Browsing by Author "Wansbrough-Jones, Mark"

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    Clinical and microbiological predictors of healing in Buruli ulcer disease
    (Journal of Clinical Tuberculosis and Other Mycobacterial Diseases, 2024-02) Agbavor, Bernadette; Agbanyo, Abigail; Laglo, Aloysius Dzigbordi; Antwi, Philemon Bosiako; Ackam, Nancy; Adjei, Jonathan; Frimpong, Venus; Boampong, Kwadwo; Frimpong, Michael; Addo, Matthew Glover; Wansbrough-Jones, Mark; Amoako, Yaw Ampem; Phillips, Richard Odame; 0000-0001-5014-6153
    Introduction: Wound measurements are relevant in monitoring the rate of healing (RoH) and may predict time to healing. Predicting the time to healing can help improve the management of Buruli ulcer. We examine three methods for the determination of RoH and their use as predictors of time to healing. Methods: Lesion measurements of Buruli ulcer patients treated from 2007 to 2022 were obtained with acetate sheet tracings (2D) or Aranz software (3D) fortnightly. RoH was determined using the absolute area, percentage area reduction and linear methods at 4 weeks post onset of antibiotic treatment. Predicted time to healing was compared to the actual healing time. Baseline characteristics were assessed for associations with healing. Results: All three methods for calculating the RoH significantly distinguished between fast and slow healers (p <0.0001). The predicted healing time using the linear method was comparable to the actual healing time for fast healers (p = 0.34). The RoH was influenced by the form of lesion, with plaques [OR 2.19 5 %CI (1.2–3.6), p =0.009], and oedemas [OR 8.5; 95 %CI (1.9––36.9), p = 0.004] being associated with delayed healing. The proportion of patients with paradoxical reactions 16 % vs 3 %, p < 0.0001), higher baseline bacterial load (75/104;72 % vs 21/47;45 %, p = 0.001) and delayed clearance of viable organisms (71/104;68 % vs 9/47;19 %, p <0.0001) was higher in the slow healers than the fast healers. Conclusion: Predicted healing rates were comparatively lower for slow healers than fast healers. Baseline characteristics associated with healing can be explored for an improved disease management plan to reduce patient and caregiver anxiety.
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    Genetic Diversity of PCR-Positive, Culture-Negative and Culture-Positive Mycobacterium ulcerans Isolated from Buruli Ulcer Patients in Ghana
    (PLOS One, 2014-02-10) Williamson, Heather; Phillips, Richard Odame; Sarfo, Fred Stephen; Wansbrough-Jones, Mark; Small, Pamela
    Culture of Mycobacterium ulcerans from Buruli ulcer patients has very low sensitivity. Thus confirmation of M. ulcerans infection is primarily based on PCR directed against IS2404. In this study we compare the genotypes obtained by variable number of tandem repeat analysis of DNA from IS2404-PCR positive cultures with that obtained from IS2404 positive, culture-negative tissue. A significantly greater genetic heterogeneity was found among culture-negative samples compared with that found in cultured strains but a single genotype is over-represented in both sample sets. This study provides evidence that both the focal location of bacteria in a lesion as well as differences in the ability to culture a particular genotype may underlie the low sensitivity of culture. Though preliminary, data from this work also suggests that mycobacteria previously associated with fish disease (M. pseudoshottsii) may be pathogenic for humans.
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    Immunosuppressive Signature of Cutaneous Mycobacterium ulcerans Infection in the Peripheral Blood of Patients with Buruli Ulcer Disease
    (Infectious Diseases Society of America, 2009-10-28) Phillips, Richard Odame; Sarfo, Fred Stephen; Guenin-Mace, Laure; Wansbrough-Jones, Mark; Albert, Matthew L.; et. al
    Buruli ulcer disease (BUD) is an emerging human disease caused by infection with Mycobacterium ulcerans, which leads to the development of necrotic skin lesions. The pathogenesis of the ulcer is closely associated with the production of mycolactone, a diffusible cytotoxin with immunomodulatory properties. To identify immunological correlates of BUD, we performed a broad screen of inflammatory mediators in serum samples and stimulated whole-blood supernatants of patients. We found that patients with active ulcers displayed a distinctive profile of immune suppression, marked by the down-modulation of selected chemokines and an impaired capacity to produce Th1, Th2, and Th17 cytokines on stimulation with mitogenic agents. These immunological defects were induced early in the disease and resolved after anti-BUD therapy, establishing their association with the presence of M. ulcerans. Interestingly, some of the defects in cytokine and chemokine response could be mimicked in vitro by incubation of CD4+ peripheral blood lymphocytes with mycolactone. Our findings support the hypothesis that mycolactone contributes to bacterial persistence in human hosts by limiting the generation of adaptive cellular responses. Moreover, we identified immunological markers of BUD, which may be helpful for confirmatory diagnosis of the disease and, especially, for monitoring the response to antibiotic treatment.
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    Pilot Randomized Double-Blind Trial of Treatment of Mycobacterium ulcerans Disease (Buruli Ulcer) with Topical Nitrogen Oxides
    (Antimicrobial Agents and Chemotherapy, 2004-08) Phillips, Richard Odame; Adjei, O.; Lucas, S.; Benjamin, N.; Wansbrough-Jones, Mark
    Mycobacterium ulcerans disease (Buruli ulcer) is a serious ulcerating skin disease which is common in many tropical countries. Standard treatment, by extensive excision and skin grafting, is not available in rural communities where the disease is common. We evaluated the efficacy and safety of treatment with topical nitrogen oxides. Thirty-seven patients with a clinical diagnosis of Buruli ulcer caused by M. ulcerans disease were randomly assigned to one of two groups. In one group, two creams containing sodium nitrite (6%, wt/wt) or citric acid monohydrate (9%, wt/wt) were applied daily for 6 weeks, while the other group received a placebo. In the second 6 weeks, both groups received the nitrogen oxide-generating combination of creams. Treatment was continued for another 4 weeks for patients whose ulcers were not healed after 12 weeks. The ulcer surface area was monitored by weekly tracings made by assessors blinded to the treatment. In the first 6 weeks, patients on sodium nitrite and citric acid monohydrate (group I, active treatment) showed a rapid decrease in ulcer size from 28.6 5.6 cm2 (mean standard error) to 12.6 3.2 cm2, a decrease significantly greater than that in group II (from 15.3 3.1 to 11.7 3.7 cm2; P 0.03). Five ulcers in the placebo group enlarged during this period, compared with one in the active group. In the second 6 weeks (both groups on active treatment), the rates of healing were similar for the two groups and there was a significant reduction in ulcer size in group II (previously on placebo) compared to the first 6 weeks. Yellow pigmentation of the skin, which disappeared 3 days after treatment was stopped, was the only side effect to date. We conclude that creams releasing nitrogen oxides increase the healing rate of ulcers caused by M. ulcerans infection with minimal adverse events. This is the first controlled trial of any form of therapy which demonstrates efficacy in treating this disease.
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    Recent advances: role of mycolactone in the pathogenesis and monitoring of Mycobacterium ulcerans infection/Buruli ulcer disease
    (John Wiley & Sons Ltd, 2015-11-13) Phillips, Richard Odame; Sarfo, Fred Stephen; Wansbrough-Jones, Mark; Simmonds, Rachel E.
    Infection of subcutaneous tissue with Mycobacterium ulcerans can lead to chronic skin ulceration known as Buruli ulcer. The pathogenesis of this neglected tropical disease is dependent on a lipidlike toxin, mycolactone, which diffuses through tissue away from the infecting organisms. Since its identification in 1999, this molecule has been intensely studied to elucidate its cytotoxic and immunosuppressive properties. Two recent major advances identifying the underlying molecular targets for mycolactone have been described. First, it can target scaffolding proteins (such as Wiskott Aldrich Syndrome Protein), which control actin dynamics in adherent cells and therefore lead to detachment and cell death by anoikis. Second, it prevents the co-translational translocation (and therefore production) of many proteins that pass through the endoplasmic reticulum for secretion or placement in cell membranes. These pleiotropic effects underpin the range of cell-specific functional defects in immune and other cells that contact mycolactone during infection. The dose and duration of mycolactone exposure for these different cells explains tissue necrosis and the paucity of immune cells in the ulcers. This review discusses recent advances in the field, revisits older findings