Hosts and transmission of Mycobacterium ulcerans: a systematic review

The control of Buruli ulcer (BU), a debilitating neglected tropical disease, is hampered by the inadequate understanding of the mode of transmission of its causative agent, Mycobacterium ulcerans (M. ulcerans). The DNA of M. ulcerans has been detected in some living organisms and non-living environmental samples of both aquatic and terrestrial sources. However, it is unclear whether the identified organisms support in vivo multiplication of the bacterium or play any role in its transmission. This paper identifies hosts of M. ulcerans, reviews progress made in unravelling the exact mode of transmission of M. ulcerans and identifies research gaps in this aspect of BU epidemiology. Using the search terms, 'niche, Mycobacterium ulcerans' and 'mode of transmission, Mycobacterium ulcerans' as well as defined inclusion criteria, information was obtained from the PubMed database and reviewed to assess their importance to the research question. Aquatic bugs of the genera Appasus and Diplonychus as well as Naucoris cimicoides and possums were identified to support in vivo multiplication of the bacterium. Bite of M. ulcerans contaminated Aedes notoscriptus, bite of aquatic bugs harboring or contaminated with M. ulcerans, and M. ulcerans contaminated skin-puncturing materials present in nature create opportunity for its transmission and infection. Appropriate protective measures may be useful to reduce the risk of exposure to M. ulcerans in BU endemic areas, and incorporation of trophic interactions of aquatic organisms known to support in vivo multiplication of M. ulcerans is needed in future research for better understanding of the spread of M. ulcerans in nature.

Secondary bacterial isolates from previously untreated Buruli ulcer lesions and their antibiotic susceptibility patterns in Southern Nigeria

Abstract INTRODUCTION: Mycolactones, secreted by Mycobacterium ulcerans, were previously believed to prevent super infection in Buruli ulcer lesions. However, little is known about secondary bacterial infections in these lesions. This study evaluated contaminating bacterial flora and their antibiotic susceptibility patterns in cases of previously untreated Buruli ulcer disease from three states in Southern Nigeria. METHODS A prospective analysis was conducted between January and June of 2015 using wound swabs from eligible patients with Buruli ulcer disease, confirmed by quantitative-polymerase chain reaction, with active ulcers. Microbiological analyses including isolation of bacteria, species identification of isolates, and drug susceptibility tests were performed. RESULTS Of 51 patients, 27 (52.9%) were female. One or more bacterial species of clinical importance was isolated from each patient. A total of 17 different microbial species were isolated; 76.4% were Gram-negative and 23.6% were Gram-positive isolates. The most common bacterial species detected was Staphylococcus aureus (24%), followed by Aeromonas hydrophila (13%), Pseudomonas aeruginosa (13%), and Klebsiella pneumoniae (11%). Drug susceptibility tests showed a particularly high frequency of resistance to commonly used antimicrobials in Nigeria for Staphylococcus aureus. CONCLUSIONS Super bacterial infections occur in Buruli ulcer lesions in Nigeria, and these infections are associated with high rates of resistance to commonly used antibiotics in the country.

Serum insulin-like growth factor-1 levels in females and males in different cervical vertebral maturation stages

OBJECTIVE: The aim of this cross sectional study was to assess serum insulin-like growth factor-1 (IGF-1) levels in female and male subjects at various cervical vertebral maturation (CVM) stages. MATERIAL AND METHODS: The study sample consisted of 60 subjects, 30 females and 30 males, in the age range of 8-23 years. For all subjects, serum IGF-1 level was estimated from blood samples by means of chemiluminescence immunoassay (CLIA). CVM was assessed on lateral cephalograms using the method described by Baccetti. Serum IGF-1 level and cervical staging data of 30 female subjects were included and taken from records of a previous study. Data were analyzed by Kruska-Wallis and Mann Whitney test. Bonferroni correction was carried out and alpha value was set at 0.003. RESULTS: Peak value of serum IGF-1 was observed in cervical stages CS3 in females and CS4 in males. Differences between males and females were observed in mean values of IGF-1 at stages CS3, 4 and 5. The highest mean IGF-1 levels in males was observed in CS4 followed by CS5 and third highest in CS3; whereas in females the highest mean IGF-1 levelswas observed in CS3 followed by CS4 and third highest in CS5. Trends of IGF-1 in relation to the cervical stages also differed between males and females. The greatest mean serum IGF-1 value for both sexes was comparable, for females (397 ng/ml) values were slightly higher than in males (394.8 ng/ml). CONCLUSIONS: Males and females showed differences in IGF-1 trends and levels at different cervical stages. .

OBJETIVO: o objetivo do presente estudo transversal foi avaliar os níveis do fator de crescimento semelhante à insulina-1 (IGF-1 sérico) em pacientes de ambos os sexos e em diferentes estágios de maturação das vértebras cervicais (MVC). MÉTODOS: a amostra consistiu de 60 pacientes, sendo 30 do sexo masculino e 30 do sexo feminino, com idades entre 8 e 23 anos. Amostras de sangue foram colhidas de todos os pacientes, cujos níveis de IGF-1 sérico foram avaliados por meio do método de imunoensaio quimioluminescente (CLIA). O estágio de MVC foi avaliado por meio de radiografias cefalométricas de perfil por meio do método descrito por Baccetti. O nível de IGF-1 sérico e o estágio de maturação das vertebras cervicais de 30 pacientes do sexo feminino foram avaliados e os dados retirados dos registros de um estudo prévio. Os dados foram submetidos aos testes de Kruskal-Wallis e de Mann-Whitney. A correção de Bonferroni foi calculada e o valor de alfa foi de 0,003. RESULTADOS: o valor de pico do IGF-1 sérico foi encontrado no estágio CS3, para mulheres, e CS4, para homens. Foram encontradas diferenças entre as médias dos valores de IGF-1 entre homens e mulheres nos estágios CS3, 4 e 5. O valor médio mais alto para os níveis de IGF-1 nos homens foi observado no estágio CS4, seguido do estágio CS5 e CS3. Nas mulheres, o valor médio mais alto foi observado em CS3, seguido do estágio CS4 e CS5. Diferenças também foram encontradas quanto à curva do IGF-1, em relação ao estágio de maturação das vértebras cervicais nos pacientes de ambos os sexos. O valor médio de IGF-1 sérico mais alto foi comparado. As pacientes do sexo feminino apresentaram valores ligeiramente mais altos (397ng/ml) em comparação aos pacientes do sexo masculino (394.8ng/ml). CONCLUSÕES: homens e mulheres apresentam valores de IGF-1 diferentes em estágios de maturação das vértebras cervicais diferentes. .

Management of complications of Mycobacterium ulcerans disease: a three-year review

Infection with Mycobacterium ulcerans [MU] causes extensive destruction of tissues with the formation of large ulcers on exposed parts of the body. Healing leads to extensive scarring and other complications which may impair function. To document the complications of MU disease and the reconstructive surgery performed to correct them. Prospective from January 2010 to December 2012. Ahafo Ano, Amansie West, Asunafo, and Upper Denkyira districts of Ghana. Patients with unhealed lesions after completing 8 weeks of rifampicin and streptomycin treatment, and patients with complications of MU disease were selected and prepared for surgical treatment. 61 patients were treated successfully with rifampicin and streptomycin without complications. 65 patients presented with complications; they comprised 34 males and 31 females. Their ages ranged from 1 year 3 months to 80 years with mean age of 29.7 [S.D. 20.1]. The types of lesions seen were ulcers [54], contractures [7], chronic osteomyelitis [one], subluxation of knee joint [one], salivary gland fistula [one] and Marjolin's ulcer [one]. The lesions were distributed as follows: 69.2% on the lower, and 23.1% on the upper limbs, 6.2% on the head and neck and 1.5% on the trunk. Wound excision with or without skin grafting was done in 84.6% of patients, surgery for contractures in10.8%, and sequestrectomy, exploration and ligation of fistula, groin dissection and above knee amputation in 4.6%. Whilst ulcers, the commonest MU lesions, are being controlled with antibiotics, rare complications of the disease are also emerging

Úlcera de Buruli / Buruli ulcer

A úlcera de Buruli, uma doença infecciosa causada pela Mycobacterium ulcerans (M. ulcerans),é a terceira micobacteriose em ocorrência, após a hanseníase e a tuberculose. Essa micobacteriose atípica tem sido relatada em mais de 30 países, principalmente, nos que têm climas tropicais e subtropicais, mas a sua epidemiologia permanece obscura. Recentemente, os primeiros casos autóctones do Brasil foram relatados, fazendo com que dermatologistas brasileiros estejam atentos a esse diagnóstico. O quadro clínico varia: nódulos, áreas de edema, placas, mas a manifestação mais típica é uma grande úlcera, que ocorre, em geral, nas pernas ou nos braços. Apesar do amplo conhecimento quanto ao seu quadro clínico em países endêmicos, nas outras áreas, esse diagnóstico pode passar despercebido. Assim, médicos devem ser orientados quanto à úlcera de Buruli, pois o diagnóstico precoce, o tratamento específico e a introdução de cuidados na prevenção de incapacidades são essenciais para uma boa evolução.

Buruli ulcer, an infectious disease caused by Mycobacterium ulcerans, is the third most prevalent mycobacteriosis, after tuberculosis and leprosy. This atypical mycobacteriosis has been reported in over 30 countries, mainly those with tropical and subtropical climates, but its epidemiology remains unclear. The first autochthonous cases of infection in Brazil have recently been described, making this diagnosis important for Brazilian dermatologists. Clinical manifestations vary from nodules, areas of edema, and plaques, but the most typical presentation is a large ulcer, usually in the limbs. Despite considerable knowledge about its clinical manifestations in some endemic countries, in other areas the diagnosis may be overlooked. Therefore, physicians should be educated about Buruli ulcer, since early diagnosis and treatment, including measures to prevent disability, are essential for a good outcome.

Buruli-like ulcer in a Palestinian woman: a case report with uncertain diagnosis

We report a case of Buruli-like ulcer in a Palestinian woman. The patient presented with a new ulcer on her left hand dorsum preceded by wet minor trauma. In view of the patient's medical history and current remnants of ulceration involving the other hand she was managed ad as a case of Buruli-like ulcer. To our knowledge, no similar cases with our patient's ulcer-features, whether Buruli ulcer, Buruli-like ulcer of Mycolactone Producing Mycobacterium marinum, were reported in the literature from Palestine and Jordan. We report this case to document an ulcer that looked like Buruli ulcer which was not proved by laboratory hard evidence

[Rate of production of inflammatory cytokines TNF and IL- by peripheral blood mononuclear cells stimulated with mycolactone]

Mycobacterium ulcerans is the etiological agent of Buruli ulcer [BU]; the third most common mycobacterial infection in humans after tuberculosis and leprosy. BU is now considered by the WHO to be an emerging infection of major concern. M. ulcerans produces mycolactone toxin, which is required for the organism's virulence. Mycolactone destroys tissue and suppresses host immune responses. In this descriptive analytical study, peripheral blood mononuclear cells from three volunteers with no history of buruli ulcer were used. IL-6 and TNF produced by these cells at different preincubation times with LPS and mycolactone were measured by using ELISA kits. This study showed hyper inhibition of IL-6 and TNF production by mycolactone. TNF levels in the control tubes [containing LPS] in 4hours reached its maximum value and then decreased. While the production of IL-6 in the tube with fresh cells [zero time] had the highest value, after 16hours, it reached its minimum. Since TNF and IL-6 are important immunity inflammatory cytokines, it can be well imagined that decrease of TNF production by this bacterium plays a role in weakening of inflammatory response. So Mycobacterium ulcerans destroys macrophages and at the same time prevents TNF production by important cells in innate immune mechanism

Búsqueda de úlcera de Buruli en el Urabá Chocoano y Antioqueño, Colombia 2006 / Search of Buruli in Choco and Antioquia, Uraba Colombia, 2006

Introducción: en Colombia no se ha reportado ningún caso de úlcera de Buruli (UB), aún teniendo regiones con características similares a zonas endémicas. En nuestro medio, la proximidad geográfica y las condiciones ambientales similares con los países de Sur y Centro América donde se han reportado casos, motivan a buscar activamente pacientes sospechosos de UB, y aplicar técnicas de laboratorio moleculares específicas para brindar un adecuado diagnóstico. Objetivo: buscar casos de úlcera de Buruli (UB) en Urabá chocoano y antioqueño, (Colombia) durante el año 2006. Materiales y métodos: se estudiaron casos provenientes de las áreas de estudio, para establecer la causa etiológica de las lesiones utilizando métodos de diagnóstico clínico, microbiológico, histopatológico y molecular. Resultados: en cinco pacientes (6%) no se pudo establecer la causa etiológica de la úlcera (leishmaniosis, micosis, úlceras venosas o arteriales, cáncer). El examen clínico de estos pacientes no fue concluyente de UB, sin embargo debido a la falta de documentación de casos en Colombia, se procesó biopsia de la lesión para detectar ADN de Mycobacterium ulcerans por reacción en cadena de la polimerasa (PCR). Todas las pruebas de PCR fueron negativas para ADN de Mycobacterium ulcerans. Conclusiones: debido a indicadores epidemiológicos que señalan a Colombia con condiciones geográficas y ambientales similares a las que se presentan en regiones endémicas, como Perú, Guyana Francesa, México, Surinam, es necesario continuar con su búsqueda.

Introduction: in Colombia there are no reported cases of Buruli ulcer (BU), however the geographic and environmental characteristics are similar to endemic regions, and the proximity to other countries in South and Central America where there are reported cases, makes it an important issue to search for them, using molecular techniques specific for BU diagnostic. Objectives: to search for Buruli ulcer (BU) at the Urabá region of Chocó and Antioquia in Colombia, during 2006. Materials and methods: patients with skin ulcer from the study region were tested to establish the etiologic cause of the lesions, using clinical, microbiological, pathological and molecular methods. Results: Five patients were tested for BU using PCR test, since other etiologic causes of the ulcer (leishmaniosis, mycosis, venous or arterial ulcer, others) were not determined. Clinical examination of the patients was not conclusive of BU; but due to the lack of documented cases in Colombia, biopsies were taken from patients for detection of M. ulcerans by PCR. All the samples samples tested negative for DNA of Mycobacterium ulcerans. Conclusions: due to the epidemiological indicators that show that Colombia has the geographic and environmental conditions similar to endemic regions, as Perú, French Guyana, México and Surinam it is necessary to continue with the search.

Evaluation of the national tuberculosis surveillance and response systems, 2018 to 2019: national tuberculosis, leprosy and buruli-ulcer control programme, Abuja, Nigeria

Introduction: Nigeria is among the countries with high Tuberculosis (TB) burden by global rating signifying the relevance of TB surveillance system evaluation in improving performance and capacity of the existing system. Hence, this evaluation was conducted in order to determine the gaps and proffer solution to enhance the TB surveillance system performance. Methods: eight questionnaires were administered to key informants using face-to-face interview method; data obtained was analyzed. Total number of TB cases and estimated number of cases for year 2018 was obtained. Percentage of positive cases using the GeneXpert test for 6 months (January to June 2019) was obtained. Available documents and publications on the National Tuberculosis, Leprosy and Buruli Ulcer Control Programme (NTBLCP) were also sought for information. Results: the NTBLCP has over 5,300 TB service points and 1,602 microscopy Centre's distributed across the country. Acceptance for the standard TB case definition was 100%, forms used are easy to fill and diagnosis is laboratory-based requiring specialized trainings for laboratory personnel. The system had 25% sensitivity, high data quality with 100% timeliness. The TB surveillance system is representative of all ages. The system was first designed as TB and leprosy control programme but later Buruli Ulcer was incorporated into the programme. First quarter supervisory visits are skipped due to late funding and delayed budget approval. Major share of the funding comes from donor partners.Conclusion: the system is useful, representative, acceptable, has good data quality, timely, and sensitive. The system is stable but needs to be funded more by the government. There is need for early funding and budget approval to avoid skipping the first quarter supervisory visits. The system is not simple due the various test that need to be conducted before, during and after treatment to detect and verify that the patient is cured. We recommend continuous training of health workers, routine monitoring and evaluation, integration of TB care and prevention into other health services programmes like HIV/AIDS and active case search at all levels to increase the sensitivity of the system. Speed up the process of integration of NTBLCP surveillance system with IDSR for data harmonization in the country

Etude des appellations et des representations attachees a l'infection a Mycobacterium ulcerans dans differents pays endemiques d'Afrique

L'objectif de ce travail est de presenter les appellations de l'infection a Mycobacterium ulcerans (ulcere de Buruli) dans les langues africaines et leurs significations. Il vise egalement a explorer les representations attachees a la maladie dans differents pays endemiques d'Afrique. La methodologie utilisee implique l'analyse d' entretiens indivi- duels et de publications scientifiques. Les entretiens individuels ont ete menes aupres de differents chefs de programme et responsables de structures de prise en charge de cette maladie. Les resultats de notre analyse montrent que dans les pays d'Afrique ou l'ulcere de Buruli est endemique (Benin; Cameroun; Congo-Brazzaville; Cote d'Ivoire; Ghana; Ouganda; Republique Democratique du Congo; Sud Soudan et Togo); les appellations de cette maladie peuvent etre classees en trois categories; suivant qu'elles evoquent les origines geographiques de la maladie; les caracteristiques des lesions observees; ou les aspects d'incurabilite et de mystere; en lien avec la sorcellerie. Les representations de cette maladie dans les langues africaines apparaissent identiques et semblent traduire une connaissance relativement bonne de la maladie dans les pays ou l'ulcere de Buruli sevit. L'impact de ces representations influence egalement les types de recours aux soins

Etude des appellations et des representations attachees a l'infection a mycobacterium ulcerans dans differents pays endemiques d'Afrique

L'objectif de ce travail est de presenter les appellations de l'infection a Mycobacterium ulcerans (ulcere de Buruli) dans les langues africaines et leurs significations. Il vise egalement a explorer les representations attachees a la maladie dans differents pays endemiques d'Afrique. La methodologie utilisee implique l'analyse d'entretiens individuels et de publications scientifiques. Les entretiens individuels ont ete menes aupres de differents chefs de programme et responsables de structures de prise en charge de cette maladie. Les resultats de notre analyse montrent que dans les pays d'Afrique ou l'ulcere de Buruli est endemique (Benin; Cameroun; Congo-Brazzaville; Cote d'Ivoire; Ghana; Ouganda; Republique Democratique du Congo; Sud Soudan et Togo); les appellations de cette maladie peuvent etre classees en trois categories; suivant qu'elles evoquent les origines geographiques de la maladie; les caracteristiques des lesions observees; ou les aspects d'incurabilite et de mystere; en lien avec la sorcellerie. Les representations de cette maladie dans les langues africaines apparaissent identiques et semblent traduire une connaissance relativement bonne de la maladie dans les pays ou l'ulcere de Buruli sevit. L'impact de ces representations influence egalement les types de recours aux soins

Basic plastic surgery skills for district and community doctors to manage Buruli ulcer in Ghana

Background: The increase in incidence of Buruli ulcer in Ghana has also been complicated by problems in the care of the patients including lack of knowledge and training by staff, unwillingness of the staff to handle the cases for fear of contracting the disease. Method: An evaluation of training workshop on basic plastic surgery skills. Results: Three basic plastic surgery skills training workshops were held in 3 hospitals in 3 different districts in the region with participation from 15 hospitals/health centers drawn from 7 districts of the Ashanti Region. In all 128 health personnel comprising of Doctors ­ 18, Medical Assistants ­ 24, Clinical Nurses ­ 60 and Others ­ 26 were trained. These trainees went on to form the core of the so-called Buruli Ulcer Management Teams (BUMTs), which are now active in 6 of the institutions that participated in the programme. Conclusion: As a result of these workshops active Buruli Ulcer Management Teams (BUMTs) have been formed in 6 health institutions in the region

The Effect of Mycolactone on the Expression of Bcl-2 Family Genes in Hep 3B Hepatoma Cells

Mycolactone is a recently reported lipid toxin of Mycobacterium ulcerans that causes Buruli ulcer, a severe human skin disease. However, the mechanism of cell death by mycolactone is still unclear. In this paper, we demonstrate that mycolactone induces apoptosis in Hep 3B hepatocellular carcinoma (HCC) cells. Morphological and biochemical evidences of apoptosis, such as membrane blebbing, cell shrinkage, increase of TUNEL-positive cells and a sub-G 1 cell population, were observed. To explain the mechanism of mycolactone-induced apoptosis, we examined the expression of Bcl-2 family genes. The mRNA expression of anti-apoptotic BclXL gene was decreased after 8 hours, while that of Mcl-l, another anti-apoptotic gene, was slowly decreased with an initial increase at second hour after treatment. Bcl-2 gene expression was extremely low both in the presence and absence of mycolactone. The expression of other Bcl-2 family genes, such as Bclw, Bad, Bak, and Bax, was not affected. By Western blotting analysis, Mcl-1 expression (not BclXL) was down-regulated. Our results suggest that the down-regulation of Mcl-1 protein expression is involved in the apoptosis of Hep 3B cells by mycolactone.