General Medicine
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- ItemComparative analysis of familial hypercholestrerolaemia in different populations(Stellenbosch : Stellenbosch University, 1999-12) Thiart, Rochelle; Kotze, Maritha J.; De Jong, G.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine.ENGLISH SUMMARY: Familial hypercholesterolaemia (FH) and familial defective apolipoprotein B-IOO (FDB) are relatively common disorders of lipid and lipoprotein metabolism caused by mutations in the low density lipoprotein receptor (LDLR) and apolipoprotein B (apo B) genes, respectively. DNA analyses at these loci were performed in 132 molecularlyuncharacterised South African, 11 Costa Rican and 13 New Zealand subjects with clinical features of heterozygous FH. Mutation R3500Q causing FDB was identified in a relatively large proportion (~30%) of the New Zealand patients. LDLR gene defects were identified in 4 Costa Rican and 6 New Zealand FH patients. Sixty-five different LDLR gene mutations were identified in South African hypercholesterolaemics, revealing ten founder-type mutations. Haplotype analysis at the LDLR and apo B loci excluded the likelihood that mutations in these two genes underlie the FH phenotype in one of the New Zealand families. The apparently autosomal dominant hypercholesterolaemia (ADH) in this family could also not be linked to a newly identified gene locus, designated FH3. Analysis of the New Zealand study cohort, although small, demonstrated both mutational and locus heterogeneity in ADH. Analysis was also extended to include subjects from the various ethnic groups within South Africa. The high prevalence of FH in Afrikaners of European descent is in striking contrast to the reported virtual absence of this lipid disorder in the Black South African population. In addition to three previously-described Afrikaner founder mutations (D154N, D206E and V408M), four minor founder mutations, D200G, S285L, C356Y and G361V, were identified in 12 Afrikaner families. Surprisingly, a 6-bp deletion in exon 2 of the LDLR gene was detected at a relatively high frequency (28%) in Black FH patients. This finding, as well as clinical correlations performed in the patients, suggests that the expression of FH mutations in the Black population may be altered due to interaction with other genetic and/or environmental factors, therefore leading to underdiagnosis of the disease. Common LDLR gene mutations have also been described in South African Indians (P664L) and Jews (del 197), most likely as a consequence of multiple introductions of defective genes into these relatively isolated communities. Caucasoid admixture was recognised as a major factor contributing to the FH phenotype in the indigenous South African population of mixed ancestry from the Western Cape, where six founder-type mutations account for the disease in 22% of cases. The high prevalence of specific LDLR gene mutations in different population groups facilitates an improved diagnostic service for FH in South Africa.
- ItemAn investigation of two animal models of anxiety : central administration of corticotropin-releasing factor on the behaviour and neurochemistry of rats, and the effect of pharmacotherapy on spontaneous stereotypical behaviour and NMDA receptor function in mice(Stellenbosch : Stellenbosch University, 2004-12) Richter, Lelanie; Daniels, W. M. U.; Stein, D. J.; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine.ENGLISH ABSTRACT: Corticotropin-releasing factor (CRF) study Background: Hypothalamic pituitary adrenal (HPA)-axis dysfunction is a common symptom of patients with anxiety disorders like posttraumatic stress disorder (PTSO), panic disorder and obsessive-compulsive disorder (OCD). Depressive patients also have HPA-axis dysfunction similar to patients with anxiety disorders. PTSD patients usually show decreased basal plasma cortisol levels whereas OCD and depressive patients show an increase in plasma cortisol. A blunted adrenocorticotropin hormone (ACTH) response to CRF is seen in these patients and mostly an increased level of CRF in their cerebrospinal fluid (CSF). It has been proposed that the CSF level of CRF is a reflection of activity of both hypothalamic and extra-hypothalamic CRF systems. Since the amygdala has been shown to be involved in the endocrine and behavioural response to stress, and CRF is involved in the mediation of this response, we investigated whether chronic elevation of CRF in the amygdala is involved in development of the symptoms of psychiatric disorders. We chronically injected rats with CRF in this area to see what the effect is on their behaviour and HPA-axis response. It has been shown that the hippocampal serotonergic (5-HT) system is involved in both anxiety and depression and that the 5-HT system is regulated by CRF. We therefore measured hippocampal 5- HT1A receptor density and affinity in CRF-injected and control rats. Materials and methods: Male Sprague-Dawley and Wistar rats were stereotaxically implanted with unilateral and bilateral chronic cannulae in the basolateral amygdala (BLA). After recovery unilaterally implanted rats were injected with 10ng (n=7) or 1DOng(n=6) of CRF or saline (n=6) daily for 5 days. Behaviour was tested on day 5 in the elevated plus-maze and open field. Rats with bilateral implants were injected with 100ng CRF (n=19) or saline (n=17) on either side for 5 days. On day 5, behaviour was tested on the elevated plusmaze and open field. Group 1 was tested at baseline levels (n=6 for saline and n=7 for CRF) and group 2 after 5 min. of restraint (n=11 for saline and n=12 for CRF). The stress response of all rats was tested 2 days later. The rats were divided into 3 groups: The first group was decapitated at baseline level (n=6 for each group), the second and third groups restrained for 10 min. and decapitated 15 min. (n=6 for saline and n=7 for CRF) and 60 min. (n=5 for saline and n=6 for CRF) after restraint stress. Blood was collected for plasma ACTH and corticosterone determinations. A group of naïve rats was also included in this experiment to control for the possible effect of the operation (n=6 for each time point). Hippocampi were dissected out and used for 5-HT1A radioligand binding studies. Results: Rats that were unilaterally injected with 1DOngCRF, showed significant increase in the amount of entries into the open arms as well as the amount of time spent in the open arms of the elevated plus-maze compared to controls and rats injected with 10ng CRF. There were no differences between the groups in other parameters of the elevated plus-maze or open field behaviour. There were no significant differences in behaviour of bilateral injected rats compared to controls, but an increase of grooming in the open field was observed in CRFinjected rats that were stressed before behavioural tests. The ACTH and corticosterone response of rats were normal as seen by a significant increase in both concentrations 15 min. after stress and a return to near basal values 60 min. post stress. There were no differences in plasma ACTH concentrations between the groups at any time point. The basal corticosterone level of CRF-injected rats was however significantly lower than controls, but no difference were found 15 or 60 min. post stress. There were no significant differences in hippocampal 5-HT1A receptor densities or affinities of CRF-injected and control rats. Conclusions: We did not observe increased anxiety levels or decreased activity in CRF injected rats. Instead, we observed increased activity in unilateral injected rats. We suspect that the lower dosage of CRF may have this effect on the behaviour of rats, since other authors have also found this result. The lack of differences in the 5-HT1A receptor populations of CRF-injected rats and control rats also confirms this result, since there was no increase in anxiety levels of CRF-injected rats. The chronic elevation of CRF in the SLA caused decreased basal levels of corticosterone in the rats and we speculate that CRF caused adrenal insufficiency although the mechanism is unknown. Stereotypical behaviour study Background: OCD affects 1-2% of the adult human population and is amongst the most common psychiatric disorders. This disorder is characterized by obsessions and compulsions. These compulsions or repetitive behaviours are suggested to be the cause of a hyperactive cortical-striatal-thalamic-cortical (CSTC) circuit in the brain, because of imbalance of the direct and indirect pathways. CSTC pathways are modulated by both 5-HT and dopaminergic (DA) neurons and it has been suggested that a hyperglutamatergic state exists in the frontal cortex of OCD patients. Two types of animal models of stereotypical behaviour are used to investigate neurotransmitter abnormalities related to OCD. These are drug induced stereotypies and environmentally induced (spontaneous) stereotypies. It has been shown that in deermice (Peromyscus manicula tis), drug induced stereotypies are topographically different from spontaneous stereotypies, and our aims were to characterize a deermice model of spontaneous stereotypy for OCD in terms of face, predictive and construct validity. We injected adult deermice, showing spontaneous stereotypies, for a time period of 8 weeks with risperidone (D2/5-HT2 antagonist), citalopram (selective serotonin reuptake inhibitor) and inositol (a metabolic precursor to the phosphatidylinositol second messenger cycle). All these drugs have been shown to improve symptoms of OCD in humans, and we investigated whether the drugs can reduce stereotypies in deermice. Materials and methods: 40 Adult deermice were raised and housed in standard laboratory cages and randomly divided into four groups (6 females and 4 males per group). After baseline recordings of behaviour (3 times per week for a total of 15 min.) the mice were injected daily for 8 weeks with risperidone, citalopram, inositol or saline. Video recordings were made for the 8 week trial and rated afterwards by raters that were blind to the medication status of the animals. A 5 sec. interval scoring system was used for ratings in which the absence or presence of a stereotypy (backward somersault) was noted. After 8 weeks of treatment, the mice were decapitated, brains were dissected and the frontal cortices were stored in liquid nitrogen until radioligand binding studies were performed on NMDA receptors. Results: There were no significant differences in the amount of somersaults between saline injected and drug treated groups when the data was analysed using an ANOVA with repeated measures. There was a significant difference between the control group and drug treated groups at week 8 in male mice when the data was analysed using a Mann-Whitney test. The amount of somersaults shown by saline injected mice increased over the 8 week trial while it stayed more constant in all three drug treated groups. There were no significant differences between the control group and treatment groups in Bmax and Kd values of NMDA receptors in the frontal cortex. There was a trend towards increased receptor densities in all treatment groups compared to the control group and a decrease in affinity in the risperidone group. Conclusions: We found limited evidence for the involvement of both 5-HT and DA systems in the development of spontaneous stereotypical behaviour of deermice. Risperidone, citalopram and inositol were useful in suppressing the increase in somersaults observed in the control group towards week 8 of the trial. This increase was presumably due to stress from handling and injections. The fact that there was a trend towards increased receptor densities in all treatment groups and decreased affinity in the risperidone group also point to the involvement of 5-HT and DA in spontaneous stereotypies. The limitation of this study was small group numbers and excessive stress experienced by the animals.
- ItemOral versus pulse intravenous cyclophosphamide: a retrospective analysis of adverse events in a high infectious diseases burdened setting(Stellenbosch : Stellenbosch University, 2014-01-14) Pretorius, Jan St Elmo; Du Toit, Riette; Davids, Mogamat Razeen; Stellenbosch University. Faculty of Medicine and Health Sciences. Dept. of Medicine: General Medicine.ENGLISH ABSTRACT: Background Cyclophosphamide (CPM) is still considered to be the first line treatment of many life-threatening autoimmune conditions. It does however carry significant risk for severe adverse events especially infections. At present CPM is either administered as a daily oral dose (DOC) or as an intravenous pulse (PIVC). There is uncertainty regarding the safety profiles of either regimen in high infectious diseases burdened settings. Objective To compare the frequency and nature of adverse events related to the use of DOC and PIVC in a high infectious diseases burdened setting. Methods A retrospective cohort of all patients treated from 1 January 2008 to 31 May 2013 with CPM for autoimmune diseases at Tygerberg Academic Hospital was studied comparing DOC and PIVC. Disease characteristics and occurrence of major adverse events of participants in each group was compared. Results A total of 134 (92 DOC and 42 PIVC) participants were included. Participants in the DOC group were treated for longer (174 vs. 101 days, p<0.01) and with higher cumulative doses (17 276 mg vs. 3 327 mg p<0.01). Risk for infection was similar in both groups although 6 vs. 0 (p=0.18) participants in the DOC group died due to leukopaenic sepsis. Nadir leukocyte counts were also lower in the DOC group (median 3.8 x 10⁹/l vs. 5.3 x 10⁹/l, p=0.02). Conclusion Infection rates in both groups were similar. DOC was, however, associated with longer treatment duration, greater cumulative CPM doses and more severe leukopaenia. If resources allow and available literature provides support for efficacy, consideration should be given to greater use of PIVC.