Browsing by Author "Todd, G"

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    Melanocyte survival and response to treatment in Vitiligo Patients
    (2009) Lapiner, Vanessa; Kidson, SH; Todd, G
    Vitiligo is a common depigmenting skin disorder with devastating psychological implications. Although evidence strongly suggests that melanocytes die in various forms of vitiligo, it is also evident, at least in certain cases, that melanocytes/melanoblasts survive in an undifferentiated stem cell form and it is from these that re-pigmentation is assumed to occur. Treatment of this distressing condition remains 'hit-or-miss' and patients' responses are unpredictable. This study aims to integrate prognostic variables such as the molecular profile of vitiliginous lesions and the patient's epidemiological profile, to develop a reliable and sensitive prognostic test enabling clinicians to plan an individualized, rational therapeutic approach for their vitiligo patients. The analysis of tyrosinase and TRP-2 mRNA expression in vitiliginous skin using quantitative RT-qPCR revealed the presence of melanoblasts/melanocytes in 60% of patients (n=21). When this survival was calculated as a percentage of the mRNA expression in the pigmented positive control specimen, it was found to range from 4% to 46% survival. Patients were subsequently treated with either potent topical corticosteroid ointment or 5% khellin cream in combination with daily sunlight exposure for 3 months and their clinical response was then assessed and correlated to the lesional melanocyte status. A good response (>50% repigmentation) was found in 3/5 patients demonstrating both tyrosinase and TRP-2 gene expression, in only 1/4 patients demonstrating TRP-2 gene expression alone and in 0/3 patients demonstrating only tyrosinase gene expression. The presence of both tyrosinase and TRP-2 mRNA expression is therefore a significant positive prognostic indicator. A significant correlation (R2 =0.8919) was found between melanocyte survival and response to khellin therapy suggesting that therapeutic modalities stimulating melanocyte proliferation and migration should be employed in patients demonstrating a melanocyte/ melanoblast reservoir. Conversely, an absence of melanocyte/melanoblast markers is predictive of a poor response to treatment with 7/9 patients lacking lesional tyrosinase or TRP-2 mRNA expression demonstrating <25% repigmentation at the conclusion of the 3 month treatment period. Therapeutic options such as surgery or cosmetic camouflage techniques should be considered for these patients. The epidemiological profile was not found to be a significant prognostic factor in predicting treatment response.
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    Stem cells and neoplasia a study of acquired melanocytic naevi
    (2012) Bonthuys, Anita; Kidson, S; Todd, G
    Melanocytic neoplasia is a multifaceted process involving a complex interplay of genetic and environmental factors. Despite recent advances, the aetiology and pathogenesis of melanocytic neoplasms remains unclear and the anatomical location and state of differentiation of the initiating cell remains to be elucidated. Traditional models propose melanoma arises from an epidermal melanocyte which passes through defined stages of increasing atypia due to the accumulation of mutational events. The newly proposed tumour stem cell hypothesis, however, advocates melanoma may arise from a mutated tissue-resident precursor cell, and not froma terminally differentiated melanocyte. The overall aim of this study was to investigate whether benign naevi contain cells with a stem cell-like phenotype, and to examine the question of whether these might be stem cell precursors of malignant melanoma. Ten formalin-fixed and paraffin embedded human naevus biopsy samples, of five different naevus subtypes, were systematically re-evaluated by direct immunofluorescence first, to understand the lineage of a “naevus” cell, and second, to evaluate whether melanocytic naevi may originate from a precursor cell and not via de-differentiation from an epidermal melanocyte. For phenotypic characterisation, results were highly suggestive of a melanocytic lineage with 85.36% of naevus cells staining positively for the melanocyte specific differentiation antigen, Melan-A, as determined by a semi-quantitative analysis. Yet, these cells showed important morphological variations and were distinct from differentiated epidermal melanocytes. Furthermore, although studies have suggested regional variations in naevi and a possible Schwann cell lineage, there was no evidence in support of a Schwann cell phenotype of naevus cells in this study. Secondly, precursor markers were identified in all naevus subtypes analysed, thereby convincingly demonstrating the presence of precursor cells within naevus tissue. The majority of positively labelled cells localised to the epidermal compartment (72.72%) and this was similar for all three markers analysed: OCT4 (77.22%), NANOG (63.72%) and p75 (57.15%). Interestingly, dysplastic naevi showed a large proportion of OCT4+ cells (5.81%), which was by far the greatest proportion of any precursor marker identified in this study. As dysplastic subtypes are associated with an increased risk of melanoma development, this may imply an increased stem cell component confers this risk. Thirdly, analysis with the proliferation marker Ki-67 revealed the epidermal compartment contained the majority of dividing naevus cells (76.17%), thereby supporting an epidermal origin of naevi. Since the majority of precursor cells identified were within the epidermal compartment, this may suggest precursor cells drive naevus development, in support of the tumour stem cell hypothesis. In addition, the predominance of these precursor cells within the interfollicular epidermis may aid in identifying a potential stem cell niche. However, no precursor cells were noted in the normal intervening interfollicular epidermis or dermis of naevi, or in the epidermis or dermis of normal human skin, as may have been expected. In conclusion, the presence of stem cell markers in naevus tissue supports the hypothesis that at least some naevus cells may arise from stem cells, and not from differentiated melanocytes.
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    A study of the antiherpes simplex virus type 1 properties of barringtonia racemosa
    (2001) Pefile, Sibongile C; Folb, Peter I; Todd, G
    The study of the aqueous extract of Barringtonia racemosa has produced strong indication of antiviral effect against herpes simplex virus type 1 in vitro.
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    Warfarin-induced skin necrosis in HIV-infected patients with tuberculosis and venous thrombosis
    (2010) Bhaijee, F; Wainwright, H; Meintjes, G; Wilkinson, R J; Todd, G; de Vries, E; Pepper, D J
    Background. At the turn of the century, only 300 cases of warfarin-induced skin necrosis (WISN) had been reported. WISN is a rare but potentially fatal complication of warfarin therapy. There are no published reports of WISN occurring in patients with HIV-1 infection or tuberculosis (TB). Methods. We retrospectively reviewed cases of WISN presenting from April 2005 to July 2008 at a referral hospital in Cape Town, South Africa. Results. Six cases of WISN occurred in 973 patients receiving warfarin therapy for venous thrombosis (0.62%, 95% CI 0.25 - 1.37%). All 6 cases occurred in HIV-1-infected women (median age 30 years, range 27 - 42) with microbiologically confirmed TB and venous thrombosis. All were profoundly immunosuppressed (median CD4+ count at TB diagnosis 49 cells/µl, interquartile range 23 - 170). Of the 3 patients receiving combination antiretroviral therapy, 2 had TB-IRIS (immune reconstitution inflammatory syndrome). The median interval from initiation of antituberculosis treatment to venous thrombosis was 37 days (range 0 - 150). The median duration of parallel heparin and warfarin therapy was 2 days (range 1 - 6). WISN manifested 6 days (range 4 - 8) after initiation of warfarin therapy. The international normalised ratio (INR) at WISN onset was supra-therapeutic, median 5.6 (range 3.8 - 6.6). Sites of WISN included breasts, buttocks and thighs. Four of 6 WISN sites were secondarily infected with drug-resistant nosocomial bacteria (methicillin-resistant Staphylococcus aureus (MRSA), Acinetobacter, extendedspectrum β-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae) 17 - 37 days after WISN onset. In 4 patients, the median interval from WISN onset to death was 43 days (range 25 - 45). One of the 2 patients who survived underwent bilateral mastectomies and extensive skin grafting at a specialist centre. Conclusion. This is one of the largest case series of WISN. We report a novel clinical entity: WISN in HIV-1 infected patients with TB and venous thrombosis. The occurrence of 6 WISN cases in a 40-month period may be attributed to (i) hypercoagulability, secondary to HIV-1 and TB; (ii) short concurrent heparin and warfarin therapy; and (iii) high loading doses of warfarin. Active prevention and appropriate management of WISN are likely to improve the dire morbidity and mortality of this unusual condition.