Julia Botha

Immuno-localisation of anti-thyroid antibodies in adult human cerebral cortex

Expression of thyroid-stimulating hormone receptor (TSH-R) has been demonstrated in adipocytes, lymphocytes, bone, kidney, heart, intestine and rat brain. Immuno-reactive TSH-R has been localised in rat brain and human embryonic cerebral cortex but not in adult human brain. We designed a pilot study to determine whether anti-thyroid auto-antibodies immuno-localise in normal adult human cerebral cortex. Forensic samples from the frontal, motor, sensory, occipital, cingulate and parieto-occipito-temporal association cortices were obtained from five individuals who had died of trauma. Although there were no head injuries, the prior psychiatric history of patients was unknown. The tissues were probed with commercial antibodies against both human TSH-R and human thyroglobulin (TG). Anti-TSH-R IgG immuno-localised to cell bodies and axons of large neurones in all 6 regions of all 5 brains. The intensity and percentage of neurones labelled were similar in all tissue sections. TSH-R immuno-label was also observed in vascular endothelial cells in the cingulate gyrus. Although also found in all 5 brains and all six cortical regions, TG localised exclusively in vascular smooth muscle cells and not on neurones. Although limited by the small sample size and number of brain areas examined, this is the first study describing the presence of antigenic targets for anti-TSH-R IgG on human cortical neurons, and anti-TG IgG in cerebral vasculature.

Student perceptions of medico-legal autopsy demonstrations in a student-centred curriculum

Objectives  Teaching autopsies in undergraduate medicine, although traditionally considered valuable by both educators and students, have been marginalised in modern curricula. This study explored medical students’ experiences of the medico‐legal autopsy demonstrations which formed part of their training in forensic medicine.

The pharmacokinetics of theophylline in premature neonates during the first few days after birth.

The aims of the study were to estimate the pharmacokinetic parameters, clearance rate (CL), and volume of distribution (V) of theophylline in premature neonates during the first few days after birth, and to identify factors contributing to interindividual variability. The authors obtained 263 serum concentrations from 105 apneic premature neonates receiving intravenous (IV) theophylline. Mean (SD) birth weight and postnatal ages were 1.3 (0.3) kg and 1.1 (0.3) days, respectively. The data were analyzed using the nonlinear mixed effects model (NONMEM). A one-compartment model with first order elimination was used. The final models were: CL (L/h) = 0.006 * WGT 0.75 * P, V (L) = 0.63 * WGT, WGT = weight (kg) P = 1.47 with oxygen support and 1.0 without oxygen support. The CL in the study population was low, resulting in long half-lives. After inclusion of the above covariates, as well as interoccasion variability, the interindividual variability in CL was 56% and in V was 47%. Interoccasion variability in CL and V was 34% and 35% respectively. Theophylline pharmacokinetics are variable in the premature neonate during the first week of life, and this high variability makes it difficult to predict drug concentrations with the same degree of accuracy as in other populations.

Low rifampicin concentrations in tuberculosis patients with HIV infection

INTRODUCTION The efficacy of tuberculosis (TB) treatment in Human Immunodeficiency Syndrome (HIV) co-infected patients may be compromised by genetic and pharmacokinetic variation in drug disposition. Rifampicin is a critical component of TB treatment. We investigated the influence of drug transporter gene polymorphisms on rifampicin concentrations in TB-HIV co-infected patients in Durban, South Africa. METHODOLOGY Rifampicin concentrations were measured 2.5 hours post-dose (approximated peak, C2.5 hr) in patients receiving either 450mg or 600mg rifampicin, randomized to either integrated or sequential antiretroviral treatment. Patients were genotyped for SLCO1B1 (rs4149032) polymorphisms. A mixed effects regression model was fitted to assess the influence of various factors on rifampicin concentrations. TB recurrence rates were also estimated. RESULTS In 57 patients, median (IQR) C2.5 hr was 3.6 (2.8-5.0) µg/mL. Polymorphism frequency in the SLCO1B1 (rs4149032) drug transporter gene was high (0.76) and was associated with low median rifampicin C2.5 hr, 3.7 (2.8-5.0) µg/mL in the heterozygous and 3.4 (2.7-4.7) µg/mL in the homozygous variant carriers. Concentrations were also low in males (p < 0.0001) and those with low haemoglobin (p = 0.02). Although reinfection could not be distinguished from reactivation for the 43 patients followed post trial, the incidence of TB recurrence was 7.1 per 100 person-years. Of the eight patients in whom TB recurred, seven had the polymorphism. CONCLUSION Approximated peak rifampicin concentrations were well below the recommended target range of 8 to 24 µg/mL in this patient population with its high frequency of the SLCO1B1 (rs4149032) polymorphism. Increased rifampicin dosage may be warranted in African, HIV- TB co-infected patients.

Influence of the Kallikrein-Kinin System on Prostate and Breast Tumour Angiogenesis

Background/Aims: Angiogenesis is important for the growth and progression of cancer cells. There is some evidence that the kallikrein-kinin system (KKS) is involved in cancer and angiogenesis. The present study investigated the effect of increasing concentrations of prostate and breast tumour cell metabolites on the proliferation of cultured endothelial cells, their tissue kallikrein (TK) secretion and KKS expression. Methods: Expression of TK and kinin receptors was investigated by immunochemistry, and secretion of TK by ELISA. Cell proliferation was measured by a chromogenic assay. KKS proteins were also immunolocalised in an endothelial tumour co-culture model. Results: KKS proteins were found in projections of all cell types as well as at points of heterogeneous contact. Tumour metabolites increased the secretion of TK from endothelial cells, with corresponding decreases in intracellular amounts, while also increasing proliferation of the endothelial cells. Conclusions: These findings indicate that the KKS may be one of the more important players in angiogenesis associated with prostate and breast tumours.

Topical herbal medicines for atopic eczema: a systematic review of randomized controlled trials.

Despite the availability of medicines with proven efficacy, many patients use complementary or alternative medicines (CAMs) to manage atopic eczema (AE). Due to the lack of objective information on topical CAMs, this systematic review evaluates the current evidence for the efficacy and safety of topical herbal preparations in AE. Using Cochrane systematic review methodology, PubMed, the Cochrane Library, the Cochrane Central Register of Controlled Trials (CENTRAL), CINAHL (via EBSCO), MEDLINE (via EBSCO), Proquest Health and Medical Complete, GREAT and CAM‐QUEST were searched from inception until June 2014. Bibliographies of retrieved studies were hand searched for further relevant trials. All controlled clinical trials of topical herbal medicines for AE in humans of any age were included regardless of the control intervention or randomization. Only English‐language publications were considered. Eight studies met the inclusion criteria. Seven investigated extracts of single plants and one an extract from multiple plants. Only two studies that showed a positive effect were considered to have a low risk of bias across all domains (those of liquorice gel and Hypericum perforatum). In these two, the test product was reported to be superior to placebo. Despite variations in diagnostic criteria and lack of validated tools for outcome assessments in one of these, the promising results may warrant continued research in better‐designed studies. No meta‐analysis was performed due to heterogeneity in all studies. There is currently insufficient evidence of efficacy for any topical herbal extract in AE. Many studies had methodological flaws and even those showing efficacy were single trials with small patient cohorts.

Corticosteroid/cyclophosphamide pulse treatment in South African patients with pemphigus.

Background.  Treatment of pemphigus remains a challenge. Corticosteroid/cyclo‐phosphamide pulse treatment has been used to reduce the morbidity associated with long‐term treatment with high‐dose corticosteroids. We describe our experience with pulse treatment in South African patients with pemphigus.

Impact of recent evidence on the use of hormone therapy in the South African private sector (2001-2005)

Abstract Background: The release of the results of the oestrogen plus progesterone therapy (EPT) arm of the Womens Health Initiative (WHI) in July 2002 started a worldwide process of reconsideration of the rationale behind hormone therapy (HT). This process was accelerated after the release of the results from the oestrogen-only (ET) arm of the same study. The results of the WHI reinforced the indications of HT to alleviate vasomotor symptoms and to prevent bone loss associated with early menopause, but refuted the possibility of cardioprotective effects and raised uncertainty around the risk of breast cancer for long-term users. In response, new guidelines and position statements were developed to aid healthcare practitioners and patients in various countries, including South Africa. The dissemination and penetration of all this information has been assessed in a number of countries, but the extent of its effect on the South African market is as yet unknown. Accordingly, the aim of this study was to assess the use of HT in the South African private sector from 2001 to 2005. Methods: Monthly HT sales data for January 2001 to October 2005 were obtained from IMS Health (SA). Three successive periods were compared: (1) January 2001 to June 2002 (discontinuation of the WHI oestrogen plus progestogen arm), (2) July 2002 to February 2004 (termination of the WHI oestrogen only arm) and (3) March 2004 to October 2005. Results: Overall, sales of HT fell 6.9% between periods 1 and 2 and 14.6% between periods 2 and 3. The total sales of ET predominated; they were more than double those of EPT. For ET, the sale of conjugated equine oestrogen (CEE) preparations exceeded those of non-CEE ET preparations, while for EPT preparations the reverse was true. The decline in ET sales was mostly accounted for by the fall in sales of CEE, by 9.8% and 20.6% for the two periods respectively. There was an increase in sales of both low-dose CEE and non-CEE, although the magnitude of increase in the case of the latter was much greater. Throughout the entire study period, CEE 0.625 mg tablets were found to account for the greatest sales volumes. Private sector sales represented 74.4% of total national HT sales over this period. Conclusion: The release of the WHI findings resulted in a modest decrease in HT sales in South Africa, although it was less dramatic than sales reported elsewhere. The change in prescribing cannot be attributed to any single factor. Factors such as publicity, adherence to new guidelines, and pharmaceutical marketing may all have contributed. Guidelines need to be updated as the results of new research continue to be published. There is also a need to periodically review prescribing trends, and to assess compliance with evidence-based guidelines, in order to improve the quality of medicines use. The majority of prescriptions for HT in South Africa are written by general practitioners, rather than by specialists. It is thus imperative that guidelines be appropriately framed for this market, as well as interpreted and applied.

Complementary therapy in atopic eczema: the latest systematic reviews

Complementary and alternative medicines (CAM) are widely used for atopic eczema (AE) with user estimates as high as 63%. Despite the availability of effective conventional therapies, the chronic nature of AE and concerns about long-term steroid use lead many patients to seek alternative treatment. Evidence of the efficacy of these alternative therapies is inconsistent and available published data have shortcomings, making it difficult for clinicians to assess their role, if any, in management. To assess the evidence, systematic reviews of controlled studies have been undertaken for Chinese herbal medicines, homeopathy, evening primrose oil, borage oil, probiotics and certain dietary supplements. This overview summarises the findings from the most recent systematic reviews. Taken together, none of the alternative therapies evaluated demonstrated obvious and indisputable evidence of efficacy. Further studies are warranted with some therapies (Chinese herbal medicines, certain probiotic strains and fish oil), whereas homeopathy failed to show any treatment effect. Further studies on homeopathy, or evening primrose oil and borage oil, are difficult to justify. It must also be remembered that CAM products are currently under-regulated and may not meet the stringent quality standards of conventional medicines.

Knowledge, attitude and practices of South African healthcare professionals towards complementary and alternative medicine use for atopic eczema – a descriptive survey

Background: Complementary and alternative medicines (CAM) are used widely for treating atopic eczema (AE), commonly in conjunction with conventional medicines prescribed by mainstream healthcare professionals (HCPs). This cross-sectional survey evaluated the knowledge, general attitudes and practices regarding CAM among dermatologists, paediatricians, general practitioners (GPs) and pharmacists treating patients with AE in Durban, KwaZulu-Natal. Methods: Questionnaires were sent via email or hand-delivered to HCPs nearby. Results: Of the 330 respondents, 220 (67%) were males and 110 (33%) females. Most (40%) were > 50 years. GPs and pharmacists were significantly more embracing of CAM compared with dermatologists and paediatricians. The majority were not familiar with most CAMs for AE. More GPs (29%) and pharmacists (43%) recommend CAM compared with dermatologists (8%) and paediatricians (5%). GPs and pharmacists were also amenable to referring patients to CAM practitioners. The majority do not initiate discussions with their patients regarding CAM use nor enquire when taking a history. Many dermatologists (65%) and pharmacists (51%) reported that their patients ask about CAM. All dermatologists, 95% of paediatricians, 87% of GPs and 55% of pharmacists reported having no training in CAM but believed it should be included in their curriculum. Most are interested in learning about CAM and agreed that it would better prepare them in managing patients. Conclusion: This study demonstrated poor CAM knowledge and communication between HCPs and patients but a strong interest amongst HCPs to learn more. There is an urgent need for continuing education programmes and inclusion in undergraduate curriculums, which will assist HCPs in influencing better patient outcomes.