Photosensitivity in epilepsy is common and has high heritability, but its genetic basis remains uncertain. Galizia et al. reveal an overrepresentation of unique variants of CHD2 — which encodes the transcriptional regulator ‘chromodomain helicase DNA-binding protein 2’ — in photosensitive epilepsies, and show that chd2 knockdown in zebrafish causes photosensitivity.

BackgroundBuruli Ulcer (BU) is a neglected, necrotizing skin disease caused by Mycobacterium ulcerans. Currently, there is no vaccine against M. ulcerans infection. Although the World Health Organization recommends a combination of rifampicin and streptomycin for the treatment of BU, clinical management of advanced stages is still based on the surgical resection of infected skin. The use of bacteriophages for the control of bacterial infections has been considered as an alternative or to be used in association with antibiotherapy. Additionally, the mycobacteriophage D29 has previously been shown to display lytic activity against M. ulcerans isolates.Methodology/Principal findingsWe used the mouse footpad model of M. ulcerans infection to evaluate the therapeutic efficacy of treatment with mycobacteriophage D29. Analyses of macroscopic lesions, bacterial burdens, histology and cytokine production were performed in both M. ulcerans-infected footpads and draining lymph nodes (DLN). We have demonstrated that a single subcutaneous injection of the mycobacteriophage D29, administered 33 days after bacterial challenge, was sufficient to decrease pathology and to prevent ulceration. This protection resulted in a significant reduction of M. ulcerans numbers accompanied by an increase of cytokine levels (including IFN-γ), both in footpads and DLN. Additionally, mycobacteriophage D29 treatment induced a cellular infiltrate of a lymphocytic/macrophagic profile.Conclusions/SignificanceOur observations demonstrate the potential of phage therapy against M. ulcerans infection, paving the way for future studies aiming at the development of novel phage-related therapeutic approaches against BU.

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Buruli ulcer is a neglected infectious disease caused byBuruli ulcer (BU) is an emerging neglected tropical disease caused by Mycobacterium ulcerans and is characterized by nonulcerative lesions that can evolve into severe ulcers (41,70).Infection by M. ulcerans poses a unique challenge for the host immune system due to the secretion of the highly cytotoxic lipidic exotoxin mycolactone (17). Mycolactone has been suggested to suppress the development of local and systemic immune responses by inhibiting cytokine production during active BU (19-21, 42, 72, 75) and compromising T-cell priming by suppressing dendritic cell function (11). However, there are no studies on the association of BU with opportunistic infections, suggesting that the immunosuppressive effects of mycolactone might not be systemic.The observations that active BU occurs in a small proportion of exposed individuals (14, 58) and when it develops frequently heals spontaneously (69) suggest the existence of protective immunity. Although the protective mechanisms remain largely unknown, several studies support that adaptive cell-mediated immunity (CMI) is relevant for the control of M. ulcerans (reviewed in reference 53). In fact, (i) M. ulcerans has an intramacrophage growth phase (66), (ii) resistance to BU is associated with the development of T helper (Th) 1 type responses and granulomata (10,20,21,23,42,48,63,70,72), (iii) the positivity of the delayed-type hypersensitivity (DTH) burulin test increases from early to advanced phases (15, 31), (iv) the histopathology of healing BU lesions in patients submitted to antibiotic treatment is consistent with CMI (49), (v) Mycobacterium bovis BCG vaccination induces transient protection in humans and in experimental infections (16,55,60,62,68), (vi) infection with HIV increases the risk of developing BU and more aggressive multifocal forms (27, 64), and (vii) the pattern of cytokine expression in BU lesions conforms with CMI and DTH (28,38,67).Therefore, to clarify whether the M. ulcerans infectious process interferes with the development of protective immunity and whether systemic immunosuppression is induced, we monitored the host immune response in the mouse model, not only in the primary site of infection but also in the draining lymph node (DLN), where the initiation of the adaptive immunity takes place. MATERIALS AND METHODSAnimals. Eight-week-old female wild-type, nude, and Rag2-deficient mice in a BALB/c background were obtained from Charles River (Barcelona, Spain). Rag-deficient BALB/c mice transgenic for the DO11.10 ␣/␤ T-cell receptor (TCR) were from Anne O'Garra (NIMR, London, United Kingdom). The studies involving animals were approved by the review committees of ICVS and the Portuguese Governmental Agency Direcção Geral de Veterinária.Experimental infections. The different M. ulcerans strains used in the present study were selected based on their virulence for mice (35,65) and on the type of mycolactone produced (26, 32, 59). M. ulcerans 5114 is a low-virulence Mexican

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BackgroundBuruli ulcer (BU) is an emerging infectious disease caused by Mycobacterium ulcerans that can result in extensive necrotizing cutaneous lesions due to the cytotoxic exotoxin mycolactone. There is no specific vaccine against BU but reports show some degree of cross-reactive protection conferred by M. bovis BCG immunization. Alternatively, an M. ulcerans-specific immunization could be a better preventive strategy.Methodology/Principal FindingsIn this study, we used the mouse model to characterize the histological and cytokine profiles triggered by vaccination with either BCG or mycolactone-negative M. ulcerans, followed by footpad infection with virulent M. ulcerans. We observed that BCG vaccination significantly delayed the onset of M. ulcerans growth and footpad swelling through the induction of an earlier and sustained IFN-γ T cell response in the draining lymph node (DLN). BCG vaccination also resulted in cell-mediated immunity (CMI) in M. ulcerans-infected footpads, given the predominance of a chronic mononuclear infiltrate positive for iNOS, as well as increased and sustained levels of IFN-γ and TNF. No significant IL-4, IL-17 or IL-10 responses were detected in the footpad or the DLN, in either infected or vaccinated mice. Despite this protective Th1 response, BCG vaccination did not avoid the later progression of M. ulcerans infection, regardless of challenge dose. Immunization with mycolactone-deficient M. ulcerans also significantly delayed the progression of footpad infection, swelling and ulceration, but ultimately M. ulcerans pathogenic mechanisms prevailed.Conclusions/SignificanceThe delay in the emergence of pathology observed in vaccinated mice emphasizes the relevance of protective Th1 recall responses against M. ulcerans. In future studies it will be important to determine how the transient CMI induced by vaccination is compromised.

The uptake of nanoparticles by cells of the mononuclear phagocytic system limits its use as colloidal drug carriers, reducing the blood circulation time and the ability to reach biological targets. In this work, the interaction between dextrin nanoparticles--recently developed in our laboratory--and murine bone marrow-derived macrophages was evaluated. Cytotoxicity and nitric oxide production were studied, using the MTT assay and the Griess method, respectively. FITC labelled nanoparticles were used to assess the phagocytic uptake and blood clearance after intravenous injection. The phagocytic uptake was analysed in vitro by confocal laser scanning microscopy and fluorescence activated cell sorting. The results show that the nanoparticles are not cytotoxic and do not stimulate the production of nitric oxide by macrophages, in the range of concentrations studied. Nanoparticles are phagocytosed by macrophages and are detected inside the cells, concentrated in cellular organelles. The blood clearance study showed that the blood removal of the nanoparticles occurs with a more pronounced rate in the first 3 h after intravenous administration, with about 30% of the material remaining in systemic circulation at this stage. Given the fairly high blood circulation time and biocompatibility, the dextrin nanoparticles are promising carriers for biomedical applications. Both applications targeting phagocytic, antigen-presenting cells (for vaccination purposes) and different tissues (as drug carriers) may be envisaged, by modulation of the surface properties.

Objectives Osteoarthritis (OA) is a chronic degenerative musculoskeletal disease that causes articular damage and chronic pain, with a prevalence of up to 50% in individuals >60 years of age. Patients suffering from chronic painful conditions, including OA, also frequently report anxiety or depression. A systematic review and meta-analysis were performed to assess the correlation between pain severity and depressive and anxious symptomatology in OA patients. Methods A systematic search was conducted using four databases (PubMed, Medline, Scopus, and Web of Science) from inception up to 14th January of 2020. We included original articles evaluating pain severity and anxiety and/or depression severity in OA-diagnosed patients. Detailed data were extracted from each study, including patients’ characteristics and pain, anxiety, and depression severity. When available, the Pearson correlation coefficient between pain and depression severity and pain and anxiety severity was collected and a meta-analysis of random effects was applied. Results This systematic review included 121 studies, with a total of 38085 participants. The mean age was 64.3 years old and subjects were predominantly female (63%). The most used scale to evaluate pain severity was the Western Ontario and the McMaster Universities Osteoarthritis Index, while for anxiety and depression, the Hospital Anxiety and Depression Scale was the most used. The meta-analysis showed a moderate positive correlation between pain severity and both anxious (r = 0.31, p < 0.001) and depressive symptomatology (r = 0.36, p < 0.001). Conclusions Our results demonstrate a significant correlation between pain and depression/anxiety severity in OA patients, highlighting the need for its routine evaluation by clinicians.