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In vitro arachidonic acid metabolism by polymicrobial biofilms of Candida albicans and Pseudomonas aeruginosa
No full textInterkingdom interactions between microorganisms facilitate the growth and survival of microbial communities, and the understanding of these interactions can be beneficial to mankind. These interactions may also be detrimental to human health, with the combination of virulence factors promoting the survival of microbial populations during infection. A relevant model for this, is the interaction between Candida albicans and Pseudomonas aeruginosa. These two microorganisms are frequently found together at infection sites. During infection, C. albicans and P. aeruginosa elicit the release of arachidonic acid (AA), utilized by the host to form immunomodulatory compounds termed eicosanoids. Among these is prostaglandins, for example, prostaglandin E2 (PGE2). Prostaglandin E2 can inhibit Th1 and promote Th2 responses. In combination to other eicosanoids, they modulate inflammation in hosts, ultimately affecting the ability of the host to clear infection. Candida albicans and P. aeruginosa are also able to produce immunomodulatory eicosanoids from exogenous AA. This study confirms the production of PGE2 by C. albicans monomicrobial biofilms, together with the production of PGF2α and 15-hydroxyeicosatetraenoic acid (15-HETE) with the use of enzyme-linked immunosorbent assay (ELISA) and LC-MS/MS for PGE2 confirmation. The production of these eicosanoids is also reported here by P. aeruginosa monomicrobial biofilms. This study is the first to identify authentic PGE2 production by P. aeruginosa biofilms. In addition, polymicrobial biofilms were shown to produce significantly more eicosanoids that monomicrobial counterparts, possibly contributing to the increased morbidity during co-infection by these pathogens.
Although the pathways and enzymes involved in eicosanoid production by mammalian systems have been well studied, the production of eicosanoids by microorganisms requires much research. This is due to the fact that microorganisms frequently don’t possess homologs to mammalian enzymes responsible for eicosanoid production. Therefore, inhibitors previously identified to inhibit C. albicans PGE2 production, were evaluated in terms of their effect on eicosanoid production by monomicrobial and polymicrobial biofilms of C. albicans and P. aeruginosa. The inhibitors used are acetylsalicylic acid (ASA, a cyclooxygenase inhibitor), ammonium tetrathiomolybdate (ATM, inhibition of copper-dependant enzymes) and nordihydroguaiaretic acid (NDGA, a potent antioxidant inhibiting various enzyme classes). A possible “shift” in eicosanoid production by C. albicans is seen in the presence of ASA as well as ATM. This phenomenon is also seen for P. aeruginosa in the presence of ATM. Interestingly, ASA increased eicosanoid production by P. aeruginosa. The anti-oxidant NDGA decreased eicosanoid production by monomicrobial, as well as polymicrobial biofilms. Different profiles for eicosanoid production obtained between monomicrobial and polymicrobial biofilms in the presence of ASA and ATM were observed suggest the complex interaction of C. albicans and P. aeruginosa in terms of eicosanoid production. In addition, the inhibitors caused dramatic alterations in polymicrobial biofilm morphology. Interestingly, although these inhibitors did not affect C. albicans metabolic activity or biofilm biomass, ASA caused a significant increase in P. aeruginosa metabolic activity. In addition, P. aeruginosa metabolic activity was significantly inhibited by NDGA. The possible clinical relevance of these findings warrant further investigation, as the use of inhibitors, such as the ones used in the present study, could possibly affect virulence and the ability of hosts to clear infection. This study also evaluated the role of a secretable 15-lipoxygenase produced by P. aeruginosa capable of converting AA to 15-HETE, although further research and methodology is needed to elucidate its role.
This study is the first to investigate the production of eicosanoids by polymicrobial biofilms of C. albicans and P. aeruginosa. The increased production of these eicosanoids compared to monomicrobial counterparts, suggest that the microbially produced eicosanoids may possibly play a role in pathogen-pathogen interaction, as well as host-pathogen interaction. This may ultimately affect the ability of the host to clear infection. In addition, with the use of inhibitors, the possible involvement of various enzymatic groups can be speculated during polymicrobial eicosanoid production. Further research into this interaction may provide valuable insight into polymicrobial eicosanoid production and may contribute to possible therapeutic intervention strategies during monomicrobial and polymicrobial infection.National Research Foundatio
Screening for autism spectrum disorders in a developmental clinic in the western cape : using the modified checklist for autism in toddlers (M-CHAT)
No full textASD has an estimated prevalence of 1 in 68, making it one of the most common neurodevelopmental disorders in children. Furthermore, its prevalence is increasing; therefore, there is a rising demand for screening tools to help achieve beneficial early diagnosis and intervention outcomes. However, there is a lack of literature around ASD and ASD screening tool validity in South Africa. This thesis adapted and assessed the use of South African English, Afrikaans and IsiXhosa versions of the 23-item Modified Checklist for Autism in Toddlers (M-CHAT) screening tool, for a Western Cape state hospital. The M-CHAT was completed by parents (N=255) of children between the ages of 1.5 and 4.99 years, at the Red Cross Children's Hospital developmental clinic. The demographic variables of Child's Age or Sex, Income and Mothers Education did not significantly affect the M-CHAT scores. Furthermore, on qualitative inspection, neither Home language nor Ethnicity of the child appeared to affect the screening scores. Final M-CHAT scores and high internal consistencies were similar across the three M-CHAT language versions, likely indicating their equivalence in flagging ASD. Even the extended age range (4.01-4.99 years) included in this study, did not appear to affect the M-CHAT scores. The M-CHAT follow-up interview was important in determining the ASD risk outcome. Overall, 67% failed the M-CHAT initially, thus requiring follow-up questioning, and of those, 40% changed their outcome and subsequently passed. Interestingly, filling out the M-CHAT in a first or second language did not affect the percentage requiring the follow-up nor the proportions changing their outcome after follow-up. The items which were poor or good discriminators between those eventually passing or failing overall were investigated. The good discriminating items were not necessarily the same as the originally suggested critical items. Thus, new critical items and the possible removal of unnecessary items for this context may need further investigation. For phase 2, a small subgroup (n=38) filling in the English M-CHAT took part in formal ASD diagnostic assessments, using the Autism Diagnostic Observation Schedule (ADOS/ADOS-2). Preliminary investigations into the English M-CHAT's predictive abilities are promising. A cut-off of 3/23 items overall indicates high sensitivity (.84) and adequate specificity (.69). The adapted cut-off of 1/6 critical items results in good sensitivity (.76) and high specificity (.92). The promising results warrant further investigations into the predictive validity of all 3 language versions of the M-CHAT. This thesis takes the first steps in validating the use of the M-CHAT in this low SES context and indicates positive prospects for its future use in state clinics in the Western Cape, and ultimately South Africa.National Research Foundatio
Commercialising research output
No full textPresentations SA PhD Project Conference: KwaZulu-Natal Province 17 August 2016
Application of comprehensive two-dimensional gas chromatography for the characterisation of the volatile composition of honeybush tea
No full textHoneybush tea (Cyclopia spp.), like many other natural products, contains a large number of
volatile compounds with different physiochemical properties and present at widely varying
concentrations. This presents a significant analytical challenge for conventional onedimensional
gas chromatography (GC). The aim of this study was to explore the potential of
comprehensive two-dimensional gas chromatography (GC×GC) for the improved analysis of
honeybush tea volatile compounds.
The first part of the study focused on the evaluation of a GC×GC system equipped with a novel
single-stage thermal modulator. A chromatographic method well suited for the analysis of
honeybush volatiles was successfully developed by systematic optimisation of instrumental
parameters. Solid phase micro-extraction (SPME) was used for extraction of volatile compounds
prior to GC×GC separation. Three Cyclopia species were analysed: C. genistoides, C.
subternata and C. maculata. Chromatographic separation of honeybush volatiles was
significantly improved on this system. 69 compounds were identified based on the retention data
obtained by injection of reference standards in combination with flame ionisation detection
(FID). Hyphenation to quadrupole mass spectrometry (qMS) was also explored, although the
slow acquisition rate of the detector provided limited scope for identification of additional
compounds. The highly reproducible performance of this modulator proved beneficial in the use
of multivariate data analysis of the GC×GC-FID data. Significant differences in the volatile
composition between the three Cyclopia species were observed, in general agreement with
sensory studies for the same set of samples.
In the second part of the study, a commercial GC×GC instrument equipped with a cryogenic
modulator and hyphenated to time-of-flight MS (TOF-MS) was used for the detailed qualitative
analysis of the same set of samples. This configuration provided new insight into the volatile
composition of honeybush tea: the combination of enhanced GC×GC separation and sensitivity,
coupled to the high-speed acquisition of TOF-MS allowed the tentative identification of 158
compounds in these samples for the first time. A total of 272 compounds were identified using
either reference standards or mass spectral and retention index (RI) data. Significant
differences in the volatile composition of C. genistoides, C. subternata and C. maculata were
also observed in the GC×GC-TOF-MS data. (E)-cinnamaldehyde was identified in honeybush
tea for the first time, only in C. maculata samples. This compound is likely responsible for the
characteristic aroma of this species identified by sensory analysis.National Research Foundatio
An investigation into the androgenic activity of 11-ketotestosterone and 11-ketodihydrotestosterone
No full textDihydrotestosterone (DHT) is regarded as the most potent natural androgen and
is implicated in the development and progression of castration resistant prostate
cancer (CRPC). Under castrate conditions, DHT is produced from the intratumoral
metabolism of the adrenal androgen precursors, dehydroepiadrostenedione (DHEA)
and androstenedione (A4). Recent studies have shown that the adrenal steroid
11β-hydroxyandrostenedione (11OHA4) serves as the precursor to the androgens
11-ketotestosterone (11KT) and 11-ketodihydrotestosterone (11KDHT). The aim of
this study was therefore to characterise the androgenic activity of these steroids.
The androgenic potencies and efficacies of 11KDHT and 11KT were determined
using promotor reporter based transactivation assays. 11KT and 11KDHT demonstrated
similar potencies and efficacies to testosterone (T) and DHT, respectively.
qPCR was subsequently employed to investigate 11KDHT and 11KT regulation
of the expression of three known AR-regulated genes (ARGs), KLK3, TMPRSS2
and FKBP5, at mRNA level in two androgen dependent prostate cancer cell lines,
LNCaP and VCaP. Both 11KT and 11KDHT induced the expression of KLK3,
TMPRSS2 and FKBP5, in both cell lines. The inclusion of the selective androgen
receptor (AR) antagonist, bicalutamide, confirmed that all measured responses were
mediated via the AR. Mass spectrometry based proteomics was used to determine
the influence of 11KDHT and 11KT on the expression of AR-regulated proteins in
VCaP cells. Proteomic analysis revealed that 11KDHT regulated more AR-regulated
proteins than DHT in VCaP cells. The induction of cell growth by 11KDHT and
11KT in LNCaP and VCaP cells was also investigated and both 11KDHT and 11KT
were found to induce cell growth in both cell lines.
In most cases, 11KT and 11KDHT upregulated the ARGs and increased LNCaP
cell growth to a significantly higher extent than T and DHT. The metabolism of
11KDHT and 11KT was therefore measured and compared to that of DHT and T
in LNCaP and VCaP cells. This study is the first to show that 11KT and 11KDHT
are metabolized at a significantly lower rate in both cell lines when compared to T
and DHT, respectively, thus likely accounting for their apparent increased activity.
The data clearly shows that 11KT and 11KDHT are potent and efficacious anii
Stellenbosch University https://scholar.sun.ac.za
drogens, comparable to T and DHT. Most importantly, the findings highlight the
fact that not only can 11KT and 11KDHT activate the androgen axis, and in so
doing drive cell growth, but that these steroids have the potential to remain active
for longer than T and DHT due to a reduced rate of metabolism. Collectively, the
data demonstrates that 11KT and 11KDHT likely play a vital, but overlooked, role
in the development and progression of CRPC.National Research Foundatio
Re-storying xenophobia in South Africa: a postfoundational, narrative exploration of ubuntu in the Eastern Cape
No full textSouth African communities have experienced levels of antipathy towards foreign migrants
since the transition to democracy in 1994. This incipient hostility erupted into widespread
violence in May 2008, where 62 foreign nationals were killed, around 700 injured, and an
estimated 35 000 foreigners were driven from their homes. What has been termed
xenophobia has simmered in communities around South Africa since then, occasionally
escalating to levels where it threatens to approach the scale of the 2008 violence, such as
the violence against foreigners that occurred in Gauteng and KwaZulu-Natal in January
and April of 2015 respectively.
Most studies that explore xenophobia in South Africa focus on offering explanations for the
eruption of overt violence against foreigners and identifying specific triggers for this
violence. A reified notion of xenophobia is taken for granted and the violence itself is
problematised rather than the construction of meaning that precedes it. While the label
of xenophobia may provide an accurate description of the symptoms of this social malaise,
there are risks that it may obscure the problems that lie behind the violence or over-simplify
them.
This study proceeded from a postfoundational, social constructionist epistemology, and
utilised a Narrative research approach to listen to the stories of people living in a rural and
an urban community in the Eastern Cape province of South Africa between 2013 and 2015.
The aim of the research was to understand how meaning was being constructed with
regard to foreigners in order to develop insights into possibilities for shaping the creation of
new meaning. Stories from within the context were listened to, described, and then
interpretations were made and developed with co-researchers. These stories were
explored in order to discover how they reflected dominant Discourses in South Africa, and
how these Discourses were being harnessed in leadership discourse, the media, and in
people’s stories to produce certain meanings in relation to foreigners. Of the various
discourses that exist, I was particularly curious about the role that ubuntu, a traditional
African social value, was playing in shaping social relationships within this context. Ubuntu
was frequently mentioned in public discourse as a solution to the violence, along with the
argument that the violence indicated a lack of ubuntu.
A transversal interdisciplinary conversation was initiated by asking scholars from the fields
of Political Science, Psychology, and Organisational Psychology to reflect on a transcript of one of the interviews. This is followed by an interdisciplinary literature review. Insights on
prejudice from Social Psychology, on conflict from Organisational Psychology, and the
post-Marxist political theory of Ernesto Laclau and Chantal Mouffe offer valuable
perspectives on the violence against foreigners in South Africa.
Meaning with regard to foreigners was produced through the confluence of multiple stories,
rather than through any particular story. Borrowing the notion of transversality from Calvin
Schrag, I propose that it is in a transversal arrangement of stories that new meanings
emerge. The points at which narratives overlap and intersect are able to both modify the
meanings of the intersecting narratives and create new meanings that arise from a
combination or even a conflation of stories. I proposed the term ‘transversal narrativity” to
describe this creation of new meanings at the intersection of various narratives.National Research Foundatio
Peer support networks #Get it done
No full textPresentations SA PhD Project Conference: Free State 25-26 February 201
Completing a PhD while in full-time employment
No full textPresentations SA PhD Project Conference: Free State 25-26 February 201
2016 ORCID South Africa workshop
No full text2016 ORCID workshop in South Africa on Tuesday July 19. The theme was "ORCID and the Research Lifecycle", with talks from the National Research Foundation, ORCID members and representatives, as well as platform providers
Characterisation of mucosal tissue in the foreskin after voluntary medical male circumcision
No full textBackground: Medical Male Circumcision (MMC) reduces the risk of HIV-1 acquisition by up to 60% as shown in a number of randomized controlled trials in Uganda, Kenya and South Africa. MMC has also been shown to reduce the prevalence of other sexually transmitted infections (STIs) like Herpes Simplex Virus (HSV) -2 and Human Papillomavirus (HPV) by 25% and 35% respectively. Asymptomatic STIs may elevate the risk of HIV-1 acquisition by recruiting HIV-1 target cells to the foreskin. The higher permeability of the inner foreskin may play a role in HIV-1 acquisition as well as the number of target cells present in the foreskin. The more inflamed inner foreskin may be increasing the risk of a productive HIV-1 infection. The aims of this dissertation was to a) examine the levels of keratinisation in the inner and outer foreskins after MMC; b) investigate the number of Langerhans, Ki67+ and CD4+ T cells in the inner and outer foreskin and c) identify the impact of asymptomatic STIs on the numbers and proliferative capacity of foreskin-resident Langerhans and CD4+ T cells.National Research Foundatio