Dissertations / Theses on the topic 'Triple T'

Le cancer du sein est le cancer féminin le plus fréquent et celui qui cause le plus de décès dans le monde. Il existe plusieurs types de cancer du sein qui diffèrent par l’expression des récepteurs aux œstrogènes, à la progestérone et du récepteur HER2. Le cancer du sein dit triple négatif (TNBC) n’exprime aucun de ces récepteurs. Le métabolisme des sphingolipides (SL) est fréquemment altéré dans les cancers du sein et semble participer à la progression tumorale. Tandis que les SL ont été décrits comme modulateurs des réponses immunitaires dans des modèles précliniques de cancer, il n’existe pas à ce jour d’étude chez l’Homme évaluant l’impact des altérations du métabolisme des SL sur le développement tumoral et la réponse immunitaire associée. Dans ce contexte, l’objectif de nos travaux est double. Le premier objectif est de caractériser une signature sphingolipidique dans des biopsies de tumeurs mammaires humaines de divers sous-types histologiques. Une analyse par spectrométrie de masse à haute résolution nous a permis d’identifier dans les TNBC des taux élevés de SL en -C24:0, qui pourraient constituer des biomarqueurs potentiels pour ce type de cancer. Le deuxième objectif est d’établir une signature sphingolipidique associée à la réponse immunitaire dans le cancer du sein. Nous avons analysé les lymphocytes infiltrant la tumeur (TIL) par cytométrie en flux et par immunohistochimie dans nos échantillons tumoraux. Ces analyses nous ont permis de montrer que, dans les TNBC, les taux de C16:0-céramide sont corrélés positivement avec la proportion de TIL CD8+ et négativement avec celle des Treg FoxP3+. Afin d’évaluer l’influence potentielle des SL sur la topologie d’infiltration des lymphocytes (intratumoral versus adjacent), nous avons aussi comparé les taux de SL dans les tumeurs ayant une forte ou une faible proportion de lymphocytes T CD8+ intratumoraux. Nous avons observé notamment des taux élevés de sphingosine-1-phosphate (S1P) dans les tumeurs faiblement infiltrées par les lymphocytes T CD8+ intratumoraux. Nos observations suggèrent que la production de C16:0-céramide soit en faveur d’un recrutement préférentiel des lymphocytes T CD8+ dans les TNBC, tandis que la S1P pourrait être un facteur d’immunoéchappement, impactant négativement sur la topologie des TIL CD8+ dans les tumeurs mammaires. L’ensemble de nos travaux indique que certains SL pourraient constituer des biomarqueurs originaux de TNBC. De plus, la reprogrammation de ce métabolisme pourrait augmenter (i) quantitativement et qualitativement l’infiltration intratumorale des lymphocytes, et (ii) potentiellement l’efficacité des immunothérapies dans le cancer du sein
Breast cancer, the most common malignancy affecting women, is responsible for the majority of woman death by cancer worldwide. There are three different breast cancer types defined by the expression of oestrogen and progesterone and HER2 receptors. The so-called triple negative breast cancer (TNBC), doesn’t express any of these receptors. Sphingolipid (SL) metabolism is frequently altered in breast cancer, alterations are associated with tumour progression. Although SL can act as immune response modulators in preclinical cancer models, there are, to date, no study assessing the impact of SL metabolism alterations on tumor development and associated immune response in Humans. In this setting, our aim was double. Our first objective was to characterize the SL signature in human mammary tumour biopsies from different pathological subtypes. Using high-resolution mass spectrometry assay, we identified elevated levels of C24:0-SL in TNBC, which could be used as potential biomarkers of this cancer subtype. Our second objective was to identify a SL signature associated with immune responses in breast cancer tissues. Tumour-infiltrating lymphocytes (TIL) were analyzed by flow cytometry and immunohistochemistry. Those analyses showed that, in TNBC, levels of C16:0-ceramide are positively correlated with the proportion CD8+ TIL and negatively correlated with that of FoxP3+ Treg TIL. In order to evaluate the potential influence of SL on the topology of infiltrating lymphocytes (intratumoural versus adjacent), we compared the SL levels in tumors depicting high or low proportions of intratumoral CD8+ T cells. We observed higher levels of sphingosine-1-phosphate (S1P) in low infiltrated intratumoral CD8+ T cells. Our observations suggest that C16:0-ceramide production could favor CD8+ T cell recruitment in TNBC, whereas S1P could act as an immune escape factor, negatively impacting on CD8+ TIL topology in mammary tumours. Our whole work indicates that a set of specific SL could constitute original biomarkers in TNBC. Moreover, reprogramming SL metabolism could improve (i) the infiltration of tumours by lymphocytes, both in terms of quality and quantity, and (ii) possibly, the efficacy of immunotherapy in breast cancer

Drug use and misuse among young people in Australia has caused concern throughout the community and has prompted nationwide action to address the problem. One component of intervention strategies with young people is drug education. Drug education in Australia represents an international philosophy of prevention and takes a harm minimisation approach to intervention. One strategy that has had international success in the area of drug education with young people, and that has been used effectively in health education in Australia since the 1970s, is peer education. Peer drug education involves young people conducting drug education sessions with their peers. An example of peer drug education in Australia is the Teenagers Teaching Teenagers' (Triple T) program, conducted in the Australian Capital Territory (ACT). Evaluations and descriptions of peer drug education programs tend to focus more on outcomes pertaining to program recipients and fail to explore in detail the specific experience of peer leaders. Existing research on the experience of peer leadership does not explore in detail the personal experience of leaders, that being the effect of peer leadership training and duties on leaders' personal perceptions of drugs, their behaviour with drugs and their own feelings and skills. This thesis explores the personal experience of a group of peer leaders who participated in the Triple T program in 1994. It considers their perceptions of the program at the time of training and then goes on to explore the impact of this experience on their formulation of ideas about drugs to the present day. The thesis is a qualitative project which utilises in-depth interviewing and focus groups to gather data and then presents a thematic analysis of participant response. The thesis asks two research questions, 1. What do young men and women involved in the Triple T program take from the experience of peer leadership training and duties? 2. In what way does the Triple T' experience appear to contribute to the development of drug related ideas of these young people in the two years following involvement in the program? The findings suggest that the participants gained information, skills and personal development from the training and generally found it to be a positive experience. However, participants distanced themselves personally from a substantial amount of the training content and did not personally reflect on the training content to any great extent at the time of training. Training processes and some aspects of leadership duties more personally affected them, although again there was personal distancing from this part of the program. In exploring the findings there was difficulty determining the influence of the training experience due to participant reluctance to attribute influence to any one source on the formulation of ideas. Instead, participants describe a complex interaction of influences on the formulation of ideas about drugs and a process which involves maintaining control, upholding the notion of informed choice and incorporating ideas about drugs into the formation of an adult identity. Influences on these ideas include the training, actual experiences with drugs and observations of others. The thesis exploration suggests that being involved in peer drug education does impact on peer leaders but this experience was not personalised to any great degree at the time of training. However, in the following two years, participants called on the training information as well as other influences as they formed their ideas about drugs. The thesis raises some issues of how to maximise leaders' personal connection to the peer drug education process, if this is in fact a desired outcome of peer education. It also suggests the need for further research into the experience of peer leaders who seem to have remained the least considered party in the peer education movement.

Dans cette thèse, on étudie la structure de quelques types d'algèbres (binaires et ternaires) munies d'une forme bilinéaire symétrique, non dégénérée et associative (ou invariante). La première partie de cette thèse est consacrée à l'étude des algèbres de Leibniz quadratiques. On montre que ces algèbres sont symétriques. De plus, on utilise la T*-extension et la double extension pour montrer plusieurs résultats sur ce type d'algèbres. Ensuite, on a remarqué que l'anti-commutativité du crochet de Lie donne naissance à de nouveaux types d'invariance pour les algèbres de Leibniz : L'invariance à gauche et l'invariance à droite. Alors, on s'est intéresse à l'étude des algèbres de Leibniz (gauche et droite) munies d'une forme bilinéaire symétrique, non dégénérée et invariante à gauche (et invariante à droite). On prouve que ces algèbres sont Lie admissibles. En second lieu, on s'intéresse aux systèmes triples de Lie et de Jordan. On débute la deuxième partie de cette thèse par la description inductive des systèmes triples de Lie quadratiques au moyen de la double extension. En plus, on introduit la T*extension des systèmes triples de Jordan pseudo-Euclidien. Finalement, on donne deux nouvelles caractérisations des systèmes triples de Jordan semi-simples parmi les systèmes triples de Jordan pseudo-Euclidiens
In this thesis, we study the stucture of several types of algebras endowed with Symmetric, non degenerate and invariant bilinear forms. In the first part, we study quadratic Leibniz algebras. First, we prove that these algebras are symmetric. Then, we use the T*-extension and the double extension to prove some properties of this type of Leibniz algebras. Besides, since we observe that the skew-symmetry of the Leibniz bracket gives rise to other types of invariance for a bilinear form on a Leibniz algebra: The left invariance and the right invariance. We focus on the study of left (resp. right) Leibniz algebras with symmetric, non degenerate and left (resp. right) invariant bilinear form. In particular, we prove that these algebras are Lie admissibles. The second part of this work is dedicated to the study of quadratic Lie triple systems and pseudo-euclidien Jordan triple systems. We start by giving an inductive description of quadratic Lie triple systems using double extension. Next, we introduce the T*-extension of Jordan triple systems. Finally, we give new caracterizations of semi-simple Jordan triple systems among pseudo-euclidian Jordan triple systems

Regulatorische CD4+CD25+ T-Zellen (Tregs) stellen eine kleine Zellpopulation dar (1-5% der peripheren Blutzellen), die hauptsächlich für die Regulierung von Immunreaktionen verantwortlich ist. In der vorliegenden Arbeit wurden diese Zellen gemeinsam mit Stammzellen syngen und allogen kotransplantiert, um ihren Effekt auf das Anwachsen der Spenderzellen und die Rekonstitution der Hämatopoese nach Ganzkörperbestrahlung zu untersuchen. Es wurden humanisierte dreifach transgene Empfängermäuse (C57Bl/6-TTG) verwendet (human CD4+, murin CD4-, human HLA-DR+), wodurch sowohl bei syngener als auch bei allogener Transplantation eine Unterscheidung zwischen Spender- und Empfängerzellen möglich ist. Zunächst wurden CD4+CD25+ T-Zellen durch Separation aus Milzzellen bzw. Buffy Coats gewonnen und in vitro mittels Durchflusszytometrie und ELISpot charakterisiert. Anschließend fanden syngene und allogene Transplantationen mit einer Laufzeit von 61 Tagen statt. Überleben und Gewicht wurden täglich ermittelt und außerdem wurden wöchentlich Blutbilder erstellt und durchflusszytometrische Chimärismusanalysen (murines und humanes CD4, CD8, MHC (H2Db, H2Kd)) durchgeführt. Durch die magnetische Separation konnte die FoxP3-Expression der murinen Zellen (Transplantat) von 1,6% in der Ausgangspopulation auf 68,5% in der CD4+CD25+ Population gesteigert werden. In den ELISpot-Assays zeigten diese separierten Zellen, wie für Tregs typisch, keine Produktion von Interleukin-2. Nach syngener Transplantation (Spender: wildtyp C57Bl/6) von 2x106 Knochenmarkzellen und 1x106 CD4+CD25+ T-Zellen überlebten 100% der Tiere, wie zu erwarten war. Dabei setzte bei Tregs-kotransplantierten Tieren die Blutbildung nach bestrahlungsbedingter Leukozytopenie aufgrund bisher nicht bekannter Mechanismen früher wieder ein und der Donor-Zell-Chimärismus war an Tag 19 nach Transplantation signifikant höher als in der Kontrollgruppe. Dies zeigt, dass regulatorische T-Zellen im syngenen Transplantationsmodell einen positiven Effekt auf die Akzeptanz bzw. das Anwachsen des Transplantats haben. Dieses Modell entspricht klinisch einer autologen Transplantation. Nach einer knochenmarkzerstörenden Therapie werden dem Patienten eigene Stammzellen reinfundiert, um die Blutbildung und das Immunsystem wieder in Gang zu bringen. Der Zusatz von regulatorischen T-Zellen zum autologen Stammzelltransplantat könnte das Anwachsen der Zellen beschleunigen und die gefährliche Phase der Immunsuppression, in der es häufig zu Sekundärinfektionen kommt, verkürzen. Die Transplantation der gleichen Zahl von allogenen Spenderzellen (wildtyp Balb/c) führte überraschend zum Tod aller dreifach transgenen Empfängertiere. Der Vergleich zu Experimenten mit wildtyp C57Bl/6-Empfängertieren zeigte, dass dreifach transgene Mäuse sehr viel höhere Zellzahlen im Transplantat zum Überleben benötigen (Daten nicht gezeigt). Das Ausbleiben der Blutbildung nach der Bestrahlung führte zu vermindertem Allgemeinbefinden, gestörter Futter- und Wassseraufnahme und Exsikkose bis zum Tod bzw. aus Tierschutzgründen zur Euthanasie. Durch Erhöhung der Zellzahl im Transplantat auf 1x107 Knochenmark + 5x106 Milzzellen überlebten 25% der Mäuse, bei 3x107 Knochenmark + 5x106 Milzzellen waren es 50%. Anders als im syngenen Modell führte die Kotransplantation 1,5x106 allogener CD4+CD25+ T-Zellen zu 3x107 Knochenmark + 5x106 Milzzellen zum Versterben der Tiere. Dies verdeutlicht, dass regulatorische T-Zellen in diesem allogenen Transplantationsmodell das Anwachsen des Transplantats behindern (Transplantatversagen). Hier gilt es zu klären, ob dieser Effekt spezifisch für die gewählten Mausstämme ist und welche Mechanismen für das Transplantatversagen verantwortlich sind. In einem dreifach transgenen Mausmodell konnte ein positiver Effekt von regulatorischen T-Zellen auf die Rekonstitution der Hämatopoese bei syngener Kotransplantation nachgewiesen werden. Im allogenen Transplantationsmodell hingegen führte die Kotransplantation CD4+CD25+ T-Zellen zum Versterben der Empfänger. Der beschriebene und schon publizierte positive Effekt spenderspezifischer Tregs zur Behandlung von Graft versus Host Disease nach allogener Stammzelltransplantation widerspricht diesen Ergebnissen nicht, da es bei diesen Patienten schon zum Engraftment von hämatopoetischen Stammzellen gekommen ist. Dies hat weitreichende Konsequenzen für die therapeutische Anwendung regulatorischer T-Zellen bei hämatologischen Erkrankungen in der Human- und Veterinärmedizin
Regulatory CD4+CD25+ T cells (Tregs) represent a small cell population (1-5% of peripheral blood cells) mainly responsible for the regulation of the immune system. In the present work, these cells were cotransplanted with syngeneic and allogeneic stem cells in order to analyze the effect of Tregs on the reconstitution of hematopoiesis after total body irradiation. Humanized triple transgenic hosts (C57Bl/6-TTG) (human CD4+, murine CD4-, human HLA-DR+) were applied allowing differentiation of donor and host cells in syngeneic and allogeneic transplantation settings. Murine and human CD4+CD25+ T cells were magnetically separated out of splenocytes or buffy-coats and characterized in vitro by means of flow cytometry and ELISpot. Afterwards syngeneic and allogeneic transplantation experiments were performed for a period of 61 days. Survival and weight were assessed daily and once a week blood parameters and chimerism analyses (murine and human CD4, CD8, MHC (H2Db/ H2Kd)) were carried out. FoxP3 expression increased from 1,6% in the initial murine cell fraction to 68,5% in the separated CD4+CD25+ T cells. ELISpot assays showed the typical lack of interleukin 2 production of Tregs. After syngeneic transplantation (donor: wildtype C57Bl/6) of 2x106 bone marrow cells and 1x106 CD4+CD25+ T cells, 100% of mice survived what was to be expected. Cotransplanted animals showed earlier reconstitution of hematopoiesis after leukocytopenia and significant higher donor-cell-chimerism on day 19 after transplantation. The mechanisms for this positive effect of Tregs in syngeneic transplantation on the engraftment have to be investigated. This model clinically correspond an autologous transplantation where patients are treated with their own stem cells after a myeloablative treatment (chemotherapy or irradiation). The addition of regulatory T cells to the transplant could accelerate the engraftment and shorten the risky period of immunosuppression. Injection of the same numbers of allogeneic cells (donor: wildtype Balb/c) did not preserve hosts from mortality. Compared to experiments with wildtype recipients, results showed that triple transgenic mice need much higher cell numbers in the transplant for survival (data not shown). The failure of hematopoiesis after irradiation led to reduced general condition, disordered ingestion and exsikkosis leading to death respectively to euthanasia for reasons of protection of animals. By scaling up the cell number in the inoculum to 1x107 bone marrow cells + 5x106 splenocytes 25% of mice survived, with 3x107 bone marrow cells + 5x106 splenocytes survival was 50%. In contrast to syngeneic experiments, cotransplantation of 1,5x106 allogeneic CD4+CD25+ T cells and 3x107 bone marrow cells + 5x106 splenocytes did not prevent animals from mortality. In this allogeneic transplantation model Tregs restrain engraftment (graft failure). It has to be clarified if this effect is specific for the utilized mouse strains and which mechanisms are responsible for the graft failure. In the syngeneic triple transgenic mouse model cotransplantation of CD4+CD25+ T cells showed a positive effect on reconstitution of hematopoiesis after irradiation. In the allogeneic setting however cotransplantation of allogeneic regulatory T cells avoided the engraftment of transplanted cells. The described and published effect of donor-specific Tregs for treatment of graft versus host disease after allogeneic transplantation does not contradict the presented results because treated patients already possessed engrafted hematopoietic stem cells. The results have wide consequences for the therapeutic appliance of regulatory T cells in hematological diseases in human and veterinary medicine

The need for donor funding has increased significantly over the last decade. Without donor funding millions of people wouldn’t be alive today. Thanks either to research finding a cure, successful treatment, funds donated for food, aid toward building infrastructure, or giving people the opportunity to further their education. Donor funding thus facilitates a better future. A literature review was conducted to give background on the health sector and how these funds were distributed, ethical clearance, different types of reporting, the role project managers pays in a project and the sustainability of projects. Expenses in different countries were evaluated by gathering data from the internet, while two international funded projects are also used to state how funders divide their line items into different categories. The empirical study used a qualitative research approach by collecting and analysing data obtained from the MDG 2010 report and other freely available data on the web. The main findings from this thesis are: *The Millennium Development Goals (MDG’s) influence donor funding as it gives donors a guide towards funding needs. Donors are also influenced by their own preferences or what poses a burden to them individually. *The different types of reporting required for funding received, delay a project and the bureaucratic structures thereof are a hindrance. *Ethical clearance plays a fundamental role in the outcome of a project, as without ethical clearance a project cannot commence. *The objectives of a project play a critical role when applying for funding. This can change the focus of a project. *Expenses differ from country to country and funders need to take this into account when giving funding to recipient countries. *Project Managers and community involvement plays a critical role in ensuring sustainability of projects. THE SUSTAINABILITY OF DONOR FUNDED PROJECTS IN THE HEALTH SECTOR *The MDG’s are not on track and aid are focus on singular goals instead of multiple goals, to ensure an overall improved result. There is a major gap between needed funds and given funds. A single injection of funds will not be the solution to our health problem; different sectors need to collaborate together as we are facing a multi-dimensional problem. Trade and reform must also form part of this aid, ensuring a sustainable progression in the life’s of people. Donor funded projects may have a sustainable future, when taking in account the abovementioned findings. With the world trend in reporting changing rapidly, cost and management accountants as well as financial accountants and project managers have to equip them to adhere to the new way of reporting, namely integrated and sustainability reporting. South Africa is way behind and needs to catch up fast if they want to stay competitive in the “global donor funding market”. The limitations in this study were that not all expenses were evaluated and only 15 countries were looked at. An indebt look was taken into Africa with the empirical review, while Asia is also combating poor health issues. Some African countries like Sierra Leone and Zimbabwe did not have sufficient data to compare with other countries. From the research conducted, the following topics were identified that require further research: *Why are most projects in Third World countries not sustainable? *What plans are put into action to ensure that the MDG goals are reached? *Investigate what works for First World countries health systems and consider how that can be applied to Third World countries to ensure that they also get the best health care available. *Do donors take into account the different costs of countries when allocating funding to that specific country? *Establishing models to evaluate the sustainability of pilot projects and normal projects. *Establishing a model on how to distribute donor funds across different needs and not only one specific need.
MCom (Management Accountancy), North-West University, Vaal Triangle Campus, 2013

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This dissertation is the result of a survey conducted in the city of Tabatinga, interior of the State of Amazonas, located in the triple border Brazil, Colombia and Peru. If addressed, in principle, consistent information to the border region, highlighting the educational, political, economic and social relations between the countries. In addition, the study highlighted the implementation of the Federal Institutes, created by Law 11.892/08, and the operation since its installation in the city of Tabatinga. Its general objective is to understand the perception of the school community about the Instituto Federal de Educa??o, Ci?ncia e Tecnologia do Amazonas (IFAM) - campus Tabatinga, weaving an analysis guided the views of internal and external students at the Institute. At first, the focus of the work focused on the presentation of the IFAM campus Tabatinga to tabatinguense school community, considering the offer of vocational technical education to the population. In the second phase, the research highlighted the perception of the school community about the training at the Federal Institute, established in the municipality. The proposal was developed through an exploratory research, with qualitative and quantitative approaches, and using the literature research, document and case study. As data collection instruments were used participant observation and questionnaires. So with the analysis of the study, we believe that the reality experienced by the school community of Tabatinga, and the prospects of these students make up aspects that enable discussion and planning strategies capable of enhancing positive actions for the educational development process, also remedying the obstacles that hinder local growth, guiding the defining issues of the direction of the institution and the region.
A presente disserta??o ? resultado de uma pesquisa realizada no ?mbito do munic?pio de Tabatinga, interior do estado do Amazonas, localizado na tr?plice fronteira Brasil, Col?mbia e Peru. Abordou-se, a princ?pio, informa??es relativas ? regi?o fronteiri?a, destacando as rela??es educacionais, pol?ticas, econ?micas e sociais entre os pa?ses. Al?m disso, o estudo ressaltou a implanta??o dos Institutos Federais, criados atrav?s da Lei 11.892/08, e a atua??o do IFAM desde sua instala??o na cidade de Tabatinga. Teve como objetivo geral a compreens?o da percep??o da comunidade escolar sobre o Instituto Federal de Educa??o, Ci?ncia e Tecnologia do Amazonas (IFAM) campus Tabatinga, tecendo uma an?lise pautada nas vis?es de alunos internos e externos ao Instituto. No primeiro momento, o foco do trabalho concentrou-se na apresenta??o do IFAM campus Tabatinga ? comunidade escolar tabatinguense, considerando a oferta da educa??o t?cnica profissional ? popula??o. No segundo momento, a pesquisa destacou a percep??o da comunidade escolar quanto ? forma??o no Instituto Federal, implantado no munic?pio. A proposta foi desenvolvida atrav?s de uma pesquisa explorat?ria com abordagens qualitativa e quantitativa, utilizando-se a investiga??o bibliogr?fica, documental e o estudo de caso. Como instrumentos de coleta de dados foram empregados a observa??o participante e o uso de question?rios. Assim, atrav?s da an?lise do estudo, considerou-se que a realidade vivenciada pela comunidade escolar de Tabatinga, bem como as perspectivas desses estudantes, comp?e aspectos que possibilitam a discuss?o e o planejamento de estrat?gias capazes de intensificar a??es positivas em prol do processo de evolu??o educacional, sanando tamb?m os entraves que dificultam o crescimento local, norteando as quest?es definidoras dos rumos da institui??o e da regi?o.

The electronic structure of the zero-gap two-dimensional graphene has a charge neutrality point exactly at the Fermi level that limits the practical application of this material. There are several ways to modify the Fermi-level-region of graphene, e.g. adsorption of graphene on different substrates or different molecules on its surface. In all cases the so-called dispersion or van der Waals interactions can play a crucial role in the mechanism, which describes the modification of electronic structure of graphene. The adsorption of water on graphene is not very accurately reproduced in the standard density functional theory (DFT) calculations and highly-accurate quantum-chemical treatments are required. A possibility to apply wavefunction-based methods to extended systems is the use of local correlation schemes. The adsorption energies obtained in the present work by means of CCSD(T) are much higher in magnitude than the values calculated with standard DFT functional although they agree that physisorption is observed. The obtained results are compared with the values available in the literature for binding of water on the graphene-like substrates
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich

The electronic structure of the zero-gap two-dimensional graphene has a charge neutrality point exactly at the Fermi level that limits the practical application of this material. There are several ways to modify the Fermi-level-region of graphene, e.g. adsorption of graphene on different substrates or different molecules on its surface. In all cases the so-called dispersion or van der Waals interactions can play a crucial role in the mechanism, which describes the modification of electronic structure of graphene. The adsorption of water on graphene is not very accurately reproduced in the standard density functional theory (DFT) calculations and highly-accurate quantum-chemical treatments are required. A possibility to apply wavefunction-based methods to extended systems is the use of local correlation schemes. The adsorption energies obtained in the present work by means of CCSD(T) are much higher in magnitude than the values calculated with standard DFT functional although they agree that physisorption is observed. The obtained results are compared with the values available in the literature for binding of water on the graphene-like substrates.
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

Drug use and misuse by young people is a problem and concern in the Australian and Australian Capital Territory (ACT) communities. There are concerns regarding illicit and licit drugs but licit drug use has been identified as the major area of concern. Young people in the ACT reflect the drug use/misuse patterns and trends of other states. Commonly used drugs by young people are alcohol, tobacco, cannabis and analgesics. Strategies to address the problem of drug use/misuse by young people include intervention and community drug education programs. Peer drug education (as an example of community drug education), trains young people as peer educators to implement drug education programs with younger age groups. A case study analysis based on qualitative, naturalistic and new paradigm research is the research method used in this thesis. An eclectic model of drug education including key components from a variety of drug education models provides a comprehensive overview of peer drug education. The literature review showed the complexity of influences on drug use/misuse. These influences relate to individual, peer, parental and family, community and societal factors. Peer drug education is generally recognised as an effective drug education strategy. Peer drug education programs (Triple T: Teenagers Teaching Teenagers) were conducted in the ACT from 1988-1990. Reports documenting these programs (including evaluation data) and a literative review are the main data analysed for the case study. The case study analysis of five ACT peer drug education programs and one interstate program showed the key planning issues for effective peer drug education were: collaborative decision making as a central concept; detailed planning and liaison with target groups; established structures within schools and communities to support the trained peer educators; team work and small group work as intrinsic and extrinsic factors within the program; clarification of responsibilities and roles of all personnel involved in the program; and facilitators/leaders with attributes and qualities that encourage peer drug educators as social change agents. Analysis of data from the case study reports showed young people can be effective peer drug educators. Residential programs are preferred over non-residential programs. Peer drug education programs are effective in both school and community agencies. The literature review and analysis of reports also indicated that peer drug education needs to focus on establishing positive norms in groups of young people. Collaborative decision making and positive role modelling assist in the establishment of these norms. Peer drug education links to the wider changes occurring in education and health settings. Peer drug education is about collaborative decision making, social justice, development of key competencies and social change. This thesis confirmed the complexity and dynamic nature of peer drug education and there were many questions raised for further research from the literature review and analysis of program reports.

This thesis deals with the measurement of transmission parameters in the new generation access networks NGA. The aim of the thesis is to build and configure a test network and scenarios for the measurement of service quality parameters and then verify the transmission stability. The theoretical part describes general functioning of NGN networks, the requirements of different telecommunications services on quality parameters, methodology and recommendations for measuring transmission parameters in packet networks. The practical part deals with the configuration of scenarios using mainly MPLS technology and methodology of their testing. Measurements were performed according to recommendations IETF RFC 2544, IETF RFC 6349 with the ExacTCP test and ITU-T Y.1564 with the EtherSAM test. For measurements were used measuring instruments of EXFO brand. In conclusion, the measurement results according to the mentioned standards were evaluated and also the advantages of using the measurement according to the given standard in NGA access networks were discussed.

The requirements for future DVB-T/H networks demand that broadcasters design and deploy networks that provide ubiquitous reception in challenging indoors and other obstructed situations. It is essential that such networks are designed cost-effectively and with minimized environmental impact. The use of transmit diversity techniques with multiple antennas have long been proposed to improve the performance and capacity of wireless systems. Transmit diversity exploits the scattering effect inherent in the channel by means of transmitting multiple signals in a controlled manner from spatially separated antennas, allowing independently faded signals to arrive at the receiver and improves the chances of decoding a signal of acceptable quality. Transmit diversity can complement receive diversity by adding an additional diversity gain and in situations where receiver diversity is not practical, transmit diversity alone delivers a comparable amount of diversity gain. Transmit Delay Diversity (DD) can be applied to systems employing the DVB standard without receiver equipment modifications. Although transmit DD can provide a gain in NLOS situations, it can introduce degradation in LOS situation. The aim of this thesis is to investigate the effectiveness in real-word applications of novel diversity techniques for broadcast transmitter networks. Tests involved laboratory experiments using a wireless MIMO channel emulator and the deployment of a field measurement campaign dedicated to driving, indoor and rooftop reception. The relationship between the diversity gain, the propagation environment and several parameters such as the transmit antenna separation, the receiver speed and the Forward Error Correction Codes (FEC) configuration are investigated. Results includes the effect of real-word parameter usually not modeled in the software simulation analysis, such as antenna radiation patterns and mutual coupling, scattering vegetation impact, non-Gaussian noise sources and receiver implementation. Moreover, a practical analysis of the effectiveness of experimental techniques to mitigate the loss due to transmit DD loss in rooftop reception is presented. The results of this thesis confirmed, completed and extended the existing predictions with real word measurement results.

En transplantation rénale, la durée de vie des greffons reste limitée par l'apparition d'une dysfonction chronique secondaire à la néphrotoxicité des CNI, mais aussi à la survenue d'un rejet chronique humoral. La triade CD28 / CD80-86 / CTLA-4, principale voie de costimulation, constitue une cible privilégiée. L'antagonisation de CD80-86, le ligand commun de CD28 et CTLA-4 par le Belatacept (CTLA4-Ig) a démontré améliorer la fonction du greffon tout en limitant l'apparition d'allo-anticorps, mais elle est associée à une augmentation du taux de rejet aigu faisant suspecter un effet délétère du blocage de CTLA-4. Préserver cette voie est le principal atout du FR104, un anti-CD28 Fab' pegylé, développé par notre équipe et ayant fait la preuve de son efficacité préclinique en transplantation rénale chez le primate. L'objectif de cette thèse était, après avoir évalué le FR104 en association avec d'autres immunosuppresseurs, de le comparer directement avec le Belatacept dans un protocole d'immunosuppression sous-optimal, dans lequel 80% des animaux sous Belatacept ont présenté des rejets cortico-résistants contrairement à ceux sous FR104 (40% de rejet, tous cortico-sensibles, avec une fonction rénale stable pendant 1 an). Cette supériorité pouvait être rapportée aux fonctions extrinsèques du CTLA-4 principalement dues aux Tregs, mais aussi aux signaux inhibiteurs directement médiés par CTLA-4. En effet la plus forte expression d'IL-21 dans les biopsies protocolaires des animaux sous CTLA4-Ig faisait suspecter un meilleur contrôle des Tfh (principale source d'IL-21), par le FR104, ce qu'ont confirmé des données in vitro chez l'homme et in vivo dans un modèle murin
Kidney graft half-life remain limited by the development of a chronic dysfunction due to CNI nephrotoxicity, but also to the occurrence of a chronic antibody mediated rejection. The major costimulation pathway CD28 / CD80-86 / CTLA-4 triad, represent a new privileged target. Antagonizing CD80-86, the common ligand of CD28 and CTLA-4 with Belatacept (CTLA4-Ig) demonstrated an improvement of renal function associated with a low occurrence of allo-antibody. However Belatacept is associated with an increased risk of acute rejection, suggesting that CTLA-4 blockade could be deleterious. Preserving this pathway, is the main advantage of FR104, an anti-CD28 Fab' antibody pegylated, developed in our team, which proved preclinical efficacy in a model of allotransplantation in primate. The goal of this thesis was, after evaluating FR104 in association with major immunosuppressive drugs, to compare it in head to head with Belatacept in a protocol of suboptimal immunosuppression. In Belatacept group 80% of the animals presented steroid resistant rejection as opposed to animals under FR104 (40% of rejection ever steroid sensitive, followed by a stable renal function during one year). This superiority might be explain by CTLA-4 extrinsic function mainly due to Treg, but also by CTLA-4 intrinsic inhibitory signaling. Indeed IL-21 gene expression was stronger in protocol biopsies of CTLA4-Ig treated animals suggesting that follicular helper T cells, his main source, were better controlled by FR104, as supported by in vitro experiment and data in vivo in mice

This diploma thesis on the theme Improving quality of GSM Banking services for T-Mobile customers deals with detailed analysis of the selected product, which the T-Mobile company has been mediating to all it´s customers for years. This analysis resides in comparing of GSM Banking services with other mobile operators operating on the contemporary Czech market. My thesis contains general theoretical and concrete practical resources, which offer possibilities of improving and innovation of the present situation.

Des progrès majeurs dans l'espérance et la qualité de vie ont étéenregistrés dans la lutte contre le VIH et le SIDA avec l'introduction des traitementsantirétroviraux combinés. De nos jours, cette thérapie réduit nettementla charge virale après quelques semaines de traitement chez la plupart des patients.Ceci conduit généralement à une reconstitution satisfaisante du nombrede cellules CD4+, mais ce n'est pas toujours le cas. Cette thèse est focaliséesur les patients ayant une réponse immunitaire insuffisante malgré une chargevirale indétectable, après au moins 6 mois de thérapie antirétrovirale combinée.A ce moment, l'Interleukine 7 (une cytokine secrétée par la moelle épinièreet le thymus) est une thérapie prometteuse pour restaurer le système immunitairedans une telle situation. Pendant ce travail de thèse, nous avons contribuéà l'analyse des études INSPIRE 2 & 3, ou 107 patients présentant une faibleréponse immunitaire ont reçu des cycles (3 injections) répétés de r-hIL-7 (Inter-leukine 7 recombinée humaine).Nous avons utilisé des modèles dynamiques basés sur des systèmes d'équationsdifférentielles pour analyser l'effet de la r-hIL-7 exogène sur les cellules CD4+lors des trois études INSPIRE. Un modèle mathématique, avec un modèle àeffets mixtes appliqué sur les paramètres biologiques et un \modèle pour les observations"forment la structure de notre travail. Une estimation par maximumde vraisemblance basée sur une méthode de type Newton est combinée avec uneestimation du maximum a posteriori dans un contexte semi-Bayésien
Fight against HIV and AIDS has shown major improvements inlife expectancy and quality of life of HIV-infected people since the introductionof the cART. Today, viral load dramatically decreases a few weeks after startingantiretroviral therapy, and it becomes undetectable after 6 months for most ofpatients. This usually leads to an adequate reconstitution of CD4+T cells pool,but this is not necessarily always true. This thesis is focalised on these \lowimmunological responder" patients, who have not reached acceptable levels ofCD4+ T cells count despite undetectable viral load 6 months after having startedthe cART therapy.Today, Interleukin 7 (a cytokine naturally secreted in the bone marrow andthe thymus) is considered as one of the rare potential solution to boost the immunesystem in this situation. During this thesis work, we have collaborated toanalyze data from the INSPIRE 2 & 3 trials, where repeated cycles (3 subcutaneousinjections) of recombinant human Interleukin 7 have been administeredto a total of 107 of these \low responder patients".We have used dynamical models based on systems of ordinary differentialequations to study the ffect of the exogenous Interleukin 7 on CD4+ T cellsthrough the three INSPIRE studies. A mathematical model together with amixed effects model applied on the biological parameters of the ODE systemand a \model for the observations" make up the structure of our work. Amaximum likelihood approach based on an adaptation of a Newton-like methodis combined with a maximum a posteriori estimation in a semi-Bayesian context

Vulval intraepithelial neoplasia (VIN) is a distressing, premalignant condition, frequently associated with type HPV16 infection, with increasing incidence in younger women. Traditional surgical treatment is sub optimal. Several different clinical studies influencing local and/or systemic immunity to HPV have been reported. Imiquimod, an immune response modifier, can stimulate local innate immunity and also drive an adaptive immune response. Therapeutic HPV vaccines are designed to generate cell-mediated immunity against HPV infected cells. The rationale of this study was that local imiquimod treatment, in addition to having a direct effect on VIN could also provide an immunological platform for the therapeutic HPV vaccination to achieve an enhanced and durable response. In this phase II trial, we used a combination of imiquimod and vaccination with TA-CIN (HPV16 E6E7L2 fusion protein). Women with biopsy proven high-grade VIN were recruited. Imiquimod treatment for 8 weeks was followed by three i.m. injections of TA-CIN. The objectives were to measure lesion size, histology, lesion HPV status, symptoms, immune responses before and after treatment as well as safety, toxicity, and tolerability. Lymphoproliferation to HPV antigens was used to analyse immunity to HPV before and after treatment. Local immune factors (CD4, CD8 and T regulatory cells) were assessed by immunofluorescence. 74, 85 and 79% of women had a ≥50% reduction in the size of lesion and 32, 58 and 63% had regression of VIN on histology at weeks 10, 20 and 52 respectively. At baseline, 79% had moderate to severe symptoms compared to 21% at week 52(P=0.01). Of the women who showed histological responses at week 52, 5/10 also cleared their HPV 16 infection. Follow-up for an average of 15 months showed 84% of patients with a ≥50% reduction in lesion size. Treatment was well tolerated. A significant post vaccination increase in proliferation to TA-CIN and its components was associated with histological responders (P=0.008) but not the non-responders (P=0.7). In the group as a whole, significant increases in the number of CD4, CD8 and T regulatory cells (Treg) were evident by week 20 compared to baseline (P=0.03, P=0.01, P= 0.04 respectively); At week 20, the increased CD4 and CD8 density was significantly associated only with the histological responders (P=0.03; P= 0.03) while increased Treg density was associated with only non-responders (P=0.05). Intralesional Treg density was significantly higher in non-responders compared to responders pre and post treatment (P=0.01, 0.05 respectively). This study demonstrated that imiquimod followed by vaccination achieved histological clearance of VIN at 52 weeks in almost 60%. Higher pre-existing and post-treatment levels of Treg cells were associated with a lack of treatment response. Lymphoproliferation of PBMC established that the vaccination was immunogenic and HPV 16 antigen specific. Importantly, these systemic immune responses to HPV 16 antigens were significantly associated with treatment responders.

The exponential growth in medical pharmaceuticals and related clinical trials have created a need to better understand the decision-making factors in the processes for developing hospital medication formularies. The purpose of the study was to identify, rank, and compare major factors impacting hospital formulary decision-making among three prescriber groups serving on a hospital's pharmacy and therapeutics (P&T) committee. Prescribers were selected from the University of Texas, MD Anderson Cancer Center which is a large, multi-facility, academic oncology hospital. Specifically, the prescriber groups studied were comprised of physicians, midlevel providers, and pharmacists. A self-administered online survey was disseminated to participants. Seven major hospital formulary decision-making factors were identified in the scientific literature. Study participants were asked to respond to questions about each of the hospital formulary decision-making factors and to rank the various formulary decision-making factors from the factor deemed most important to the factor deemed least important. There are five major conclusions drawn from the study including three similarities and two significant differences among the prescriber groups and factors. Similarities include: (1) the factor "pharmacy staff's evaluation of medical evidence including formulary recommendations" was ranked highest for all three prescriber groups; (2) "evaluation of medications by expert physicians" was ranked second for physicians and midlevel providers while pharmacists ranked it third; and (3) the factor, "financial impact of the treatment to the patient" was fifth in terms of hospital formulary decision-making statement and ranking by all three prescriber groups. Two significant differences include: (1) for the hospital-formulary decision making statement, "I consider the number of patients affected by adding, removing, or modifying a drug on the formulary when making hospital medication formulary decisions," midlevel providers considered this factor of significantly greater importance than did physicians; and (2) for the ranked hospital formulary decision-making factor, "financial impact of treatment to the institution," pharmacists ranked this factor significantly higher than did physicians. This study contributes to a greater understanding of the three prescriber groups serving on a P&T committee. Also, the study contributes to the body of literature regarding decision-making processes in medicine and specifically factors impacting hospital formulary decision-making. Furthermore, this study has the potential to impact the operational guidelines for the P&T committee at the University of Texas, MD Anderson Cancer Center as well as other hospitals.

Regulatorische CD4+CD25+ T-Zellen (Tregs) stellen eine kleine Zellpopulation dar (1-5% der peripheren Blutzellen), die hauptsächlich für die Regulierung von Immunreaktionen verantwortlich ist. In der vorliegenden Arbeit wurden diese Zellen gemeinsam mit Stammzellen syngen und allogen kotransplantiert, um ihren Effekt auf das Anwachsen der Spenderzellen und die Rekonstitution der Hämatopoese nach Ganzkörperbestrahlung zu untersuchen. Es wurden humanisierte dreifach transgene Empfängermäuse (C57Bl/6-TTG) verwendet (human CD4+, murin CD4-, human HLA-DR+), wodurch sowohl bei syngener als auch bei allogener Transplantation eine Unterscheidung zwischen Spender- und Empfängerzellen möglich ist. Zunächst wurden CD4+CD25+ T-Zellen durch Separation aus Milzzellen bzw. Buffy Coats gewonnen und in vitro mittels Durchflusszytometrie und ELISpot charakterisiert. Anschließend fanden syngene und allogene Transplantationen mit einer Laufzeit von 61 Tagen statt. Überleben und Gewicht wurden täglich ermittelt und außerdem wurden wöchentlich Blutbilder erstellt und durchflusszytometrische Chimärismusanalysen (murines und humanes CD4, CD8, MHC (H2Db, H2Kd)) durchgeführt. Durch die magnetische Separation konnte die FoxP3-Expression der murinen Zellen (Transplantat) von 1,6% in der Ausgangspopulation auf 68,5% in der CD4+CD25+ Population gesteigert werden. In den ELISpot-Assays zeigten diese separierten Zellen, wie für Tregs typisch, keine Produktion von Interleukin-2. Nach syngener Transplantation (Spender: wildtyp C57Bl/6) von 2x106 Knochenmarkzellen und 1x106 CD4+CD25+ T-Zellen überlebten 100% der Tiere, wie zu erwarten war. Dabei setzte bei Tregs-kotransplantierten Tieren die Blutbildung nach bestrahlungsbedingter Leukozytopenie aufgrund bisher nicht bekannter Mechanismen früher wieder ein und der Donor-Zell-Chimärismus war an Tag 19 nach Transplantation signifikant höher als in der Kontrollgruppe. Dies zeigt, dass regulatorische T-Zellen im syngenen Transplantationsmodell einen positiven Effekt auf die Akzeptanz bzw. das Anwachsen des Transplantats haben. Dieses Modell entspricht klinisch einer autologen Transplantation. Nach einer knochenmarkzerstörenden Therapie werden dem Patienten eigene Stammzellen reinfundiert, um die Blutbildung und das Immunsystem wieder in Gang zu bringen. Der Zusatz von regulatorischen T-Zellen zum autologen Stammzelltransplantat könnte das Anwachsen der Zellen beschleunigen und die gefährliche Phase der Immunsuppression, in der es häufig zu Sekundärinfektionen kommt, verkürzen. Die Transplantation der gleichen Zahl von allogenen Spenderzellen (wildtyp Balb/c) führte überraschend zum Tod aller dreifach transgenen Empfängertiere. Der Vergleich zu Experimenten mit wildtyp C57Bl/6-Empfängertieren zeigte, dass dreifach transgene Mäuse sehr viel höhere Zellzahlen im Transplantat zum Überleben benötigen (Daten nicht gezeigt). Das Ausbleiben der Blutbildung nach der Bestrahlung führte zu vermindertem Allgemeinbefinden, gestörter Futter- und Wassseraufnahme und Exsikkose bis zum Tod bzw. aus Tierschutzgründen zur Euthanasie. Durch Erhöhung der Zellzahl im Transplantat auf 1x107 Knochenmark + 5x106 Milzzellen überlebten 25% der Mäuse, bei 3x107 Knochenmark + 5x106 Milzzellen waren es 50%. Anders als im syngenen Modell führte die Kotransplantation 1,5x106 allogener CD4+CD25+ T-Zellen zu 3x107 Knochenmark + 5x106 Milzzellen zum Versterben der Tiere. Dies verdeutlicht, dass regulatorische T-Zellen in diesem allogenen Transplantationsmodell das Anwachsen des Transplantats behindern (Transplantatversagen). Hier gilt es zu klären, ob dieser Effekt spezifisch für die gewählten Mausstämme ist und welche Mechanismen für das Transplantatversagen verantwortlich sind. In einem dreifach transgenen Mausmodell konnte ein positiver Effekt von regulatorischen T-Zellen auf die Rekonstitution der Hämatopoese bei syngener Kotransplantation nachgewiesen werden. Im allogenen Transplantationsmodell hingegen führte die Kotransplantation CD4+CD25+ T-Zellen zum Versterben der Empfänger. Der beschriebene und schon publizierte positive Effekt spenderspezifischer Tregs zur Behandlung von Graft versus Host Disease nach allogener Stammzelltransplantation widerspricht diesen Ergebnissen nicht, da es bei diesen Patienten schon zum Engraftment von hämatopoetischen Stammzellen gekommen ist. Dies hat weitreichende Konsequenzen für die therapeutische Anwendung regulatorischer T-Zellen bei hämatologischen Erkrankungen in der Human- und Veterinärmedizin.
Regulatory CD4+CD25+ T cells (Tregs) represent a small cell population (1-5% of peripheral blood cells) mainly responsible for the regulation of the immune system. In the present work, these cells were cotransplanted with syngeneic and allogeneic stem cells in order to analyze the effect of Tregs on the reconstitution of hematopoiesis after total body irradiation. Humanized triple transgenic hosts (C57Bl/6-TTG) (human CD4+, murine CD4-, human HLA-DR+) were applied allowing differentiation of donor and host cells in syngeneic and allogeneic transplantation settings. Murine and human CD4+CD25+ T cells were magnetically separated out of splenocytes or buffy-coats and characterized in vitro by means of flow cytometry and ELISpot. Afterwards syngeneic and allogeneic transplantation experiments were performed for a period of 61 days. Survival and weight were assessed daily and once a week blood parameters and chimerism analyses (murine and human CD4, CD8, MHC (H2Db/ H2Kd)) were carried out. FoxP3 expression increased from 1,6% in the initial murine cell fraction to 68,5% in the separated CD4+CD25+ T cells. ELISpot assays showed the typical lack of interleukin 2 production of Tregs. After syngeneic transplantation (donor: wildtype C57Bl/6) of 2x106 bone marrow cells and 1x106 CD4+CD25+ T cells, 100% of mice survived what was to be expected. Cotransplanted animals showed earlier reconstitution of hematopoiesis after leukocytopenia and significant higher donor-cell-chimerism on day 19 after transplantation. The mechanisms for this positive effect of Tregs in syngeneic transplantation on the engraftment have to be investigated. This model clinically correspond an autologous transplantation where patients are treated with their own stem cells after a myeloablative treatment (chemotherapy or irradiation). The addition of regulatory T cells to the transplant could accelerate the engraftment and shorten the risky period of immunosuppression. Injection of the same numbers of allogeneic cells (donor: wildtype Balb/c) did not preserve hosts from mortality. Compared to experiments with wildtype recipients, results showed that triple transgenic mice need much higher cell numbers in the transplant for survival (data not shown). The failure of hematopoiesis after irradiation led to reduced general condition, disordered ingestion and exsikkosis leading to death respectively to euthanasia for reasons of protection of animals. By scaling up the cell number in the inoculum to 1x107 bone marrow cells + 5x106 splenocytes 25% of mice survived, with 3x107 bone marrow cells + 5x106 splenocytes survival was 50%. In contrast to syngeneic experiments, cotransplantation of 1,5x106 allogeneic CD4+CD25+ T cells and 3x107 bone marrow cells + 5x106 splenocytes did not prevent animals from mortality. In this allogeneic transplantation model Tregs restrain engraftment (graft failure). It has to be clarified if this effect is specific for the utilized mouse strains and which mechanisms are responsible for the graft failure. In the syngeneic triple transgenic mouse model cotransplantation of CD4+CD25+ T cells showed a positive effect on reconstitution of hematopoiesis after irradiation. In the allogeneic setting however cotransplantation of allogeneic regulatory T cells avoided the engraftment of transplanted cells. The described and published effect of donor-specific Tregs for treatment of graft versus host disease after allogeneic transplantation does not contradict the presented results because treated patients already possessed engrafted hematopoietic stem cells. The results have wide consequences for the therapeutic appliance of regulatory T cells in hematological diseases in human and veterinary medicine.

December, 2003.
Includes bibliographical references (leaves 190-200)
xiii, 249 leaves : ill. ; 30 cm.
Title page, contents and abstract only. The complete thesis in print form is available from the University Library.
Thesis (Ph.D.)--University of Adelaide, Medical School, Dept. of Public Health, 2004