No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

No description available.

Sudden unexpected death in infants (SUDI) is a devastating event, and unfortunately occurs frequently in South Africa. The emerging molecular autopsy has added value to SUDI investigations by revealing genetic variants which contributed to their demise. Motivated by the value of this concept to family members as well as the limited research of SUDI locally, the aim of this study was to explore molecular autopsies in the medico-legal investigation of SUDI cases in South Africa. A 5-year retrospective study of 1.199 SUDI admissions to Salt River Mortuary, Cape Town showed that 110 (9.%) cases were still under investigation, while most had infectious causes of death. An ethical framework was established and used to prospectively recruit 201 SUDI cases from Salt River Mortuary. A pilot quality assessment of DNA from blood, buccal cells and formalin fixed paraffin embedded tissue motivated the prospective collection of blood samples. Three variants previously associated with the risk of infections (IL-6 rs1800795.G>C; TNF-α rs1800629.G>A; TLR4 rs4986790.A>G) were genotyped in the sampled cohort. The allele frequency data generated suggested a possible association between each of these variants and an infection-related cause of death in SUDI. Targeted genotyping of candidate variants revealed several pathogenic mutations, including a twin who was homozygous T/T for a founder mutation, GALT rs111033690.C>G/T, causative of galactosaemia (previously undiagnosed). Follow up with the family revealed that the other twin had subsequently demised. Additionally, 43 genes previously associated with cardiac arrhythmias, were sequenced in a subset of cases (n.=.19) and parental samples. Putative pathogenic variants were identified in four infants, and four additional novel variants were found. Lastly, using a hypothesis-free approach, clinical exome sequencing was performed on two cases, which suggested one infant was immune-compromised and the second may have had bronchopulmonary dysplasia. The findings in this study highlight possible new candidate variants to assess in SUDI cases, and has directly contributed to the development of a molecular autopsy which is locally relevant. It is evident that until newborn screening becomes routine and accessible in South Africa, molecular autopsies should include testing for inherited metabolic disorders, as it holds potential to save lives.

Background: The heritabilities of bipolar disorder (BD) and borderline personality disorder (BPD) are 80% and 65%, respectively, indicating substantial genetic contributions to both disorders. BD and BPD are often comorbid, and both disorders have a polygenic architecture. These variants are thought to subtly affect multiple pathways, associated with structural brain abnormalities commonly observed in patients with BD and BPD. Brain regions have been shown to be highly heritable and under distinct genetic influences. However, the overlap in genetic risk between BD and BPD and altered brain regions, respectively, has not yet been determined. Aims and Objectives: The aim of this project was to determine whether genetic risk for BD and BPD overlaps with genetic risk for altered brain regions. Methods: Genome-wide association study (GWAS) summary statistics for BD (Ncases=20,352; Ncontrols= 31,358), BPD (Ncase=998; Ncontrol=1,545), eight subcortical brain volumes (nucleus accumbens, amygdala, caudate nucleus, hippocampus, pallidum, putamen and thalamus) and intracranial volume (ICV) (N=27,087), and cortical surface area and thickness (N=37,479) were obtained. Pleiotropy and concordance were assessed using SNP-Effect Concordance Analysis. Conditional false discovery rate (cFDR) was used to condition BD and BPD GWAS results on genetic variants that influence brain regions. Linkage Disequilibrium Score Regression was used to examine genome-wide correlations between BD, BPD and brain regions. Mendelian randomization was used to test for causal associations between BD, BPD and each brain region, respectively. Results: There was evidence of significant pleiotropy and positive concordance between BD and BPD (ppleiotropy=5x10-4; pconcordance=1x10-6, OR=1.29). Significant pleiotropy was observed between BD and the thickness of several cortical regions and two gyri, namely the lateral occipital (p=2.25x10-5), pars triangularis (p=1.1x10-4), rostral anterior cingulate regions (p=2.18x10-4) and post central (p=7.9x10-6) and supramarginal gyri (p=1.45x10-7). Significant positive concordance was noted between BPD and thickness of the lateral occipital region (p=3x10-4; OR=1.02). After conditioning BD onto BPD and each regional brain GWAS, 171 additional variants were significantly associated with BD (FDR<0.05). Three additional SNPs were significantly associated with BPD when conditioned on thickness of the lateral orbitofrontal, lingual, precentral and supramarginal regions. Discussion: The findings here of genetic overlap between BD, BPD and altered brain structure, while novel, are consistent with previous work. The cFDR analyses, highlight synapse and neurotransmitter regulation as a key underlying mechanism between BD and altered brain regions. Further fine-grained delineation of the role of the environment in these relationships and the inclusion of non-European populations are critical next steps, as they may provide insight into risk factors, new areas of treatment and aid in early detection of at risk individuals.

Breast cancer is the second most commonly diagnosed cancer and the leading cause of cancer deaths in women. Several factors, such as the costs of anti-cancer drugs, drug resistance and relapse, make it difficult to treat this disease effectively. In the South African context this is exacerbated by poor socio-economic conditions. Thus, there is a dire need to develop novel anti-breast cancer drugs which are safe, effective and cheap. In this regard, natural products serve as a highly exploitable medicinal resource and indeed, many successful commercially available drugs have been derived from natural products. Plants, especially those used as food or medicine, are a particularly robust source of beneficial phytochemicals. Thus, this study investigated the anti-cancer effects of extracts derived from three varieties of African millets as well as from the indigenous Kraalbos plant, Galenia africana, against the MCF-7 oestrogen receptor positive and the MDA-MB-231 triple negative breast cancer cell lines. The millet extracts tested were derived from Sorghum bicolor (Enforcer), Pennisetum glaucum (Babala) and Eragrostis tef (Tef) using both a reflux-based and a cold extraction procedure. MTT assays reveal that the millet extracts derived from the reflux-based extraction show no short-term cytotoxicity against both breast cancer cell lines tested. Extracts derived from the cold extraction were subjected to fractionation using HPTLC. Results from these extracts show that only the methanol fractions of the Babala and Enforcer millets exhibited short-term cytotoxic activity against the MCF-7 and the MDAMB- 231 breast cancer cell lines. Five Kraalbos extracts (KB1, KB2, KB3, KB4 and KB5) were tested for their short-term cytotoxicity against the MCF-7 and MDA-MB-231 breast cancer cell lines. KB2 was found to display the most potent activity and its anti-cancer activity was characterized further. Clonogenic assays revealed that KB2 also displayed long-term cytotoxicity against breast cancer cells but not normal breast epithelial cells. Scratch motility assays and western blotting with antibodies to epithelial to mesenchymal transition markers showed that KB2 inhibited the migratory ability of breast cancer cells. To understand the mechanism(s) underpinning the anti-cancer activity of KB2, ROS-GloTM H2O2 and GSH-GloTM Glutathione assays were performed and the results revealed that KB2 induced the production of reactive oxygen species. Furthermore, western blotting with antibodies to γH2AX showed that KB2 induced double strand DNA breaks in breast cancer cells. Flow cytometry and western blotting with antibodies to p53, p21, cyclin A and cyclin B1 further revealed that KB2 causes breast cancer cells to arrest in the S and G2/M phases. A sub-G1 peak, indicative of cell death, was also observed in the flow cytometry analyses. Indeed, using western blotting with antibodies to markers of apoptosis (caspases 3, 7, 8, and 9 and PARP) and necroptosis (p-MLKL and p-RIP3) KB2 was found to induce cell death via the intrinsic and extrinsic apoptotic pathways and necroptosis. Western blotting and immunocytochemistry with an antibody to LC-3 also showed that KB2 induces autophagy in the breast cancer cells but whether it functions as a pro-death or pro-survival mechanism remains to be elucidated. Taken together, this study demonstrates that extracts derived from millets and Kraalbos show anti-cancer activity against oestrogen receptor positive and triple negative breast cancer cells and that KB2 is worth progressing to pre-clinical studies.