Browsing by Author "Robson, Simon"

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    Coagulation disturbances and fibronectin fragmentation in preeclampsia
    (1995) De Jager, Celeste Annemarie; Kirsch, Ralph; Shephard, Enid; Robson, Simon
    Preeclampsia or gestational proteinuric hypertension (GPH) is a major cause of maternal death worldwide. Patients may present with hypertension and proteinuria alone or may develop progressively more severe disease, ending in a fulminant syndrome with disturbed coagulation, vascular injury and end-organ damage. The reasons for this progression are unclear and can only be reversed by termination of pregnancy. There are currently no early, generally acceptable, laboratory markers of disease severity. We have shown that patients with severe preeclampsia have significantly raised plasma levels of plasminogen activator-I, tissue plasminogen activator. fibronectin and fibrin(ogen) degradation product. The tissue plasminogen activator and fibrin(ogen) degradation product concentrations were found to progressively increase with progression of the syndrome. These findings support the hypothesis of the participation of disturbed coagulation and vascular injury processes in the aetiology of preeclampsia. The additional finding that the endothelium of umbilical cords from patients with preeclampsia was disrupted and characterised by increased deposits of fibronectin further supports of this proposal. Plasma fibronectin from patients with preeclampsia was found to be degraded, with fibronectin from plasma of patients with severe preeclampsia having larger amounts of low molecular weight fibronectin degradation products than the plasma from patients with mild preeclampsia. Comparison of the apparent molecular weights of these fibronectin degradation products, with those generated from pure fibronectin by plasmin, suggest that they may arise from the action of plasmin. These fibronectin degradation products were found to inhibit the opsonic activity of intact fibronectin and to cause an underestimation in the determination of plasma fibronectin concentration by enzyme-linked immunosorbent assay. Furthermore, plasma fibronectin degradation products and fibronectin degradation products, generated by plasmin cleavage of intact pure fibronectin, were able to disrupt endothelial monolayers in in vitro culture. This was not due to cytotoxic activity, but rather due to the generation of urokinase plasminogen activator from the endothelial cells, and subsequent urokinase plasminogen activator conversion of plasminogen to plasmin. The ability of a 29 kilodalton heparin-binding fragment to cause this disruption suggests that heparin-binding fragments may, in part, be responsible for the observed effect on endothelial cells in culture. It is tenable from the results of this study that fibronectin degradation products, generated as a result of initial endothelial damage, perpetuates further damage to the endothelium. Escape of these products into the maternal circulation may be postulated to give rise to maternal endothelial cell damage and the generalised organ failure observed in preeclampsia.
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    Epidemiology, molecular characterisation and tropism of the Hepatitis G Virus / GBV-C
    (1999) Tucker, Timothy Johan Paul; Kirsch, Ralph; Robson, Simon
    The hepatitis G virus and GBV-C are recently discovered variants of the same virus belonging to the family Flavivirus (HGV/GBV-C). Although initially thought to be a hepatitis virus, it has been shown to have no association with liver disease. No work has been performed on the prevalence or molecular characteristics of HGV/GBV-C in southern Africa. In addition, although it is clear that the liver is not the primary site of replication, there is no data on the sites of HGV/GBV-C replication in normal subjects. Thus, this study aimed to assess the prevalence of HGV/GBV-C carriage in the urban and rural adult Black communities of the Western and Eastern Cape Provinces of South Africa, and compare it to the prevalence of serological markers of the hepatitis viruses A-E. In addition, this study aimed to assess the molecular features of South African HGV/GBV-C isolates and demonstrate the organs where viral replication was present. The mean prevalences of antibodies to hepatitis A lgG, hepatitis B surface antigen and antibodies to hepatitis B surface antigen were 98%, 4.3% and 61.1 % respectively. The mean prevalence of antibodies to hepatitis C was 1.8%. No significant differences in prevalence were shown between the urban and rural regions for these viruses. The mean anti-hepatitis E prevalence varied from 5.8% to 19.1 % in the different regions. Those living in mud houses without access to chlorinated tap water had a significantly higher prevalence of antihepatitis E. No anti-hepatitis D positive samples were isolated. The overall prevalence of HGV/GBV-C was 26.9%, with rural communities having a significantly lower prevalence than urban communities. A significant relationship was observed between HGV/GBV-C infection with the use of illicit drugs, female gender, younger age and past blood transfusions. Phylogenetic analysis demonstrated a novel fourth South African HGV/GBV-C genotype, distinct from the previously described genotypes 1-3. In addition, certain isolates showed a major deletion in the highly conserved 5' non-coding region of HGV/GBV-C. Analysis of 23 tissue biopsies from infected cadavers suggested that the spleen and bone marrow were the primary sites of HGV/GBVC replication.
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    Purinergic angiogenesis : an investigation of the role of extracellular nucleotide mediated signaling in angiogenesis
    (2006) Jackson, Shaun William; Robson, Simon; Kirsch, Ralph
    Angiogenesis refers to the growth and maturation of new vessels from pre-existing differentiated blood vessels. Co-ordination of angiogenic responses is crucial for a wide range of physiological and pathological processes. In particular, angiogenesis is hypothesized to facilitate tumour growth and promote metastasis, prompting research into anti-angiogenesis based cancer therapies. CD39/NTPDasel is an ectoenzyme expressed by vascular endothelium that hydrolyses extracellular nucleoside di- and triphosphates to the monophosphate derivatives. As such, this enzyme has a role in modulating endothelial responses to mucleotides that bind specific receptors termed Purinergic-type 2(P2) receptors. Since a number proliferation and migration in vitro, we propose that nucleotide signalling influences the process of angiogenesis in vivo.