Development of novel therapeutics and in vitro models for spinal cord injury

Spinal cord injury (SCI) is a devastating condition, which results from trauma to the cord, resulting in a primary injury response which leads to a secondary injury cascade, causing damage to both glial and neuronal cells. Following trauma, the central nervous system (CNS) fails to regenerate due to a plethora of both intrinsic and extrinsic factors. Unfortunately, these events lead to loss of both motor and sensory function and lifelong disability and care for sufferers of SCI. There have been tremendous advancements made in our understanding of the mechanisms behind axonal regeneration and remyelination of the damaged cord. These have provided many promising therapeutic targets. However, very few have made it to clinical application, which could potentially be due to inadequate understanding of compound mechanism of action and reliance on poor SCI models. This thesis describes the use of an established neural cell co-culture model of SCI as a medium throughput screen for compounds with potential therapeutic properties. A number of compounds were screened which resulted in a family of compounds, modified heparins, being taken forward for more intense investigation. Modified heparins (mHeps) are made up of the core heparin disaccharide unit with variable sulphation groups on the iduronic acid and glucosamine residues; 2-O-sulphate (C2), 6-O-sulphate (C6) and N-sulphate (N). 2-O-sulphated (mHep6) and N-sulphated (mHep7) heparin isomers were shown to promote both neurite outgrowth and myelination in the SCI model. It was found that both mHeps decreased oligodendrocyte precursor cell (OPC) proliferation and increased oligodendrocyte (OL) number adjacent to the lesion. However, there is a difference in the direct effects on the OL from each of the mHeps; mHep6 increased myelin internode length and mHep7 increased the overall cell size. It was further elucidated that these isoforms interact with and mediate both Wnt and FGF signalling. In OPC monoculture experiments FGF2 treated OPCs displayed increased proliferation but this effect was removed when co-treated with the mHeps. Therefore, suggesting that the mHeps interact with the ligand and inhibit FGF2 signalling. Additionally, it was shown that both mHeps could be partially mediating their effects through the Wnt pathway. mHep effects on both myelination and neurite outgrowth were removed when co-treated with a Wnt signalling inhibitor, suggesting cell signalling mediation by ligand immobilisation and signalling activation as a mechanistic action for the mHeps. However, the initial methods employed in this thesis were not sufficient to provide a more detailed study into the effects the mHeps have on neurite outgrowth. This led to the design and development of a novel microfluidic device (MFD), which provides a platform to study of axonal injury. This novel device is a three chamber device with two chambers converging onto a central open access chamber. This design allows axons from two points of origin to enter a chamber which can be subjected to injury, thus providing a platform in which targeted axonal injury and the regenerative capacity of a compound study can be performed. In conclusion, this thesis contributes to and advances the study of SCI in two ways; 1) identification and investigation of a novel set of compounds with potential therapeutic potential i.e. desulphated modified heparins. These compounds have multiple therapeutic properties and could revolutionise both the understanding of the basic pathological mechanisms underlying SCI but also be a powered therapeutic option. 2) Development of a novel microfluidic device to study in greater detail axonal biology, specifically, targeted axonal injury and treatment, providing a more representative model of SCI than standard in vitro models. Therefore, the MFD could lead to advancements and the identification of factors and compounds relating to axonal regeneration.

The development of the accounting professional in a postcolonial context: evidence from Sierra Leone

Despite increasing interest in the development of the accountancy profession and constitutive professional bodies in ex-colonies, little is known about the development of professional accountants as individuals. Similarly, although the continuing influence of the legacies of colonialism and imperialism on the accounting professionalisation trajectory in ex-colonies has been recognised, little attempt has been made to theorise such continuing colonial intervention as a postcolonial condition of accommodation and resistance, with implications for the development of professional accountants. This thesis fills this vacuum by employing four aspects of the critical lens of postcolonial theory – local-global nexus, psycho-existential complex, postcolonial hybridity and diaspora - to gain an insight into the development of accounting professionals in ex-colonies with specific reference to Sierra Leone. Specifically, it examines the current model of accounting professionalisation adopted in Sierra Leone and implications for the development of professional accountants in the country; investigates the historical and ideological legacies of colonialism that shaped and continue to influence the professionalisation trajectory in Sierra Leone; explores the perceptions of Sierra Leonean chartered and aspiring accountants of their professional identity in terms of their professional development within Sierra Leone; and explores the lived experiences of Sierra Leonean chartered and aspiring accountants in the diaspora and the diaspora effect on accountancy in Sierra Leone. The empirical evidence presented here emanated from two sources: a web-based survey and semi-structured interviews with Sierra Leonean chartered and aspiring accountants both within and outside the country at the time of the study. The model for developing professional accountants in Sierra Leone comprises a partnership between the local professional body, ICASL, and the British-based global body, the ACCA. A postcolonial analysis of the empirical evidence reveals that an unintended consequence of this model is that the local is co-opted within the global while the global becomes increasingly localised. The analysis also shows that the presence of a perceived global body ‘inferiorises’ the local body to the point of undesirability among local chartered and aspiring accountants. Thus the partnership has to date done little by way of developing ICASL’s capacity to ensure the development of a localised profession and professionals. Instead, it produces, within the Sierra Leone accountancy space, professional hybrids that at once pose as global as well as local accountants. This has significant implications for the local profession because many of the hybrid professional accountants who could potentially drive the local profession forward end up in the diaspora, which leaves the local profession in a weaker state. Also, given the established link between a robust accountancy profession and sustainable economic development, such professional diasporisation could negatively impact on the country’s economic development. In sum, Sierra Leone has failed to establish an accounting professionalisation model that develops professional accountants (through contextualised professional education and training) that meets the specific accounting needs of its growing economy.