Potential of a Bioscaffold to Enhance the Healing of the MCL Following a Mop-End Tear: An Animal Model Study

Isolated medial collateral ligament (MCL) injuries occur frequently (95,000 per year in the US) and heal with conservative treatment. Long-term clinical outcome is generally excellent because the structural properties of the Femur-MCL-Tibia complex (FMTC) naturally return to normal especially the stiffness. However, the quality of the healing ligament, as described by its histomorphological appearance, as well as biochemical, mechanical, and viscoelastic properties, remain poor [37, 70, 108, 109, 116]. Functional tissue engineering techniques such as the use of extracellular matrix (ECM) bioscaffolds have shown promise in improving healing of soft tissues after injury. In particular, small intestine submucosa (SIS) is especially attractive due to its chemoattractant properties, organized fiber alignment, and natural concentration of growth factors [9, 13, 48]. The objective of this thesis is to use SIS to improve MCL healing in a clinically relevant injury model. Sixteen New Zealand white rabbits were subjected to a mop-end tear (Weiss et al. 1991) in order to simulate a clinically relevant injury, which included damage to the ligament insertion sites, over-stretching of collagen fibers, and a frayed appearance of the torn ligament ends. After 12 weeks of healing, seven rabbits per group were euthanized and subjected to a well-established biomechanical testing protocol [111], including a load to failure test. The remaining rabbits (n=2 per group) were evaluated histologically. It was found that SIS treatment resulted in a marked improvement for the tangent modulus of the healing MCL midsubstance over non-treatment (404 ±120 MPa vs. 273 ± 91 MPa, respectively, p<0.05). However, this difference did not translate into a change in the measured structural properties of the FMTC. Nearly half of the specimens in each treatment group failed at the tibial insertion, this indicates asynchronous healing between the ligament insertion and midsubstance. In conclusion, these results confirm SIS enhances the quality of the healing MCL. SIS positively effects the local healing response of an MCL regardless of injury model. This work provides a basis to explore the effect of applying SIS to ligaments which do not heal well naturally, such as the anterior cruciate ligament

The Role of RNA Interference in the Control of Leishmania RNA virus 1 Infection

The presence of Leishmania RNA virus 1 (LRV1) in parasites of the Leishmania (Viannia) subgenus increases the virulence of the parasite in mouse models of leishmaniasis and is correlated with treatment failure, relapse, and the development of mucocutaneous disease in humans. LRV1 is not shed or infectious; rather, the infection is persistent, and as yet it is unknown how the parasite controls virus levels. Many eukaryotic organisms use RNA interference (RNAi) to limit virus replication, and Leishmania (Viannia) parasites have an active RNAi pathway. To determine whether Leishmania are capable of using RNAi to control LRV1, we sequenced sRNAs from LRV1-containing L. braziliensis and L. guyanensis and found that these cells have abundant LRV1-derived sRNAs. Further, I targeted LRV1 using an RNAi transgene in these species, which resulted in a loss of virus. Together, these data suggest that RNAi can limit LRV1 replication. In contrast, knockout of the RNAi effector protein gene Argonaute1 resulted in only a small increase in LRV1 levels, as opposed to the expected dramatic increase. While we did not find evidence of a role for Dicer1/2 or Piwi in control of LRV1, we cannot rule out that such a role exists. These studies suggest that RNAi may play a role in control of LRV1, but that other mechanisms may contribute more or be redundant. In addition to these studies, I also developed a new genetic tool for the manipulation of Leishmania in the laboratory. These popout constructs use GFP expression to facilitate the removal of the construct after it has been integrated into the parasite genome, and will allow short-term expression of genes and RNAi transgenes in Leishmania (Viannia) species. Finally, I present investigations into the effect of RNAi transgenes on parasite biology and virulence. I found that the presence of an RNAi transgene impairs knockdown of an unrelated target, results in an accumulation of stable dsRNA and transposable element transcripts, and may increase parasite virulence. These findings suggest that caution is warranted when using these constructs

The Role of SMAC in NSAID-induced Apoptosis

Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in cancer prevention and have been shown to suppress the formation of colorectal tumors in both humans and rodents. The chemopreventive action of NSAIDs is believed to be mediated through induction of apoptosis in preneoplastic cells. However, the precise molecular mechanisms of NSAID-induced apoptosis remain unclear. Previous studies demonstrated that second mitochondria-derived activator of caspase (SMAC) plays an important role in executing NSAID-induced apoptosis in colon cancer cells. SMAC-knockout HCT116 colon cancer cells are resistant to NSAID-induced apoptosis, and are deficient in caspase activation and cytosolic release of cytochrome c and apoptosis inducing factor (AIF). In this study, we tested the hypothesis that SMAC regulates the release of cytochrome c and activation of caspase cascade through a feed-back amplification loop. We found that the N-terminal AVPI domain of SMAC is required for the proapoptotic activity of SMAC. Following NSAID treatment, SMAC promotes dissociation of caspase-3 from inhibitor of apoptosis proteins (IAPs), which in turn leads to mitochondrial dysfunction. We also studied the effects of pharmacological manipulation on NSAID-induced apoptosis by employing small-molecule compounds that functionally mimic the AVPI domain of SMAC. A synergistic action of NSAIDs and SMAC mimetics was observed in inducing a robust apoptotic response in several colon cancer cell lines, as well as in NSAID-resistant BAX-KO and SMAC-KO cell lines. SMAC mimetics appear to potentiate NSAID-induced apoptosis by stimulating the release of cytochrome c from mitochondria and activation of caspases. Together, these results suggest that SMAC may be useful as a target for the development of more effective chemopreventive agents

An Alternative Approach to Child Rescue: child emigration societies in Birmingham and Manchester, 1870-1914

This study analyses the operations and activities of two child emigration societies based in Birmingham and Manchester between 1870 and 1914. It argues that both societies marketed and promoted their work as an alternative approach to ‘child rescue’. Doing so places them in the wider context of a child emigration movement and a child rescue movement, both of which flourished between the end of the nineteenth century and start of the twentieth century. It also suggests that the founders and staff at these child emigration societies reflected and exploited contemporary ideals, beliefs and fears, particularly about the role of the child and the family within society, the expense of poor law relief, social problems in urban cities and the need for empire strengthening. To persuade people that transplanting children overseas was an alternative form of child rescue, the two societies in Birmingham and Manchester presented a self-created image of their work, which they could change, manipulate and re-adjust to suit their purposes. Chapter One analyses the motivating factors for child emigration societies to begin their work in Birmingham and Manchester, as well as the subsequent justifications they used to explain their work. Chapter Two assesses the communication and co-operation between the regional child emigration organisations and others involved in child rescue, their relations with government agencies and the ways in which external influences shaped their activities. Chapter Three analyses how the two societies generated and maintained support for their activities through interaction with local people, in both England and Canada. Chapter Four examines how they responded to contemporary challenges and criticisms regarding the welfare of children under their guardianship. This includes an analysis of the ways in which they explained their methods of caring for, training and protecting the children as an alternative approach to child rescue

The information systems and technology innovation process: a study using an agent-based approach

Mestrado em Gestão de Sistemas de InformaçãoUm modelo abstracto baseado em agentes é utilizado para estudar a inovação em Sistemas de Informação e em Tecnologia de Informação, no plano organizacional, utilizando uma aproximação sócio-cognitiva. A conclusão do estudo indica que o poder dos profissionais conhecedores de tecnologias de informação na decisão de adopção de uma determinada inovação varia com o nível de concordância de ideias entre eles e os decisores, ao mesmo tempo que depende da taxa de depreciação das transacções, conduzindo a uma forte flutuação de poder quando o ambiente é instável.An abstract Agent Based Model is used to study Information Systems and Information Technology innovation on an organizational realm, using a socio-cognitive approach. Conclusion is drawn that the power of the knowledge workers in the decision to adopt an IS/IT innovation within an organization varies with the matching level of ideas between them and the top management, while being dependant of the transactions’ depreciation rate, leading to a strong fluctuation of power when the environment is unstable

Portals to Learning: Threshold Concepts in Art History Teaching and Learning

Threshold concepts are conceived of as portals to learning that open previously inaccessible ways of thinking. They encompass specific ideas within a discipline that must be mastered before the learner can progress. The process of identifying threshold concepts can reveal hidden or unacknowledged fundamental disciplinary beliefs and epistemology. Integrating a threshold concepts framework into the scholarship of teaching and learning in art history (SoTL-AH) can help faculty diagnose and anticipate when students are likely to encounter troublesome knowledge within an art history course. Distinguishing these thresholds can aid instructors in designing courses that prepare for specific stages that present conceptual or affective difficulty and turn those into transformative experiences that promote reconstituted and integrated knowledge. Threshold concepts can also be applied more broadly to benefit curriculum design, assessment, and the profession. This paper explains threshold concepts and bottlenecks, describes the benefits of using threshold concepts, identifies potential limitations in utilizing them in the design of teaching strategies, and proposes some preliminary threshold concepts in art history

Rebuilding the Tower of Babel: Ælfric and Bible Translation

The Old English homilist Ælfric is well known for his reluctance to translate the Bible and other patristic works into the vernacular; nonetheless, his corpus includes a large number of such translations. This paradox is partly resolved through an examination of Ælfric's perspective on the biblical narratives of the Tower of Babel, Christ's sending out of the disciples, and Pentecost. For Ælfric, the linguistic diversity of the Tower of Babel creates problems for translating the very sensitive texts of the Bible from one language into another, yet the narratives of Christ's sending out of the disciples and of Pentecost not only provide biblical sanction for translation but stress the necessity of translation in the evangelization process

Monitoring atrazine-degrading and atrazine-tolerant bacterial populations in Lower Rio Grande Valley agricultural canals using quantitative-PCR and internal atzA primers

The research hypothesis was that atrazine-degrading bacteria would be detectable during the planting and rainy seasons with their populations dissipating during non-planting and dry seasons in 2010-2011. Atrazine concentration was detected in March, May, June and August for all canals with June having the highest average concentration of 0.77ppb. Gene atzA abundance was detected from June through August with July samples having the highest gene abundance of 250.6 (pg). Tolerant bacterial densities were detectable from March through June. Atrazine concentration and population abundance were not statistically different during planting and non-planting, rainy and dry seasons, although there was a trend of increased atrazine concentration, denser atrazine-tolerant bacterial populations and increased atzA abundance during rainy months. These results indicate atrazine-degrading and atrazine- tolerant bacteria are present in these canals; these organisms potentially degrade excess atrazine in the Lower Rio Grande Valley