Thesis (MScMedSc)--Stellenbosch University, 2013. / ENGLISH ABSTRACT: Parkinson's disease (PD) is a severely debilitating neurodegenerative disorder that results in motor circuit dysregulation and ultimately, causes impairment of movement. This condition is due to the selective degradation of the dopaminergic neurons in the substantia nigra pars compacta in the midbrain, which subsequently results in the pathological symptoms namely bradykinesia, resting tremor, postural instability and rigidity. It was initially hypothesized that individuals who develop PD were exposed to an environmental trigger(s) that caused the onset of the disease, but more recently, a significant genetic component, coupled to environmental factors have been implicated in disease pathogenesis. Currently, there are eight genes (Parkin, PINK1, LRRK2, SNCA, DJ-1, ATP13A2, EIF4G1 and VPS35) that have been directly implicated in PD. Worldwide, the prevalence of neurodegenerative disorders is increasing as populations are living longer. In Europe, Canada and USA, it has been projected that the prevalence of PD may increase by a factor of two between 2010 and 2050; approximately a 92% increase. In Tanzania (the only study done in sub-Saharan Africa) an even larger increase of 184% between 2005 and 2025 is predicted, due to the fact that the speed of populations ageing in developing countries, will exceed that of developed countries. Research into the causes and risk factors underlying neurodegenerative disorders such as PD is therefore urgently needed for policy makers and governments in developing nations to take appropriate action to deal with this impending health care problem. The aim of the present study was to investigate the molecular aetiology of a group of South African PD patients. A total of 262 patients from various ethnic backgrounds were recruited for the study, and 35% had a positive family history of PD with the average age at onset (AAO) being 54.3 years of age (SD = 12.5 years). Mutation screening of the known PD genes (Parkin, PINK1, LRRK2, SNCA and DJ-1) was performed using high resolution melt and Sanger sequencing. Genotyping was done using fluorescently-labelled PCR primers followed by electrophoresis on an ABI 3130xl genetic analyser (for CTG repeats in JPH3) and with a KASP™ Genotyping Assay (for a 16bp indel in DJ-1). In order to identify a novel PD-causing gene, whole exome sequencing (WES) was conducted on three Afrikaner probands with an Illumina Genome Hiseq 2000TM and the sequences were aligned using the NCBI Human Reference Genome 37.2. The BORG (Bio-Ontological Relationship Graph) semantic database, which models the relationship of human and model organism genes to functions, pathways and phenotypes, was used to filter and prioritise genetic variants shared between the three PD exomes. It was determined that the known PD genes do not play a significant role in disease pathogenesis in the South African patients as only 15/262 (5.7%) of the patients harboured mutations: seven in Parkin, one in PINK1, six in LRRK2 and one in SNCA. Only one of the patients harboured a 16bp indel variant at the transcription start site of DJ-1. None of the Black PD patients had pathogenic repeat expansions in JPH3 thereby excluding Huntington disease-like 2 as a cause of the disease phenotype. Genealogical analysis revealed that six of the apparently unrelated Afrikaner PD probands were related to a founder couple that immigrated to South Africa in the 1600s which suggests that there is a possible founder effect for the disease. Bioinformatics analysis of WES data on three of the probands identified 21 variants in 12 genes that were present in all three PD exomes and fulfilled various criteria. Sanger sequencing was used for verification of five variants and of these, two (in CDC27 and NEDD4) were found to be artefacts. The remaining three (in HECDT1, TBCC and RNF40) were excluded based on the lack of cosegregation with disease and the high frequency of the allele in controls. Further work is necessary to verify the presence of the remaining sixteen variants and to characterise each of them for their possible pathogenicity. The discovery of novel PD-causing genes is important as this may shed light on the pathways or processes that are involved. A current hypothesis implicates the lysosome-dependent pathway as a unifying biochemical pathway that can account for the phenotypic spectrum within PD. Notably, although Mendelian forms are thought to account for only about 10- 15% of cases, the study of Mendelian inherited variants is likely to provide insight into the pathophysiology of the more common sporadic form of this condition. Dissecting the key molecular mechanisms underlying PD will provide critical information for improved treatment strategies and drug interventions that will ultimately prevent or halt neuronal cell loss in susceptible individuals. / AFRIKAANSE OPSOMMING: Parkinson se siekte (PS) is 'n erge neurodegeneratiewe bewegings-siekte, wat motorstroombaan disregulasie veroorsaak. Dit lei uiteindelik tot beperkte bewegings vermoëns. Hierdie toestand word veroorsaak weens die selektiewe agteruitgang van die dopaminergeniese neurone in die substantia nigra pars compacta in die midbrein, wat later lei tot die patologiese simptome naamlik: bradykinesia, rustende spiersametrekkings, posturale onstabiliteit en rigiditeit. Daar is aanvanklik vermoed dat individue wat PS ontwikkel, aan 'n omgewingsfaktor(e) blootgestel is wat die aanvang van die siekte veroorsaak het, terwyl meer onlangs is daar 'n aansienlike genetiese komponent tesame met omgewingsfaktore geïdentifiseer, wat betrokke is by die patogenese van die siekte. Tans is daar agt gene (Parkin, PINK1, LRRK2, SNCA, DJ-1, ATP13A2, EIF4G1 en VPS35) wat direk by PS geïmpliseer is. Wêreldwyd is daar ‗n toenemende voorkoms van neurodegeneratiewe siektes aangesien bevolkings langer leef. In Europa, Kanada en die VSA, is daar geprojekteer dat die voorkoms van PS tussen 2010 en 2050 met 'n faktor van twee verhoog kan word. Dit is ongeveer 'n 92%- verhoging. In Tanzanië (die enigste studie wat tot dusver in sub-Sahara Afrika gedoen is) word daar selfs ‗n groter toename, van 184% tussen 2005 en 2025 voorspel. Dit is te danke aan die feit dat die bevolkings- veroudering in ontwikkelende lande die van ontwikkelde lande sal oorskry. Ondersoeke na die oorsake en risiko-faktore onderliggend aan neurodegeneratiewe siektes, byvoorbeeld PS, word dus dringend benodig deur beleidmakers en regerings in ontwikkelende lande, sodat hulle die nodige stappe kan neem om hierdie dreigende gesondheidsorg-probleem op te los. Die doel van die huidige studie was om ondersoek in te stel na die molekulêre etiologie van 'n groep Suid-Afrikaanse PS pasiënte. 'n Totaal van 262 pasiënte van verskillende etniese agtergronde, is gewerf vir die studie. Hiervan het 35% 'n positiewe familiegeskiedenis van PS en die gemiddelde aanvangs ouderdom (AAO) was 54,3 jaar (SD = 12,5 jaar). Mutasie-analise van die bekende PS gene is uitgevoer met behulp van hoë resolusie smelt en Sanger volgordebepaling. Genotipering is gedoen met behulp van fluoresserend geëtiketteerde PKR inleiers met elektroforese, op 'n ABI 3130xl genetiese analiseerder (CTG herhalings in JPH3), en met 'n KASP ™ Genotipering toets (vir 'n 16bp indel in DJ-1). Ten einde, om 'n nuwe PSveroorsakende geen te identifiseer was heel eksoom volgordebepaling (WES) uitgevoer op drie Afrikaner PS positiewe pasiënte met 'n Illumina Genome Hiseq 2000™ en die volgorders is gerangskik met behulp van die NCBI Menslike Verwysings Genoom 37.2. Die BORG (Bio- Ontologiese Verhoudings Grafiek) semantiese databasis, wat gebaseer is op die verhouding van die mens en model organisme gene funksies, paaie en fenotipes, en is gebruik om genetiese variante, wat gedeel word tussen die drie PS exome te filtreer en te prioritiseer. Daar is vasgestel dat die bekende PS gene nie 'n belangrike rol in die patogenese van die siekte in die Suid-Afrikaanse pasiënte speel nie. Dit is aangesien slegs 15/262 (5.7%) van die pasiënte bekende mutasies dra: sewe in Parkin, een in PINK1, ses in LRRK2 en een in SNCA. Slegs een van die pasiënte het 'n 16bp delesie variant in die transkripsie promotor area van DJ-1 gedra. Geen van die Swart PS pasiënte het patogeniese herhalings in JPH3 vertoon nie. Gevolglik is Huntington siekte-agtige 2 uitgesluit as 'n oorsaak van die siekte fenotipe. Genealogiese analise het getoon dat ses van die skynbaar onverwante Afrikaner PS pasiënte verwant is aan 'n stigter paartjie wat in die 1600's na Suid-Afrika geïmigreer het, wat daarop dui dat daar 'n moontlike stigter effek vir die siekte is. Bioinformatiese analise van WES data vir drie van die pasiënte, het 21 variante in 12 gene geïdentifiseer, wat in al drie PS exome teenwoordig was en verskeie kriteria vervul het. Sanger volgordebepaling is gebruik vir die bevestiging van vyf variante en van hierdie, is twee (in CDC27 en NEDD4) bevind om artefakte te wees. Die oorblywende drie (in HECDT1, TBCC en RNF40) is uitgesluit gebaseer op die gebrek aan gesamentlike-segregasie met die siekte en die hoë frekwensie van die allele in die kontrole groep. Verdere werk is nodig om die teenwoordigheid van die oorblywende variante te verifieer en om elkeen van hulle te karakteriseer vir hulle moontlike patogenisiteit. Die ontdekking van die nuwe PS-veroorsakende gene is belangrik aangesien dit lig kan werp op die stelsels of prosesse wat betrokke is. 'n Huidige hipotese impliseer die lisosoom-afhanklike pad as 'n verenigende biochemiese padweg, wat verantwoordelik is vir die fenotipiese spektrum binne PS. Alhoewel Mendeliese vorms vermoedelik verantwoordelik is vir slegs omgeveer 10-15% van die gevalle, is die studie van Mendelse gene geneig om insig te verkry in die patofisiologie van die meer algemene sporadiese vorm van hierdie toestand. Ontleding van die kern molekulêre meganismes onderliggend aan PS sal kritiese inligting vir beter strategieë vir behandeling en geneesmiddel-intervensies voorsien, wat gevolglik neuronale sel verlies in vatbare individue sal voorkom of beëindig. / Medical Research Council / National Research Foundation / Harry Crossley Foundation

Thesis (MMed)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Background Rectovaginal endometriosis accounts for 5-10% of cases of endometriosis and constitutes one of the forms of deep infiltrating endometriosis. . Deep infiltrating endometriosis involving the bowel is most frequently encountered in the rectovaginal septum and is considered to be the most severe form of the disease and the most difficult to treat surgically owing to its invasive nature. There are currently no studies on this topic pertaining to a South African context. Study Objective To document the outcomes in 112 patients undergoing laparoscopic surgery for rectovaginal endometriosis. Methods A retrospective audit of 112 women undergoing laparoscopic surgery for rectovaginal endometriosis at Vincent Pallotti's Aevitas Fertility Clinic was undertaken. Eligibility was established by identifying women from a surgical database based on medical aid coding as well as a review of individual case notes. Patients were telephonically contacted to gather any missing information and to assess further outcomes. Design Classification Study number S11/11/036. This study was approved by the Health Research Ethics Committee at Stellenbosch University and was conducted according to ethical guidelines and principles of The International Declaration of Helsinki, South African Guidelines for Good Clinical Practice and the Medical Research Council (MRC) Ethical Guidelines for Research. Setting Vincent Pallotti’s Aevitas Reproductive Medicine Clinic Patients 112 consecutive patients suffering from rectovaginal endometriosis Interventions: Laparoscopic surgery for treatment of deep infiltrating, namely rectovaginal endometriosis Measurements and Main Results Primary outcome: Complications of laparoscopic surgery for rectovaginal endometriosis included one patient requiring a blood transfusion (0,9%), three cases of rectovaginal fistula (2,7%), two bowel injuries (1,8%)-detected and managed intra-operatively , one ureteric injury (0,9%), one pelvic abscess (0,9%) and the need for three urgent re-operations (2,68%). Secondary outcome: Of the 71 patients desiring fertility 39 (54,9%) fell pregnant of which 27 (69,2%) were spontaneous. Conclusion To our knowledge this is the first study assessing surgical outcomes in the management of deep infiltrating endometriosis from South Africa. These outcomes are in keeping with complication rates quoted in the international literature. Most of the surgery was performed using the shaving technique, in keeping with international trends, whilst fourteen cases required the performance of a segmental resection owing to extensive disease. In trained hands laparoscopic surgery is a valid management option in the management of rectovaginal endometriosis. / AFRIKAANSE OPSOMMING: Agtergrond Vyf tot tien persent van alle endometriose gevalle kan toegeskryf word aan rektovaginale endometriose. Dit word beskou as een van die vorme van diep infiltrerende endometriose. Diep infiltrerende endometriose van die derm kom meestal in die rektovaginale septum voor en word as die ernstigste vorm van die siekte beskou. Dit is die moeilikste om chirurgies te behandel weens sy indringende aard. Daar is tans geen studies beskikbaar oor hierdie onderwerp in die Suid-Afrikaanse konteks nie. Doel van die studie Om die uitkomste te dokumenteer van 112 pasiënte wat laparoskopiese chirurgie vir rektovaginale endometriose ondergaan het. Metodes 'n Retrospektiewe oudit is by Vincent Pallotti se Aevitas Fertiliteitskliniek gedoen van 112 vroue wat laparoskopiese chirurgie vir rektovaginale endometriose ondergaan het. Geskikte pasiënte is geïdentifiseer vanaf 'n chirurgiese databasis gebaseer op mediese kodering, sowel as vanaf 'n oorsig van pasiënt notas. Pasiënte is telefonies genader om ontbrekende inligting in te samel en verdere uitkomste te evalueer. Klassifikasie Ontwerp Studie nommer S11/11/036. Hierdie studie is deur die Gesondheids Navorsing Etiese Komitee van die Universiteit van Stellenbosch goedgekeur en uitgevoer volgens die etiese riglyne en beginsels van die Internasionale Verklaring van Helsinki, Suid-Afrikaanse Riglyne vir Goeie Kliniese Praktyk en die Mediese Navorsingsraad (MNR) se Etiese Riglyne vir Navorsing. Instelling Vincent Pallotti se Aevitas Reproduktiewe Medisyne Kliniek Pasiënte 112 agtereenvolgende pasiënte met rektovaginale endometriose. Ingrepe: Laparoskopiese chirurgie vir die behandeling van diep infiltrende, rektovaginale endometriose. Resultate Primêre uitkoms: Komplikasies van laparoskopiese chirurgie vir rektovaginale endometriose het ingesluit: een pasiënt wat 'n bloedoortapping benodig het (0,9%), drie gevalle van rektovaginale fistels (2,7%), twee dermbeserings (1,8%) - intraoperatief gediagnoseer en herstel, een ureter besering (0,9%), een bekkenabses (0,9%) en drie dringende herhaal operasies (2,68%). Sekondêre uitkoms: Van die 71 pasiënte wat fertiliteit verlang het: 39 (54,9%) het swanger geraak, waarvan 27 (69,2%) spontaan was. Gevolgtrekking Sover ons kennis strek, is dit die eerste Suid-Afrikaanse studie waar daar na die chirurgiese uitkomste in die behandeling van diep infiltrerende endometriose gekyk is. Hierdie uitkomste stem ooreen met internasionale literatuur in terme van komplikasie syfers. Die meeste van die operasies is uitgevoer met behulp van die skeer-tegniek, in ooreenstemming met internasionale tendense, terwyl veertien gevalle segmentele reseksies vereis het weens uitgebreide siekte. In goed opgeleide hande is die laparoskopiese behandeling van rektovaginale endometriose ‘n geldige behandelings opsie.

Thesis (MMed)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Introduction Pregnancies in women with a previous unexplained stillbirth may be jeopardized by increased antenatal surveillance and higher rates of induction of labour and caesarean delivery without clear evidence of benefit. Despite the fact that there have been no studies that adequately tested fetal benefit in routine induction of labour for a previous stillbirth, a policy of routine induction of labour at 38 weeks, with all the associated maternal, fetal and health-care associated costs, was in practice at Tygerberg Hospital for the past 30 years. This study aimed to investigate the safety of continuation of these pregnancies until term (≥39 weeks). Aims and Objectives To assess the clinical outcome and impact on the health service in a pregnancy with a previous unexplained intra-uterine demise (IUD) by routine induction of labour at term instead of at 38 weeks. Methodology This was a prospective observational study on the safety of a new hospital protocol which was introduced in 2012. The protocol extended the gestation for induction after a previous IUD from 38 weeks to term. The study population included all pregnant patients with a current singleton pregnancy, and a previous unexplained or unexplored (no data available) singleton fetal demise ≥24 weeks/500grams. All patients with a previous stillbirth in the metropolitan drainage area of Tygerberg Hospital are referred to Tygerberg for further care; and all referrals during 2012 were recruited for the study. Patients with known or recurrent risks for intra-uterine death were managed according to the relevant clinical condition and were excluded from the study. Results During the audit period, 306 patients with a previous intra-uterine fetal death were referred for further management. Of these, 161 had a clear indication for either earlier intervention or no intervention and were excluded from the protocol. Of the remaining 145 patients, 9 met exclusion criteria and there were 2 patients who defaulted. Forty-two of the study patients (with no known previous medical problems) developed complications during their antenatal course that necessitated a change in clinical management and earlier (<39 weeks) delivery. Of the remaining 92 patients in the audit, 47 (51%) went into spontaneous labour before their induction date. There were no intra-uterine deaths prior to delivery. Conclusions Careful follow up at a high risk clinic identifies new or concealed maternal or fetal complications in 29% of patients with a previous IUD and no obvious maternal or fetal disease in the index pregnancy. When all risks are excluded and the pregnancy allowed to progress to 39 weeks before an induction is offered, 51% will go into spontaneous labour. / AFRIKAANSE OPSOMMING: Inleiding Swangerskappe in vroue met vorige onverklaarbare stilgeboorte mag in gevaar gestel word deur meer intense voorgeboorte sorg en ‘n groter hoeveelheid induksies van kraam en keisersnitte sonder duidelike bewyse dat dit tot voordeel strek. Ten spyte van die feit dat daar geen studies is wat bewys het dat roetine induksie van kraam vir ‘n vorige stilgeboorte op 38 weke tot voordeel van die baba was nie, was ‘n beleid van roetine induksie van kraam op 38 weke, met al die geassosieërde moederlike en fetale risikos daaraan verbonde; asook die hoë gesondheidskostes, roetine praktyk in Tygerberg Hospitaal vir die afgelope 30 jaar. Hierdie studie het ten doel gehad om die veiligheid van voortsetting van hierdie swangerskappe tot voltyd (≥39 weke) te ondersoek. Doelwitte Om die kliniese uitkoms; asook die impak op gesondheidsdienste te evalueer in ‘n swanger vrou met n vorige onverklaarbare intra-uteriene sterfte; deur roetine induksie van kraam aan te bied op voltyd in plaas van 38 weke. Metodologie Hierdie was n prospektiewe kohort studie om die veiligheid van ‘n nuwe hospitaal protokol wat in 2012 geïmplimenteer is, te bepaal. Hierdie protokol het die gestasie tydperk van induksie van kraam van alle swanger pasiënte na ‘n vorige onverklaarbare stilgeboorte van 38 weke na voltyd verleng. Die studiepopulasie het alle swanger pasiënte met ‘n huidige enkelswangerskap en ‘n vorige onverklaarbare of onbekende (geen data beskikbaar) enkelvoudige fetale sterfte ≥24 weke/500gram, ingesluit. Alle pasiënte in die metropolitaanse dreineringsarea van Tygerberg Hospitaal met ‘n vorige stilgeboorte word na Tygerberg verwys vir verdere hantering, en alle verwysings gedurende 2012 was gewerf vir die studie. Pasiënte met bekende of herhalende risikofaktore vir ‘n intra-uteriene sterfte was hanteer volgens die relevante kliniese inligting en was uitgesluit by die studie. Resultate Drie-honderd-en-ses pasiënte met ‘n vorige intra-uteriene fetale sterfte was gedurende die oudit periode verwys vir verdere hantering. In 161 pasiënte was daar ‘n duidelike indikasie vir of vroeër intervensie of geen intervensie nie; en hulle was uitgesluit van die protokol. Van die oorblywende 145 pasiënte is 9 pasiënte uitgesluit as gevolg van die uitsluitingskriteria en daar was 2 pasiënte wat versuim het om op te volg. Twee-en-veertig pasiënte (met geen bekende vorige mediese probleme nie) het komplikasies gedurende hulle voorgeboorte verloop ontwikkel wat gelei het tot verandering in kliniese hantering en vroeëre verlossing (≤39 weke) genoodsaak het. Van die oorblywende 92 pasiënte in die oudit, het 47 (51%) in spontane kraam gegaan voor hulle induksiedatum. Daar was geen intra-uteriene sterftes voor verlossing nie. Gevolgtrekkings Noukeurige opvolg by ‘n hoërisiko kliniek identifiseer nuwe of versteekte moederlike en fetale komplikasies in 29% van pasiënte met ‘n vorige intra-uteriene sterfte sonder enige duidelike moederlike of fetale siekte in die indeks swangerskap. Wanneer alle risikos uitgesluit word en die swangerskap toegelaat word om voort te gaan tot 39 weke voor ‘n induksie aangebied word, sal 51% van pasiënte spontaan in kraam gaan.

Thesis (PhD)-- Stellenbosch University, 2014. / ENGLISH ABSTRACT: Schizophrenia is a phenotypically heterogeneous disorder believed to have a strong genetic component. Limiting its clinical heterogeneity by means of subtyping may help to shed light on some of the genetic underpinnings of the disease. This study describes the application of factor analysis (FA), latent class analysis (LCA) and factor mixture modeling in a sample of 734 Xhosa-speaking schizophrenic subjects using factor analytically derived variables previously identified in an independent sample of this population. LCA was performed on the following 8 SANS and SAPS items identified by preliminary exploration of the data: eye contact, auditory hallucinations, global hallucinations score, global delusions score, grooming, affective non-responsiveness, spontaneous movement, and commenting voices. A four class model provided the best fit. Classes 1 and 2 were characterized by predominantly positive and predominantly negative symptoms, respectively, class 3 by both positive and negative symptoms and class 4 by few or absent symptoms. A history of cannabis use or abuse increased the probability of a subject being allocated to class 1, while being male made a person more likely to be included in class 2. Factor mixture modelling was performed by first using latent class analysis, then factor analysis and then the factor mixture analysis were done. The fit among these three types were then investigated. The results show that factor mixture modelling uncovered a heterogeneous latent variable structure that fits the data well with the latent classes capturing distinct positive symptom/behaviours and factors capturing severity variations. This study, the first to report on the latent class structure of schizophrenia in a sample of patients from a sub-Saharan African population, supports the universality of specific latent classes across ethnic boundaries. The results further support reports that gender, sibpair status and cannabis use may influence the phenomenology of schizophrenia. The identification of subgroups may represent an intermediate step in the search for endophenotypes of schizophrenia. / AFRIKAANSE OPSOMMING: Skisofrenie is „n psigiatriese steuring met „n heterogene fenotipe en „n vermoedelik sterk genetiese vatbaarheid. Ten einde die lig te werp op die genetiese onderbou van skisofrenie word gepoog om die kliniese heterogenisiteit te beperk deur middel van subgroepering. Hierdie studie beskryf die gebruik van latente klas analise (LKA) in „n groep van 734 Xhosa-sprekendes met skisofrenie. Die LKA word baseer op die gebruik van veranderlikes wat deur middel van faktor analise op simptome in „n onafhanklike studiegroep van Xhosa-sprekendes met skisofrenie verkry is. Die LKA is gedoen op die volgende 8 “SAPS” en “SANS” veranderlikes wat deur voorlopige ondersoek van die data ge-indentifiseer is: oogkontak, gehoorshallusinasies, globale hallusinasie telling, globale waantelling, selfversorging, affektiewe nie-responsiwiteit, spontane beweging en stemme wat kommentaar lewer. „n Vierklas oplossing het die beste passing getoon. Klas 1 en 2 is gekenmerk deur oorwegend positiewe en negatiewe simptome onderskeidelik, klas 3 het beide positiewe en negatiewe simptome gehad en klas 4 het baie min of geen simptome getoon nie. „n Geskiedenis van kannabis gebruik of misbruik het die kans verhoog dat die individue in klas 1 gevind sou word, terwyl manlike geslag as veranderlike die kanse verhoog het vir allokasie in klas 2. Faktor mengsel modelering is gedoen deur eers „n latent klas analise te voltooi, gevolg deur „n faktor analise, en laastens „n factor mengsel analise. Die passing tussen die drie analises is daarna evalueer. Faktor mengsel modelering toon „n heterogene latente klas struktuur wat voldoen aan die passingsvereistes. Die latente klasse blyk spesifieke positiewe simptome/gedrag te verteenwoordig, terwyl die factor grad van erns variasie aandui. Hierdie studie is die eerste om die latente klas struktuur van skisofrenie in „n subsahara-Afrika populasie, die Xhosa, te beskryf. Die resultate onderstreep die universialiteit van die latente struktuur van skisofrenie se simptome oor etniese grense heen. Verder ondersteun die resultate die moontlike rol van geslag, aangetaste sibstatus en kannabis gebruik in skisofrenie se fenomenologie. Die identifisering van die subgroepe mag „n intermediêre stap in die soektog vir endofenotipes van skisofrenie verteenwoordig.

Thesis (PhD)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Background The changes in cognition, brain structure, and neurological soft signs which are characteristic of schizophrenia appear to have been present before the onset of the phenotype. They therefore find relevance as potential vulnerability markers of the disease. Neurological soft signs are of particular interest because they can be elicited quickly, reliably and cheaply. They have also been touted as markers of certain characteristics of schizophrenia. The most convincing evidence for these assertions come from prospective longitudinal studies of first episode, medication naive patients with schizophrenia. Most of these studies have been based on wholly Caucasian or mixed samples of Caucasians and other races. The present study provides important reference data on the nature of neurological soft signs in indigenous African subjects and clarifies the trait or state marking signs in this population. Method A total of 84 patients with first episode, schizophrenia, schizo-affective disorder, or schizophreniform disorder meeting criteria in the fourth edition of the Diagnostic and Statistical Manual for Mental Disorders were consecutively recruited. Information on demographic characteristics, personal medical and psychiatric history, as well as family history was obtained at baseline. Neurological assessment was based on the 26 item Neurological Evaluation Scale. An exploratory factor analysis of the items in the scale was conducted using the baseline measurements. The derived sub-sets of neurological soft signs were then followed up longitudinally and in parallel with the ‘functional categories’ of the signs. The study describes the profile of neurological soft signs across the one year course of schizophrenia, as well as their relationship with a wide range of clinical and outcome variables. The severity of the baseline psychopathology was evaluated by administering the Positive and Negative Syndrome Scale. The overall clinical status was assessed using Clinical Global Impression. Additional assessments included the Calvary Depression Scale for Schizophrenia, Birchwood Insight Scale, Social and Occupational Functioning Assessment Scale, and the World Health Organisation Quality of Life Scale (WHO QoL-BREF). Pre-morbid adjustment was assessed using the Pre morbid Adjustment Scale, while extra-pyramidal effect of antipsychotics was assessed using the Extra-pyramidal Symptoms Rating Scale. Assessments were repeated at three monthly intervals for the full 12 months. Results Neurological soft signs were present in 96.4% of the sample at baseline. The signs loaded into a four factor structure: perceptual and motor sequencing (audio-visual integration, fist-edge palm, rhythm tapping, extinction, and right-left confusion), eye movements (synkinesis, convergence, and gaze impersistence), motor co-ordination and graphaesthesia (tandem walk, adventitious flow, and graphaesthesia), as well as stegreognosis. The scores for the perceptual and motor sequencing factor, as well as those for the sequencing of complex motor acts ‘functional category’ were stable across three measurements over 12 months (F=1.26, p=0.287, and F=1.87, p=0.158 respectively). The sequencing of complex motor act signs was not significantly correlated with the clinical and outcome characteristics of schizophrenia. However, other signs, as well as the NES total score were significantly correlated with more severe negative and disorganized psychopathology, as well as poorer outcome in terms of functioning and quality of life. Conclusion Neurological soft signs were present at a high frequency at baseline. A preponderance of the signs was associated with a more severe negative and disorganization psychopathology, as well as a poorer functional outcome and quality of life. Abnormal sequencing of complex motor act signs, and signs of abnormal cognitive processing of perceptual stimuli where resistant to changes in psychopathology, and thus may represent viable trait markers for schizophrenia in this cohort.

Thesis (MScMedSc (Biomedical Sciences. Anatomy and Histology)--Stellenbosch University, 2008.

Assignment (MMed)--University of Stellenbosch, 2007. / ENGLISH ABSTRACT: Lipoprotein X (LpX) is an abnormal cholesterol-containing particle that may be present in the serum of subjects with cholestasis, lecithin:cholesterol acyltransferase (LCAT) deficiency and parenteral nutrition. The biochemistry, metabolism, clinical significance and laboratory analysis of LpX is discussed in this study. This laboratory-based project investigated icteric samples received at the Chemical Pathology laboratory, Tygerberg Hospital, for serum predictors of LpX and the use of a modified non-denaturing polyacrylamide gradient gel electrophoresis system in the detection of LpX. The study showed that the non-denaturing polyacrylamide gradient gel electrophoresis system (2-8%) is a useful test in demonstrating LpX in icteric plasma and has potential for a screening test in LCAT deficiency. Serum concentration of conjugated bilirubin, alkaline phosphatase, gamma glutamyltransferase, free cholesterol, phospholipid, free cholesterol: total cholesterol ratio and conjugated bilirubin: total bilirubin ratio are all good predictors of LpX. The ratio of free cholesterol to total cholesterol (FC/TC > 0.6) was the best predictor of LpX. In the setting of obstructive liver disease LpX is seen in 66% of patients if total cholesterol is > 7.5 mmol/L. / AFRIKAANSE OPSOMMING: Lipoproteien X (LpX) is ‘n abnormale cholesterol-bevattende partikel wat teenwoordig mag wees in die serum van persone met cholestase, lesitien:cholesterol asieltransferase (LCAT) gebrek en parenterale voeding. Die biochemie, metabolisme, kliniese belang en laboratorium analise van LpX word bespreek in hierdie werkstuk. Hierdie laboratorium-gebaseerde projek het geelsugtige monsters ondersoek wat ontvang is by die Chemiese Patologie laboratorium, Tygerberg Hospitaal, vir serum voorspellers van LpX en die gebruik van ‘n gemodifiseerde nie-denaturerende polie-akrielamied gradiënt gel elektroforese sisteem in die demonstrasie van LpX. Die bevindinge was dat die nie-denaturerende polie-akrielamied gradient gel elektroforese sisteem (2-8%) is ‘n nuttige toets om LpX te demonstreer in geelsugtige plasma en het potensiaal as ‘n siftingstoets in LCAT gebrek. Serum konsentrasie van gekonjugeerde bilirubien, alkaliese fosfatase, gamma glutamieltransferase, vry cholesterol, fosfolipied, vry cholesterol:totale cholesterol verhouding en gekonjugeerde bilirubien:totale bilirubien verhouding is alles goeie voorspellers van LpX. Die verhouding van vry cholesterol tot totale cholesterol (VC/TC > 0.6) was die beste voorspeller van LpX. In gevalle van obstruktiewe lewersiekte word LpX gesien in 66% van pasiente as die totale cholesterol meer as 7.5 mmol/l is.

MPhil (Rehabilitation) / Thesis (MPhil (Interdisciplinary Health Sciences))--University of Stellenbosch, 2009. / ENGLISH ABSTRACT: A stroke comes suddenly and has a devastating effect on the lives of the patient and the caregiver. It is disabling and often leaves the patient dependent on care. Providing this care can put tremendous physical, emotional, social and financial demands on the caregiver. The purpose of the study is to determine the impact of caregiving on the primary caregivers of patients who suffered a stroke and were admitted to the Western Cape Rehabilitation Centre (WCRC), for intensive rehabilitation during 2006. This is a descriptive study that utilised both quantitative and qualitative methods of data collection. Quantitative data were collected through two data coding forms, one for caregivers and one for patients, the Bartel Index, the Caregiver Strain Index (CSI) and the Satisfaction With Life Scale (SWLS). Qualitative data were collected through indepth interviews with caregivers. Fifty-seven caregivers participated in the study. According to CSI findings 58% of caregivers were under levels of strain high enough to require support and intervention. The SWLS indicated that the life areas most adversely affected were employment and self and social life. Loss of employment by the caregiver (p = 0.04) and financial difficulties (p = 0.06), cognitive and perceptual problems (p = 0.01), personality changes (p = 0.01), level of physical dependency of patient (0.0012) and nervous strain experienced by the caregiver (0.01) were found to significantly impact on caregiver strain. Caregivers perceived their caregiving duties as overwhelming and a great strain. This was aggravated in some instances by poor health care service delivery at the time of the stroke, no or inadequate explanations on stroke, poor or no training of caregivers, no home visits and a lack of follow-up services in the community. They experienced the period just after discharge as especially challenging and required support, assistance and guidance at that time. Caregivers identified a need for community rehabilitation facilities, adult day care centres, outpatient rehabilitation services, home-based nursing care and caregiver support groups in the community. / AFRIKAANSE OPSOMMING: ’n Beroerte gebeur skielik en sonder enige waarskuwing met ’n vernietigende uitwerking op die lewens van die pasiënt asook die versorger. Dit veroorsaak gestremdheid en laat dikwels die pasiënt afhanklik van sorg. Die voorsiening van hierdie sorg kan erge fisiese, emosionele, sosiale en finansiele eise aan die versorger stel. Die doel van die navorsing is om die impak van versorging op die primêre versorger van beroerte pasiënte, wat gedurende 2006 intensiewe rehabilitasie by WKRS ontvang het, te ondersoek. Dit is ’n beskrywende studie wat gebruik gemaak het van beide kwantitatiewe en kwalitatiewe metodes om data in te samel. Kwantitatiewe data was verkry deur twee datakoderingsvorms, een vir pasiente en een vir versorgers, die Bartel Index, die Caregiver Strain Index (CSI) en die Satisfaction With Life Scale (SWLS). In diepte onderhoude was gevoer met versorgers om kwalitatiewe data te verkry. Sewe en vygtig versorgers het aan die studie deelgeneem. Bevindinge van die CSI dui daarop dat 58% van versorgers hoë vlakke van spanning ervaar en ondersteuning sowel as intervensie benodig. Volgens die SWLS was die areas wat die ernstigste be-invloed was werk en eie en sosiale lewe. Die volgende areas het volgens resulate ’n statisties beduidende impak op die spanning wat versorgers ervaar het gehad: finansiële spanning en verlies van werk (p = 0.04), in gevalle waar pasiente persoonlikheids veranderinge ondergaan het (p = 0.01) of kognitiewe en perseptuale skade oorgehou het (p = 0.01) na die beroerte en die emosionele impak van versorging (p = 0.01). Versorgers het hulle versorgings take as oorweldigend en as ’n bron van groot spanning gesien. Dit is in sommige gevalle vererger deur swak ondersteuning van gesondheidssorgdienste direk na die beroerte, geen of swak verduidelikings oor wat ’n beroerte is, geen of swak opleiding aan versorgers, geen tuisbesoeke en ’n tekort aan opvolg dienste in die gemeenskap. Die tydperk direk na ontslag uit die rehabilitasie sentrum was besonder uitdagend en hulle het ondersteuning, hulp en leiding nodig in daardie tyd. Swak ondersteuning en ’n tekort aan of afwesigheid van hulpbronne in die gemeenskap het die situasie vererger. Versorgers het ’n behoefte aan gemeensskapsrehabilitasie fasiliteite, volwasse dagsorg sentrums, buite patiënte rehabilitasie dienste, tuis verpleegsorg en ondersteuningsgroepe uitgespreek.

Thesis (PhD) -- University of Stellenbosch, 2001. / ENGLISH ABSTRACT: The advent of the new millennium saw the complete sequencing of the entire human genome. Only approximately 30 000 genes, much less than was initially predicted, have been identified to be responsible for the genetic diversity in humans. This discovery has prompted a shift in the approach to disease research, since one gene can be involved in numerous diseases. This phenomenon seems to be especially true for the low-density lipoprotein receptor (LDLR) gene. Various substances beside sterols can induce transcription of the LDLR gene. Non-communicable diseases (e.g. hypertension) are common in the developing world and contribute significantly to mortality rates. The fmding that a promoter variant (-175 g~t) in the LDLR gene is associated with elevated diastolic blood pressure may explain the phenomenon of high LDL-cholesterollevels in hypertensive individuals. Studies have demonstrated that the lowering of cholesterol, especially LDL-cholesterol, can reduce the incidence of hypertension. The -175 g~t variant is located in a newly described cis-acting regulatory element which contains a putative binding site for Yin Yang (YY)-l and also demonstrates great homology to the cAMP response element (CRE) which bind the Ca2+- dependent transcription factor, CRE binding protein (CREB). The fact that Ca2+ can induce transcription of the LDLR gene may, at least in part, explain the association between the - 175g~t variant and elevated diastolic blood pressure. Cholesterol is important for various processes, such as apoptosis, maintenance of cellular membranes and immune function. The -59 c-ot mutation in repeat 2 of the LDLR gene abolishes binding of the sterol regulatory element binding protein(SREBP) to the SRE-l site. SREBP is proteolytically activated during apoptosis by two caspases (CPP32 and Mch3) to induce cholesterol levels. Our results imply that the -59C/T mutation, in repeat 2 of the LDLR gene promoter, may inhibit apoptosis under normal immunological conditions. Atherosclerosis can be considered an immunological disease, since various humoral and cellular immune processes can be detected throughout the course of the disease. The fmding that certain lipoproteins can protect against infection by binding and lysing of pathogens, or competing with pathogens for cellular receptors, prompted the investigation into the potential role of variation in the LDLR gene promoter in immune function. A significant difference in allelic distribution was detected between asymptomatic HIY -infected subjects and fast progressors for the -124 c-ot variant (P=O.006), shown to increase (~160%) transcriptional activity of the LDLR gene. Of relevance to this particular study is the fact that human herpesvirus (HHV) 6 can transactivate CD4 promoters through a partial CRE site. It has been shown that the CREB and YYl can regulate viral and cellular promoters, and these transcription factors can potentially bind to the LDLR promoter at the FP2 site. The mutation enrichment in the LDLR gene promoter seen in the South African Black and Coloured population groups can possibly provide insight into the pathogenesis of various diseases. This could also potentially, provide novel targets for treatment, since manipulation of cholesterol levels may affect the pathogenesis of various diseases. / AFRIKAANSE OPSOMMING: Die volledige DNA volgorde bepaling van die mensgenoom is voltooi vroeg in die nuwe millennium. Slegs ongeveer 30 000 gene is geidentifiseer, heelwat minder as wat in die verlede voorspel is, wat verantwoordelik is vir die genetiese diversiteit in die mens. Hierdie ontdekking het gelei tot 'n verandering in die benadering van navorsing ten opsigte van siektes, aangesien een geen 'n rol by verskeie siektes kan speel. Hierdie gewaarwording blyk veral waar te wees vir die lae digtheids lipoproteien reseptor (LDLR) geen. Verskeie stimuli, buiten sterole, kan transkripie van die LDLR geen inisieer. Verskeie siektes soos hipertensie is algemeen in die ontwikkelende wereld, en dra by tot die hoe mortaliteit syfers. Die bevinding dat 'n promoter variant in die LDLR geen (-175g-H) geassosieer is met verhoogde diastoliese bloeddruk, kan moontlik verhoogde lipiedvlakke in hipertensiewe individue verklaar. Studies het aangetoon dat die verlaging van cholesterol, veral LDL-cholesterol, die voorkorns van hipertensie kan verlaag. Die -175 g~t variant is gelee in 'n cis-regulerende element wat na bewering 'n bindingsetel vir die Yin Yang (YY)-l transkripsie faktor bevat asook sterk homologie met die cAMP respons element (CRE) toon, wat bind aan die Ca2 +_ afhanklike transkripie faktor, CRE bindings proteiene (CREB). Die feit dat Ca2+ transkripsie van die LDLR geen kan inisieer, kan dalk tot 'n mate, 'n verklaring bied vir die assosiasie tussen die -175 (g~t) variant en verhoogde diastoliese bloeddruk. Cholesterol is noodsaaklik vir verskeie prosesse soos apoptose, die instandhouding van selmembrane sowel as immuun funksies. Die -59 c-ot mutasie in die sterol regulerende element 1 (SRE-l) van die LDLR geen vernietig binding van die sterol regulerende element bindingsprotei'en (SREBP) aan SRE-l. SREBP word proteolities geaktiveer tydens apoptose deur twee kaspases (CPP32 en Mch3) om cholesterolvlakke te induseer. Ons resultate impliseer dat die -59C/T mutasie, in herhaling-2 van die LDLR-geen promoter, apoptose kan inhibeer onder normale immunologiese toestande. Aterosklerose kan beskou word as 'n immunologiese siekte, aangesien verskeie humorale en sellulere immuun prosesse deur die verloop van die siekte waargeneem kan word. Die feit dat Iipoproteiene beskermend kan wees teen infeksies, deur binding en lisering van virusse of kompeteer met patogene vir sellulere reseptore, het aanleiding gegee tot 'n ondersoek na die potensiele rol van variasies in die promoter area van die LDLR geen in immuun funksie. Betekenisvolle verskille in alleel verspreiding vir die -124c~t variant (P=0.006) is waargeneem tussen asimptomatiese MIV -geinfekteerde pasiente en individue met vinnige siekte progressie. In vitro studies het voorheen getoon dat die -124c~t 'n verhoging in LDLR geen transkripsie (160%) tot gevolg het. Dit is noemenswaardig dat 'n vroee studie getoon het dat die mens like herpesvirus-6 (MHV6) transaktivering van die CD4 promoters deur 'n gedeeltelike CRE bindingsetel kan bewerkstellig. Beide CREB en YYl kan virus en sellulere promotors reguleer, en hierdie transkripsie faktore toon bindingshomologie met die FP2 element van die LDLR promotor Die mutasie verryking van die LDLR geen promoter soos waargeneem in Suid Afrikaanse Swart en Kleurling populasies, kan moontlik lig werp op die patogenese van verskeie siektetoestande. Hierdie bevindinge kan potensieel nuwe teikens vir behandeling identifiseer, aangesien manipulasie van cholesterolvlakke 'n effek mag he op die patogenese van verskeie siektes.

Dissertation (PhD)--University of Stellenbosch, 2003. / ENGLISH ABSTRACT: The Effect of Statins on Bone and Mineral Metabolism Both statins and amino-bisphosphonates reduce the prenylation of proteins which are involved in cytoskeletal organization and activation of polarized and motile cells. Consequently statins have been postulated to affect bone metabolism. We investigated the effects of different doses of simvastatin (1,5,10 and 20mg/Kg/day), administered orally over 12 weeks to intact female Sprague-Dawley rats, and the effect of simvastatin 20mg/Kg/day in sham and ovariectomised rats, on femoral bone mineral density (BMD) and quantitative bone histomorphometry (QBH), compared to controls. Similarly, the affect of atorvastatin (2,5mg/Kg/day) and pravastatin (10mg/Kg/day) on BMD was investigated and compared to controls. BMD was decreased by simvastatin 1mg/Kg/day (p = 0.042), atorvastatin (p = 0,0002) and pravastatin (p = 0.002). The effect on QBH parameters differed with different doses of simvastatin (ANOVA; p = 0.00012). QBH parameters of both bone formation and resorption were equivalently and markedly increased by simvastatin 20mg/Kg/day in two independent groups of intact rats, and reflected by a relatively unchanged BMD. At lower doses, simvastatin 1mg/Kg/day decreased bone formation while increasing bone resorption as reflected by a marked decrease in BMD. Ovariectomised animals receiving simvastatin 20mg/Kg/day showed no change in BMD relative to the untreated ovariectomised controls, their increase in bone formation was smaller than in sham-operated rats receiving simvastatin and there was no change in bone resorption. The dose response curves of simvastatin for bone formation and resorption differed from each other. From these studies it is concluded that:- a) low-dose simvastatin (1mg/Kg/day), atorvastatin 2.5mg/Kg/day) and pravastatin 10mg/Kg/day) decrease BMD in rodents;b) 1mg/Kg/day simvastatin decreases bone formation and increases bone resorption and is reflected by a reduced BMD; c) 20mg/Kg/day simvastatin increases bone formation and resorption and results in an unchanged BMD; d) the effects of simvastatin on QBH differ at different dosages; e) the dose-response curves for QBH parameters of bone resorption and bone formation differ from each other; f) the effects of simvastatin seen in intact rats are not observed in ovariectomised rats; g) simvastatin is unable to prevent the bone loss caused by ovariectomy. / AFRIKAANSE OPSOMMING: Die Effek van Statiene op Been en Mineraal Metabolisme Beide statiene en aminobisfosfonate verminder die prenelasie van proteïene wat betrokke is in die sitoskeletale organisasie en aktivering van gepolariseerde en beweeglike selle. Gevolglik is dit gepostuleer dat statiene ‘n invloed sal hê op been metabolisme. Ons het die effekte van verskillende dossisse van simvastatien (1, 5, 10 en 20mg/Kg/dag), mondelings toegedien oor 12 weke aan intakte vroulike Sprague-Dawley rotte, en die effek van simvastatien 20mg/Kg/dag op skyn- en ge-ovariektomeerde rotte, op femorale been mineral digtheid (BMD) en kwantitatiewe been histomorfometrie (KBH), vergeleke met kontroles, ondersoek. Op ‘n soortgelyke manier is die effek van atorvastatien (2,5mg/Kg/day) en pravastatien (10mgKg/dag) op BMD ondersoek en vergelyk met kontroles. BMD is verminder deur simvastatien 1mg/Kg/dag (p = 0.042), atorvastatien (p = 0.0002) en pravastatien (p = 0.002). Die effekte op KBH parameters het verskil met verskillende dossisse van simvastatien (ANOVA; p = 0.00012). KBH parameters van beide been vormasie en resorpsie is vergelykend en merkbaar verhoog deur simvastatien 20mg/Kg/dag in twee onafhanklike groepe van intakte rotte en is vergesel deur ‘n relatiewe onveranderde BMD. Met laer dossisse het simvastatien 1mg/Kg/dag been vormasie verminder terwyl been resorpsie verhoog is en is weerspieël deur ‘n merkbaar verminderde BMD. Ge-ovariektomeerde diere wat simvastatien 20mg/Kg/dag ontvang het, het geen verandering in BMD relatief tot die onbehandelde geovariektomeerde kontroles getoon nie, en die toename in been vormasie was kleiner as in die skyngeopereerde rotte wat simvastatien ontvang het en daar was geen verandering in been resorpsie nie. Die dosis-respons kurwes vir simvastatien vir been vormasie en resorpsie het van mekaar verskil. Uit hierdie studies word die volgende gevolgtrekkings gea) lae-dosis simvastatien (1mg/Kg/dag), atorvastatien 2.5mg/Kg/dag en pravastatien 10mg/Kg/dag verminder BMD in knaagdiere; b) 1mg/Kg/dag simvastatien verminder been vormasie en verhoog been resorpsie en veroorsaak gevolglik ‘n velaging in die BMD; c) 20mg/Kg/dag simvastatien verhoog been vormasie en resorpsie met ‘n gevolglike onveranderde BMD; d) die effekte van simvastatien op KBH verskil met verskillende dossisse; e) die dosis-repons kurwes van been resorpsie en been vormasie veskil van mekaar f) die effekte van simvastatien wat waargeneem in intakte rotte word nie gesien in ge-ovariektomeerde rotte nie; g) simvastatien kannie die verlies van been wat veroorsaak word deur ovariektomie voorkom nie.