Theses and Dissertations (Internal Medicine)

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'n Ontleding van die gebruik van dwelmmiddels en sekere gevolge daarvan, met klem op cannabis sativa, by 'n monster jongmans opgeroep vir militere diensplig
(University of Pretoria, 1974) Snyman, H.W.; Levin, Aubrey
Afrikaan: 'n Ontleding van die patrone van gebruik van dwelmmiddels deur 'n mon- ster 448 jong Blanke Suid-Afrikaanse mans bet getoon dat Cannabis sativa verreweg die algemeenste middel van misbruik was; nie minder as 443 (98,83 persent) was Cannabisafhanklik nie. Cannabis is enkele middel deur 137 (30,2 persent) gebruik. 306 pasiente (68,3 persent) bet Cannabis sowel as antler dwelmmiddels gebruik. Die tweede middel in rangorde was amfetamien (33,0 persent). As derde middel bet LSD (30,6 persent), met fenfluramien (25,7 persent) as vierde gevolg. Onder algemene misbruikte middels is opiaatbevattende boesmidde1s (22, 1 persent), alkobol (27,4 persent), rou opium (21,4 per- sent) (alboewel daar twyfel is omtrent bierdie middel), inademingsmiddels (20,3 persent), propielbeksedrien (16,9 persent), barbiturate (15,9 per- sent), Datura stramonium (8,3 persent), "Mandrax" (7,8 persent), morfien ( 7, 1 persent), bensbeksol ( 6, 7 per sent) , kokaien ( 5, 1 per sent), "Red upon" (4,9 persent), heroen (3,8 persent), bensodiasepiene en analgetika (3,6 persent). Die graad van Cannabisafhanklikheid was swaarder as by en1ge ander soort- gelyke ondersoek in Suid-Afrika of in die buiteland tot dusver bekend. Nie minder nie as 38,2 persent het Cannabis onder optimale omstandighede ten minste daagliks gebruik. Meer as 'n kwart van die dwelmmiddelafhanklikes het optimaal meer as 115 g (+- 4 onse) rou Cannabis per week gebruik. "Durban Poison" en "Rooibaars" 1s die twee plaaslike Cannabis-soorte wat · voorkeur geniet het. Die rookrnetode is deur feitlik al die Cannabisafhanklikes bo inname deur die spysverteringstelsel verkies. Die gewildste rookmetodes is d.m.v. 'n "sjaloempie" (pyp) in 21, 1 persent, die "bottelnek" in 14,3 persent en sigaret in 30,8 persent. Slegs 3,6 persent het enige dwelmmiddel ingespuit. Hoe meer Cannabis gebruik is (bepaal in terme van massa gerook of gereeld- heid van gebruik), hoe groter was die neiging om ook ander dwelmmiddels te gebruik. Tydens die ondersoektydperk wat gestrek het van 1 Januarie 1971 to 31 Augustus 1973, is bepaal dat aanvanklike veranderings in dwelmmiddelpa- trone ingetree het. Cannabis-gebruik het geneig om 'n meer bimodale ver- spreiding te toon; met 'n neiging na swaarder of ligter afhanklikheid. Die gebruik van amfetamien het vanaf 56 persent na 24,8 persent gedaal, maar die gebruik van fenfluramien, propielheksedrien, bensheksol, bensodiasepiene en "Mandrax", het onder andere onlangs vermeerder. Plaasvervanging word gepostuleer. 'n Ondersoek van die monster het getoon dat 58 persent self (vrywilliglik) aangemeld het vir behandeling, terwyl 16 persent weens besit van dagga verwys is. Nuuskierigheid is die belangrikste enkele etiologiese faktor in die ont- staan van die probleem (43,75 persent), maar portuurgroepinvloede, permis- s1ewe lewenspatroon, 'n soektog na verligting van onderliggende psigiatriese simptome soos angs en depressie, is ook belangrike faktore wat die ontstaan en voortgesette gebruik van dwelmmiddels aan die hand gewerk bet.
Clinical presentation and echocardiographic diagnosis of rare and subtle congenital cardiovascular anomalies in the adult
(University of Pretoria, 2019-09-10) Van Heerden, W.F.P. (Willem Francois Petrus), 1958-; Tintinger, Gregory Ronald; jker@wol.co.za; Ker, James A.
In his thesis, Clinical presentation and echocardiographic diagnosis of rare and subtle congenital cardiovascular anomalies in the adult, the candidate submitted thirty six articles published by him during the preceding thirteen years. These articles all have a central theme, namely the clinical and echocardiographic presentation of rare and subtle congenital cardiovascular anomalies in the adult. These articles have all been published in international, peer reviewed journals with significant impact. In addition, these thirty six articles have been widely cited and some have been included in textbooks on cardiology. The articles in this thesis have therefore contributed to this specific field of study in cardiology and is currently guiding further research in the field as evident by the number of citations for this work.
Characterization of efflux pumps genes involved in second-line drug resistance of tuberculosis
(University of Pretoria, 2017) Fourie, P.B. (Petrus Bernardus); Stoltz, Anton Carel; Van der Walt, Martha L.; lesibana.malinga@mrc.ac.za; Malinga, Lesibana Anthony
In this study, we used molecular and proteomic methods to detect novel changes within drug-resistant tuberculosis (TB) strains. Our goal was to detect changes within efflux pump (EP) genes of extensively drug resistant (XDR-TB) strains using genomic and transcriptomic methods. We firstly sequenced multiple genes in discordant samples that lacked molecular markers present on the GenoType® MTBDRsl assay. Further analysis by whole genome sequencing was done on XDR-TB strains. Transcriptomic changes of EP genes were detected by RNA sequencing strains. The minimum inhibitory concentration (MIC) of second-line drugs in the presence and absence of efflux pump inhibitors was also measured. Proteomic expression by cloning and expression of three efflux pump genes (Rv1258c, Rv1634 and Rv0194) was done and effect on MICs of second-line drugs measured in the presence and absence of efflux pump inhibitors. We analysed molecular markers responsible for resistance to second-line drugs of ofloxacin (OFX), amikacin (AMK), kanamycin (KAN) and capreomycin (CAP) in 636 drug-resistant strains using GenoType® MTBDRsl. We compared GenoType® MTBDRsl with phenotypic second-line drug susceptibility testing. After comparison, 102 (14.8%) strains were discordant between the two methods. In the discordant population, genetic regions of gyrA, gyrB, rrs, eis, tlyA and EP genes (Rv1634, Rv1258c and Rv0194) were sequenced and analysed in search of mutations. Combining sequencing and GenoType® MTBDRsl significantly improved the diagnosis of XDR-TB and second-line drugs. The Rv0194 belongs to the ATP (adenosine triphosphate) binding cassette (ABC) family while Rv1258c and Rv1634 belong to the major facilitator superfamily (MFS) transporters. Since these genes are implicated in multiple drug resistance, our hypothesis was that possible mutations in these genes could confer cross-resistance. Our analysis revealed the appearance of Rv1258c and Rv0194 mutations in strains with cross-resistance to second-line injectable drugs. Further analysis revealed rrs G878A mutation that was specific to EuroAmerican X3 lineage (P<0.001) and linked to CAP resistance. The inclusion of G878A in new rapid assays might be beneficial for rapid CAP resistance detection. Whole genome sequencing with increased resolution and depth was used to study two XDR-TB strains. Drug resistant mutations were detected for all other drugs except for OFX in one strain. We further analysed EP genes for mutations. Bioinformatic prediction tools detected protein changes related to EP gene mutations belonging to Rv0987, Rv2039 and Rv0402. Two of the efflux pump genes (Rv0987, Rv2039) belong to the ABC family, while Rv0402 is of resistance nodulation-cell division (RND) family. Mutations within lipid metabolism and secretion pathways were also detected. To fully understand the role of EP gene mechanisms at a transcriptional level, we sequenced RNA molecules of 11 XDR-TB, five MDR and two susceptible strains. The RNA signatures of EP and lipid metabolism genes detected in XDR-TB strains were characterized. Further analysis of four XDR strains with MIC data with or without efflux pump inhibitors (EPIs) was performed in relation to RNA sequenced data. The ABC Rv2686/87/88c operon was significantly over-expressed in the background on strains with gyrA mutations causing OFX resistance. The Rv1258c, Rv0194 and Rv1634 EP genes were consistently over-expressed in XDR TB strains. Efflux pump inhibitor of piperine was effective in reducing MICs to hydrophilic drugs of AMK and OFX whereas verapamil reduced MIC of hydrophobic CAP drug. Protein-protein interaction pathways revealed novel associations between ABC, RND and type VII secretion (T7S) proteins. Finally, we cloned and expressed Rv1258c, Rv0194 and Rv1634 EP genes in Mycobacterium vectors. These genes have the potential to cause multidrug resistance. We did not detect increased MIC levels of second-line drugs in the presence of the clones. However, a reduction of MICs in the presence of the EPI, piperine, was observed. Bioinformatic approaches also revealed transmembrane motifs, domains and loops. Since EP genes are implicated in transport of substrates across cell membrane, we used biofilm formation assays to determine the role of each clone. Both Rv1258c and Rv0194 clones showed biofilm formation. Such discovery highlights the secretion of lipid bodies on the cell wall of the bacteria through EP genes/proteins. This information will allow us to develop novel strategies to treat drug-resistant TB. Our study emphasises the importance of EP gene mechanisms in causing drug resistance. The combination of EP and target genes is important in the detection of second-line drugs. Furthermore, it is suggested that EPIs combined with second-line drugs might be effective in the treatment of XDR-TB.
Clinical and laboratory markers of disease activity and response to therapy in South Africans with rheumatoid arthritis with disease duration less than two years
(University of Pretoria, 2015) Anderson, Ronald; Tintinger, Gregory Ronald; tar@up.ac.za; Ally, Mahmood Moosa Tar Mahomed
Rheumatoid arthritis (RA) is a chronic inflammatory disorder resulting in joint pain, stiffness and joint destruction. This can lead to considerable loss of physical and psycho-social function and even premature death. However, numerous advances in the management of RA have led to remarkable life-changing effects, especially when therapy is initiated early. Joint inflammation occurs following an abnormal immune response to some yet unidentified agent. The inciting agent or process is not well understood but exceptional advances have been made in characterising the molecular and cellular components of the ensuing inflammatory response. This has culminated in the identification of novel therapies and potential biomarkers to enhance patient care. Genetic and environmental factors play an important role with varying clinical manifestations and unpredictable outcomes on an individual basis. Globally, RA accounts for considerable morbidity and of particular concern in the developing world, is the lack of resources that may adversely affect outcome. There is a paucity of research on various aspects of RA in the developing world. This study will review immune-pathogenic aspects of RA, the potential use of clinical features and serological biomarkers and report on aspects of the analysis of a prospective observational study of patients with early RA, prior to starting and 6 months following therapy. A cohort of 171 early RA patients (disease duration less than 2 years) was recruited from the rheumatology clinics of two tertiary academic hospitals, located in Gauteng, South Africa. The objective of the study was to review clinical, demographic, radiological and serological aspects over a two year period. Outcome measures of this study included; i) characterisation of disease burden with respect to both physical and psycho-social aspects; ii) response of disease to therapy in routine care; iii) to characterize auto-antibody, cytokine, cartilage metabolites and genotype profiles associated with disease activity and response to therapy; and iv) clinical and serological measures associated with radiographic damage. Clinical measures included the simplified disease activity index (SDAI) and functional scores (HAQ-DI and SF-36). At baseline and 6 months rheumatoid factor (RF), Anti-citrullinated peptide antibodies (ACPA), circulating cytokines and growth factors were measured. Cartilage metabolites COMP and matrix metalloproteinase (MMP)-3 were measured only at baseline. Genotyping for the shared epitope (SE) HLA-DRB1 allele was performed and classified according to the du Montcel classification. Radiographs of the hands and feet were taken at baseline and at yearly intervals and evaluated for erosive disease and scored according to the Larsen grading system. The cohort recruited was mostly female (140) with a mean age of 47 years. Despite a mean symptom duration of 12 months, patients had severe disease with a mean SDAI of 39.4, with nodulosis and erosive diseases seen in 23% and 51 % respectively. Auto-antibody tests revealed high sensitivity (83%) and specificity (85%) for ACPA with the highest specificity (95%) if both RF and ACPA were positive. Shared epitope positivity was found in 92% of patients and correlated strongly with ACPA. Cytokine levels were globally increased favouring a T helper cell (Th)1, macrophage and pro-angiogenic cytokine profile in certain sub-groups. MMP-3 levels correlated with measures of disease activity but did not perform better than routine laboratory measures such as the C-reactive protein (CRP). Serial measurement of auto-antibodies and cytokine profiles at 6 months revealed significant decreases in tandem with a decrease in disease activity. A more robust decline in cytokine levels was noted in patients who achieved a low disease activity state (SDAI<11) and in patients who received prednisone in addition to methotrexate (MTX). Of the auto-antibodies and biomarkers tested only MMP-3 was predictive (OR 2.8) of an SDAI>11 at 6 months. Only 28% of patients achieved a low disease activity state at 12 months. Predictors of outcome at 12 months included low level of education, unemployment, radiographic damage and a high disease activity. Conclusion: RA in sub-Saharan Africa is strongly associated with SE and ACPA status and a high disease burden at presentation. Despite therapy, only a small percentage of patients achieved an acceptable level of disease activity in routine care underscoring the need for a more aggressive therapeutic approach. Serial measurement of auto-antibodies and cytokines had limited clinical value in routine patient care, but may guide future therapies with the potential to help in stratifying patients. The measurement of serum MMP-3 at baseline may identify a subgroup of patients with a poorer prognosis and hence allow for a more intensive therapeutic approach from the outset.
Naturally occurring canine osteosarcoma in the dog animal model for research of targeted radiotherapy using beta-emitting radioisotopes with various ligands
(University of Pretoria, 2013) Dormehl, I.C.; Louw, Werner; Milner, Rowan James
Please read the abstract in the thesis.
Naturally occurring canine osteosarcoma in the dog animal model for research of targeted radiotherapy using beta-emitting radioisotopes with various ligands
(University of Pretoria, 2013) Dormehl, I.C.; Louw, Werner; milnerr@ufl.edu; Milner, Rowan James
Metastatic and primary bone cancers are devastating diseases of paediatric and adult humans because of the morbidity associated with bone pain. Controlling bone pain from multiple metastatic sites can be difficult in end-stage cancers using conventional therapies. Bone-seeking radiopharmaceuticals have been successful in this area as radiation can be delivered with moderate selectivity to the target. Unfortunately, targeted radiotherapy using radiopharmaceuticals have been relegated to palliative therapy as myelosuppression largely limits the radiation dose to sub-therapeutic levels. Efforts to overcome this therapeutic limitation include autologous bone marrow transplants in combination with chemotherapy-radiosensitization and the development of new radiopharmaceuticals. Development work using laboratory rodent models has been complicated by dosimetric limitations because of size and inherent problems with human xenografted tumour models in rodents. To address this need we studied naturally occurring canine osteosarcoma as a translational model for human bone cancer. Central to our hypothesis was that naturally occurring canine osteosarcoma would serve as an investigational model for comparing the pharmacokinetics (biodistribution), dosimetry, toxicity, and therapeutic effect of 153Sm-EDTMP, 188Re-HEDP, 186Re-HEDP, and a novel ligand, polyethyleneiminomethyl phosphonic acid (PEI-MP). Data collected from existing radiopharmaceuticals was then compared to PEI-MP labelled with 99mTc, 153Sm, and 186Re. This innovative and unique study allowed for the evaluation of various radiopharmaceuticals in a naturally occurring animal model of bone cancer, documenting the pharmacokinetics and dosimetry of a novel radiolabelled-ligand (PEI-MP). Benefits resulting from the successful completion of the study would allow more rapid transfer of rodent preclinical data into a naturally occurring cancer model more resembling to the human diseases and would thus more likely identify problems with pharmacokinetics and toxicity before proceeding to expensive clinical trials. The expected outcomes of the study were originally formulated based on limited previous published data in dogs. For instance, no data exists describing the pharmacokinetics or toxicity of 188Re-HEDP and 186Re-HEDP in the dog. The study was conducted in two phases. The first phase deals with the evaluation of 153Sm-EDTMP, 188Re-HEDP, and 186Re-HEDP in the dog model. Phase-two was the development of a novel ligand (PEI-MP) in the dog model of osteosarcoma, which has the characteristics of an ideal ligand. Pharmacokinetic results for 153Sm-EDTMP in normal dogs (n=4) for blood were similar to published reports for dogs and human. When compared statistically to human data the majority of results were the same, lending credence to the hypothesis that dogs could serve as models for human radiopharmaceutical research. Normal dogs and the osteosarcoma dog did differ from human pharmacokinetics in the urine elimination phase (t½-â). This can most likely be explained by the tumour burden in the human research populations or due to the fact that most humans were aged and likely to have some renal disease. Certainly, the trend in dogs with osteosarcoma was to have a prolonged urine elimination phase (t½-â) compared to normal dogs which supported the hypothesis that the biodistribution and pharmacokinetics results from dogs were similar to human published data. Statistical comparisons were also made between normal dogs receiving 188Re-HEDP and 153Sm-EDTMP. The prolonged urine elimination phase (t½-â) and increased blood retention of 188Re-HEDP was most likely a reflection of prolonged bone washout and soft issue retention. This could be attributed to the differences between the antiresorptive capability of bisphosphonate ligands e.g., EDTMP (lexidronam) with a greater than 100-fold antiresorptive capability than HEDP (etidronate). Additional observational biodistribution studies using macro- and micro-autoradiography techniques were also performed in canine tissue and Sprague-Dawley rats. Results from the studies showed heterogeneous uptake within tumours in dogs. In rats, localization of 153Sm-EDTMP in red marrow areas would lead to a high radiation dose to blood producing elements. In addition, high uptake was documented at the metaphyseal growth plate confirming the likelihood of a delay or cessation of growth if 153Sm-EDTMP were used in growing children. Phase-one of the clinical trial in dogs with naturally occurring osteosarcoma identified only mild toxicity at the dosage rate of 37 MBq/kg (1 mCi/kg) for both 153Sm-EDTMP and188Re-HEDP. In addition, a pilot trial was conducted in dogs receiving 153Sm-EDTMP which also received a carboplatin infusion at the time of the radiopharmaceutical administration followed by another 3 cycles of carboplatin at 3 weekly intervals. No differences in toxicity were noted between the carboplatin group and dogs receiving only 153Sm-EDTMP. As a part of the 188Re-HEDP clinical trial, 3 dogs with osteosarcomas received weekly dose of 188Re-HEDP at 37MBq/kg for 4 weeks in which only mild toxicity was noted. Unfortunately, there was no cessation in growth of the tumours, with all dogs showing progression. The median survival time for both radiopharmaceuticals was 4 months, significantly shorter than the 10-month median survival time for amputation and chemotherapy. Interestingly six dogs that had 99mTc-MDP and 153Sm-EDTMP showed scans of tumours that had consistently lower 99mTc-MDP uptake ratios (normal bone compared to cancerous bone) compared to solely 153Sm-EDTMP. In contrast, this was not evident for uptake ratios between 188Re-HEDP and 99mTc-MDP scans. Once again, this finding highlights the differences between the antiresorptive capabilities of the bisphosphonates ligands. Interestingly, another three dogs were scanned with 99mTc-MDP , 153Sm-EDTMP, and 99mTc-PEI-MP (10-30 kDa) showed a variation in uptake between scans of the same tumours. More importantly, the uptake ratios of 99mTc-MDP and 153Sm-EDTMP scans showed wide variation with a coefficient of variance of 52% and 39% respectively. However, the range in uptake from the 99mTc-PEI-MP (10-30 kDa) scan was narrow with a coefficient of variance of only 6%. This could be attributed to more consistent uptake ratio of the unique ligand PEI-MP and its hypothesized mechanism of action: enhanced permeability and retention (EPR) in tumour vasculature. This requires further investigation with larger groups. In phase-two, the pharmacokinetic result for the novel ligand PEI-MP was initially studied labelled with 99mTc. Various molecular weights were tested in normal dogs and compared to previously published results in baboons. Results from the dog studies were found to be similar to those from the primate study. As in the primate study, molecular weight and charge played a significant role in 99mTc-PEI-MP pharmacokinetics. Increasing the size of the macromolecules and altering their charge resulted in marked changes in their pharmacokinetics and biodistribution. The PEI-MP molecular weight of 10-30 kDa and 20-30 kDa were the most promising and fulfilled the hypothesized criteria of an ideal radiopharmaceutical. In keeping with the aims of the study, the 20-30kDa polymer was considered more desirable because of its faster clearance. However, because of the limitations imposed by the percentage yield of the different molecular weights of the ligand during filtration, we decided to label the 10-30kDa molecular weight MW-fraction with 153Sm. Unexpectedly, the 153Sm-PEI-MP 10-30 kDa had a prolonged urine elimination phase (t½-â) associated with increased liver uptake when compared to 99mTc-PEI-MP10-30 kDa. To explain this, computer modelling for blood plasma (ECCLES) was done which predicted that there would be some chemical dissociation of the 153Sm from the PEI-MP polymer in blood. This is due to interaction between the radiopharmaceutical and citrate, forming 153Sm-citrate. The ECCLES model for blood plasma also predicted that the anionic MW-fraction, PEI-MP 10-30kDa, would be a poor ligand complexed to 166Ho, 212Pb, 213Pb, and 89Sr, but was expected to be effective when complexed to 186Re or 188Re, based on their close proximity to 99mTc on the periodic table. As a preliminary study 186Re was complexed to 20-30 kDa (n=2) and 30-50 kDa (n=1) MW-fractions and tested in dogs. The results were similar to 99mTc-PEI-MP 10-30 kDa. The biodistribution data and pharmacokinetic data were also used to do comparative dosimetry between radiopharmaceuticals. Not surprisingly, the dosimetry data confirmed the high red marrow dose for 153Sm-EDTMP and the increased soft-tissue dose of the radionuclides complexed to HEDP. The radiation dose to the tumour for all radiopharmaceuticals fell within the range of 26Gy to 44Gy. This is well within the range used to treat canine osteosarcoma using external beam radiotherapy. When compared to external beam radiotherapy, the probable lack of tumour response in our clinical trial relates to the heterogenous distribution of the radiopharmaceutical in the tumour and the inherent resistance of osteosarcoma cells to continuous low-dose radiation delivery (CLDR) inherent in radionuclide -particle decay. The study met the majority of outcomes with the exception of labelling PEI-MP with 153Sm. This was due to the interaction of the 153Sm-PEI-MP complex with citrate ions in blood. Rapid deterioration of the Rhenium-188 generator also led to earlier than expected curtailment of the 188Re-HEDP therapeutic trial although sufficient data was available to be used in a comparative study.
Autoimmune hepatitis : a clinical study
(University of Pretoria, 2011-01-10) Fevery, Johan; Van Gelder, Antoine; elwinbuchel@yahoo.com; Buchel, Elwin Herbert
This study involved the analysis of 112 patients with autoimmune hepatitis (AIH), during which process several specific issues or problems were identified. One subgroup included pregnant patients, and another patients diagnosed at an older age (>65 years). The diagnosis of AIH is not always easy, and the investigations revealed that some patients diagnosed with AIH had features of an overlap syndrome (with primary sclerosing cholangitis) or in fact never had AIH, but as retrospectively diagnosed, had toxic hepatitis masquerading as AIH. Some patients who were initially documented as clearly having chronic hepatitis C, also had autoantibodies in their serum and were (or could have been) incorrectly diagnosed as AIH. The results showed a large variability in symptoms and complaints at the time of diagnosis of AIH. The disorder can present as an acute or chronic disease. In some patients only vague symptoms are reported and in others, the diagnosis is an incidental discovery because of abnormal liver enzymes. In contrast, other patients present with acute liver failure. The diagnosis must be considered in patients with non-viral liver disease with significantly raised ANA and SMA and high serum gammaglobulin concentrations. No fixed age predisposition was found, but rather an even spread over various age groups. The male:female ratio is 1:2.5. This disorder can for the most part be well treated with a combination therapy of corticosteroids and azathioprine. Experience shows that high doses of corticosteroids can cause serious complications, particularly in older patients. A lower dose is mostly adequate, although biochemical normalisation may take longer. In approximately half of the patients, corticosteroid-therapy was discontinued, with azathioprine as the only treatment. The long-term survival of adequately treated patients is almost equal to that of the control group. In the cohort, ten patients died: three who had presented with acute liver failure, two who later developed a hepatocellular carcinoma and one who died because of cerebral lymphoma. Three older patients died of sepsis, possibly co-induced by high doses of steroids. Five patients underwent liver transplantation, of which one died of aspergillosis.
The effect of exercise training on the autonomic function, disease activity and functional capacity in females suffering from rheumatoid arthritis
(University of Pretoria, 2012-10-04) Ker, James A.; christa.jansevanrensburg@up.ac.za; Janse van Rensburg, Dina Christina
Introduction: Rheumatoid arthritis (RA) is a chronic disease and one of the more common auto-immune diseases. Patients with RA rely almost solely on pharmaceutical intervention to manage the disease. Autonomic impairment has been proven in previous studies on patients with RA. The positive effect of exercise on autonomic impairment has also previously been demonstrated, but not in the RA population. The purpose of this study was firstly to confirm autonomic impairment in a South African based female population with RA and secondly to evaluate the effect of exercise on the autonomic cardiac function (as measured by short-term heart rate variability), disease activity and functional capacity. Methods: The study was conducted at the University of Pretoria during 2009 and 2010. In the first phase of the study female RA patients were recruited from all rheumatology practices in Pretoria and healthy controls were recruited from family and friends of the research team and of the RA group. Cardiac autonomic function was compared between the two groups by means of short-term heart rate variability. Three techniques were used: time domain, frequency domain and Poincare plot analysis. In the second phase of the study, females with confirmed RA were randomly assigned to an exercise group and a control group. The exercise group was requested to train under supervision two to three times per week for a period of twelve weeks, while the control group continued with their sedentary lifestyle. At study completion the two groups were compared for the effect of exercise intervention on the following three aspects:
Autonomic function (as measured by heart rate variability)
Disease activity (as measured by Disease Activity Score, Visual Analogue Scale and Health Activity Questionnaire)
Functional capacity (as measured by strength, flexibility and aerobic capacity)
Results: In the first phase of the study comparing females with RA (n=45) to healthy females (n=39), the basal heart rate was significantly higher in the RA group. In the supine position significant differences existed between the RA group and the control group (p ≤ 0.01). Indicators of parasympathetic activity showed significantly lower variation in the RA group [RMSSD=14.70, pNN50=0.50, SD1=10.50, HF(ms2)=31] compared to the control group [RMSSD=29.40, pNN50=7.8, SD1=20.9, HF(ms2)=141.00]. Indicators of sympathetic variation were also significantly lower in the RA Group [SD2=36.70, LF(ms2)=65) compared to the Control group (SD2=49.50, LF(ms2)=175]. In the standing position 8 variables indicated autonomic impairment by significant differences (p≤0.01) between the 2 groups. The response of the RA Group to an orthostatic stressor showed less vagal withdrawal, [p-values for RMSSD=0.038, pNN50=0.022, SD1=0.043 and HF(ms2)=0.008 respectively]; and lower sympathetic response [p-values for SD2=0.001 and LF(ms2)<0.001] when compared to the Control group. In the second phase of the study, comparing an RA exercise group to a RA sedentary group, three aspects were evaluated: 1. Heart rate variability At baseline the control group (n=18) had significantly higher variability compared to the exercise group (n=19) for most heart rate variability (HRV) indicators. At study completion the variables showing significant changes (p=0.01 to 0.05) favoured the exercise group in all instances. Wilcoxon signed rank tests were performed to assess changes within groups from start to end. The exercise group showed significant improvement for most of the standing variables, including measurements of combined autonomic influence e.g. SDRR (p=0.002) and variables indicating only vagal influence e.g. pNN50 (p=0.014). The control group mostly deteriorated with emphasis on variables measuring vagal influence [RMSSD, pNN50, SD1 and HF(ms2)]. 2. Disease activity At baseline the two groups were comparable. At the end of the intervention, the exercise group had significant improvement for the tender joint count (p=0.015), swollen joint count (p=<0.001), physician global assessment (p=0.003) and DAS score (p=0.003) compared to the control group. To assess changes that happened within each group from start to end, Wilcoxon signed rank tests were performed. The exercise group improved significantly with regards to tender joint count (p=0.002), swollen joint count (p=0.001), physician global assessment (p=0.001), DAS score (0.001) and the visual analogue scale (p=0.032). The sedentary group improved significantly only in the health assessment questionnaire (p=0.032). 3. Functional capacity Comparing the groups at baseline the exercise group had better knee- and hip flexion on the left hand side but it took them longer to complete the arm curl test. At study completion the exercise group was mostly favoured with regards to flexibility (significant p-values ranging between 0.001 – 0.049), strength (handgrip right p<0.001, leg strength p=0.035, arm curl test p=0.010, sit to stand test p=0.025) and aerobic fitness (1 mile walk test p<0.001 and VO2 max p=0.007). Changes within each group were assessed by Wilcoxon signed rank tests. The exercise groups showed significant changes for many parameters in the three categories, i.e. flexibility (8 of 18), strength (5 of 5), and aerobic fitness (4 of 8). The control group mostly deteriorated in flexibility, while their strength also improved, but not to the same extent as for the exercise group. Their aerobic fitness did not change. Discussion: In the first phase of this study, using standardised methods to measure short-term HRV, females with RA showed less variability compared to a healthy age- and sex matched control group. An inability of the autonomic nervous system to efficiently compensate to internal and external environmental changes may predispose RA patients to arrhythmias thereby increasing cardiovascular mortality. All 3 methods used showed the same outcome, implying decreased HRV and thus an increased risk for arrhythmias in RA patients. Evaluating the autonomic nervous system might be critical in planning management of RA. In the second phase study results indicated that twelve weeks of exercise intervention, had a positive effect on cardiac autonomic function as measured by short-term HRV, in females with RA. Several of the standing variables indicated improved vagal influence on the heart rate. Exercise can thus potentially be used as an instrument to improve cardiac health in a patient group known for increased cardiac morbidity. The exercise programme was also effective in decreasing perception of pain as well as disease activity in female RA patients. Given our findings it seems warranted to include physical exercise as part of the treatment prescription of patients with class I and II RA. Lastly this research has shown that regular, controlled exercise for RA patients with controlled disease can decrease joint stiffness and improve joint mobility, strength and aerobic capacity without exacerbating pain or disease activity. Also, if one observes the decline in the sedentary group for many parameters, it is important to note that this happened over a relative short time period and that even a small change may have a detrimental impact on the RA patient. The current report supports previous literature on autonomic impairment in patients suffering from RA as well as the meaningful positive effect of exercise on disease activity and functional capacity. It is the only study on the effect of an exercise intervention on the cardiac autonomic function of RA patients. Future research in this field should aim for larger study samples, longer intervention periods and perhaps add analysis of blood pressure variability to support results obtained by HRV analysis.
The effects of providing pre-test ordering cost information on laboratory test costs in an Internal Medicine ward of a tertiary care hospital
(University of Pretoria, 2011-07-14) Rheeder, Paul; Soma, Prashilla; ellemdin@Imaginet.co.za; Ellemdin, Sirajudeen
Objectives: The aim of the study was to ascertain the efficacy of an intervention -where laboratory test costs were provided to clinicians as a pocket-sized brochure - to reduce the laboratory test costs over a 4 month period. Design: This was a non randomised intervention study where the intervention. group was compared to a similar and concurrent control group regarding the difference in laboratory test costs over a specified period in a specific year. The costs incurred were also computed for the same 2 groups over an identical time period and seasonal period in the preceding year, referred to as the control period. Setting and Subjects: The study was conducted in the Internal Medicine Wards at the Steve Biko Academic Hospital. The intervention period was during the winter months of May to August 2008 and the pre-intervention period was in the same months of the preceding year. Outcome measures: In the two (2007 and 2008) 4 month periods, for each patient admitted, the number of days in hospital and the laboratory tests ordered were computed. For the Intervention and control groups, pre and post intervention cost and days in hospital were estimated. The differences in logcosts per day were compared over time using ANOVA with group (1-2), time (1-2) and group*time as factors. Results: The mean cost per patient admitted in the intervention group decreased from R 2864.09 to R 2097.47 as a result of the intervention – a 27 % reduction in cost. The mean cost per day in the intervention group as a whole also decreased from R 442.90 to R 284.14 due to the intervention – a 36% reduction in cost. By contrast, in the control group, all costs increased in the control group from the pre-intervention to intervention periods – mean cost per admission in this group increased from R 1859.87 to R 2429.25 – an increase of 23%. The mean cost per day admitted in this group also increased from R 363.54 to R 371.92 – an increase of 2.2%. Conclusion: A heightened awareness of the cost of a laboratory test be it prospectively or retrospectively is a cost-effective and sustainable method of making doctors order tests rationally and appropriately.
Inpatient diabetes care : evaluation and intervention
(University of Pretoria, 2012-05-08) Rheeder, Paul; danie.vanzyl@up.ac.za; Van Zyl, Danie G.
The management of patients hospitalised with diabetes mellitus is neglected in South Africa. The research on which this thesis is based assessed factors contributing to glycaemic control as well as evaluated an intervention aimed at improving of such control in diabetic inpatients. A survey of doctors and nurses measuring their perceptions, knowledge and attitudes regarding care of diabetic inpatients was done. This indicated a need for special training in inpatient diabetes care, where 90.5% of respondents realised that diabetes is a serious condition and 92.2% valued the importance of tight glycaemic control. Despite these perceptions, the knowledge of doctors and nurses caring for diabetic inpatients was suboptimal. A before and after study regarding an intervention to improve glycaemic control of diabetic inpatients consisted of a training programme and the introduction of an inpatient management protocol. The mean blood glucose on day one of admission after the intervention was significantly higher than before the intervention (p < 0.001). A significant improvement in mean blood glucose from day 1 to day 7 of hospitalisation was seen after the intervention (p < 0.001), which was not significant before (p = 0.33). The proportion of patients achieving glycaemic control did not significantly differ before and after the intervention (43.0% versus 43.7%, p = 0.97). A double blind randomised controlled trial to assess superiority of Ringer’s lactate solution compared to 0.9% Sodium chloride solution in the normalisation of pH in patients with diabetic ketoacidosis was done. The outcome of this study indicated that the time to normalisation of venous pH (pH > 7.32) (HR: 1.863, CI: 0.937 to 3.705, p = 0.758) was not significantly different between the two resuscitation fluid groups The time to reach a blood glucose of 14 mmol/L was significantly longer in the Ringer’s lactate group (p = 0.044) and patients needed significantly more insulin (p = 0.02). The overall conclusion of this study is that there is no significant benefit in using Ringer’s lactate solution as initial resuscitation fluid compared to the currently advised 0.9% Sodium chloride solution.
Die herkenning van koronêre hartsiektes in stedelike swart mense (Afrikaans)
(University of Pretoria, 2007-04-05) Van Gelder, Antoine; upetd@ais.up.ac.za; Loock, Margaretha Elizabeth
The paucity of data concerning the etiology and development of coronary heart disease (CHD) and its risk factors prompted this case-control study. The prevalence of CHD and its accompanying CHD-risk factors among black people from Africa during the twentieth century is covered in the literature review. Differences between developed and developings countries and the possible role of multivariate analyses for the recognition of CHD are addressed. The aims and objectives follow the discussion of the literature review. Between 1982 and 1986 we identified 89 black South African patients with CHD, according to > 2 criteria of the World Health Organization (WHO) for CHD. The diagnosis of underlying coronary artery disease (CAD) was confirmed using coronary angiography, and/or necropsy until 1994. Exercise-radionuclide imaging was also used to confirm manifestations of underlying CHD. A control group of 356 black people living in the same study area and with no evidence of underlying CHD (< 2 WHO criteria or no CHD signs/symptoms along with negative and/or questionable exercise-induced/stress electrocardiography) were also selected. The two study groups were stratified according to age, sex and ethnicity. Using Stata Corp 2001 statistical software release 7, and a multiple logistic regression procedure three models with large surfaces under the Receiver Operator Characteristic (ROC)-curve (0,9331, 0,9350 and 0,9592) were built, for the recognition of CHD in black people. According to the Odds Ratios [95% Confidence Interval] the family history (FH) of myocardial infarction (MI; FHMI): 11,55 [2,63; 50,76]; >Gr II retinopathy (KWB): 8,18 [2,45; 27,26]; left ventricular hypertrophy (LVH): 7,13 [3,08; 16,55]; total cholesterol (TC): 6,4 [2,14; 19,09]; peripheral vascular disease (PVD): 3,72 [1,3; 9,99]; renal target organ damage: 3,41 [1,49; 7,78]; family history of hypertension (FHHT): 2,12 [0,89; 5,01]; and personal history of type 2 diabetes mellitus (NIDDM-II): 2,09 [0,65; 6,57] contributed significantly to the development of CHD in urban black people. From the comparisons between the models it can be concluded that the life-long exposure to lifestyle-related CHD risk factors (hypertension, NIDDM-II and elevated cholesterol levels), which were poorly controlled, along with genetic factors (FHMI and FHHT), lead to the development of CHD and target organ damage. It was accompanied by environmental factors such as poor socio-economic background and extended exposutre to urbanisation. The high prevalence rates of the known CHD risk factors resembled those of African American people with confirmed CHD. The Framingham absolute score for selected risk factor categories gave credibility to the risk factor status of both CHD patients as well as the control group. This is the first South-African study confirming the link between atherosclerotic CHD and the traditional CHD risk factors. A separate substudy using age- and sex-adjusted standardised mortality rates (MR) for CHD (ICDC 410-414) for the total white and black South African populations between 1970 and 1980 revealed a possible changing trend. The decline in white CHD MR in the younger age groups contrasts with those of black people. The observed (O) relative to the expected (E) CHD MR exceeded the 100% mark in the younger age groups. This observation is in agreement with the cumulative incidence rate (3,41) with a 95% confidence interval [2,51; 6,53] of this study relative to the study by Seftel et al. (1965-1968). Shortcomings in the reporting of CHD MR and the datasets, as well as inaccurate vital statistics, provide additional evidence of CHD mortality and morbidity in South African black people. The suggestion of a changing trend remains unsure. The two profiles of CHD in South African black people, 30-40 years apart, form the platform for proposed cardiovascular research in African black people. The study concludes with recommendations leveled at the National Department of Health for the treatment and prevention of CHD in South African black people.

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