A Deoxyribonucleic Acid Decoy Trapping DUX4 for the Treatment of Facioscapulohumeral Muscular Dystrophy

Facioscapulohumeral dystrophy (FSHD) is characterized by a loss of repressive epigenetic marks leading to the aberrant expression of the DUX4 transcription factor. In muscle, DUX4 acts as a poison protein though the induction of multiple downstream genes. So far, there is no therapeutic solution for FSHD. Because DUX4 is a transcription factor, we developed an original therapeutic approach, based on a DNA decoy trapping the DUX4 protein, preventing its binding to genomic DNA and thereby blocking the aberrant activation of DUX4’s transcriptional network. In vitro, transfection of a DUX4 decoy into FSHD myotubes reduced the expression of the DUX4 network genes. In vivo, both double-stand DNA DUX4 decoys and adeno-associated viruses (AAVs) carrying DUX4 binding sites reduced transcriptional activation of genes downstream of DUX4 in a DUX4-expressing mouse model. Our study demonstrates, both in vitro and in vivo, the feasibility of the decoy strategy and opens new avenues of research

Report of the laboratory confirmation of cases from the CDTUB Pobé, Benin

In 2009, 420 diagnostic samples (corresponding to 301 patients suspected of M. ulcerans infection) from the Centre de Dépistage et de Traitement de l’Ulcère de Buruli of Benin were subjected to IS2404 PCR at the Centre Hospitalier Universitaire of Angers. 180 samples (corresponding to 141 patients) were confirmed positive to M. ulcerans infection by PCR

Seasonal and Regional Dynamics of M. ulcerans Transmission in Environmental Context: Deciphering the Role of Water Bugs as Hosts and Vectors

Buruli ulcer, caused by Mycobacterium ulcerans, is a devastating skin disease. Most cases of Buruli ulcer occur in poor rural communities. As a result, treatment is frequently sought too late and about 25% of those infected—particularly children—become permanently disabled. Outbreaks of Buruli ulcer have always been associated with swampy areas. However, the route(s) of bacillus transmission is (are) still unclear. This Mycobacterium species resides in water where it colonizes many ecological niches such as aquatic plants, herbivorous animals and predatory/carnivorous insects. For several years the role of water bugs as hosts and vectors of M. ulcerans was suspected and was demonstrated under laboratory conditions. The aim of this work was to further assess the role of water bugs as hosts and vectors of M. ulcerans in environmental context. This work identifies several water bug families as hosts of M. ulcerans in Buruli ulcer endemic area. The detection of bacilli in saliva of human biting insects provides further evidence for their role in M. ulcerans transmission. Interestingly, three of these insects are good flyers, and as such could participate in M. ulcerans dissemination

Buruli Ulcer (M. ulcerans Infection): New Insights, New Hope for Disease Control

Buruli ulcer is a disease of skin and soft tissue caused by Mycobacterium ulcerans. It can leave affected people scarred and disabled. What are the prospects for disease control

Development of Highly Organized Lymphoid Structures in Buruli Ulcer Lesions after Treatment with Rifampicin and Streptomycin

Buruli ulcer (BU) is a debilitating disease of the skin presenting with extensive tissue destruction and suppression of local host defence mechanisms. Surgical removal of the affected area has been the standard therapy until in 2004 WHO recommended eight weeks' treatment with the anti-mycobacterial drugs rifampicin and streptomycin. We performed a detailed histological analysis of the local immune response in biopsies from five children medicated according to WHO provisional guidelines. One patient still revealed all histopathological signatures of an active BU lesion with huge bacterial clusters in areas of fatty tissue necrosis. Different factors can contribute to treatment failure, such as poor patient compliance and resistant bacterial strains. In four patients, different compartments of the skin presented active immune processes with only limited residues of bacterial material persisting. We demonstrated that antibiotic treatment not only directly controls the infectious agent but is also associated with fulminant host immune responses. Characterization of the healing process in BU due to therapy is highly relevant to increase our knowledge of the impact of treatment strategies to fight the disease

Landscape Diversity Related to Buruli Ulcer Disease in Côte d'Ivoire

Buruli ulcer (BU) is one of the most neglected but treatable tropical diseases. The causative organism, Mycobacterium ulcerans, is from the family of bacteria that causes tuberculosis and leprosy. This severe skin disease leads to long-term functional disability if not treated. BU has been reported in over 30 countries mainly with tropical and subtropical climates, but Côte d'Ivoire is one of the most affected countries. M. ulcerans is an environmental bacterium and its mode of transmission to humans is still unclear, such that the disease is often referred to as the “mysterious disease” or the “new leprosy”. Here, we explored the relationship between environmental and socioeconomic factors and BU cases on a nationwide scale. We found that irrigated rice field cultures areas, and, to a lesser extent, banana fields as well as areas in the vicinity of dams used for irrigation and aquaculture purposes, represent high risk zones for the human population to contract BU in Côte d'Ivoire. This work identifies high-risk areas for BU in Côte d'Ivoire and deserves to be extended to different countries. We need now to obtain a global vision and understanding of the route of transmission of M. ulcerans to humans in order to better implement control strategies

Complex temporal climate signals drive the emergence of human water-borne disease

Predominantly occurring in developing parts of the world, Buruli ulcer is a severely disabling mycobacterium infection which often leads to extensive necrosis of the skin. While the exact route of transmission remains uncertain, like many tropical diseases, associations with climate have been previously observed and could help identify the causative agent's ecological niche. In this paper, links between changes in rainfall and outbreaks of Buruli ulcer in French Guiana, an ultraperipheral European territory in the northeast of South America, were identified using a combination of statistical tests based on singular spectrum analysis, empirical mode decomposition and cross-wavelet coherence analysis. From this, it was possible to postulate for the first time that outbreaks of Buruli ulcer can be triggered by combinations of rainfall patterns occurring on a long (i.e., several years) and short (i.e., seasonal) temporal scale, in addition to stochastic events driven by the El Nino-Southern Oscillation that may disrupt or interact with these patterns. Long-term forecasting of rainfall trends further suggests the possibility of an upcoming outbreak of Buruli ulcer in French Guiana

Risk Factors for Buruli Ulcer: A Case Control Study in Cameroon

Buruli ulcer (BU) is a neglected tropical infectious disease caused by Mycobacterium ulcerans. While BU is associated with areas where the water is slow-flowing or stagnant, the exact mechanism of transmission of the bacillus is unknown, impairing efficient control programs. Two hypotheses are proposed in the literature: previous trauma at the lesion site, and transmission through aquatic insect bites. Using results from a face-to-face questionnaire, our study compared characteristics from Cameroonian patients with Buruli ulcer to people without Buruli ulcer. This latter group of people was chosen within the community or within the family of case patients. The statistical analysis confirmed some well-known factors associated with the presence of BU, such as wearing short lower-body clothing while farming, but it showed that the use of bed nets and the treatment of wounds with leaves is less frequent in case patients. These newly identified factors may provide new insight into the mode of transmission of M. ulcerans. The implication of domestic or peridomestic insects, suggested by the influence of the use of bed nets, should be confirmed in specific studies

Risk of Buruli Ulcer and Detection of Mycobacterium ulcerans in Mosquitoes in Southeastern Australia

Buruli ulcer (BU) is a destructive skin condition caused by infection with the environmental bacterium, Mycobacterium ulcerans. BU has been reported in more than 30 countries in Africa, the Americas, Asia and the Western Pacific. How people become infected with M. ulcerans is not completely understood, but numerous studies have explored the role of biting insects. In 2007, it was discovered that M. ulcerans could be detected in association with mosquitoes trapped in one town in southeastern Australia during a large outbreak of BU. In the present study we investigated whether there was a relationship between the incidence of BU in humans in several towns and the likelihood of detecting M. ulcerans in mosquitoes trapped in those locations. We found a strong association between the proportion of M. ulcerans-positive mosquitoes and the incidence of human disease. The results of this study strengthen the hypothesis that mosquitoes are involved in the transmission of M. ulcerans in southeastern Australia. This has implications for the development of strategies to control and prevent BU