The establishment and use of tissue engineered vascular models to investigate the pleiotropic effects of statins

Cardiovascular disease (CVD) has been identified as the leading cause of mortality in westernised society. The triggering factor for the majority of cardiovascular diseases is atherosclerosis, defined as an accumulation of fatty materials in the vascular sub-endothelial space. This results in the initiation and propagation of inflammatory responses that result in the narrowing of the vascular lumen, as well as thickening and hardening of arteries. The initiating stimulus in atherosclerosis is elevated levels of low-density lipoprotein (LDL) in circulation, and the cells involved in this process are primarily endothelial cells-which interact with blood-, smooth muscle cells-which facilitate the contraction and relaxation of large diameter blood vessels-, and macrophages, which are immune cells that are able to take up and store lipids. As inflammation progresses, the endothelium becomes dysfunctional and expresses adhesion molecules that facilitate the entry of monocytes into the sub-endothelial space, where they differentiate into macrophages, take up LDL and become foam cells. These lipid rich foam cells are a key component of atherosclerotic plaques, together with dead cells that make up the necrotic core. Statins have been established as the gold standard for the treatment of atherosclerosis, and have been useful in decreasing morbidity and mortality in CVD patients. They function by preventing cholesterol synthesis through inhibition of HMG-CoA, thus lowering amounts of circulating cholesterol. In addition to this function, a number of pleiotropic effects have been associated with statin treatment including, increasing numbers of circulating endothelial progenitor cells (EPCs), reduce inflammation, improve atherosclerotic plaque stability and improve engraftment of MSCs into sites of vascular injury. To investigate these pleiotropic effects of this ubiquitous drug used in the treatment of the most prevalent disease, we developed tissue engineered blood vessel models that incorporated endothelial cells (Human umbilical vein endothelial cells (HUVECs)) and smooth muscle cells (Human cardiac artery smooth muscle cells (HCASMCs)) to represent the intimal and medial layers of the vasculature and could be used individually (Tissue engineered intimal layer-TEIL and tissue engineered medial layer-TEML) or in concert as a full blood vessel (tissue engineered blood vessel-TEBV). These vessel models/constructs were subjected to shear stress and used to evaluate the effect atorvastatin has on the homing of endothelial progenitor cells, the production of SDF-1 and expression of its receptor CXCR4. Further to this, the effect of atorvastatin on initiating cholesterol efflux was also investigated with considerations made to examine the role of HUVECs and smooth muscle cells in this process. The experiments conducted for this thesis were able to determine that atorvastatin increases the density of cells attached onto the surface of a lesioned construct. This was observed for the partial blood vessel models (TEIL and TEML) as well as the TEBV. This effect was noted for human mesenchymal stem cells (hMSCs) as well as EPCs. Observations in EPCs were consistent under both high (22.16 dyne/cm2) and low (2.2 dyne/cm2) shear stress. We were also able to determine that atorvastatin is more functional when used in conditions of oxidative stress through examination of different lesioning techniques. FeCl3 induced oxidative damage resulted in the recruitment of more cells to the surfaces of the lesioned constructs as well as higher levels of SDF-1, compared to the mechanical lesion which generated a mild surface abrasion. It was also possible to demonstrate that atorvastatin increases secretion of SDF-1 and expression of CXCR4, which are the main cytokine and receptor associated with cell homing and migration. This effect was determined to be both time and dose dependent. Through the use of different blood vessel models, it was determined that the cells in each layer have differing responses to the composite tissue model i.e., observations of cell attachment and SDF-1 production on TEBV were an amalgam of TEIL and TEML responses. Through the use of nanofiber inserts to create a novel HUVEC RAW264 co-culture system, we were able to demonstrate that atorvastatin triggers consistent cholesterol efflux from cultured foam cells compared to drug free controls, resulting in up to a 13% reduction in amounts off internalised cholesterol, a phenomenon that is affected by HUVEC integrity i.e., lesioned HUVECs promoted cholesterol efflux, especially in the presence of atorvastatin and IFN-γ. Atorvastatin was also able to restrict nitric oxide (NO) production in macrophages and may reverse the effects of the inflammatory cytokine IFN γ. The models used here proved a useful tool for investigating the effects of atorvastatin, and could prove useful in evaluating cellular responses to a wider array of pharmacologic, or other stimuli

Addressing ethnic based politics in Kenya: a socio-legal perspective

Submitted in partial fulfillment of the requirements of the Bachelor of Laws Degree at Strathmore University Law SchoolThe political pillar of Kenya’s Vision 2030 seeks to achieve the development a political system that is issue-based, people-centered, result-oriented and accountable to the public. Despite these aspirations, politics in Kenya falls short of the ideals and best practices of a democratic political system. The political arena in Kenya is characterised by ethnic based politics, that is, the formation and sustenance of ethnically motivated and ethnically based political parties and coalitions. This research assesses whether the current constitutional efforts and those of the National Cohesion and Integration Commission of Kenya (NCIC) are effective tools to mitigate ethnic-based politics in Kenya. More specifically, the study assesses the role of ethnicity in politics and the degree to which the Constitution of Kenya (2010) and the NCIC have been effective in mitigating this. Finally, the study identifies ways in which these two might be strengthened and recommends what other additional legal solutions might be adopted in order to deal with ethnic-based politics.The study was conducted through literature review on polarization of ethnicity and the formation of ethnic based political parties and coalitions, and adopted a qualitative analysis. It established that though the law may help to mitigate the ethnicity component of politics in Kenya, the long term goal of the NCIC of promoting and strengthening national social cohesion is the only truly effective remedy for the eradication of ethnic based politics in Kenya. Through a comparative analysis with other jurisdictions the study was able to identify practical measures which can be put in place to promote a national identity and decrease the saliency of ethnic identities in Kenyan politics.In order to mitigate ethnic based politics in Kenya, the study recommends the strengthening of the NCIC. It also recommends the facilitation of conditions for full social, economic and political participation of all people irrespective of their ethnic identity. Furthermore, it proposes the strengthening of checks on political parties and the promotion of policy-oriented coalitions. In the end, the study makes the conclusion that the current legal framework is still wanting and that the sustained saliency of ethnicity in politics requires further reform of existing frameworks

Beyond elections rituals - Rethinking public participation in Kenya's public finance management

Submitted in partial fulfillment of the requirements of the Bachelor of Laws Degree, Strathmore University Law SchoolPublic participation is one of the edicts of the Constitution of Kenya, 2010 which aims to promote transparency and accountability of public resources to the people of Kenya. One of the principles of public finance in Kenya is to promote transparency and accountability in the process of public finance. This paper seeks to find out ways in which different levels of government have breathed new life into this principle of good governance. Before the enactment of the Constitution of Kenya, 2010 Kenya did not have any kind of legislative statute that promoted transparency in the public finance system; it was done at the whim of the executive. Budget statements would be read at the request of the President; finance bills would be legislated in Parliament at any period during a financial year, parliament would rubber stamp budget statements without scrutiny and most importantly the people of Kenya were not involved in the process-apart from watching the Minister for Treasury annually posing with the popular briefcase engraved with the court of arms and thereafter reading the budget statement live on state television. This events allowed the researcher to explore what really is public participation. Public participation is the process by which government consults with interested or affected individuals, organizations, and other necessary stakeholders before making a decision. Other terms sometimes used are “public involvement,” “community involvement,” or “stakeholder involvement. The study has gone further to identify important principles that should be adhered to in order to build a successful model of public participation. In conclusion, the study proposes a two way communication system which allows deliberation rather than mere participation. In order to strengthen the democratic principles upon which the country is founded upon, the executive and legislature must go beyond legislative intent and allow the people’s contribution to influence public debate and policies. It cannot be that public finance matters are left to the few technocrats at the Ministry of Treasury and Parliament

A Critique of police oversight mechanisms in Kenya with regard to extrajudicial killings

Submitted in partial fulfillment of the requirements of the Bachelor of Laws Degree, Strathmore University Law SchoolIn 2016, there were 152 complaints made relating to police shootings and deaths. This is a problem insofar as there are two bodies that are tasked with police oversight in Kenya. This study was aimed at finding out why this is the case. This is because with two oversight bodies and a robust legal framework, it would be expected that the number of extrajudicial killings should have reduced. This study will also look at whether there are any weaknesses with the current oversight system in comparison with the previous system in order to establish what needs to be improved. This study has been conducted through the literature review of legislation in Kenya that provides for police oversight as well as reports which show what has been happening on the ground. It has established that there are various challenges posed to police oversight over extrajudicial killings. These are the failure of accountability, investigation and proper law enforcement; the widespread nature of extrajudicial killings and police involvement in the extrajudicial killings; inadequate mandate and resources and improper co-ordination of internal and external oversight mechanisms. This has led to the oversight mechanisms being inadequate despite the existence of an extensive legal regime. This study proposes that IAU be given a clear mandate as well as IPOA being given prosecutorial powers in order for these mechanisms to adequately discharge of their mandate and ensure that the number of extrajudicial killings in the country reduce

Developing biomimetic hydrogels of the arterial wall as a prothrombotic substrate for in vitro human thrombosis models

Current in vitro thrombosis models utilise simplistic 2D surfaces coated with purified components of the subendothelial matrix. The lack of a realistic humanised model has led to greater study of thrombus formation in in vivo tests in animals. Here we aimed to develop 3D hydrogel-based replicas of the medial and adventitial layers of the human artery to produce a surface that can optimally support thrombus formation under physiological flow conditions. These tissue-engineered medial- (TEML) and adventitial-layer (TEAL) hydrogels were developed by culturing human coronary artery smooth muscle cells and human aortic adventitial fibroblasts within collagen hydrogels, both individually and in co-culture. Platelet aggregation upon these hydrogels was studied using a custom-made parallel flow chamber. When cultured in the presence of ascorbic acid, the medial-layer hydrogels were able to produce sufficient neo-collagen to support effective platelet aggregation under arterial flow conditions. Both TEML and TEAL hydrogels possessed measurable tissue factor activity and could trigger coagulation of platelet-poor plasma in a factor VII-dependent manner. Biomimetic hydrogel replicas of the subendothelial layers of the human artery are effective substrates for a humanised in vitro thrombosis model that could reduce animal experimentation by replacing current in vivo models

Publicizing the african cause: evaluating global media discourses regarding the celebrity-led "make poverty history" campaign

ABSTRACT This study examined global media discourses regarding the coverage of an anti-poverty campaign for Africa by celebrities in Europe by comparing media coverage of this event in the UK, US, and African press. The Make Poverty History campaign was organized in 2005 to pressure G8 leaders meeting in Glen eagles Scotland to cancel African aid, increase aid, and make trading conditions fairer. Former rock star, and humanitarian Sir Bob Geldof, rocker Bono, and filmmaker Richard Curtis, were the central figures in organizing this campaign on the global justice movement side of things. On the political arena, former British premier, Tony Blair, also had an agenda that put Africa and climate change at the top of the G8 agenda in 2005. Given Africa's historical negative coverage in the media, this study sought to investigate how a celebrity campaign which sought to change the perception of Africa as a pitiable place in need of charity, to one of a wronged continent in need of justice, would alter, if at all, the traditional coverage of Africa. The study sought to address three questions in particular: what were global media discourses regarding the Make Poverty History campaign; how were the major players in this campaign portrayed by the press in the United Kingdom, the center of the campaign, the United States, the key player in the G8, and in Africa, the continent in which all this attention was being directed to; and lastly to establish to what degree differences existed between media coverage of this campaign, and colonial/postcolonial discourses on the continent. The findings from the Western press showed both continuities and discontinuities of colonial rhetorical modes. These discursive continuities are classification, affirmation, debasement, idealization, and negation. These discourses are not static but have variations and shifts but some clear outlines of a continuation of colonial discourses were apparent. Classification refers to arranging nations according to a single standard of political and economic development. The Western press constantly held up industrialized countries as the ideal for Africa to follow. Affirmation has to do with confirming the moral superiority of the rich nations' publics. The Western media esteem the ability of the Western public, for example, to serve as the conscience of big business to restrain them from exploiting Third World countries. The leaders of the campaign also painted outstanding leaders on a mission to save the world, while the beneficiaries of the campaign were not involved. Debasement has to do depicting the "Other" in a degrading manner. This recurred in the coverage except the trope of debasement and idealization operated together with African leaders acting as the "villains" and the ordinary people as "noble" and "unspoilt" continuing the ambivalence of colonial discourse. Negation had to do with the media being ahistorical and denying historical links between Africa's deprivation in the past and its present reality. Even the campaign itself was in denial of Africa's past by adopting its slogan as Make Poverty History. Nonetheless, accommodation is a new discourse that came out of the reading and signified diverse perspectives within Western media coverage. Some perspectives from the activist public considered left-wing have entered the mainstream, for example, acknowledgment that subsidies given to farmers in wealthy countries make African countries less competitive contributing to poverty levels. African media texts had different perspectives. These can be classified as: self-affirmation (quest for global inclusion and /raising Africa's global profile); sovereignty (quest for economic independence); and self-reliance. African publications sought to reaffirm the place of Africa within the community of nations. They also sought resist what they considered undue interference by outsiders in the inside affairs of the continent. But there was some ambivalence because they still expressed concern over being forgotten by the rest of the world. Lastly, African media texts called for Africans to fashion their own solutions to the problems they encounter instead of waiting for outside help. These discursive strategies could be seen as defensive and in direct response to Africa's portrayal in the international media. Nevertheless, the African media provided perspective and continually drew the link between Africa's current problems and its historical development and place in global relations. While the Western press focused on Africa's present dilemma, the African press provided an alternative reading of the situation by illustrating global connections in Africa's plight

Socio-Cultural and Economic Drivers for Women Participation in Leadership of Nyeri County Cooperatives, Kenya

Social-cultural and economic drivers affect women's involvement and equal participation in leadership in cooperative movements. Although many countries have been able to develop the appropriate measures, implementations are still the major throwback to the realization of these development agendas. For sustainability, an enabling environment should be created to enable all stakeholders to actively take part in cooperative movement regardless of the various challenges. The study aimed to research on how the social, economic and cultural drivers determine women’s ability to participate in the running of and day-to-day activities of the cooperative movement in Kieni East Sub County, in Nyeri County, Kenya. The study used a descriptive research design to accomplish its objectives and the target population was 205 women. The study employed purposive sampling and the target members were identified and then a selection of the members done with regard to the study objectives. The study used primary data and secondary data. The data was collected by use of both semi-structured questionnaires and interview guides. Data analysis was conducted objectively. Statistical Package for Social Sciences (SPSS) version 20.0 was utilized to analyze the collected data. Data analysis employed both quantitative and qualitative analysis; quantitative analysis used both descriptive and inferential statistics. Qualitative analysis on the other hand used content analysis. The findings were presented with the help of tables, frequencies, and percentages. Pilot test of the measures was conducted against a prospective sample population to measure validity and reliability. Test re-test method was used to measure the validity of the research instruments. The study concluded that social-cultural factors affect women in participating in leadership positions in cooperative movements. It is therefore the mandate of every individual, the government and the non-governmental organization to look on how to create awareness concerning women in leadership in order to reduce the gap that has been evident in the study. Future studies should try to comparatively compare these results to other sub-county away from Mt. Kenya, or also seek to evaluate how these factors affect women's participation in a leadership position in other sectors like the private sector of employment