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The plasminogen activator synthesized by human mesangial cells was identified as tissue-type plasminogen activator (t-PA). Glomerular epithelial cells synthesized t-PA and urokinase (u-PA). Both mesangial cells and glomerular epithelial cells synthesized plasminogen activator inhibitor-1 (PAI-1) into culture supernatant. In this study experimental techniques were developed to allow quantification of matrix-associated PAI-1. PAI-1 associated with the matrix of mesangial cells was less than 1% of the total PAI-1 synthesized by the cells. Similar amounts were detected in the matrix of human umbilical vein endothelial cells and Hep G2 cells. When cultured in the presence of transforming growth factor- (TGF-), PAI-1 synthesized by mesangial cells was significantly increased and this up-regulation was shown to occur at the mRNA level. PAI-1 associated with the matrix of mesangial cells also significantly increased, though matrix-associated PAI-1 still constituted less than 1% of the total PAI-1 synthesized by the cells. TGF- stimulated the synthesis of PAI-1 by whole glomeruli, epithelial cells and epithelial-mesangial cell co-cultures, while decreasing their overall plasminogen activator synthesis. When cultured in the presence of platelet-derived growth factor-BB (PDGF-BB) there was no effect on either PA or PAI-1 synthesized by the glomerular cells examined. TGF- has been implicated in the development of glomerulonephritis via an effect on matrix production. Our results suggest tht TGF- also plays a role in the proteolytic balance within the glomerulus, leading to an environment favouring its deposition.

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M.A. / In this study an attempt is made to understand the phenomenological experience of women in spontaneous premature menopause. There is very little literature available about spontaneous premature menopause and even less about the experiences of women in spontaneous premature menopause. Spontaneous premature menopause is viewed as a negative experience in the woman’s life and medical staff recommend that she should receive treatment for spontaneous premature menopause. In this study the woman, herself, was asked how she feels about spontaneous premature menopause and how it affects her life. Phenomenological research procedures are used in this study. Interviews were conducted with three participants. They were asked to tell the researcher about their experience of spontaneous premature menopause and how it affected their lives. Hermeneutic phenomenology is used to analyse the participants’ experience of spontaneous premature menopause. Themes and categories that stood out during analyses are discussed and interpreted. Results of the study show that spontaneous premature menopause can cause bodily changes in women; it can lead to several different menopausal symptoms and it can have a negative effect on her relationship with her family, friends and other people. Bodily changes that can occur, because of spontaneous premature menopause include weight gain, changes in the breasts, changes to the vagina, skin changes, bladder changes, itchy skin, heart palpitations and changes to the pelvic floor. Symptoms that can occur during spontaneous premature menopause include hot flushes, night sweats, headaches, sleep difficulties, tiredness, depression, forgetfulness, mixed emotions and pain in different areas of the body. Participants felt that their bodies, their doctors and their family and friends failed them. They had no one to turn to, because significant people in their lives did not believe that they are in spontaneous premature menopause. They were told that it must be something else like depression. The participants had shock reactions due to feelings of loss. They no longer had the body of a young woman. They had lost their youthful appearance, their sexuality, their abilty to bear children and to function satisfactorily in their daily duties. These women had to come to grips with the fact that their youthful days were over and that they were aging before their time. It is suggested that cross-cultural research be done in the future to establish how women in other cultures experience spontaneous premature menopause. Comparisions can be made and if there are any differences efforts can be made to establish what causes these differences. Cultures where spontaneous premature menopause is viewed as a positive event in a woman’s life can be researched to establish how this experience can be turned into a positive experience in cultures where it is viewed negatively.

Hypertension and heart failure are intimately related with the incidence of heart failure among hypertensive subjects between 1% and 2% per year. Structural and functional myocardial abnormalities identified in hypertensive patients contribute to the progression of myocardial dysfunction. Systolic abnormalities in hypertension begin to develop in the early stages of the disease despite normal left ventricular (LV) ejection fraction (EF) and contribute to the progressive deterioration of LV systolic performance. However, these systolic abnormalities are initially not detectable by conventional echocardiographic methods. Speckle tracking echocardiography (STE) is a sensitive quantitative technique for assessing LV function. LV twist is an important contributing factor to the systolic function of the LV in health and disease and may be a better index of systolic function than ejection fraction (EF) in hypertensive patients (HTP). The remodelling process of the left ventricle in hypertension entails a complex interplay between myocyte hypertrophy and dysfunction, with qualitative changes in the extracellular matrix contributing to progressive dysfunction. Adverse LV remodeling in HTP is associated with an imbalance in collagen degradation and may contribute to the remodelling phenotype and systolic dysfunction in hypertension. Increased matrix metalloproteinase-1 (MMP1) levels contribute to development of LV dilatation and failure with higher levels of MMP1 in the myocardium of hypertensive patients with low EF than those with normal EF. Hypertension can cause systolic dysfunction as a consequence of adverse remodelling and LV hypertrophy, but given the multitude of factors involved in LV decompensation mediated by mechanical, neurohormonal and cytokine routes, the exact mechanisms that contribute to the adverse remodelling and EF deterioration are not fully elucidated. LV twist may be a contributing factor to systolic dysfunction independent of other factors, thus, a focus on abnormalities in the cardiac mechanics of twist in the left ventricle may be helpful in understanding the pathogenesis behind the transition from compensated to decompensated heart failure. Furthermore, the changes in the extracellular matrix may account for the varying morphology, EF and LV twist in HTP. The purpose of this thesis was to 1) determine LV twist in healthy adults of different age groups (n=127), 2) evaluate LV twist changes in African HTP with low (EF<50%) and preserved EF (EF ≥ 50%) (n=82) and 3) examine the relationship between LV twist and biomarkers of collagen degradation in HTP with preserved and low EF. Parasternal short-axis images of three consecutive end-expiratory cardiac cycles at LV basal and apical levels were obtained. Apical rotation (AR) and basal rotation (BR) during ejection and instantaneous LV peak systolic twist (net twist, defined as maximal value of instantaneous AR minus BR) were measured. 127 normal subjects were divided into four age groups: 20-29 (n=34); 30-39 (n=33); 40-49 (n=29); and 50-65 (n=31) years. LV twist and markers of collagen turnover (serum concentrations of matrix metalloproteinase -1 (MMP1), tissue inhibitor of MMP1 (TIMP1) and ratio of MMP1:TIMP1) were measured in 82 hypertensive patients, 41 with EF < 50% (HTLEF) and 41 with EF ≥ 50% (HTNEF). Rigid body rotation (RBR) was defined as AR and BR occurring in the same direction. Serum biomarkers were log transformed before analysis. LV twist increased with age in normal subjects. Multivariate linear regression analysis showed age as the main predictor of net LV twist (R2=0.82, P<0.0001) in normal subjects. Net LV twist was lower in HTLEF compared with HTNEF (3.34 + 1.10 vs. 11.70 + 0.67, p < 0.0001). Of 41 HTLEF patients, 28 (68%) had normal twist pattern while 13 (32%) exhibited RBR. The subgroup with RBR showed greater LV dysfunction (EF: 27.9±5.8% vs. 35±7.5%; p=0.005) and more spherical LV geometry (p=0.0009) compared with those who had normal pattern of twist. Log TIMP1, Log MMP1 and Log MMP1:TIMP1 ratio levels were higher in HTLEF compared with HTNEF (12.32 ± 0.25 vs. 11.81 ± 0.13, p<0.0001; 9.08 ± 0.32 vs. 8.00 ± 0.18, p<0.0001; -3.25 ± 0.30 vs. -3.81 ± 0.18, p<0.0001; respectively). There was an inverse correlation between Log MMP1:TIMP1 and net LV twist after adjusting for EF (r = -0.41, p <0.0001). This study established normative data and patterns for myocardial deformation (strain and LV twist) in a normal black-African adult population across different age groups and can be used as a baseline for future studies. Age was the major determinant of increased LV twist in a normal black population. LV twist may be a compensatory mechanism to preserve EF and maintain normal systolic function with advancing age and in hypertension. LV twist varies with the degree of remodeling and systolic function in hypertension. RBR represents a novel assessment of more severe LV remodeling and LV systolic dysfunction in hypertensive patients. Alterations in collagen turnover not only accompanies more adverse remodelling but also contributes to LV twist differences observed between HTLEF and HTNEF patients. The inverse relation between LV twist and loss of myocardial collagen scaffolding suggests that integrity of the extracellular matrix may play an important role in preservation of LV twist. These findings highlight the value of LV twist as a sensitive global parameter of LV systolic myocardial performance. Longitudinal studies assessing LV twist may provide significant value in clinical practice as an early marker for risk stratification in hypertensive patients who may benefit from aggressive medical therapy to prevent LV remodelling and heart failure.

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, in partial fulfilment of the requirements for the degree of Master of Medicine in the branch of Internal Medicine.Johannesburg, 2013 / Chronic Kidney disease (CKD) is emerging as a global threat to health. In sub-Saharan Africa, most patients do not receive renal replacement therapy due to lack of funds. Measures to retard the progression of CKD are important. METHOD: A retrospective review of 122 patients attending a renal clinic, over a two a year period was performed. Patients with CKD from hypertension, diabetes mellitus, tubulo-interstitial disease were inluded. Patients with CKD due to viruses, malignancies and autoimmune RESULTS: Diabetes mellitus and hypertensiion were the leading causes of CKD. BP control improved, though 765 were on ≥3 anti-hypertensives. Serum creatinine doubled in 8.2% of patients. BP, acidosis and anaemia were independent risk factors for progression of CKD. The two year renal survival rate was 82%. CONCLUSION: Renal function progressed in few patients, which would be related to low levels of proteinuria, good BP control and us of RAS blockers

From various surveys, steel bolted end plate connections are used widely in construction projects throughout the UK. The most popular connections are flush end plated ones with extended end plated ones just behind in popularity. These connections are chosen over other connections types mainly due to their ease of construction and fabrication. The main objectives of this project was to develop a design philosophy to predict column web failure moments based on a series of full scale tests (flush and extend end plates) carried out at the University of Abertay Dundee. Buckling of the column web was observed in a large number of the bolted beam-to-column connections tested. Three dimensional finite element prediction models were developed using the software package ABAQUS, these consisted of 3 flush end plates and 4 extended endplates connections. Investigation of Eurocode 3-Annex J was also undertaken with emphasis on the 7 connections that failed by column web buckling. Comparison between the three different prediction methods were investigated, this involved comparing physical test, Eurocode 3 and finite element results (ABAQUS).

Increases in internal dimensions of the chambers of the heart (cardiac dilatation), mediated by right shifts in cardiac chamber diastolic pressure-volume (P-V) relations, predict mortality in patients with established heart failure. However, the mechanisms responsible for the transition from concentric cardiac hypertrophy to cardiac dilatation are unclear. Recent evidence suggests that decreases in the cross-linked properties of myocardial collagen may increase the propensity of collagen to cleavage and hence reduce cardiac myocyte tethering, thus promoting cardiac dilatation. However, decreases in myocardial collagen cross-linking may also reduce myocardial stiffness, thus explaining right shifts in cardiac diastolic P-V relations. In the present dissertation I evaluated whether right shifts in diastolic P-V relations produced by chronic β-adrenoreceptor activation (isoproterenol, a β-adrenoreceptor agonist, 0.02 mg.kg-1.day) in spontaneously hypertensive rats (SHR) with compensated cardiac hypertrophy (12 months of age), can be explained by adverse chamber remodelling or alterations in the myocardial material properties of the heart. After 7 months of daily isoproterenol administration, SHR had marked right shifts in left ventricular (LV) diastolic P-V relations as determined in isolated, perfused hearts, with increases in the volume intercept of these relations, a change that translated into increases in LV cavity diameters (echocardiography). LV dilatation was associated with reductions in LV pump function (decreases in LV endocardial fractional shortening and the slope of the LV systolic P-V relation [LV E]). The reductions in pump function were attributed to the LV dilatation rather than to alterations in intrinsic myocardial contractile properties as LV midwall fractional shortening and myocardial systolic elastance (LV En) were unchanged. Although SHR not receiving isoproterenol had increases in the LV diastolic wall thickness-to-radius ratio, a change commensurate with compensatory concentric LV hypertrophy, LV wall thickness-to-radius ratio in SHR exposed to chronic β-adrenoreceptor activation was reduced to values similar to those noted in normotensive Wistar Kyoto (WKY) control rats, despite further increases in LV weight. SHR not receiving isoproterenol had a marked increase in myocardial stiffness (slope of the linearized LV diastolic stress-strain relationship) as compared to WKY rats, a change that was associated with an increased myocardial collagen of the cross-linked phenotype. Although SHR receiving daily isoproterenol had further increases in myocardial collagen, this did not translate into changes in LV diastolic myocardial stiffness, as the further increase in myocardial collagen was of the non cross-linked phenotype. However, through a susceptibility to digestion, this collagen phenotype could have contributed to LV dilatation. In conclusion, these data suggest that LV dilatation in SHR following chronic β-adrenoreceptor activation is attributed to adverse chamber remodelling rather than to alterations in myocardial material properties as indexed by diastolic stress-strain relations.

Le sepsis, caractérisé par une réponse systémique inadaptée, demeure une des principales causes de mortalité. Les principaux mécanismes des défaillances d’organes induites par le sepsis sont d’étiologie vasculaire et/ou inflammatoire. Notre hypothèse est que la dysfonction vasculaire entraîne une baisse exagérée de la perfusion et de l’oxygénation des organes et ainsi une détérioration de leur fonction, l’ensemble pouvant mener au décès.Dans ce contexte physiopathologique complexe, l’objectif était d’étudier 2 pistes thérapeutiques nouvelles qui modulent, l’une la réponse inflammatoire des organes par l’érythropoïétine (EPO) et l’autre l’un des principaux effecteurs de la dysfonction vasculaire, l’adrénomédulline (ADM). Nos résultats montrent que, lors du sepsis :- l'EPO prévient la réponse inflammatoire et le stress oxydant dans les organes etdans le plasma et a un effet positif sur la mortalité précoce. Cependant, les doses pour obtenir ces effets cytoprotecteurs sont élevées.- l’Adrezicumab (ADZ), anticorps inhibant partiellement l’ADM, restaure une pression artérielle et un débit cardiaque corrects précocement. Si l’ADZ prévient les dysfonctionsvasculaire, métabolique et cardiaque au cours du sepsis et/ou diminue la nécessité de recours aux vasopresseurs, cela ouvrirait des perspectives thérapeutiques majeures.En conclusion, les pistes thérapeutiques testées sont d’intérêt. Pour établir le potentiel chez l’Homme, l’utilisation de dérivés non-hémapoïétiques de l’EPO serait engageante et demande d’autres investigations. L’approche immunologique, telle celle ciblant l’ADM est prometteuse, les effets à long terme sont encore à établir. , / Sepsis, characterized by inadequate systemic response with organ failure, remains amajor cause of death worldwide. The main mechanisms of sepsis-induced organ dysfunctionare from vascular and inflammatory etiologies. Our hypothesis was that vascular dysfunctioninduced a major drop in perfusion and oxygenation of organs and in turn a deterioration offunction, all of which lead to death.In this multifactorial pathophysiological background, our objective was to investigate2 novel therapeutic approaches able to modulate, one the inflammatory response of failingorgans through the use of erythropoietin (EPO) and the other one the key effector ofvascular dysfunction in sepsis, adrenomedullin (ADM).Our results show that during sepsis:- EPO prevents, inflammatory response and oxidative stress in organs and in theplasma and in turn death. The doses for these cytoprotective effects are high.- the Adrezicumab (ADZ) through the partial inhibition of the ADM and themodulation of vasodilation, rapidly improved, during sepsis, blood pressure and cardiacoutput and could thus prevent the onset of organ dysfunction related to sepsis. IfAdrecizumab prevents vascular, metabolic and cardiac dysfunction during sepsis and/orreduces the need for use of vasopressors, it would open major therapeutic perspectives.In conclusion, all together we provide new evidence that on one hand the use of nonhematopoieticderivatives of EPO could be promising but request further investigations andon the other, the immunologic approach such as targetting ADM could be of high interest inthe treatment of sepsis.

This dissertation investigates three issues on business failure causality and prediction. First, a nonlinear model for mathematical programming based discriminant analysis is studied. This study proposes a nonlinear model that builds on the existing linear and quadratic models and allows for a more flexible degree of nonlinearity through a set of power parameters. The proposed nonlinear model is solved using a genetic algorithm and is tested against linear and quadratic models using real financial data. The results show that each model is better in certain cases, but the nonlinear model turns out to be the best overall among the three. Better performance of this nonlinear model appears likely, but a more robust solver would be required. Second, the relationship between aggregate business failures and macroeconomic conditions is studied from a causality perspective. A structural Vector Autoregression (VAR) is used while incorporating the recently developed causal inference method Directed Acyclic Graph (DAG). Particularly, DAG is used to provide a contemporaneous causal structure and the VAR results are summarized using innovation accounting techniques. The results show that during the period from 1980 to 2004 in the U.S., aggregate business failures were influenced by interest rates, but overall these failures appear to be far more exogenous than was found previously. Third, the effect of incorporating macroeconomic variables into business failure prediction models is investigated with a focus on the U.S. airline industry from 1995 to 2005. The attention is placed on prediction accuracy, parameter stability, and the effect of particular macroeconomic variables. The results show that the stability of parameters in the prediction model is improved when macro variables are added. In terms of prediction accuracy, the model augmented with a macro variable performed better in a jackknife prediction, but not in out-of-sample predictions. The macroeconomic variable found to be significant is the change of interest rate, which is probably related to the high level of leverage common in this particular industry. Also, the results demonstrate that a probability score can be used as a more informative evaluation measure than the current one based on cutoff probabilities.