des actifs ainsi que les facteurs d’incertitude. Néanmoins, ces variables sont restées très mal explorées, ce qui pointe la nécessité de nouvelles contributions théoriques sur ce sujet. Dans le deuxième chapitre, je cherche à comprendre ce qui explique la variété des formes plurielles. Je propose un modèle théorique intégrant la spécificité des actifs et l'incertitude pour pronostiquer l’existence des formes plurielles et non plurielles. Ensuite, je souligne que les formes plurielles sont hétérogènes et je construis des hypothèses mettant en relation différents types d’incertitude avec des formes plurielles différentes. Dans les deux chapitres suivants, le modèle théorique et les hypothèses sont confrontés à des données empiriques qualitatives. Le troisième chapitre confronte le modèle théorique à une étude de cas clinique menée au sein d’une entreprise, l’entreprise Korin (Brésil), qui produit et vend divers produits bios. Enfin dans le chapitre quatre, le modèle théorique et les hypothèses sont confrontés à des données recueillies à partir d’une enquête sur l’approvisionnement en ‘inputs’ auprès de 24 entreprises opérant dans le secteur agricole brésilien. Je trouve dans ces deux articles des concordances fortes à l’appui de mon modèle et des hypothèses que j’en ai dérivées, ce qui ouvre la voie à de nouvelles recherches. / This dissertation is composed of four chapters and addresses an empirical regularity about which very little is known: “plural forms”. In the first chapter, I intend to verify what has been theorized about plural forms and how this field has evolved over time. I identified two variables that underlie most of the theoretical explanations for the existence and stability of plural forms: asset specificity and uncertainty. However, these variables are very seldom explored, which points towards the need for novel contributions. In the second chapter, I am concerned with explaining the variety of plural form manifestations. I built a theoretical model integrating asset specificity and uncertainty to predict plural and non-plural forms. Next, I stressed that plural forms are heterogeneous and built hypotheses relating different types of uncertainty to different types of plural forms. In the next two chapters, I empirically confront my theoretical model and hypotheses with qualitative data. In the third chapter, I confront my model by performing an embedded clinical case study on the Korin company (in Brazil), which produces and commercializes multiple organic products; while in the final chapter, I intend to empirically confront both my theoretical model and my hypotheses and survey the procurement of inputs by 24 companies operating in the Brazilian Agribusiness sector. I find support for my model and for my hypotheses on both of these papers, indicating a path for further analyses.

Orientador: José Ricardo de Arruda Miranda / Banca: Cristina Helena dos Reis Serra / Banca: Oswaldo Baffa Filho / Banca: Raul César Evangelista / Banca: Eryvaldo Sócrates Tabosa do Egyto / Resumo: A administração oral de drogas é uma prática comum na terapia e as formas farmacêuticas sólidas são amplamente utilizadas. A variação no perfil de absorção ao longo do trato gastrintestinal (TGI) humano e a possibilidade de liberar drogas em diferentes regiões são os maiores desafios para o desenvolvimento de novos produtos. Desse modo, avaliar formas farmacêuticas sólidas in vivo fornece um entendimento mais profundo quando um efeito sistêmico ou local é desejado. Geralmente, estes estudos são realizados por meio da cintilografia e técnicas biomagnéticas. A Biosusceptometria de Corrente Alternada (BAC) é uma técnica que merece destaque por suas características, acurácia dos resultados obtidos e versatilidade. A BAC propiciou imagens do processo de desintegração de comprimidos tanto in vitro quanto no estômago humano, introduzindo outra perspectiva na análise desse processo. Os resultados também foram correlacionados com sucesso com aqueles obtidos por metodologias específicas, garantindo uma análise mais acurada dos parâmetros físicos envolvidos com a desintegração de comprimidos. A utilização da BAC permitiu avaliar a motilidade gastrintestinal e o processo de desintegração de cápsulas de hidroxipropilmetilcelulose (HPMC) revestidas no cólon humano. Além disso, também foi possível investigar a influência do estado prandial no esvaziamento gástrico e no trânsito gastrintestinal de um sistema multiparticulado magnético. Todos esses trabalhos fortaleceram a BAC como um método alternativo na pesquisa farmacêutica demonstrando seu potencial para avaliar diferentes processos, apesar das suas limitações. Sintetizando, a BAC é uma ferramenta valiosa, com a vantagem de ser livre de radiação e inócua aos voluntários, e vasta aplicabilidade na pesquisa farmacêutica, farmacológica e fisiológica. / Abstract: Oral administration is widely accepted route for drug delivery and solid dosage forms are commonly administered. The variation of absorption profiles along the human gastrointestinal tract (GIT) and the ability to target drugs by adequate dosage forms to distinct sites is the challenge in the pharmaceutical development of solid dosage forms. An understanding of the factors involved in drug absorption and how the gastrointestinal variables can interfere with this process is important to develop more reliable drug delivery systems. The performance of pharmaceutical dosage forms must be fully investigated in vivo to provide more reliable information when a local or systemic effect is desirable. Generally, in vivo investigation on the behavior of dosage forms has been made by using gamma‐scintigraphy and biomagnetic techniques. AC Biosusceptometry (ACB) deserves consideration due to its features, accuracy and versatility. By using ACB technique, it was possible to monitor the disintegration process through acquisition of magnetic images in vitro and in human stomach. The results also were successfully correlated with those obtained with standard methods which provided a more reliable analysis on the physical parameters involved in the disintegration process of tablets. ACB allowed evaluating the gastrointestinal motility and the disintegration of hydroxipropylmethylcellulose (HPMC) coated capsules in human colon. Moreover, it was possible to investigate the gastric emptying and gastrointestinal transit of a magnetic multiparticulate system under influence of prandial state. All these studies have contributed to establish the ACB as an alternative method for pharmaceutical research and, despite some limitations, it was feasible to evaluate different pharmaceutical processes. In summary, ACB is a radiation free and non‐invasive technique with wide applicability in pharmaceutical, physiological and pharmacological researches. / Doutor

For some of Plato’s commentators some passages of the Republic and the Parmenides provide a clear guideline regarding the extension of the noetic “world”, namely, a criterion that allows us to know what kind of Platonic forms there are, and which there are not. There are forms only for a pair of opposite properties such as “big” and “small”; indeed, smallness itself is not what appears to the senses, since each sensible instance of smallness appears “mixed” with its opposite, bigness. On the contrary, things that are perceived by the senses such as fingers, do not have an eidos. However, a more careful reading of the relevant passages, taking into account what Socrates says in 476a about the unity and multiplicity of the forms, will show us the incorrectness of this interpretation. / Algunos intérpretes de Platón consideran que algunos pasajes de la República y el Parménides nos proveen de un criterio para delimitar la extensión del ámbito ediético, es decir, para saber qué tipos de Ideas hay y qué tipos no. Hay ideas solo para pares de propiedades opuestas, como “grande” y “pequeño”, ya que la pequeñez no es lo que aparece a los sentidos, pues en cada instancia sensible suya la encontramos mezclada con su opuesto, la grandeza. Contrariamente, aquellas cosas que son tal como aparecen a los sentidos, como los dedos, no tienen un eidos. Sin embargo, una lectura más cuidadosa de los pasajes relevantes, tomando en cuenta lo que Sócrates dice sobre la multiplicidad y unidad de las ideas en República 476a, nos mostrará lo equivocado de esta interpretación.

Made available in DSpace on 2016-08-11T14:41:31Z (GMT). No. of bitstreams: 1 DeboraNJR_DISSERT.pdf: 1718335 bytes, checksum: d44051499461c839e06ab5fc2aaa7215 (MD5) Previous issue date: 2015-02-26 / Fundação de Apoio a Pesquisa do Estado do Rio Grande do Norte / Toxoplasmosis is a cosmopolitan infection caused by the protozoan Toxoplasma gondii, achieving high rates of infection in Brazil and worldwide. The infective forms of the parasite (taquezoítos, bradyzoites and oocysts) that allow humans and other species of animals become infected in several ways, by transplacental form (congenital, from mother to child); handling feces of cats; handling of soil (sand); eating raw or undercooked meat, among other forms. However, infection with Toxoplasma gondii can be mitigated by carrying out preventive measures, such measures are directly related to behavioral and hygienic habits of the population. Thus, starting from pre supposed that the knowledge about the modes of transmission and preventive measures of toxoplasmosis would be precursor to inhibit the increase of infection, the study aimed to assess the population's knowledge about the modes of transmission and preventive measures of toxoplasmosis in Mossoró - RN. Then, a field study was conducted in the municipality, and followed by visits to the Basic Health Units in six districts, with a population of 384 women in the age group classified as reproductive (18-49 years). They were submitted to a questionnaire containing 40 questions, which dealt with the knowledge of transmission and preventive measures of toxoplasmosis. The data obtained from the questionnaires were statistically analyzed with the aid of R program, and use of non-parametric test to compare Fisher Exact women's knowledge about the modes of transmission and their schooling. It was found that most women are unaware of the main frame forms of transmission of toxoplasmosis, this ignorance, had statistical relationship with the education of the respondents. In what refers to preventive measures, most of the population practices without even having knowledge about the ways of transmission. It was concluded that the fact that women practice preventive measures, even knowing the modes of transmission, can is related to lifestyle and custom of the population. It was also observed that most of the women surveyed do not know the IgG test for toxoplasmosis, adding yet, the fact of not having the examination or not knowing respond if at some point would have already done / A toxoplasmose é uma infecção cosmopolita, causada pelo protozoário Toxoplasma gondii, atingindo altos índices de infecção no Brasil e no mundo. As formas infectantes do parasita (taquezoítos, bradizoítos e oocistos) permitem que o ser humano e as outras espécies de animais se infectem de várias formas como, pela forma transplacentária (congênita, de mãe para filho); manuseio de fezes de felinos; manuseio de solo (areia); ingestão de carne crua ou mal passada, entre outras formas. No entanto, a infecção pelo Toxoplasma gondii pode ser atenuada com a realização de medidas preventivas, tais medidas, estão diretamente relacionada a hábitos comportamentais e higiênicos da população. Dessa forma, partindo do pré-suposto que o conhecimento sobre as formas de transmissão e medidas preventivas da toxoplasmose seria precursor para inibir o aumento da infecção, a pesquisa teve como objetivo avaliar o conhecimento da população sobre as formas de transmissão e medidas preventivas da toxoplasmose em Mossoró RN. Então, foi realizado um estudo de campo no município, e seguiu por visitas as Unidades Básicas de Saúde em seis bairros, com uma população de 384 mulheres na faixa etária classificada como reprodutiva (18 a 49 anos). As mesmas foram submetidas a um questionário contendo 40 questões, as quais versavam sobre o conhecimento das formas de transmissão e medidas preventivas da toxoplasmose. Os dados obtidos nos questionários foram submetidos à análise estatística com auxílio do Programa R, e utilização do teste não paramétricos Exato de Fisher para comparar o conhecimento das mulheres sobre as formas de transmissão e sua escolaridade. Constatou-se que a maioria das mulheres desconhecem as quatro principais formas de transmissão da toxoplasmose, esse desconhecimento, teve relação estatística com a escolaridade das entrevistadas. Já no que se refere às medidas preventivas, a maioria da população pratica, mesmo sem ter conhecimento sobre as formas de transmissão. Concluiu-se que o fato das mulheres praticarem as medidas preventivas, mesmo desconhecendo as formas de transmissão, pode está relacionado aos hábitos de vida e costume da população. Observou-se também, que a maioria das mulheres pesquisadas não conhecem o teste de IgG para toxoplasmose, somando-se ainda, o fato de não terem realizado o exame ou não saberem responder se em algum momento já teriam o realizado

This research developed a pro forma document for use in police rape investigations in South Africa. The immediate context for the research is the alarmingly high incidence of rape in South Africa. The rape statistics vary to an extent, largely due to the fact that a large proportion of the rapes that occur in South Africa are not reported to the police. These statistics expose the limited success of the South African Police Services (SAPS) in terms of investigating rape cases in this country, as well as the public perception of the effectiveness of the South African Police Services in this regard as evidenced by the non or under-reporting of rape in South Africa. The pro forma document is an investigative tool designed to standardise and systematise rape investigations by providing set guidelines for obtaining the essential information about each rape case. This is a prerequisite for Tender profiling, which involves predicting the relationship between offence and offender variables. Profiling can only be successful if the investigator obtains all the information about a crime. Hence the pro forma document, as an investigative instrument designed to access essential information about a crime, is a key requirement for the development of informed and accurate profiles of offenders. As a standardised form, the document will allow for systematic and thorough rape investigations in South Africa. The researcher employed the qualitative methodology of action research. This entailed involving the participants in all stages of the research process. The data was collected by means of focus group interviews with detectives from the Serious and Violent Crimes Unit and the Child Protection Unit in Grahamstown. Additional sources of data were various investigative documents that originated from a number of different countries. Analysis of the data followed a number of procedural steps specifically suggested for focus group interview research and involved a process of coding. The codes identified during the analysis provided the foundation for the items that were included in the pro forma document. In keeping with the action research approach, the participants were caned upon to evaluate the progress of the research after the initial data collection and analysis were completed, and a draft version of the pro forma document had been compiled. This feedback provided another source of data which contained suggestions for amendments to the pro forma document which the researcher implemented. The research process was hindered to a certain extent by the unpredictable nature of police work which influenced the data gathering procedure. This could point to a possible limitation of the research. Furthermore, the aim of the research was to develop a pro forma document for use in rape investigations in South Africa. This aim did not encompass marketing the document. Herein lies another possible limitation of the research in that the document has not yet been used and tested in real cases. A discussion of the research process includes issues involved in practically implementing the pro forma document in rape investigations.

Beta blockers are commonly prescribed for the chronic treatment of hypertension, one of the most prolific disease states worldwide. The beta blockers selected for this study include acebutolol hydrochloride, labetalol hydrochloride, metoprolol tartrate oxprenolol hydrochloride and propranolol hydrochloride. All of these compounds have a short elimination half-life, necessitating multiple dose per day regimens and therefore the development of sustained release dosage forms incorporating these agents was considered beneficial in terms of extending the dosing interval, with the aim of improving patient compliance and subsequent therapeutic outcomes. Preformulation studies that were conducted included moisture content analysis by Karl Fischer titration, and DSC, a method used to predict potential interactions between the drugs and tablet excipients. Tablets were manufactured by both wet granulation and direct compression techniques, and the resultant drug release characteristics were evaluated using the USP Apparatus 3(BIO.DIS). A validated isocratic HPLC method, capable of separating the five drug candidates simultaneously, was developed and used for the analysis of drug samples. Tablet quality was assessed using analyses that included the physical assessment of weight, diameter, thickness, hardness and friability, as well as content uniformity of tablets, before and after dissolution testing. Direct compression tablet formulations containing each of the five beta blockers were successfully adapted from a prototype wet granulation matrix tablet containing metoprolol tartrate, and various formulation variables were investigated to establish,their effect on the rate and extent of drug release from these tablets. The grade and quantity of ethylcellulose used in the wet granulation and direct compression formulae influenced the release rate of some drug candidates. In addition, an alternative formulation method, involving freeze-drying of the drug with an ethylcellulose dispersion, was shown to have potential for altering release rates further. Anti-frictional agents, talc and colloidal silicon dioxide, did not affect drug release from these matrices,however, they affected the physical character:istics such as tablet weight and thickness, of the resultant tablets. All of the matrix tablets formulated were shown to release drug according to square root of time kinetics, in a sustained manner over a 22 hour period.

The use of minocycline for the treatment of a broad range of systemic infections and for severe acne has been associated with vestibular side effects. The severity of side effects may lead to poor adherence to therapy by patients. The use of sustained release formulations of minocycline that display slow dissolution of minocycline following administration may be beneficial in reducing the incidence and severity of side effects. Therefore, sustained release capsule dosage forms containing 100 mg minocycline (base) were manufactured and assessed for use as sustained release oral dosage forms of minocycline. Minocycline sustained release capsules were manufactured based on matrix technologies using hydroxypropylmethyl cellulose (HPMC) and Compritol® as release retarding polymers. The rate and extent of minocycline release from the capsules was evaluated using USP Apparatus 1 and samples were analysed using a validated High Performance Liquid Chromatographic (HPLC) method with ultraviolet (UV) detection. Differences in the rate and extent of minocycline release from formulations manufactured using HPMC or Compritol® were influenced by the concentration of polymer used in the formulations. The rate and extent of minocycline release was faster and greater when low concentrations of polymer were used in formulations. The effect of different excipients on the release pattern(s) of minocycline and particularly their potential to optimise minocycline release from experimental formulations was investigated. The use of diluents such as lactose and microcrystalline cellulose (MCC) revealed that lactose facilitated minocycline release when HPMC was used as the polymer matrix. In contrast, the use of lactose as diluent resulted in slower release of minocycline from Compritol® based formulations. The addition of sodium starch glycolate to HPMC based formulations resulted in slower release of minocycline than when no sodium starch glycolate was used. Compritol® based formulations were observed to release minocycline faster following addition of sodium starch glycolate and Poloxamer 188 to experimental formulations. In vitro dissolution profiles were compared to a target or reference profile using the difference and similarity factors, ƒ1 and ƒ2 , and a one way analysis of variance (ANOVA). In addition, the mechanism of minocycline release was elucidated following fitting of dissolution data to the Korsmeyer-Peppas, Higuchi and Zero order models. Minocycline release kinetics were best described by the Korsmeyer-Peppas model and the values of the release exponent, n (italics), revealed that drug release was a result of the combined effects of minocycline diffusion through matrices and erosion of the matrices. These in vitro dissolution profiles were better fit to the Higuchi model than to the Zero order model. Two formulations that displayed a fit to the Zero order model were identified for further studies as potential dosage forms for sustained release minocycline.

L’agence européenne du médicament (EMA) stipule que les entreprises pharmaceutiques se doivent d’améliorer continuellement le contrôle de leur production afin de garantir la qualité des médicaments et préserver la santé des patients. Les outils analytiques classiques sont, par exemple, capables d’examiner l’intégralité d’un comprimé pharmaceutique pour contrôler la qualité et la quantité des substances actives utilisées et estimer leurs profils de libération dans l’organisme. Ils ne permettent cependant pas de cartographier la distribution des composés chimiques pourtant considérée comme un critère important pour la qualité du médicament. Des techniques d’imagerie chimique comme la MSI MALDI sont donc utilisées afin de déterminer par une analyse unique la répartition spatiale et la structure des composés constituant les médicaments. Toutefois, la MSI MALDI nécessite une préparation des échantillons relativement complexe et génère des données de grande taille difficilement exploitables. Ces caractéristiques, ainsi que l’absence de spectromètre de masse adapté à l’analyse de formes pharmaceutiques solides, complexifient la mise en place de la MSI MALDI au sein de laboratoires industriels. Les travaux réalisés durant cette thèse ont eu pour objectifs d’améliorer le protocole de préparation des échantillons, d’optimiser le système d’acquisition et de mettre en place les outils chimiométriques et informatiques nécessaires à l’analyse des images MALDI au sein de l’entreprise Technologie Servier. Les développements réalisés et les résultats obtenus ont finalement permis la résolution de problématiques inexplicables jusqu’alors par les techniques analytiques classiques. / European Medicines Agency (EMA) recommendations stipulate that pharmaceutical companies have to continually improve manufacturing efficiency to ensure drug product quality. The commonly used analytical tools provide information about drug substance quality and dosage or the drug release profile by dissolving the whole tablet. However these analytical tools are not able to highlight the distribution of chemical compounds contained in the tablet. This is why chemical imaging such as MALDI MSI are used to extract the spatial and spectral information from pharmaceutical solid dosage forms. This hyperspectral imaging technique needs complex sample preparation and generates huge dataset. These two features, as well as the lack of optimized mass spectrometers to study tablets, make difficult the implementation of the MALDI MSI in industrial laboratories. During this thesis, the sample preparation protocol has been improved, the mass spectrometer has been optimized to analyze tablets and chemometrics tools has been developed in order to implement MALDI MSI within Technologie Servier company.