Dissertations / Theses on the topic 'Guide and mediator'

Five study guides prepared for two productions of I, Claudia by Kristen Thomson will serve as a case study to determine the nature and orientations of the tools provided by theatre companies to pedagogues, who in turn teach students how to understand and read theatrical performance. More specifically, this case study will seek to explain how processes typical of “cultural mediation” help students accumulate what Pierre Bourdieu names “cultural” or “social capitals”, both necessary when training future citizens. This thesis will thus serve as a first critique of the workings, strengths and failings of a sociological mechanism typical of English Canadian theatre designed to help teachers mediate theatre and create more informed audience members.

The thesis presents a critique of the nature of 13 to 15 year-old students' images of futures. Arguments are made for their importance to the individual community and culture and their value and use in a science learning setting.This study of the nature of futures images is based upon data collected from small samples in two school settings between 1990 and 1999 using a guided fantasy approach. The diversity of student hopes and fears for futures is categorised using several research tools developed from the futures literature. The results identify a range of futures scenarios ranging from highly utopic to highly dystopic and themes including human interactions, the natural and built environment and the nature and use of futuristic technologies.The importance of student images of futures is discussed from the personal perspective of the students and then considered in the broader context of society and Western culture. The data are examined through a number of theoretical frames including psychology, history and the futures field of enquiry. The consensus seems to be that expectations of the future are inseparable from human nature and influential in determining the viability of cultures.The value of student images of futures in science learning is explored through a case study of one of my own Year 9 classes. In teaching this class I used the technique of futures imaging integrated into a critical futures teaching approach utilising a constructivist planning model. I found that students' futures images revealed a broader aspect of student worldviews than is usual in science learning environments, and were valuable in exposing student prior knowledge, interests and concerns. Student learning seemed to be enhanced using this futures oriented approach.

While interagency collaboration among Children’s Aid Societies and violence against women (VAW) agencies have been mandated by the Ontario Ministry of Community and Social Service, little is known about these local collaboration agreements. This study seeks to explore how the Ottawa CAS/VAW Collaboration Agreement mediates the work of VAW agencies to protect women and children. Using a purposive sample, a total of eight VAW informants were interviewed. Smith (1999) argued that people’s everyday experiences are organized, often unknowingly, by the actions of people located outside the local setting and that this organization is textually-mediated. This study used institutional ethnography and the listening guide approach to critically examine the collaboration process. The results explore the narratives and standpoints as they relate to the informants’ understanding of the agreement and their descriptions of doing collaboration. This study also adopts the mapping technique developed by institutional ethnographers to map social relations. The findings indicate that informants differed in their familiarity and knowledge of the contents of the collaboration agreement – only two informants indicated that they have reviewed and read the document. The findings also show that although most informants were able to describe positive experiences of collaboration, most also described negative experiences. This study concludes that the collaboration agreement has made VAW workers’ work with women more focused and specific to helping women address Children Aid Society’s concerns. The findings demonstrate that the collaboration agreement requires an update and further research is required to evaluate these collaborations and whether they improve outcomes for women and their children.

Our world is made up by millions of colors. Everywhere we go we see a variation of colors that describes the environment. Artists use colors to give an emotion to the viewer and give a deeper meaning to the art. Companies have different colors in their logos and on their websites. For example, a red colored logo can give a feeling of passion, energy and power. But used in a different situation, a red color can implicate dangerand death. The research about colors goes very deep, but there is still alot that has not been tested or discovered. This study will examine whether companies can use colors to mediate the right feeling to their customers. The method to do this included a lot of theoretical background and knowledge about colors. When data was collected a mid-fi prototype of a website was created. This mid-fi website was then transformed into three different high-fi prototypes. The three prototypes had the same content but what put them apart was their color schemes. The tests was done face to face or over the internet. The test person had to answer a short questionnaire were the person described the feelings that appeared when using the three different prototypes. After the test a short interview with each test person took place were some expressions from the test was discussed. The result for the first and second website showed a correlation between the two websites. The users had similar answers on these websites, but they also had some comments that separated the websites. The second website was in the end the most popular website which supported the hypothesis.The conclusion from the study is that colors are a very powerful tool to use if a company wants to attract more customers. This was a quite small study and to draw the conclusion that the right colors actually gives more clicks on a website, a larger and longer study must be made. This is so that the study can compare previous years sales with the year werethey introduced the new color scheme.

L’objet de cette thèse consiste à analyser une expérience pédagogique en maternelle sur deux ans dans le cadre d’une association lyonnaise « Philosoph’art ». Dans cette recherche, nous interrogeons le statut d’innovation de cette expérience et nous étudions, plus précisément, la posture des animateurs pendant les ateliers à visée philosophique et pendant les ateliers artistiques et nous examinons ce qui fait l’originalité d’une telle expérience mise en perspective avec des travaux déjà existants sur la philosophie avec les enfants et les pratiques artistiques. De plus, nous exposerons la mise en place de ce projet et les conditions qui ont assuré la transférabilité d’une telle expérience au Liban
The subject of this thesis consists in an analysis of an experiment that took place over the course of two years, at the kindergarten level, in association with « Philosoph’art », an organization from Lyon. In this research, we interrogate the status of innovation of this experience and we focus on the posture of the quizmaster during workshops with philosophical content as well as artistic projects. We closely examine what sets apart such experiences from those already in use in philosophy with children and artistic practices. Furthermore, we will explain the set up of this project and the conditions in which it has been made transferable for use in Lebanon

On pourrait dire que le projet de cette thèse consiste à comprendre l’articulation dans l’espace, du tourisme et de la communication dans des situations qui mettent en tension un sujet individuel, dévoilant toute la singularité de son désir dans des récits ou des pratiques et des acteurs collectifs engagés dans les politiques touristiques, les médias et les institutions du tourisme.Notre réflexion s’organise ainsi en suivant les modalités de l’articulation entre ces dimensions réelle, symbolique et imaginaire du tourisme. Dans le champ des SIC et particulièrement grâce à des modèles permettant de formaliser la médiation touristique, notre approche conceptuelle permet d’appréhender les significations du tourisme. Nous modéliserons les composantes, les liens et interrelations de la médiation touristique pour proposer une approche théorique de ce que l’on peut appeler la signification touristique de l’espace.En premier lieu, nous abordons les définitions, un état de la recherche en tourisme et le lexique du tourisme par l’étymologie et l’analyse lexicale des termes les plus fréquents : « tour », « tourisme », « touriste », « loisir », « villégiature », « vacances » et « voyage ».En second lieu, nous proposons de poser les bases du champ de la médiation touristique et de montrer que la pratique sociale du tourisme est une médiation. Nous présenterons, commenterons et analyserons, en nous fondant sur un schéma de la médiation touristique, les différentes relations de communication en jeu dans la médiation touristique. Puis nous présenterons les structures de la médiation touristique pour fonder « une théorie critique » de la médiation touristique.Par la suite, nous approfondirons le concept en présentant les opérateurs, les acteurs et les politiques de l’organisation du tourisme, en nous fondant sur l’analyse d’exemples et d’études concernant principalement la médiation et les médiateurs dans le cas de la France pour comprendre comment pratiques et scènes de tourisme s’organisent. Par la suite, nous décrirons et analyserons le système d’information touristique en deux points. Le premier concerne l’énonciation de l’espace produit par le touriste, les touristes et les médiateurs du tourisme (énonciation de la parole du guide par exemple) au travers des récits pluri et multimédias. L’autre concerne la mise en œuvre des stratégies par les destinateurs (opérateurs et acteurs de l’organisation du tourisme privés et publics) au travers des médias du tourisme (généralistes, spécifiques du tourisme et guide touristiques). Un travail d’analyse de discours porte sur des exemples de documents textuels et/ou iconiques des guides touristiques et des labels touristiques
It may be said that this thesis aims at understanding the spatial articulation between tourism and communication in such situations as those in which an individual subject – expressing the whole peculiarity of his or her desire through telling or practices – and collective actors are brought together.My reflection thus organises itself in accordance with the modalities of the articulation between the three dimensions of tourism: the practical dimension, the symbolic dimension and the imaginary dimension.Tourist activity consists in travelling and in visiting a site, a place or a destination; tourist mediation means the range of activities that are organised around tourism or those that are associated to it. Tourist mediation concerns the agents and the practices in the field of tourism. In this context, I wish to show that tourist mediation structures the perceptions, the interpretations and the practises of space.I address the definitions; give an overview of academic research on tourism and address the notions of tourism through the etymology of its main words (tour, tourism, and tourist) and through the differences that exist between tourism and other notions similar to it such as leisure, vacations, holiday and travelling. These notions are necessary to the comprehending of tourist mediation.I intend to lay the foundations of the field of tourist mediation and to demonstrate that the social practise of tourism is a form of mediation. I will present the tourist objects that structure the tourist practises of space. The structures of tourist mediation will then be laid; this will enable me to craft a “critical theory” of tourist mediation. With a view to understanding how the practises and the scenes of tourism organise, I will subsequently widen the concept by presenting the operators, the agents and the policies of the tourist organisation; the examples and the studies of the latter are mainly concerned with mediation and mediators in the case of France. I situate tourist mediation in relation to the experience of otherness and to the relationship to the others, to wanderlust, to the tourist imagination and to cultural imagination too. I then describe and give a two-point analysis of the tourist information system. The first point is concerned with the enunciation of space produced by the tourist, the tourists and by the tourist mediators (the enunciation of the guide’s discourse for instance) through various multimedia telling. The second point is concerned with the enunciation, through the tourist media (non-specialised or tourism media, tourist guides), by the speakers (e.g. operators and private or public agents of the tourist organisation) of the communication strategies and of the tourist descriptive signing. This discourse analysis relates to examples of textual and/or iconic documents

Often neglected in voice study is the understanding that a singer’s instrument lives in his/her body and therefore cannot be packed away like other musical objects. Yoga and mindfulness compliment the belief of a whole body instrument. Data gathered on college campuses report that stress and anxiety are on the rise, thus reinforcing the need for MBSR and yoga as beneficial and proven tools for stress relief. The current state of research in the realm of mental health in colleges merits the study of a cohesive layout of these exercises and their expected outcomes in singing as well as stress management. Therefore, this document will present yoga sequences that align with the core aspects of singing including breath support, fluid vocal production and artistic expression. Exercises founded on principles of mindfulness are provided to bring awareness of mental qualities within a singer. Mental qualities gained from meditation practice include improved self-esteem, lowered anxiety, and increased focus. Yoga sequences will focus on certain areas of the body commonly addressed in voice studies. Collections of yoga asana, or postures, are featured to allow singers to recognize tightness and inefficiencies in their bodies, thus improving vocal function. This guide will combine yoga traditions along with mindfulness research to introduce ancient philosophies to singers and their teachers, resulting in meaningful and productive voice lessons.

Frogs, toads, and salamanders are well known for harboring an array of distasteful (and poisonous) secondary metabolites, presumably as antipredator defenses; yet few experiments have rigorously demonstrated the efficacy of amphibian chemical defenses against ecologically relevant consumers. For example, despite an absence of rigorous statistical evidence showing their distastefulness to predators, eastern newts (Notophthalmus viridescens (Rafinesque))--a common salamander in lentic North American habitats--are assumed to tolerate diverse predator assemblages because newts secrete tetrodotoxin (TTX), a neurotoxin. Here we combine laboratory and field-based ecology with bioassay-guided separation of chemical extracts to show that eastern newts--although chemically protected against ecologically important consumers in lentic systems--nonetheless suffer substantial predation when tethered in the field. When offered newts with alternative prey (paedomorphic Ambystoma talpoideum), red swamp crayfish (Procambarus clarkii) and largemouth bass (Micropterus salmoides) were 9-10x as likely to feed on A. talpoideum as newts. Additionally, juvenile bluegill (Lepomis machrochirus) were 70% less likely to consume newt eggs compared to control food pellets. We also show that different newt tissues were differentially palatable to predatory fish. All bluegill tested consumed a palatable control food, but only 20% consumed dorsal skin, only 35% ate ventral skin, but 75% fed on newt viscera, suggesting that deterrent metabolites are concentrated in the skin. Bioassay-guided fractionation revealed that crude and water-soluble newt chemical extracts inhibited bluegill feeding, definitively establishing the chemical nature of newt antipredator defenses, although we were unsuccessful at isolating the chemical compounds responsible for unpalatability. Yet, deterrent activity in the polar but not the lipophilic chemical fraction and bioassay results demonstrating that naıve predators rapidly learn to avoid natural concentrations of TTX support the possible role of TTX in suppressing predation on newts. However, when tethered in the field, newt mortality was 55% higher in ponds with predatory fishes than in ponds lacking fishes (62% vs. 40% respectively), indicating the possible existence of other predators that are resistant to (or tolerant of) newt chemical defenses. Together, these results stress the importance of rigorous, ecologically relevant, and hypothesis-driven experimentation to better understand the complexity of chemically- mediated predator-prey interactions, even for well-studied species like N. viridescens.

Design and evaluation of real-time descriptive mediation (RTDM) for live aquarium exhibits was proposed to support the participation of visitors with and without vision loss. RTDM was developed to address learning, entertainment, restorative, and social motivations. Data was collected during a lab study with adults to get feedback about the RTDM and compare it to traditional docent presentations and audio tours. Findings show that the RTDM made it possible for participants to address their exhibit motivations and led to specific personal and social aspects of participation. A majority of participants with and without vision loss reported that the RTDM was supportive of their motivations and perceived it to be more effective at supporting learning, social, and restoration motivations compared to audio tour and docent mediation. The main contributions of this work are in: 1) developing evidence-based information design criteria for mediation at live animal exhibits; 2) demonstrating that mediation designed to support exhibit motivations can facilitate participation in adults with and without vision loss; and 3) validating participation as a design goal.

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Refletir sobre a pessoa com surdocegueira e, sobretudo, o atendimento direcionado ao surdocego no contexto socioeducacional, constitui-se uma necessidade acadêmica, seja sobre a produção de conhecimentos teóricos quanto às intervenções práticas. Esta problemática configura os caminhos percorridos pela presente Tese de Doutorado, a fim de investigar a atuação do profissional Guia-intérprete no atendimento a pessoas com surdocegueira na cidade de Salvador-Ba, identificando os procedimentos de intervenção utilizados pelos profissionais, a partir das práticas comunicativas com surdocegos e caracterizando os fatores e aspectos que interferem em sua atuação profissional enquanto mediadores para a socialização do surdocego. A partir das contribuições teóricas sócio-interacionistas apresentadas por Vygosty (2007), este trabalho pauta suas reflexões, compreendendo que a relação do sujeito surdocego com o meio, constitui fator essencial para o desenvolvimento dos indivíduos, assim como apresenta Amaral (2002), Dorado (2004), Maia (2004), Cader-Nascimento (2007), Galvão (2010) e outros sobre a compreensão das formas de comunicação desenvolvidas entre os profissionais e os surdocegos, e a dinâmica do seu atendimento nos espaços sociais. A escolha metodológica define um caminho do estudo de caso, e a partir dos instrumentos de investigação definidos pela entrevista e observação direta, permite a análise sobre a falta de informações e de conhecimentos específicos sobre a deficiência como um fator determinante para o surgimento de barreiras de ordem estrutural, programática, atitudinal, arquitetônica, que atingem tanto à qualidade dos serviços prestados ao surdocego, quanto à realidade social deste indivíduo, constituindo assim uma realidade excludente e de segregação.
ABSTRACT Reflect on the person with deafblindness and especially the care directed to the deafblind in the social and educational context, constitutes an academic need, whether on produação of theoretical knowledge on the practical interventions. This issue sets the paths taken by this Doctoral Thesis in order to investigate the performance of professional guide-interpreter in caring for people with deafblindness in the city of Salvador, Bahia, identifying intervention procedures used by professionals from the communicative practices with deafblind and caracterizan factors and aspects that interfere with their professional work as mediators for the socialization of deafblind. From the socio-interactionist theoretical constribuições presented by Vygosty (2007) This work charted their thoughts, realizing that the relationship of the subject deafblind with the environment, an essential factor for the development of individuals, as well as presents Amaral (2002), Dorado (2004), Maya (2004), Cader-Birth (2007), Galvão (2010) and others to understand the forms of communication developed between professionals and deafblind and the dynamics of your atentimento in social spaces. The methodological choice defines a way of case study, and from research tools interviews and direct observation will allow the analysis of the lack of information and expertise on disability as a factor in the emergence of structural barriers, programmatic, attitudinal, architectural, which affect both the quality of services to deafblind, the social reality of this individual, thus providing an exclusive and segregation reality

L´objectiu d´aquesta tesi és analitzar com s´integra una acció pedagògica a l'aula d'interpretació consecutiva. Aquesta acció pedagògica es basa en un enfocament socioconstructivista i pretén fomentar els processos autoreguladors en l´aprenentatge. Es concreta en la incorporació d'una bateria de pautes metacognitives dissenyades específicament per a desenvolupar les habilitats que requereix l'aprenentatge de la interpretació consecutiva. El nostre centre d´interès és l'estudi del pas de l´heteroregulació a l´autoregulació mitjançant la incorporació de les pautes metacognitives, enteses com a instruments de mediació.
Conceptualment, la recerca pren com a principals referents teòrics l'autonomia de l'aprenent i la relació d´aquest àmbit amb la teoria sociocultural i amb els processos d'autoregulació. Pel que fa a la metodologia, seguim els pressupòsits de la recerca etnogràfica i els de l'aproximació ecològica de la recerca.
Un dels reptes importants d'aquest tipus de recerca és el de trobar un model d'anàlisi que serveixi de base per a l'estudi de les dades resultants de la reflexió metacognitiva. Per fer-ho, ens hem aproximat a l´anàlisi del discurs. Un cop segmentades les dades, per a l'anàlisi interpretativa hem tingut en compte, entre altres, els aspectes següents:
a) la relació que s'estableix entre els enunciats a través dels marcadors i els connectors del discurs
b) la localització temporal
c) la modalització i la polifonia de veus en el discurs.
Entre els resultats obtinguts, destaca que els instruments ´diari de l´aprenent- i ´pauta metacognitiva- esdevenen formes vàlides per a verbalitzar la reflexió metacognitiva. I també que l´autoregulació de l'aprenentatge es desenvolupa en un procés de reflexió, cíclic i dinàmic. En aquest procés es fan evidents diversos graus o nivells. Identificar-los ajuda a integrar i a treballar el component metacognitiu a l´aula. I ha de permetre elaborar un programa d´aprendre a aprendre enfocat a l'ensenyament de la interpretació consecutiva. Un programa que respecti els microprocessos relacionats amb els nivells de consciència identificats i que, a la vegada, esdevingui útil per a propòsits didàctics.
El objetivo de esta tesis es analizar cómo se integra en el aula de interpretación consecutiva una acción pedagógica basada en un enfoque socioconstructivista y que pretende fomentar los procesos autoreguladores en el aprendizaje. Esa acción se concreta en la incorporación de una batería de pautas metacognitivas diseñadas específicamente para desarrollar las habilidades que requiere el aprendizaje de la interpretación consecutiva. Nuestro interés se centra en el paso de la heteroregulación a la autorregulación mediante la citada incorporación de pautas metacognitivas entendidas como instrumentos de mediación.
Conceptualmente, la investigación adopta como principales referentes teóricos la autonomía del aprendiz en su relación con la teoría sociocultural y con los procesos de autorregulación. En cuanto a la metodología, seguimos los presupuestos de la investigación etnográfica y los de la aproximación ecológica a la investigación.
Uno de los retos fundamentales de ese tipo de investigación consiste en hallar un modelo de análisis que sirva de base para el estudio que permita estudiar los datos resultantes de la reflexión metacognitiva. A tal fin partimos del análisis del discurso, procediendo de modo que, una vez segmentados los datos, se lleva a cabo una interpretación de los mismos definida según los siguientes criterios:
a) la relación que se establece entre los enunciados recurriendo a los marcadores y conectores discursivos
b) la localización temporal
c) la modalización y la polifonía de voces en el discurso.
Entre los resultados más destacados del presente trabajo cabe citar, por una parte, que los instrumentos 'diario del aprendiz' y 'pauta metacognitiva' resultan fórmulas válidas para verbalizar la reflexión metacognitiva. Por otra parte, hay que referirse al hecho de que la autorregulación del aprendizaje se desarrolla en un proceso de reflexión cíclico y dinámico en el que se dan distintos grados o niveles, la identificación de los cuales permite integrar y trabajar el componente metacognitivo en el aula. Ello, por su parte, debe posibilitar la elaboración de un programa de ´aprender a aprender- aplicado a la didáctica de la interpretación consecutiva y que se ajuste a los microprocesos relacionados con los niveles de conciencia metacognitiva identificados.
The purpose of this research is to analyse how a teaching action is integrated into the consecutive interpreting classroom. This teaching action is based on a socio-constructivist approach and attempts to encourage self-regulation processes in learning. The action takes the form of a battery of metacognitive guides designed specifically for developing the skills required for learning consecutive interpreting.
Our focus of interest is the study of the move from hetero-regulation to self-regulation through the incorporation of instruments of mediation - the metacognitive guides - designed to develop the skills required for learning consecutive interpreting.
Conceptually, the research takes as its main theoretical references learner autonomy and the relationship of this field with socio-cultural theory and the processes of self-regulation. As for methodology, we follow the criteria of ethnographic and ecologial approach to research.
One of the important challenges of this kind of research is finding a model of analysis that serves as a basis for studying the data resulting from metacognitive reflection. To do this, we have used a discourse analysis approach. Once the data has been segmented, for the interpretive analysis we have taken into account the following aspects, among others:
a) the relationship between the sentences through the markers and connectors;
b) the location in time;
c) the modalization and the polyphony of voices in the speech.
Among the main results obtained, the mediation instruments, ´learner´s diary- and ´metacognitive guide-, prove to be valid forms for verbalizing metacognitive reflection. Also, that self-regulation of learning is developed in a cyclical and dynamic reflection process. In this process, different degrees or levels become clear. Identifying them helps to integrate and work with the metacognitive element in the classroom. And it should make it possible to draw up a learning-to-learn program focused on teaching consecutive interpreting: a program that respects the micro-processes related to the levels of consciousness identified and which, at the same time, should prove useful for teaching purposes.

Thesis (Ph. D.)--University of Wisconsin--Madison, 1998.
Typescript. eContent provider-neutral record in process. Description based on print version record. Includes bibliographical references (leaves 121-141).

The clinical efficacy of chemotherapy in solid tumours is limited by systemic toxicity and the inability to deliver a cytotoxic concentration of anticancer drugs to all tumour cells. Temperature sensitive drug carriers provide a mechanism for triggering the rapid release of chemotherapeutic agents in a targeted region. Thermally mediated drug release also leverages the ability of hyperthermia to increase tumour blood flow, vessel permeability, and drug cytotoxicity. Drug release from thermosensitive liposome drug carriers in the tumour vasculature serves as a continuous intravascular infusion of free drug originating at the tumour site. However, localized drug release requires precise heating to improve drug delivery and efficacy in tumours while minimizing drug exposure in normal tissue. Focused ultrasound can noninvasively heat millimeter-sized regions deep within the body, and can be combined with MR thermometry for precise temperature control. This thesis describes the development of strategies to achieve localized hyperthermia using MRI-controlled focused ultrasound, for the purpose of image-guided heat-triggered drug release from thermosensitive drug carriers. First, a preclinical MRI-controlled focused ultrasound system was developed as a platform for studies of controlled hyperthermia and drug delivery in rabbits. The feasibility of using ultrasound hyperthermia to achieve localized doxorubicin release from thermosensitive liposomes was demonstrated in normal rabbit muscle. Second, strategies were described for using MR thermometry to control ultrasound heating at a muscle-bone interface based on MR temperature measurements in adjacent soft tissue, demonstrating localized drug delivery in adjacent muscle and bone marrow. Third, fluorescence microscopy was employed to demonstrate that increased overall drug accumulation in rabbit VX2 tumours corresponds to high levels of bioavailable drug reaching their active site in the nuclei of tumour cells. The results of this thesis demonstrate that image-guided drug delivery using thermosensitive liposomes and MRI-controlled focused ultrasound hyperthermia can be used to noninvasively achieve precisely localized drug deposition in soft tissue, at bone interfaces, and in solid tumours. Clinical application of this work could provide a noninvasive means of enhancing chemotherapy in a variety of solid tumours.

Use of chemotherapeutics in treatment of solid tumors suffers from insufficient and heterogeneous drug delivery, systemic toxicity and lack of knowledge of delivered drug concentration. The overall objectives of this work were: 1) to address these shortcomings through development and characterization of a treatment system capable of real-time spatiotemporal control of drug distribution and 2) to investigate the role of MR-image-able tissue transport parameters in predicting drug distribution following hyperthermia-triggered drug release from nanoparticles. Towards these objectives, a combination of potentially synergetic technologies was used: 1) image-able low temperature-sensitive liposomes (iLTSLs) for drug delivery, 2) quantitative drug delivery and transport parameter imaging with magnetic resonance imaging (MRI), and 3) control over drug release with magnetic resonance-guided high intensity focused ultrasound (MR-HIFU). The overall hypothesis of this work is that the drug distribution in the targeted zone spatially correlates with the image-able transport-related parameters as well as contrast enhancement due to release of contrast agent during treatment.

We began by developing and characterizing iLTSLs, which were designed using a lipid formulation similar to one that is in clinical trials in the US (ThermoDox®) and a gadolinium-based MR contrast agent that is in widespread clinical use (Prohance®) and least likelihood of toxicity due to nephrogenic systemic fibrosis (NSF). The resulting liposome was found to stably encapsulate both an anthracycline chemotherapeutic, doxorubicin, and the MR contrast agent. Release rates were similar for these two species in physiologic buffer as well as in human plasma. The next step towards control and imaging of release with this drug delivery system (DDS) was development of algorithms that allowed for large-volume mild hyperthermia with MR-HIFU that would be required to move this combination of technologies into the clinic.

Optimal drug delivery with iLTSL requires a sustained period of heating of the entire target to the range of temperatures that are optimal for liposomal release and maintenance of perfusion (40 - 45 C). The MR-HIFU technology was developed and used mainly for rapid thermal ablation or mechanical disruption of tissue in small ellipsoid volumes. Variability and size of common clinical lesions called for modifications that would enable stable conformal heating of large tumor volumes to the sub-ablative temperature range of mild hyperthermia (40 - 45 C). Therefore, we set out to develop an algorithm that would allow rapid attainment and maintenance of mild hyperthermia in larger volumes of variable shape that were typically encountered in the clinic. We approached this goal through a series of successive steps that addressed different aspects of mild hyperthermia treatment: 1) controlled heating to mild hyperthermia, 2) conformity of heating and 3) ability to heat large volumes.

To achieve controlled heating to mild hyperthermia we implemented a simple binary mild hyperthermia feedback mechanism that adequately maintained mild hyperthermia for extended periods of time in small ellipsoidal volumes. We then developed a conformal small-volume mild hyperthermia algorithm that could provide spatial control over heating in an environment with spatially heterogeneous perfusion. This algorithm used electronic steering of the HIFU focus to heat each MR image voxel with different power, depending on temperature measured within that voxel. Finally, to heat large volumes conformally, we developed an algorithm that combined mechanical displacement of the MR-HIFU transducer (to cover large areas) with electronic deflection of the HIFU beam (to heat sub-volumes conformally). This advancement allowed us to quickly attain mild hyperthermia (<8.1 min to steady state) in larger volumes (cross-sectional area = 8.4 cm, ~12 times larger than previous methods).

Following their characterization, we examined iLTSL pharmacokinetics and combined MR-HIFU large volume mild hyperthermia with iLTSL to deliver doxorubicin to large Vx2 carcinomas in the hindlimb muscle of rabbits. To determine MR image-able correlates to the intratumoral drug distribution, we assessed the spatial pattern of drug distribution with fluorescence microscopy and examined spatial correlations of this pattern to several parameters measured with MRI, including the spatial distributions of temperature, contrast enhancement following injection of iLTSL, dynamic contrast-enhanced MRI (DCE-MRI) parameters, and maps of apparent diffusion coefficient (ADC). Dynamic contrast-enhanced MRI parameters have been used extensively in literature to approximate a mixture of parameters critical to drug delivery, such as perfusion (F), permeability-vascular surface area product (PS) and vascular volume and ADC has been previously correlated with cellular density in tumors. Possible utility of such spatial correlations was examined for future use in treatment planning, intraprocedural feedback control and post-treatment evaluation.

Highly perfused peripheral regions of Vx2 tumors in rabbit hindlimb displayed high Ktrans and ve, indicative of high perfusion. Maps of ADC obtained with low b-values also showed high ADC in the periphery of these tumors, indicating high perfusion there. ADC maps that were weighted more towards diffusion (using higher b-values) showed that diffusion was largest in the tumor core, indicating destruction of the cellular membranes and greater mobility of water. Microscopic examination of excised tumors was spatially registered to the MRI datasets and showed that most of the tumor core is necrotic, though some highly vascularized and viable tissue was present in strands or segments that traversed the necrotic regions. Those segments also showed bright doxorubicin fluorescence following treatment with MR-HIFU and iLTSL. The two control groups - free drug and iLTSL without mild hyperthermia - showed minimal to no doxorubicin fluorescence in the tumor.

Susceptibility effects due to use of contrast agent caused large errors (up to 15 °C) in MR thermometry measurements. To address this phenomenon, experiments were designed to arrive at steady state heating (target temperature = 41 °C), and employ an algorithm to learn the spatiotemporal distribution of power that was needed to maintain steady state heating. This heating pattern was then played back several times to verify maintenance of steady state, and if satisfactory, image-able liposomes were injected. Since temperature feedback was replaced by the learned steady-state heating, injection of image-able liposomes likely did not alter the heating performance. Following injection, changes in T1 and magnetic susceptibility were most pronounced in regions that previously showed greatest enhancement during DCE-MRI and displayed larger values of ADC with perfusion-weighted, low b-value scans. Maps of T1 were obtained in real time using a variable flip angle sequence during heating, and were corrected for inhomogeneity of the B1 field and calibrated against a more accurate, T1 mapping technique.

After treatment with MR-HIFU and iLTSL, the drug was preferentially distributed in the viable tissue, in and around the tumor. Doxorubicin fluorescence was greatest in zones that were heated, though the drug distribution did not display a clear boundary between heated and unheated tissue. While iLTSL provided intraprocedural feedback via enhancement of T1-weighted image intensity, susceptibility-related effects of iLTSL on MR thermometry complicate their prospects of clinical use, where precise temperature feedback is required for control of therapy and MR thermometry techniques that are in widespread use would be affected. Spatial correlations between drug delivery with iLTSL and MR-imageable parameters may serve as a predictive tool to identify areas that will not receive adequate drug. Such a-priori knowledge of correlates to the approximate tumor drug distribution has the potential to inform treatment planning by revealing the extent to which drug dose could be painted with a combination of LTSL and MR-HIFU. These studies point to an adjustment of course in further development of drug dose painting this combination of technologies, towards informing treatment planning, and not only painting the dose, but predicting it. These results also point to the need to develop rational combinations other treatments, such as ablation and radiation, to treat regions that will not receive sufficient drug.

Dissertation

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