Genetic variant detection in a South African haemophilia B population.

BACKGROUND: Haemophilia B is characterised by a deficiency of factor IX (FIX) protein due to genetic variants in the FIX gene (F9). Genetic testing may have a vital role in effectively managing haemophilia B. However, in many developing countries, comprehensive genetic variant detection is unavailable. This study aimed to address the lack of genetic data in our country by conducting genetic variant detection on people affected by haemophilia B in our region. METHODS: Twenty-one participants were screened with a direct Sanger sequencing method to identify variants in the F9 gene. The identified variants were then compared to previously published variants and/or to a reference database. RESULTS AND DISCUSSION: A total of ten F9 genetic changes were detected, with five of them being novel. These identified variants were distributed across different domains of the FIX protein. Only one participant had a history of inhibitor formation against FIX replacement therapy. Notably, this participant had two distinct genetic changes present adjacent to each other. Thus, we hypothesise that the presence of multiple variants within the same functional region of the gene may increase the risk for inhibitor development. CONCLUSION: The discovery of novel pathogenic variations in the F9 gene highlights the importance of genetic analysis in specific geographical regions. The possible link between a complex variant and inhibitor formation illustrates the potential role that genetic screening has as a pre-treatment tool in predicting treatment reactions and outcomes.

Post-mortem evidence of a diverse distribution pattern of atherosclerosis in the South African population.

Cardiovascular diseases (CVDs) are the number one cause of mortality worldwide. The disease profile of CVD varies considerably between different demographic groups and socioeconomic status. Atherosclerosis remains a major risk factor for CVD, and thus, believed to be a good indicator of the CVD profile in a population, yet little is known on its prevalence in sub-Saharan African populations. We aimed to determine the prevalence of atherosclerosis in a diverse South African population as found with post-mortem investigations. A retrospective file-audit was done on 10,240 forensic post-mortem reports done at a forensic pathology mortuary in South Africa, over 10-years. European descent males had the highest prevalence, with roughly one-quarter having coronary artery (CA) or large vessel (LV) atherosclerosis. European descent females followed closely, with one-fifth of the population having CA atherosclerosis and approximately a quarter having LV atherosclerosis. African descent males and females had a substantially lower prevalence in atherosclerosis for both CAs and LVs than European descendants. The mixed-ancestry population had a slightly higher prevalence of atherosclerosis in CAs and LVs than in the African population; however, it was still far lower than the European group. Some deviations in prevalence were noted within certain groups over the course of 10-years. The substantial difference in prevalence of atherosclerosis shows that in our region a diverse distribution pattern between ethnic groups and genders is present. However, follow-up studies are required to elucidate aetiological factors in cardiovascular health in our region.

Polyunsaturated fatty acids cause apoptosis in C. albicans and C. dubliniensis biofilms.

BACKGROUND: Polyunsaturated fatty acids (PUFAs) have antifungal properties, but the mode by which they induce their action is not always clear. The aim of the study was to investigate apoptosis as a mode of action of antifungal PUFAs (stearidonic acid, eicosapentaenoic acid and docosapentaenoic acid) which are inhibitory towards biofilm formation of C. albicans and C. dubliniensis. METHODS: Candida biofilms were grown in the absence or presence of 1mM PUFAs (linoleic acid, stearidonic acid, eicosapentaenoic acid, docosapentaenoic acid) for 48h at 37°C. The effect of these PUFAs on the membrane fatty acid profile and unsaturation index, oxidative stress, mitochondrial transmembrane potential and apoptosis was evaluated. RESULTS: When biofilms of C. albicans and C. dubliniensis were exposed to certain PUFAs there was an increase in unsaturation index of the cellular membranes and accumulation of intracellular reactive oxygen species (ROS). This resulted in apoptosis, evidenced by reduced mitochondrial membrane potential and nuclear condensation and fragmentation. The most effective PUFA was stearidonic acid. CONCLUSIONS: The resultant cell death of both C. albicans and C. dubliniensis is due to apoptosis. GENERAL SIGNIFICANCE: Due to the increase in drug resistance, alternative antifungal drugs are needed. A group of natural antifungal compounds is PUFAs. However, understanding their mechanisms of action is important for further use and development of these compounds as antifungal drugs. This paper provides insight into a possible mode of action of antifungal PUFAs.

Tirofiban versus abciximab: tirofiban is administered at suboptimal dosages when evaluated in an arterial thrombosis model in non-human primates.

To prevent thrombosis in high-risk acute coronary syndrome patients undergoing percutaneous coronary intervention for re-vascularisation, concomitant administration of a glycoprotein IIb/IIIa inhibitor, such as abciximab, tirofiban or eptifibatide, is recommended. Abciximab and eptifibatide are mostly preferred over tirofiban, which is less effective in preventing ischaemic events. We compared the efficacy and bleeding potential of escalating doses of tirofiban and abciximab in non-human primates. The efficacy of tirofiban and abciximab in inhibiting cyclic flow reductions (CFRs) was tested in a high shear arterial thrombosis model. Bleeding was evaluated with the template bleeding time and an incision bleeding model. Abciximab completely inhibited arterial thrombosis after injection of its therapeutic bolus dose. With tirofiban, a dose three times higher than the recommended therapeutic dose caused weak inhibition characterised by a return of CFRs after re-injury. At nine times the recommended therapeutic dose, complete inhibition was observed, and the efficacy of tirofiban was comparable to abciximab at its therapeutic bolus dose. Blood loss was less than with abciximab at its effective dose. In this model, tirofiban compared favourably with abciximab, although only at a dose of 3-9 times the therapeutic dose, and caused less bleeding than abciximab.