The blood-brain barrier restricts the access of many compounds, including therapeutic agents, to the brain. Several human studies indicate that nasal administration of hydrophilic compounds, such as peptides, can bypass the blood-brain barrier. The aims of this thesis were to develop and refine models for this direct nose-to-brain transfer. In a mouse model, [3H]-dopamine was given as a unilateral nasal dose. The resulting radioactivity in the ipsilateral olfactory bulb was significantly higher than that in the contralateral bulb and peaked at 4 h. Tape section autoradiography showed that the radioactivity was concentrated in the olfactory nerve layer and the glomerular layer of the olfactory bulb. The olfactory transfer of dopamine was also studied in vitro. At a lower donor concentration, the mucosal-to-serosal dopamine permeability was higher than the serosal-to-mucosal permeability, but at a higher concentration, the permeability coefficients were similar. Together, these results suggest that the olfactory transfer of dopamine has an active component. Olfactory transfer of fluorescein-labeled dextran through the epithelium and deeper tissues was studied in a rat model, which enabled visualization of the transfer using fluorescence microscopy. Although the epithelial transfer appeared to be mainly intracellular, transfer in the following deeper tissues was extracellular. Without altering the route of uptake, a gellan gum formulation enhanced the uptake of fluorescein dextran. The enhancing effect was considered likely to be the result of an increased residence time in the nasal cavity. In conclusion, dopamine and fluorescein-labeled dextran were identified as suitable model compounds for the study of olfactory drug transfer mechanisms and the influence of drug formulation. Two new in vitro models of olfactory transfer were compared. Also, a rat model, which enabled the visualization of the entire nose-to-brain transfer, was developed.

A stochastic operator is a positive linear contraction, P : L1 --+ L1, such that llPfII2 = llfll1 for f > 0. It is called asymptotically stable if the iterates pn f of each density converge in the norm to a fixed density. Pf(x) = f K(x,y)f(y)dy, where K( ·, y) is a density, defines a stochastic kernel operator. A general probabilistic/ deterministic model for biological systems is considered. This leads to the LMT operator P f(x) = Jo - Bx H(Q(>.(x)) - Q(y)) dy, where -H'(x) = h(x) is a density. Several particular examples of cell cycle models are examined. An operator overlaps supports iffor all densities f,g, pn f APng of 0 for some n. If the operator is partially kernel, has a positive invariant density and overlaps supports, it is asymptotically stable. It is found that if h( x) > 0 for x ~ xo ~ 0 and ["'" x"h(x) dx < liminf(Q(A(x))" - Q(x)") for a E (0, 1] lo x-oo then P is asymptotically stable, and an opposite condition implies P is sweeping. Many known results for cell cycle models follow from this. / Mathematical Science / M. Sc. (Mathematics)

Submitted by Marco Antonio Oliveira da Silva (maosilva@ipen.br) on 2017-11-08T16:10:07Z No. of bitstreams: 0 / Made available in DSpace on 2017-11-08T16:10:07Z (GMT). No. of bitstreams: 0 / O aumento na longevidade humana fez surgir uma série de doenças com a idade; em contrapartida o avanço da medicina possibilitou o diagnóstico precoce e o tratamento de várias doenças antes incuráveis. Esse cenário atual estendese também aos animais domésticos (cães e gatos - PETs) que dobraram sua expectativa de vida nas últimas décadas, fato que os humanos demoraram séculos para alcançar. Do mesmo modo que os humanos, esse aumento na longevidade dos animais veio acompanhado de doenças relacionadas com a idade, entre elas o câncer. Uma das terapias utilizadas atualmente no tratamento do câncer é a radioterapia, técnica que utiliza a radiação ionizante para destruir as células tumorais (volume-alvo) com mínimo prejuízo aos tecidos circunvizinhos sadios (órgãos de risco). Essa técnica exige a realização periódica de testes de controle de qualidade, incluindo a dosimetria com a utilização de objetos simuladores equivalentes ao tecido, de modo a verificar a dose de radiação recebida pelo paciente em tratamento e compará-la posteriormente com a dose de radiação calculada pelo sistema de planejamento. A rápida expansão do mercado de impressoras 3D abriu caminho para uma revolução na área da saúde. Atualmente os objetos simuladores por impressão 3D estão sendo usados em planejamentos de Radioterapia para a localização espacial e mapeamento das curvas de isodose, realizando, assim, um planejamento mais personalizado para cada campo de radiação, além da confecção de implantes dentais, customização de próteses e confecção de bólus. Diante do exposto esse trabalho projetou e desenvolveu um objeto simulador chamado de \"Canis Morphic\" utilizando uma impressora 3D e materiais tecido-equivalentes para a realização dos testes de controle de qualidade e otimização das doses na área de Radioterapia em animais (cães). Os resultados obtidos demonstraram-se promissores na área de criação de simuladores por impressão 3D, com materiais de baixo custo, para aplicação no controle de qualidade em Radioterapia veterinária. / Tese (Doutorado em Tecnologia Nuclear) / IPEN/T / Instituto de Pesquisas Energéticas e Nucleares - IPEN-CNEN/SP

Switches play an important regulatory role at all levels of biology, from molecular switches triggering signaling cascades to cellular switches regulating cell maturation and apoptosis. Medical therapies are often designed to toggle a system from one state to another, achieving a specified health outcome. For instance, small doses of subpathologic viruses activate the immune system’s production of antibodies. Electrical stimulation revert cardiac arrhythmias back to normal sinus rhythm. In all of these examples, a major challenge is finding the optimal stimulus waveform necessary to cause the switch to flip. This thesis develops, validates, and applies a novel model-independent stochastic algorithm, the Extrema Distortion Algorithm (EDA), towards finding the optimal stimulus. We validate the EDA’s performance for the Hodgkin-Huxley model (an empirically validated ionic model of neuronal excitability), the FitzHugh-Nagumo model (an abstract model applied to a wide range of biological systems that that exhibit an oscillatory state and a quiescent state), and the genetic toggle switch (a model of bistable gene expression). We show that the EDA is able to not only find the optimal solution, but also in some cases excel beyond the traditional analytic approaches. Finally, we have computed novel optimal stimulus waveforms for aborting epileptic seizures using the EDA in cellular and network models of epilepsy. This work represents a first step in developing a new class of adaptive algorithms and devices that flip biological switches, revealing basic mechanistic insights and therapeutic applications for a broad range of disorders.