Exotic species often invade new areas and displace native species. The problems associated with such invasions are well known, but for many exotic species, experimental work has not yet been done to predict which, and under what conditions they may become a problem. Two greenhouse experiments were devised to investigate the plasticity, shade tolerance, and phenotypic differences of full-siblings from 3 populations of Cardamine impatiens, a Eurasian species potentially invasive in North America. Potted plants were subjected to 0, 54, 76, or 91% shade created by neutral density shade cloth application. In addition, the impact of a cold pre-treatment of seedlings on the growth and reproductive output of C. impatiens plants was examined. In our first experiment, we subjected Cardamine impatiens to non-shaded cages, 54%, or 76% shade intensity. Plants died very quickly, so LD50 data were used as a relative measure of fitness, and relative growth indices were calculated over time. Other relative measures of fitness included canopy area, leaf area, number of leaves, number of leaves per canopy area, and final plant weight. Plants in cages with no shade treatment grew faster than those in cages with shade cloth and final plant weight decreased as shade treatment percentage increased. In each population, the number of leaves increased over time and the number of leaves per canopy area decreased over time under shade treatments. Our second experiment involved the application of 54%, 76%, and 91% shade intensity. The additional shade treatment of 91% was applied to determine the extent of plant tolerance and plasticity in response to light reduction. Due to high plant mortality in our first experiment, we treated Cardamine impatiens with a 4 week cold period prior to treatment, which simulates its biennial growth form in its natural western Virginia region habitat. Since this second experiment took place later in the year, day length was extended to more accurately duplicate the conditions during the first experiment. LD50 calculations were not necessary, and 7 of the 135 plants produced seed. Relative measures of fitness included canopy area, leaf area, number of leaves, number of leaves per canopy area, and final plant weights. As in experiment one, the number of leaves per plant increased over time, final plant weight decreased as shade treatment increased, and the number of leaves per canopy area decreased as shade treatment increased. From these two experiments, we determined that Cardamine impatiens is a species that exhibits phenotypic plasticity and therefore may pose a threat as an invasive species. C. impatiens is able to grow and exhibit plasticity of plant architecture under the conditions of very low light. The number of leaves per canopy area decreased as shade increased, suggesting that C. impatiens is highly adaptable to low light conditions, and therefore may be exhibiting phenotypic plasticity by reallocating its resources by producing fewer leaves while maintaining canopy area. This data along with other C. impatiens traits such as high levels needed for seed production, its persistence in seed banks, along with a lack of known major enemies, indicates that they have a great capacity to invade a wide variety of habitats. We also determined that a cold treatment is necessary in order for C. impatiens to obtain optimal growth and reproduction. / Master of Science

No

Master of Science / Department of Agronomy / Walter H. Fick / Rough-leaved dogwood (Cornus Drummondii Meyer) is one of the most invasive woody plants in rangeland of Kansas. Reduced prescribed burning due to drought and urban encroachment probably has contributed to its spread. Herbicides are commonly recommended for control of rough-leaved dogwood, but minimal data exists for recommendation development. Ten herbicide treatments were applied in June during late flowering at two locations in northeast Kansas in 2005 and 2006. Each treatment was replicated three times in a randomized complete block design with individual plot sizes of 3 x 3 m. Herbicides were applied with hand sprayers in 1017 L/ha solution. Visual evaluations of defoliation were made about 1 and 12 months after treatment (MAT) and mortality was estimated about 1 year after treatment (YAT). Defoliation 1 MAT varied among herbicides with significant location by year and herbicide by year interactions. Treatments providing greater than 70% defoliation 12 MAT both years were triclopyr + 2,4-D (1.12 + 1.06 kg ae/ha), triclopyr + fluroxypyr (1.83 + 0.61 kg ae/ha), picloram + fluroxypyr (0.41 + 0.41 and 0.82 + 0.82 kg ae/ha), and picloram + 2,4-D + triclopyr (0.66 + 2.44 + 2.44 kg ae/ha). Rough-leaved dogwood is difficult to control with a single herbicide application, but treatments exist that will substantially reduce stands. Tebuthiuron pellets (Spike 20P) are another control measure recommended for rough-leaved dogwood. Treatments of 4.4 kg ai/ha (3/4 oz per 100 square feet) tebuthiuron pellets were applied in December 2004. A visual estimate of control indicated tebuthiuron reduced dogwood cover by 65% compared to a 3% decrease on untreated plots. Dogwood density was reduced by 2.2 stems/m2 (P<0.08). Total woody plant cover increased on untreated plots by 6.2 percentage units, but was decreased by 20.9 percentage units on tebuthiuron treated plots. Other woody plants decreased in both treated and untreated plots. Shading by a large elm tree likely caused variation between replications including increases in cover and density of rough-leaved dogwood on treated plots. Tebuthiuron is a photosynthetic inhibitor that often is not effective on shaded plants. Tebuthiuron pellets applied at 4.4 kg ai/ha was an effective control option for unshaded rough-leaved dogwood.

This dissertation examines nursery/garden centre compliance with Invasive Alien Plant (IAPs) legislation in eThekwini and uMsunduzi, South Africa. Despite South African governmental programmes, an apparent lack of public awareness regarding IAPs persists. The cost to clear IAPs in South Africa is estimated to be 12 billion Rand over 20 years. Nurseries/garden centres should be able to increase customer awareness of IAPs. However, Government regulation/instruction of nurseries/garden centres seems inadequate. A mixed methods approach involving quantitative and qualitative analyses of questionnaires, observations and interviews was used in this study. There was little evidence that nurseries/garden centres stocked/sold CARA plants. However, they were stocking/selling NEMBA plants in spite of knowing CARA, NEMBA and indigenous alternatives. There is little interaction with relevant government/industry programmes. It is recommended that the Department of Environmental Affairs institute a IAPs Advisory Committee to see to the dissemination and provision of relevant information and training concerning IAPs to the industry.

Our aim was to determine the characteristics, treatments and outcomes of patients with primary spinal glioblastomas (GB) or gliosarcomas (GS) reported in literature until March 2015. PubMed and Web of Science were searched for peer-reviewed articles pertaining to cases of glioblastomas / gliosarcomas with primary spinal origin, using predefined search terms. Furthermore we performed hand searches tracking the references from the selected papers. Eighty-two articles published between 1938 and March 2015 were eligible. They reported on 157 patients. Median age at diagnosis was 22 years. The proportion of patients who received adjuvant chemo- or radiotherapy clearly increased from the time before 1980 until present. Median overall survival from diagnosis was 8.0 ± 0.9 months. On univariate analysis age influenced overall survival, whereas tumor location, gender and the extent of initial resection did not. Outcomes did not differ between children (< 18 years) and adults. However, the patients who were treated after 1980 achieved longer survival times than the patients treated before. On multivariable analysis only age (< 60 years) and the time period of treatment (>1980) were confirmed as positive independent prognostic factors. In conclusion, primary spinal GB / GS mainly affect younger patients and are associated with a dismal prognosis. However, most likely due to the increasing use of adjuvant treatment, modest therapeutic progress has been achieved over recent decades. The characteristics and treatments of primary spinal glioblastomas should be entered into a central registry in order to gain more information about the ideal treatment approach in the future.

Thesis (PhD (Conservation Ecology and Entomology))--University of Stellenbosch, 2009. / ENGLISH ABSTRACT: Natural and semi-natural ecosystems and human communities worldwide are under siege from a growing number of destructive invasive alien species. Alien species are those whose presence in an area is due to intentional or accidental introduction as a result of human activities. Some alien species become invasive, and some cause tremendous destruction to the ecosystem and their stability, but we do not yet understand fully the many factors that determine the levels of invasiveness in alien species. However, management of alien plants requires a detailed understanding of the factors that make them invasive in their new habitat. The aim of this study was to explore in detail the processes and potential for invasion of Schinus molle (Peruvian pepper tree) into semiarid savanna in South Africa and to examine the potential for this species to invade further in these ecosystems, and in other South African biomes. In this thesis I explored the patterns and processes of invasion of S. molle in semiarid savanna using small-scale experiments to investigate physical and ecological barriers to invasion that prevent or accelerate the invasion of this species. I examined factors such as pollination; seed production; seed dispersal; seed predation and viability, all known to contribute to invasiveness. I highlighted the critical role of microsite conditions (temperature, humidity, water availability) in facilitating S. molle seedling establishment in semi-arid savanna and demonstrated that microsite type characteristics need to be considered for management and monitoring of the species in South Africa. I demonstrated the ability of S. molle to out-compete indigenous woody plants for light and other resources and also showed that disturbance of natural ecosystems was not a prerequisite for invasion, although human activities such as tree planting have played a major role in disseminating this species in South Africa. Predicting the future distribution of invasive species is very important for the management and conservation of natural ecosystems, and for the development of policy. For this reason, I also assessed the present and potential future spatial distribution of S. molle in South Africa by using bioclimatic models and a simulation-based spread model. I produced accurate profiles of environmental conditions (both biophysical and those related to human activities) that characterize the planted and naturalized ranges of this species in South Africa, by linking species determinants, potential habitat suitability and likely spread dynamics under different scenarios of management and climate change. All those components provided insights on the dynamics of invasions by fleshy-fruited woody alien plants in general, and on S. molle invasions in South Africa in particular. I developed a conceptual model that described S. molle population dynamics leading to an understanding of the processes leading to the invasive spread of this species in South Africa. This work also emphasized the need for policy review concerning the invasive status of S. molle in South Africa, and recommendations are made for future research. / AFRIKAANSE OPSOMMING: Die natuurlike and half-natuurlike ekosisteme sowel as menslike gemeenskappe wereldwyd word bedreig deur ‘n groeiende hoeveelheid indringerplantspesies. Indringerplantspesies (daardie spesies wie se teenwoordigheid toegeskryf kan word aan opsetlike of toevallige inbringing deur menslike toedoen) is ‘n bedreiging nie net vanweë die massiewe verwoesting van die ekosisteme en ekosisteemstabilitiet nie, maar ook omdat ons nog nie ten volle verstaan hoe hulle van skaars in hul natuurlike omgewing tot dominant in hul nuwe habitat gaan nie. Bestuur van indringer plante vereis ’n begrip van biologise en ekologiese faktore wat lei tot hulle indringing in die nuwe habitat. Die primêre doel van hierdie studie was om in detail uit te vind wat die prosessesse en potensiaal is vir die indringing van S. molle (die Peruviaanse peper boom) in droë savanna en om indringingspatrone in droë savanna met huidige en potensieële toekomstige patrone in ander Suid-Afrikaanse biome te vergelyk. In hierdie tesis ondersoek ek die patrone en prosesse wat verband hou met die indringing van S. molle in droë savanna deur gebruik te maak van kleinskaalse eksperimente om fisiese en ekologise hindenisse te ondersoek wat indringing van S. molle in Suid-Afrika voorkom of versnel. Dit sluit faktore in wat bekend is om by te dra tot indringing van plant spesies, soos bestuiwing, saadproduksie, saadpredasie en kiemkragtigheid. Ek het die kritieke rol beklemtoon van mikroomgewingskondisies (temperatuur, humiditeit, waterbeskikbaarheid) in die fasilitering van S. molle saailingvestiging in droë savanna en het gedemonstreer dat die tipe mikroomgewingskarakteristieke in ag geneem moet word by betuur en monitering van die verspreiding van S. molle in Suid-Afrika. Ek het die vermoë van S. molle om inheemse plante te uitkompeteer gedemonstreer, en het gewys dat versteuring van natuurlike ekosisteme nie ’n voorvereiste vir S. molle indringing was nie, hoewel menslike aktiwiteite soos boomaanplantings ’n groot rol speel deur by te dra tot indringing van hierdie spesie in Suid-Afrika. Voorspelling van toekomstige verspreiding van indringerspesies is baie belangrik vir die bestuur en bewaring van natuurlike ekosisteme, sowel as vir ontwikkeling van wetgewing. Daarom is die huidige en potensiele toekomstige ruimtelike verspreiding van S. molle in Suid-Afrika bereken deur inkorporering van bioklimaatsmodelle en simulering gebasseer op ’n verspreidingsmodel. Ek het derhalwe akkurate profiele van omgewingstoestande (beide fisiese en daardie wat verband hou met menslike aktiwiteite) wat die aangeplante en natuurlike omvang van die spesie in Suid-Afrika kenmerk geproduseer deur spesiedeterminante, potensieële geskiktheid van habitatte en moontlike verspeidingsdinamika onder verskillende bestuursscenarios en kimaatsverandering te koppel. Al hierdie komponente verskaf insig in die dinamika van die indringing van houtagtige plante met vlesige vrugte oor die algemeen en S. molle in besonder in Suid- Afrika. Hierdie werk beklemtoon ook die behoefte vir hersiening van beleidsrigtings wat betrekking het op die indringerstatus van S. molle in Suid-Afrika en maak aanbevelings vir toekomstige navorsing.

Die pyogene Spondylodiszitis als bakterielle Osteomyelitis der Wirbelsäule ist eine seltene Entität der bakteriell-entzündlichen Pathologien des Stütz- und Bewegungsapparates. Trotz adäquater Behandlungsstrategien, wird auch heute noch eine Mortalitätsrate von 5% bis 20% beschrieben. Vor allem die in dem vorwiegend älteren Patientenkollektiv deutlich erhöhte Prävalenz an metabolischen oder kardiopulmonalen Komorbiditäten fordert moderne Therapiekonzepte, die eine risikoarme, jedoch effektive Eradifizierung des bakteriell-entzündlichen Fokus mit schneller Wiederherstellung der prämorbiden Mobilität ermöglichen. Ausgehend von zwei grundlagenwissenschaftlichen Studien, wurden in der vorliegenden Habilitationsschrift zunächst die komplexen Zusammenhänge von lokaler Gewebsveränderungen und systemischer Entzündung erörtert. Hierbei zeigten die Analysen humaner degenerativer und traumatischer Bandscheibenzellen, dass die Apoptose, insbesondere die Herabregulation anti-apoptotischer Schlüsselkomponenten wie das Bcl-2, als mögliche Schnittstelle im katabolen Stoffwechsel der extrazellulären Bandscheibenmatrix diskutiert werden kann. In der generalisierten bakteriellen Entzündung (Sepsis), ließ sich durch die gentherapeutisch gewebsständige Überexpression von antiapoptotischen und antiinflammatorischen Interleukin-10 (IL-10), auch im IL-10-defzienten Organismus, eine deutliche Reduktion der systemischen proinflammatorischen Immunantwort mit verbesserter Überlebensrate septischer Tiere erzielen. Jedoch birgt der substantielle Gewebeschaden bei pyogener Spondylodiszitis nicht selten die Gefahr der konsekutiven Instabilität mit neurologischen Komplikationen und stellt damit eine besondere chirurgische Herausforderung dar. Daher wurden in drei weiteren klinischen Studien unsere, in den letzten 10 Jahren etablierten, lösungsorientierten Strategien erläutert. Zur Überbrückung größerer knöcherner Defekte gelang mit der Implantation expandierbarer Titancages eine sichere knöcherne Durchbauung mit vollständiger Ausheilung des Infektes. Im Beobachtungszeitraum von mehr als 3 Jahren war bei keinem der Patienten ein Infektrezidiv zu verzeichnen. In komplexen Fällen von monosegmentaler Spondylodiszitis der LWS mit multisegmentaler epiduraler Abszedierung, führte die epidurale Katheterspülung über den dorsalen Zugang für die Spondylodese zu einer folgenlosen Ausheilung. Damit konnte ein zusätzliches, iatrogenes Trauma mit multisegmentalen Lamintomien über die Distanz des epiduralen Abszesses vermieden werden. In einer weiteren Studie mit einem Beobachtungszeitraum von bis zu 5 Jahren, erzielte die Implantation von Poly-Ether-Ether-Keton (PEEK) Cages zur dorsalen intersomatischen Fusion bei pyogener Spondylodiszitis eine sehr gute, stabile knöcherne Durchbauung des infizierten Segmentes, ebenfalls ohne Infektrezidiv. Diese Abweichung vom herkömmlichen Standard mit Titanimplantaten erwies sich somit als sichere Alternative mit den für PEEK charakteristischen, verbesserten Eigenschaften. Im Vergleich zu herkömmlichen Operationsverfahren, verspricht die Integration dieser Ergebnisse in die Weiterentwicklung minimal-invasiver Techniken, insbesondere im multimorbiden Patientenklientel, mindestens gleichwertig gute Ergebnisse bei deutlich reduziertem Operationstrauma.

Invasive Pilzinfektionen stellen ein großes Problem bei Transplantatempfängern dar. Candida und Aspergillus spp. sind die häufigsten pathogenen Pilze bei Patienten nach KMT und Organtransplantationen. Diese Infektionen sind durch eine hohe Morbidität und Mortalität gekennzeichnet, insbesondere bei Patienten mit persistierender Granulozytopenie und damit jene nach allogener KMT. Die Mortalitätsrate kann durch eine Frühdiagnostik und durch Gabe einer geeigneten Therapie wesentlich reduziert werden. Die Symptome und Zeichen einer systemischen Pilzinfektion sind bei Transplantatempfängern untypisch. Die serologische Diagnostik von invasiven Candidosen oder Aspergillosen stellt eine zusätzliche Möglichkeit zur klinischen Untersuchung und anderen diagnostischen Maßnahmen dar. Diese Untersuchung umfasste 252 Patienten (17 Patienten nach KMT) und 235 Patienten von Intensivtherapiestationen (z. B. nach Organtransplantationen) in den Jahren 1991-1994 von der Humboldt-Universität zu Berlin (Charite). Die Patientenseren wurden routinemäßig auf das Vorkommen einer Candida- und Aspergillus Antigenämie geprüft. Zum Nachweis von zirkulierendem Galactomannan wurde ein Latex Agglutinationstest- Pastorex Candida und Aspergillus, Sanofi Diagnostics Pasteur, genutzt. Invasive Aspergillus-Pilzinfektionen wurden bei acht von 235 Patienten unter Intensivtherapie gefunden. Alle acht Patienten mit invasiver Aspergillose hatten einen positiven Aspergillus-Antigen-Test. Der direkte Nachweis von Antigenbestandteilen von Candida oder Aspergillus spp. erwies sich als vielversprechender frühdiagnostischer Test bei kritisch kranken und immunsupprimierten Patienten. / Invasive fungal infections are a major problem in transplant recipients. Candida and Aspergillus spp. are the most common fungal pathogens causing infection in patients undergoing BMT or solid organ transplantation. These infections are characterised by high morbidity and mortality, especially in patients with persistent granulocytopenia and in these receiving allogeneic bone marrow transplant. The mortality rate can be substantially reduced if an early diagnosis is made and the proper therapy given. The symptoms and signs of deep fungal infection in the transplant recipients are unreliable and often absent regardless of the type of organism or the site of infection. Laboratory tests are essential to establish the diagnosis of invasive fungal infection. The serological diagnosis of invasive candidosis or aspergillosis is at best an adjunct to clinical evaluation and other diagnostic procedures. The study comprises 252 patients undergoing allogeneic bone marrow transplantation (17 patients) and 235 patients from intensive care units (for instance after solid organ transplantation) in the years 1991-1994 at the Humboldt-University of Berlin (Charité). The serum of the patients were routinely screened for the occurrence of Candida and Aspergillus antigenemia (circulating galactomannan was detected using a latex agglutination test-Pastorex Candida and Aspergillus, Sanofi Diagnostics Pasteur). Invasive Aspergillus fungal infection was found in eight of the 235 intensive care patients. All these eight patients with invasive aspergillosis had an positive Aspergillus antigen test. The direct detection of antigenic components of Aspergillus and Candida spp. in serum appears promising as an early diagnostic test in critical ill and immunocompromised patients.

Le syndrome d'apnée du sommeil (SAS) est une maladie multifactorielle caractérisée par des épisodes récurrents de pauses respiratoires ou des réductions significatives de l'amplitude respiratoire pendant le sommeil. Ces épisodes peuvent provoquer des réactions cardiorespiratoires aiguës; délétères à long terme. Plusieurs thérapies ont été proposées, étant la pression positive continue des voies respiratoires (CPAP) le traitement de référence. Malgré ces excellents résultats chez les patients symptomatiques, le taux de refus initial est de 15% et une adhésion à long terme est difficile à atteindre. Par conséquent, le développement de méthodes de traitement non invasives, avec une meilleure acceptabilité, reste d’une importance majeure. Dans ce contexte, l’hypothèse qui sous-tend ce travail est qu’une stimulation kinesthésique contrôlée, délivrée au cours de la phase précoce de l’apnée, peut réduire la durée des événements respiratoires et, par la suite, limiter les désaturations d’oxygène associées, par une activation contrôlée du réflexe de sursaut. La première partie de ce manuscrit est consacrée à la description d'un nouveau système (PASITHEA) de surveillance en temps réel et de neuromodulation thérapeutique, qui fonctionne comme un dispositif polyvalent de diagnostic et de traitement de SAS par stimulation kinesthésique. Les principales contributions de cette thèse se concentrent sur les aspects du traitement du signal et du contrôle de ce système, ainsi que sur l'électronique associée. Une autre contribution est liée à l'évaluation de ces méthodes et dispositifs par des protocoles cliniques spécifiques. Dans une deuxième partie, nous proposons une première méthode de contrôle On/Off optimale pour délivrer la stimulation, en utilisant comme variable de contrôle la sortie d'un détecteur d'événements respiratoires en temps réel. Lors de la détection d'un événement, une stratégie de stimulation unique avec amplitude de stimulation constante est appliquée, cette dernière a été mise en œuvre dans le cadre d'un premier protocole clinique dédié à l'évaluation de la réponse du patient au traitement. Les résultats ont montré que 75% des patients répondaient correctement au traitement en termes de durées des épisodes respiratoires. De plus, des diminutions significatives de la variabilité du SaO2 ont également été constatées lors de la mise en œuvre d'une nouvelle méthode d'analyse aiguë. Puisque nous avons supposé qu'une sélection inappropriée des patients pourrait expliquer l'absence de réponse observée chez 25% des patients. Nous avons proposé une méthode pour différencier les patients qui pourraient bénéficier de cette thérapie, basée sur l'estimation d'indices de variabilité cardiaque. Les résultats de ces analyses ont montré que l'efficacité de cette thérapie semble corrélée à un système nerveux autonome fonctionnel. Enfin, une méthode améliorée de contrôle en boucle fermée, intégrant des correcteurs proportionnels-dérivés (PD) couplés et simultanés a été proposée afin de modifier de façon adaptative l’amplitude de stimulation kinesthésique délivrée au patient par le système thérapeutique, en utilisant comme variables de contrôle des signaux physiologiques enregistrés en temps réel. Un deuxième protocole clinique visant à valider l'algorithme de contrôle de la stimulation kinesthésique adaptative spécifique au patient a été initié. Plusieurs améliorations ont été effectuées à la première version du système afin de permettre l'intégration du contrôleur proposé. Les résultats préliminaires de cette étude ont validé le fonctionnement de notre contrôleur et ont montré que notre système était capable de fournir une stimulation kinesthésique adaptative en fonction des réponses propres au patient. Une autre phase de cette étude, mettant en œuvre le contrôleur avec un ensemble des paramètres de contrôle présélectionnés, est actuellement en cours. / Sleep apnea syndrome (SAS) is a multifactorial disease characterized by recurrent episodes of breathing pauses or significant reductions in respiratory amplitude during sleep. These episodes may provoke acute cardiorespiratory responses along with alterations of the sleep structure, which may be deleterious in the long term. Several therapies have been proposed for the treatment of SAS, being continuous positive airway pressure the gold standard treatment. Despite its excellent results in symptomatic patients, there is a 15% initial refusal rate and long term adherence is difficult to achieve in minimally symptomatic patients. Therefore, the development of non-invasive SAS treatment methods, with improved acceptability, is of major importance. The objective of this PhD thesis is to propose new signal processing and control methods of non-invasive neuromodulation for the treatment of SAS. The hypothesis underlying this work is that bursts of kinesthetic stimulation delivered during the early phase of apneas or hypopneas may elicit a controlled startle response that can activate sub-cortical centers controlling upper airways muscles and the autonomic nervous system, stopping respiratory events without generating a cortical arousal. In this context, the first part of this manuscript is dedicated to the description of a novel real-time monitoring and therapeutic neuromodulation system, which functions as a multi-purpose device for SAS diagnosis and treatment through kinesthetic stimulation. This system has been developed in the framework of an ANR TecSan project led by our laboratory, with the participation of Sorin CRM SAS. The main contributions in this thesis are focused on the signal processing and control aspects of this system, as well as the electronics associated. Another contribution is related to the evaluation of these methods and devices through specific clinical protocols. In a second part, we propose a first optimal On/Off control method for delivering kinesthetic stimulation, using as control variable the output of a real-time respiratory event detector. A unique stimulation strategy where a constant stimulation amplitude is applied upon event detention was implemented in a first clinical protocol, dedicated to assessing the patient response to therapy. Results showed that 75% of the patients responded correctly to therapy, showing statistically significant reductions in respiratory event durations. Also, significant decreases in the SaO2 variability were also found when implementing a novel acute analysis method. Since we hypothesized that inappropriate patient selection could explain the observed lack of response in 25% of patients, we proposed a method to differentiate patients who could benefit from this therapy based on the estimation of complexity-based indexes of heart rate variability. Results of these analyses showed that the effectiveness of this therapy seems correlated to a functional autonomic nervous system. Finally, an improved closed-loop control method integrating concurrent, coupled proportional-derivative (PD) controllers in order to adaptively change the kinesthetic stimulation was proposed. It uses as control variables three physiological signals recorded in real-time: Nasal pressure, oxygen saturation and the electrocardiogram signal. A second clinical protocol with the main objective of validating the control algorithm for patient-specific adaptive kinesthetic stimulation was launched. Several improvements to the first version of the system were developed to allow the integration of the proposed controller. Preliminary results from the first phase of this study validated the proposed controller operation and showed that the controller was able to provide adaptive kinesthetic stimulation in function of the patient-specific responses. A second phase of this study implementing the proposed controller and the set of the selected control parameters from the first phase is currently ongoing.

Thioredoxin is a small ubiquitous oxido-reductase found in all species. The highly conserved active site, which facilitates thioredoxins redox activity, contains two redox active cysteine residues. Thioredoxin has numerous protein substrates to which it donates H+ ions and it can also function as a free radical scavenger. Through these activities thioredoxin is able to influence the redox state of not only its protein targets, but also the entire cellular environment. Thioredoxin has been implicated in many biological functions, and one mechanism by which it influences these functions is through interactions with a number of transcription factors including NF-kappa-B and p53. Thioredoxin also has numerous extracellular biological roles. It has been shown that thioredoxin is actively secreted from a number of normal and transformed cell lines including fibroblasts and activated B and T cells. This study investigates the role of thioredoxin in embryonic implantation and cancer cell metastasis, two physiological functions which rely on the same basic processes. Thioredoxin expression has previously been shown to be increased in many cancers. However it has not yet been established whether this increase is a causative or a side effect of the cancerous phenotype. Similarly thioredoxin expression has previously been shown to be increased during different phases of the oestrus cycle and pregnancy. This thesis describes the role of thioredoxin in embryonic implantation using a marmoset model. A thioredoxin cDNA was isolated and subsequently sequenced. Preliminary antibody experiments indicated that the anti human thioredoxin monoclonal antibodies available in our laboratory would recognise marmoset thioredoxin. Subsequently immunocytochemistry using anti human thioredoxin antibodies was carried out on sectioned marmoset uterus and embryonic tissue. The results indicated that thioredoxin is expressed by cells at the embryonic-maternal interface of early implantation sites. Further studies demonstrated that thioredoxin is also expressed and secreted by cultured blastocysts in vitro. This thesis also describes the role of thioredoxin in cancer cell metastasis. Results of this study indicate that thioredoxin is actively involved in facilitating the invasive phenotype of breast cancer cells. The two cell lines utilised were MCF-7, a well differentiated, relatively non-invasive breast cancer cell line; and MDA-MB-231, a poorly differentiated, highly invasive breast cancer cell line. The cell lines were transfected with thioredoxin sense, antisense and 1SS (encodes thioredoxin with both active cysteine residues mutated to serine residues and is thus redox inactive) constructs. The results demonstrate that when endogenous thioredoxin levels are increased, i.e. transfected with a sense thioredoxin construct, the invasive breast cancer cell line MDA-MB-231 becomes more invasive, conversely when endogenous levels are decreased, i.e. transfected with antisense or 1SS constructs, the invasive capacity of these cells decreases. However, when the endogenous level of thioredoxin was manipulated in the relatively non-invasive cell line MCF-7 very little effect was observed. Results also indicate that thioredoxin has the ability to act as a chemoattractant for actively invading breast cancer cells. Both of these functions appear to be dependent on thioredoxin's redox activity. Additional studies described in this thesis have shown that thioredoxin is involved in the regulation of Sp1 in vitro. Sp1 is a transcription factor known to regulate the transcription of a number of genes whose products are intimately involved in the invasive phenotype. The results in this study suggest that Sp1 DNA binding is regulated by thioredoxin such that when reduced by the enzyme its binding to DNA is facilitated. Results also indicate that Sp1 may regulate the transcription of thioredoxin by binding to Sp1 sites within the thioredoxin promoter.