The thesis is a philosophical analysis of the consumption based capital asset pricing model (CCAPM), investigating in particular its epistemological and methodological foundations. Financial markets are integral parts of advanced and developing economies. They matter because they channel unspent household income into banks’ savings accounts and assets such as bonds and stocks. Financial economists have traditionally taken interest in the pricing mechanism that underlies this capital allocation. The consumption based capital asset pricing model (CCAPM) is a prominent effort to describe, explain and predict such prices. It tells a story of investors’ trade-off between consumption now and later and which portfolio of assets to hold. The CCAPM based narrative intuitively makes sense, and the chosen methodology involving theoretical assumption, mathematical models and empirical tests follows the professions’ standards of good scientific practise. But does CCAPM’s research programme provide knowledge for use? My thesis seeks to answer this question in a novel way. Instead of embarking on yet another asset pricing research project, I let Philosophy of Science inform my analysis. Following a “primer” introducing essential CCAPM topics and notations, I discuss, in turn, its theoretical foundation, mathematical model, and empirical test results from a philosophy of science perspective. I find that a few fundamental principles and several auxiliary assumptions combine to develop a simplified, partial and idealized theory of investors, financial markets and assets. The model reflects and represents this theory but also makes narrow claims that are distances away from the real situations they target. Unsurprisingly, ideal model assertions fail standard statistical tests of significance. I conclude that mathematical deductive modelling rooted in orthodox, a priori based fundamental principles create ideal and fictional settings that limit their scope and portability. The development of even more granular models within this orthodox paradigm that searches for “event regularities” will not render the desired knowledge for use. The real situations are possibly too complex to be captured in simplified assumptions, ideal theories and mathematical structures. Novel methodological and ontological approaches to asset pricing are in demand. Hence, claims about tendencies in the real data might replace the current focus on point-forecasts.

The purpose of this thesis is to provide a robust epistemological justification for Evidence Based Medicine (EMB), and thereby to demonstrate the epistemological short comings of Complementary and Alternative Medicine (CAM). CAM has received support from both philosophers, such as Rorty and Feyerband, and the Sociology and Anthropology of Medicine. The thesis will thus review both the internal coherence and the application of non-realist arguments, and counter non-realism with the realist epistemology and philosophy of science that is represented by C.S. Peirce’s pragmatism. Rorty and Feyerabend and others have developed radical forms of scientific antirealism in the latter 20th century. Subsequently, sociologists developed even more intractable forms of anti-realism, which they applied to the social study of science. This approach served to challenge the legitimacy of orthodox scientific practice (including EMB). A practical expression of this controversy was immediately identified in the question of the role of scientific authority in a democratic society. That question was immediately applied to the status of alternative medical systems and their legitimacy vis-a-vis EBM in terms of the controversy over what has come to be termed "medical pluralism": If scientific medicine has no particular authority, should other, medical systems, epistemically incompatible with EBM, be made available as well? The thesis will suggest that non-realism is in fact a marginal position within the philosophy of science. Scientists, medical researchers and medical practitioners may thus appeal to the philosophy of science in order to justify their authority in the face of challenges from CAM. However, it will be suggested that they are frequently ill-served by a reliance on a simplistic understanding of the philosophy of Karl Popper. An alternative will be proposed in the philosophy of C. S. Peirce. His pragmatism offers to medical research and medical practice a way of understanding and justifying the scientific process, a justification of realism in the face of non-realism, and a resource for the criticism of CAM and medical pluralism, as at once epistemologically ill grounded and potentially dangerous to patients and the general public.

Endothelin-1 (ET-1) binds to endothelin A (ETA) and B (ETB) receptors on vascular smooth muscle cells, resulting in profound vasoconstriction and cellular proliferation. In contrast, activation of endothelial cell (EC) ETB receptors releases nitric oxide (NO) and prostacyclin (PGI2), which are anti-mitotic and mediate vasodilatation. ETB receptors are also responsible for the clearance of ET-1 from the circulation and renal ETB receptors contribute to sodium and water balance. Pharmacological blockade and genetic models featuring total ETB ablation, demonstrate salt sensitive hypertension. However, these do not allow the role of the EC ETB in cardiovascular homeostasis to be determined. Mice featuring loxP sites flanking exons 3 and 4 of the ETB gene (floxed ETB mice: FF/--) were crossed with Tie2-Cre mice (WW/Tie2-Cre), in which the expression of a Cre recombinase cDNA transgene is limited to EC, to generate EC-specific ETB down-regulated mice (FF/Tie2-Cre). Having demonstrated EC-specific down-regulation of ETB receptors using autoradiography, the role and relative contribution of the EC ETB to the regulation of systemic BP, to the clearance of ET-1 from the plasma, as well as to the development of pulmonary arterial hypertension were investigated. Autoradiography revealed significant down-regulation of ETB in EC-rich tissues such as lung of FF/Tie2-Cre animals (8 ± 3 amol.mm-2) compared to controls (80 ± 21 amol.mm-2) (n=4; p<0.05). Levels of ETA expression were preserved despite higher concentrations of plasma ET-1 in the FF/Tie2-Cre samples (12.4 ± 3.0 pg.ml-1) compared to controls (3.0 ± 0.8 pg.ml-1) (n=6; p<0.001). Using radiotelemetry, mean arterial blood pressure of FF/Tie2 mice was not significantly different to that of FF/- controls on low salt (FF/Tie2-Cre: 122.7 ± 1.52 mmHg, n=10; FF/--: 125.7 ± 0.58 mmHg, n=12), normal salt (FF/Tie2-Cre: 133.8 ± 4.0 mmHg, n=10; FF/--: 131.5 ± 3.33 mmHg, n=12) or high salt diet (FF/Tie2-Cre: 149.2 ± 2.71 mmHg, n=10; FF/--: 143.9 ± 2.97 mmHg, n=12). Similarly no differences in SBP, DBP or HR were seen between genotypes. The clearance of an intravenous bolus of radiolabelled ET-1 was significantly impaired in FF/Tie2-Cre mice (0.054 ± 0.006 ml.sec-1) compared to control mice (0.175 ± 0.032 ml.sec-1) (n=5; p<0.01). ETB blockade of control mice reduced ET-1 clearance to that of untreated FF/Tie2-Cre animals (n=4). Two weeks of hypobaric hypoxia induced an exaggerated increase in systolic right ventricular pressure in FF/Tie2-Cre mice (34.4 ± 1.2 mmHg, n=10) compared with FF/-- mice (24.6 ± 1.4mmHg, n=10; p<0.05), associated with an increased right ventricular/ left ventricular + septum ratio in FF/Tie2-Cre mice (normoxia: 0.224 ± 0.009; hypoxia: 0.285 ± 0.017; p<0.01), but not in FF/-- mice. Hypoxia increased the percentage of remodeled vessels in FF/-- mice (normoxia: 5.6 ± 0.6%; hypoxia: 11.4 ± 0.6%; n=6; p<0.001), and this was augmented in FF/Tie2-Cre mice (normoxia: 7.1 ± 0.5%; hypoxia: 18.5 ± 1.2%; n=6; p<0.001). The EC ETB receptor does not play a significant role in the BP response to salt, suggesting that ETB signalling on other cell types is responsible for ETB mediated natriuresis. However, the EC ETB receptor is crucial to the elimination of ET-1 from the circulation and is protective against the development of pulmonary arterial hypertension, most likely by preventing remodeling of small pulmonary arteries.

Thesis (DMed)--Stellenbosch University, 2011. / ENGLISH ABSTRACT: Background and Objective: The most common cause of severe proteinuria/nephrotic syndrome (NS) in children worldwide is minimal change disease (MCD). This is also the pattern observed in white and Indian children in South Africa (SA). By contrast, black and mixed race/coloured children of Southern Africa in the 1960s to 1990s were shown to have a different pattern of NS. One of the main differences was the frequency of hepatitis B virus (HBV) associated glomerulonephritis, usually membranous glomerulonephritis (MGN). The objective of this project was a clinicopathological study of this subgroup of nephrotic children to document the disease further and in particular to seek correlations between pathological and clinical features including prognosis. A central focus was to document the detailed ultrastructural examination of the renal biopsies of these children and to correlate the spectrum of pathological features with demographic, clinical, laboratory and prognostic features. The hypothesis was that the clinicopathological features of HBV MGN in children differed substantially from idiopathic MGN in general (children and adults) and also from HBV MGN in adults and that HBV MGN in children should be viewed as a distinct disease. Patients and methods: The childhood (12 years and younger) patient cohort was 309 children with severe proteinuria/nephrotic syndrome who presented at Tygerberg Hospital (TBH) over a 21 year period from 1974-1995, including 67 children from Namibia. The study group was 71 children with HBV MGN who were followed up to 2005. The comparative adult group was 45 adults with MGN of whom 12 had HBV MGN and 33 idiopathic MGN. (A comparison could not be made with idiopathic MGN in childhood as this centre only had 2 such patients during the study period.) Demographic, clinical, laboratory and renal pathology data were collected, compared and correlated. Results: HBV associated MGN was the most frequent cause of NS in the Namibian subgroup, 25/67 (37%) and the third most frequent, 71/309 (23%) in the childhood cohort as a whole. The MGN group was 86% (71/83) of the total HBV childhood nephrotic cohort, by far the dominant subgroup. The average age of the 71 children with HBV MGN was 6.0 years (range 2-12 years) at presentation and boys comprised 80% of the group. Hepatitis B envelope antigen (HBeAg) was identified in the serum of 87% of children tested. Laboratory features different from idiopathic MGN included more prominent haematuria, mildly raised serum transaminases and more frequently lowered serum C3 and C4 levels. Light microscopic examination of renal biopsies showed mesangial proliferation in all patients but with minimal glomerular sclerosis and interstitial disease. On ultrastructural examination mesangial and subendothelial deposits were common and prominent as was mesangial interposition. The MGN of HBV in children therefore frequently showed mesangiocapillary glomerulonephritis (MCGN) features in addition to the subepithelial deposits of MGN. The subgroup of 23 whose renal biopsies displayed severe mesangial interposition in addition to the subepithelial deposits of MGN were termed the mixed HBV MGN-mesangiocapillary GN group. Virus like bodies and tubuloreticular inclusion bodies were both found in more than 80% of biopsies of childhood HBV MGN. HBeAg was identified in the subepithelial deposits in the glomeruli. This was the first time this feature was demonstrated in Africa. The 46 South African children with HBV MGN showed a cumulative remission rate of 25% at 2 years and 52% at 4 years. Seven of the children (10%) of the total cohort developed chronic renal failure (CRF). Age of 6 years and above at presentation and severe mesangial deposits on biopsy correlated with fewer remissions and poorer outcome. In 3 patients the interval between the diagnosis of HBV MGN and the onset of CRF was more than 19 years with the longest being 23 years. The 358 cases of childhood HBV MGN from Southern Africa constitute 37% of the reported childhood patients. Comparative data A comparison was made between the 71 children with HBV MGN, 12 adults with HBV MGN and 33 adults with idiopathic MGN. The main differences were that both HBV MGN groups included only coloured and black patients and were more predominantly male while the idiopathic MGN group included all races. In the HBV patients, haematuria was more frequent and severe, liver enzymes were frequently raised and C3 more frequently reduced than in the idiopathic cohort. Both groups of adult MGN patients had normal C4 levels while the childhood HBV MGN group had reduced C4 levels. The immune complex pattern in both of the HBV MGN adult and childhood groups on biopsy was similar with more mesangial and subendothelial deposits as well as mesangial interposition than the idiopathic group. Despite this similarity between the two HBV groups, both adult groups showed more glomerular sclerosis and interstitial disease than the childhood group. The clinical outcome of the children’s cohort was better than the other 2 groups with remission (52%) more frequent at 4 years (p<0.01) and better renal and patient survival. Including the 83 cases from this series, at least 1243 renal biopsy proven cases of HBV MGN have been reported in the English literature; children (80%) and adults (20%). The male gender predominance in both age groups for HBV MGN is similar (children 79%; adults 84%) and significantly greater than for idiopathic MGN. Conclusions: The findings confirm that HBV MGN in children is a distinct form of GN which broadens the classical morphologic description of MGN by often including a number of mesangiocapillary GN features. The subgroup of renal biopsies with the most severe mesangiocapillary GN features was classified as the mixed HBV MGNmesangiocapillary GN group. The MGN spectrum as a whole comprised 86% of the HBV positive childhood group. HBV MGN was the most frequent association with NS/severe proteinuria in the Namibian subgroup (37%) and the third largest group (19%) in the SA children. It showed a relatively high spontaneous remission rate but at least 10% of the children developed renal failure. Age of 6 years and above at presentation and severe mesangial deposits on biopsy correlated with fewer remissions and poorer outcome. Extended follow up (more than 15 years) was required to demonstrate renal failure in some patients in the poor outcome group. Urbanisation, associated with lower HBV carrier rates, and HBV vaccination (initiated routinely in 1995 in SA), have already lead to a sharply decreasing incidence of this disease in SA. HBV MGN has been a valuable and possibly unique model of human GN and MGN in particular in that the HBeAg has been identified in both the serum and glomeruli enabling confirmation of the aetiological role of HBeAg. het ’n kumulatiewe remissie koers van 25% teen 2 jaar en van 52% teen 4 jaar getoon. Sewe van die kinders (10%) van die hele kohort het kroniese nierversaking (KNV) ontwikkel. Ouderdom van 6 jaar en meer by presentasie en erge mesangiale neerslae in ‘n biopsie het met minder remissies en ’n swakker uitkoms gekorreleer. Drie pasiënte het meer as 19 jaar na aanvanklike voordoening ooglopende KNV ontwikkel, waarvan 23 jaar die langste interval was. Die 358 gevalle van kinderjare HBV MGN van Suidelike-Afrika maak 37% uit van die gerapporteerde kinder pasiënte. Vergelykende data ’n Vergelyking is getref tussen die 71 kinders met HBV MGN, 12 volwassenes met HBV MGN en 33 volwassenes met idiopatiese MGN. Die hoof verskille was dat beide HBV groepe net kleurling en swart pasiënte ingesluit het en meer oorwegend manlik was, terwyl die idiopatiese groep alle rasse ingesluit het. In die HBV pasiënte was hematurie meer algemeen en erg, lewer ensieme meer dikwels verhoog en C3 meer dikwels verlaag as in die idiopatiese kohort. Beide groepe van volwasse MGN pasiënte het normale C4 vlakke getoon terwyl die kindergroep met HBV MGN verlaagde C4 vlakke bewys het. Die immuunkompleks patroon in biopsies van die HBV MGN volwasse en kindergroepe was soortgelyk met meer mesangiale en subendoteliële neerslae asook meer mesangiale interposisie as in die idiopatiese groep. Ten spyte van hierdie ooreenkoms tussen die twee HBV groepe, het die twee volwasse groepe meer glomerulêre sklerose en interstisiële siekte as die kindergroep vertoon. Die kliniese uitkoms van die kinderkohort was beter as die ander twee groepe met remissie (52%) wat meer algemeen was teen 4 jaar (p< 0.01) en met beter nier- en pasïent oorlewing. Ingeslote die 83 gevalle van hierdie reeks, is ten minste 1243 nierbiopsie bewysde gevalle van HBV MGN in kinders (80%) en volwassenes (20%) in die Engelse literatuur gerapporteer. Die manlike oorheersing in beide ouderdomsgroepe van HBV MGN is soortgelyk (kinders 79%; volwassenes 84%) en betekenisvol meer as vir idiopatiese MGN. Gevolgtrekkings: Die bevindinge bevestig dat HBV MGN in kinders ’n afsonderlike vorm van GN is wat die klassieke beskrywing van MGN verbreed deur die algemene insluiting van ’n aantal mesangiokapillêre GN kenmerke. Die ondergroep van nier biopsies met erge mesangiokapillêre GN kenmerke is as die gemengde HBV MGNmesangiokapillêre GN groep geklassifiseer. Die MGN spektrum in geheel het 86% van die HBV positiewe kindergroep behels. HBV MGN was die mees algemene assosiasie met NS/erge proteïenurie in die Namibiese subgroep (37%) en die derde grootse groep (19%) onder die SA kinders. Die siekte het ’n relatiewe hoë spontane remissiekoers getoon, maar ten minste 10% van die kinders het nierversaking ontwikkel. Ouderdom van 6 jaar en meer by presentasie en erge mesangiale neerslae in ‘n nierbiopsie het met minder remissies en ’n slegter uitkoms gekorreleer. Uitgebreide opvolg (meer as 15 jaar) was nodig om nierversaking in sommige van die swak uitkomsgroep aan te toon. Verstedeliking is geassosieerd met laer HBV draersyfers en hierdie faktor saam met algemene HBV inenting in die kinderjare (wat in 1995 in SA begin was), het ’n skerp daling in die voorkoms van hierdie siekte in SA teweeg gebring. HBV MGN is ’n waardevolle en moontlik unieke model van menslike GN en MGN, veral omdat die HBeAg in beide die serum en glomeruli identifiseer kon word om die etiologiese rol van HBeAg te bevestig. / AFRIKAANSE OPSOMMING: Agtergrond en Doelwit: Die algemeenste oorsaak van erge proteïenurie/nefrotiese sindroom (NS) in kinders wêreldwyd is minimale veranderingsiekte. Hierdie patroon kom ook voor in blanke- en Indiër kinders in Suid-Afrika. In teenstelling hiermee is aangetoon dat swart en kleurling/gemengde ras kinders in Suider Afrika tussen die jare 1960s tot 1990s ’n ander patroon van nefrotiese sindroom gehad het. Een van die hoof verskille was die algemene voorkoms van hepatitis B virus (HBV) geassosieerde glomerulonefritis, gewoonlik membraneuse glomerulonefritis (MGN). Die doelwit van hierdie projek was ’n klinies-patologiese studie van hierdie subgroep van nefrotiese kinders ten einde die siekte verder te beskryf en veral om korrelasies te tref tussen patologiese en kliniese kenmerke insluitende prognose. Die gedetaileerde ultrastrukturele ondersoek van die kinders se nierbiopsies en die korrelasie van die spektrum patologiese kenmerke met demografiese, kliniese, laboratorium en prognostiese kenmerke was ‘n sentrale fokusarea. Die hipotese was dat die klinies-patologiese kenmerke van HBV MGN in kinders wesenlik van idiopatiese MGN in die algemeen verskil (in kinders en volwassenes) en ook van HBV MGN in volwassenes, en dat die beeld in kinders as ’n afsonderlike siekte beskou behoort te word. Pasiënte en metodes: Die kinder kohort (12 jaar en jonger) was 309 kinders met erge proteïenurie/nefrotiese sindroom wie in Tygerberg Hospitaal (TBH) behandel was oor ‘n 21 jarige periode vanaf 1974 tot 1995, insluitende 67 kinders van Namibië. Die studiegroep was 71 kinders met HBV MGN wie waar moontlik tot 2005 opgevolg was. Die vergelykende volwasse groep was 45 volwassenes met MGN van wie 12 HBV MGN gehad het en 33 idiopatiese MGN. (’n Vergelyking met idiopatiese MGN in kinders kon nie gedoen word nie omdat hierdie sentrum net twee sulke pasiënte tydens die studietyd behandel het.) Demografiese, kliniese, laboratorium en nierpatologie inligting is versamel, vergelyk en gekorreleer. Resultate: HBV geassosieerde MGN was die algemeenste oorsaak van NS in die Namibiese subgroep, 25/67 (37%) en die derde mees algemeen, 71/309 (23%) in die kinder kohort as geheel. Die MGN groep was 86% (71/83) van die totale HBV kinder nefrotiese kohort en verreweg die oorheersende subgroep. Die gemiddelde ouderdom van die 71 kinders met HBV MGN by presentering was 6.0 jaar (reikwydte 2-12 jaar) en seuns het 80% van die groep behels. Hepatitis B omhullingsantigeen (envelope antigen- HBeAg) is aangetoon in die serum van 87% van die kinders wie daarvoor getoets is. Laboratoriumkenmerke wat van idiopatiese MGN verskil het, het ingesluit meer prominente hematurie, gering verhoogde serum transaminases en meer dikwels verlaagde serum C3 en C4 vlakke. Ligmikroskopiese ondersoek van die nierbiopsies het mesangiale proliferasie in elke pasiënt getoon, maar met minimale glomerulêre sklerose en interstisiële siekte. Met ultrastrukturele ondersoek was mesangiale en subendoteliële neerslae asook mesangiale interposisie algemeen. Die MGN van HBV in kinders het dus dikwels kenmerke van mesangiokapillêre glomerulonefritis getoon bo en behalwe die subepiteliële neerslae van MGN. Die ondergroep van 23 van wie die nierbiopsies erge mesangiale interposisie aangetoon het asook die subepiteliale neerslae van MGN is die gemengde HBV MGN-mesangiokapillêre GN groep genoem. Virustipe liggaampies en tubuloretikulêre insluitingsliggaampies is in meer as 80% van die biopsies bevestig. HBeAg was in die subepiteliële neerslae identifiseer. Dit was die eerste keer dat hierdie kenmerk in Afrika identifiseer is. Die 46 Suid-Afrikaanse kinders

In the thesis I explain why an immanent approach in philosophy means taking contingency to be "irreducible". I show why Deleuze and Guattari believe this to be the case and why they think Hegel fails to do this. I then go on to show in what way Hegel incorporates contingency into his system and how he also creates his own sense of "necessity" that emerges from the systematic treatment of contingent concepts. In this way I show how Hegel can respond to the demand for immanence made by Deleuze and Guattari. I suggest that freedom, for Hegel, consists in the systematic treatment of contingency in our lives and in our thinking.

The principal aim of this thesis is to mobilize the conceptual apparatus of the philosophy of Martin Heidegger in order to recuperate an understanding of life as it is concretely known and experienced in the immediacy of its actual being-lived-out, or simply, to develop a distinctly Heideggerian conception of primordial phenomenal life.

I have three main aims in writing this thesis on the social thought of Henri Bergson: to establish what society is in his view, to work out the implications of this for individuality, and to demonstrate the contemporary value of his philosophy as a whole, thus construed. It will be the task of the first two chapters to establish that society is a biological and cultural reality for Bergson. This will involve the demonstration that Bergson’s understanding of living systems can be applied to groups as well as to single organisms, and that while the biological evolution of society underlies both individual actions and cultural evolution they nevertheless remain irreducible to it. In chapter three, I will consider the implications of his account of society for our understanding of the individual. These implications will be quite serious, as Bergson attributes an irreducible agency to society that immediately demands a re-assessment of the agency of the individual in terms of a participation in wider natural and cultural processes, and specifically a re-assessment of the central Bergsonian notion of individual freedom in the context of this natural and cultural evolution. In the conclusion, I will make a case that the value of Bergson’s philosophy today is that it can help us to move beyond the mechanistic paradigm that has dominated western thought since the scientific revolution by providing a powerful image of our relation to each other and to nature that is based on participation rather than control. In addition, there are two themes running through the thesis. One concerns Bergson’s critique of dogmatism both in philosophy and in the sciences, and his insistence that new ways of thinking be developed in response to new experience that cannot be integrated into existing interpretive models. In order to remain true to the spirit of his thought it has in many places been necessary to re-think his conclusions in relation to a new scientific context, rather than merely repeat what he says. The other concerns Bergson’s strong commitment to the role that philosophy can play in overcoming the natural tendency to control our environment, a tendency that he saw gaining a dangerous hold over the human spirit in the age of industrial capitalism. The essence of philosophy in this context is revealed to be a shift in attitude from control to participation.

published_or_final_version / Microbiology / Doctoral / Doctor of Philosophy

published_or_final_version / abstract / Paediatrics and Adolescent Medicine / Master / Master of Philosophy

published_or_final_version / abstract / Pathology / Doctoral / Doctor of Philosophy