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Nebenzahl-Guimaraes H.,Harvard University | Nebenzahl-Guimaraes H.,National Institute for Public Health and the Environment RIVM | Nebenzahl-Guimaraes H.,University of Minho | Nebenzahl-Guimaraes H.,PT Government Associate Laboratory | And 4 more authors.
Journal of Antimicrobial Chemotherapy

Background: Improving our understanding of the relationship between the genotype and the drug resistance phenotype of Mycobacterium tuberculosis will aid the development of more accurate molecular diagnostics for drug-resistant tuberculosis. Studies that use direct genetic manipulation to identify the mutations that cause M. tuberculosis drug resistance are superior to associational studies in elucidating an individual mutation's contribution to the drug resistance phenotype. Methods: We systematically reviewed the literature for publications reporting allelic exchange experiments in any of the resistance-associated M. tuberculosis genes. We included studies that introduced single point mutations using specialized linkage transduction or site-directed/in vitro mutagenesis and documented a change in the resistance phenotype. Results: We summarize evidence supporting the causal relationship of 54 different mutations in eight genes (katG, inhA, kasA, embB, embC, rpoB, gyrA and gyrB) and one intergenic region (furA-katG) with resistance to isoniazid, the rifamycins, ethambutol and fluoroquinolones. We observed a significant role for the strain genomic background in modulating the resistance phenotype of 21 of these mutations and found examples of where the same drug resistance mutations caused varying levels of resistance to different members of the same drug class. Conclusions: This systematic review highlights those mutations that have been shown to causally change phenotypic resistance in M. tuberculosis and brings attention to a notable lack of allelic exchange data for several of the genes known to be associated with drug resistance. © The Author 2013. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. Source

Cotter J.,Centro Hospitalar Do Alto Ave | Cotter J.,University of Minho | Cotter J.,PT Government Associate Laboratory | Dias de Castro F.,Centro Hospitalar Do Alto Ave | And 2 more authors.
Journal of Crohn's and Colitis

Background and aims: Small bowel capsule endoscopy (SBCE) may detect proximal small bowel lesions that have been previously missed by ileocolonoscopy and small bowel imaging in patients with known ileal and/or colonic Crohn's disease (CD). We aimed to evaluate whether the therapeutic management is influenced by SBCE findings. Methods: Retrospective single center study. Inclusion of consecutive patients with known non-stricturing and non-penetrating ileal and/or colonic CD, submitted to SBCE to evaluate disease extension and activity, with ≥ 1. year follow-up. Lesions were classified with the Lewis score (LS) as non-significant (LS. <. 135), mild (135. ≤. LS. ≤. 790), or moderate-to-severe (LS. >. 790). Therapeutic changes were assessed three months after SBCE. Results: Fifty consecutive patients (35. ±. 13. years, 52% females) were included. At ileocolonoscopy, disease location was ileal (L1) in 60%, colonic (L2) in 10% and ileocolonic (L3) in 30% of the patients. In 33 patients (66%) SBCE detected significant proximal lesions previously missed by other modalities. The proportion of patients on thiopurines and/or biologics before SBCE was 2/50 (4%); this was significantly higher three months after SBCE, 15/50 (30%), p. = 0.023. Treatment with thiopurines and/or biologics was started more often in patients with proximal small bowel lesions [13/33 (39%) vs. 1/17 (6%), p. = 0.011, relative risk (RR) 6.5], particularly when severe (6%, 36% and 45% of patients with non-significant, mild and moderate-to-severe inflammation, respectively). Conclusions: SBCE diagnoses previously undetected lesions and it influences therapeutic management of CD, triggering an earlier introduction of immunomodulators and/or biological therapy. © 2014 European Crohn's and Colitis Organisation. Source

Bruchfeld J.,Karolinska University Hospital | Correia-Neves M.,University of Minho | Correia-Neves M.,PT Government Associate Laboratory | Kallenius G.,Karolinska Institutet
Cold Spring Harbor Perspectives in Medicine

Tuberculosis (TB) and human immunodeficiency virus/acquired immunodeficiency syn-drome (HIV/AIDS) constitute the main burden of infectious disease in resource-limited countries. In the individual host, the two pathogens, Mycobacterium tuberculosis and HIV, potentiate one another, accelerating the deterioration of immunological functions. In high-burden settings, HIV coinfection is the most important risk factor for developing active TB, which increases the susceptibility to primary infection or reinfection and also the risk of TB reactivation for patients with latent TB. M. tuberculosis infection also has a negative impact on the immune response to HIV, accelerating the progression from HIV infection to AIDS. The clinical management of HIV-associated TB includes the integration of effective anti-TB treatment, use of concurrent antiretroviral therapy (ART), prevention of HIV-related comorbidities, management of drug cytotoxicity, and prevention/treatment of immune reconstitution inflammatory syndrome (IRIS). © 2015 Cold Spring Harbor Laboratory Press; all rights reserved. Source

Costa R.R.,University of Minho | Costa R.R.,PT Government Associate Laboratory | Custodio C.A.,University of Minho | Arias F.J.,University of Valladolid | And 4 more authors.

In this work, biomimetic smart thin coatings using chitosan and a recombinant elastin-like recombinamer (ELR) containing the cell attachment sequence arginine-glycine-(aspartic acid) (RGD) are fabricated through a layer-by-layer approach. The synthetic polymer is characterized for its molecular mass and composition using mass spectroscopy and peptide sequencing. The adsorption of each polymeric layer is followed in situ at room temperature and pH 5.5 using a quartz-crystal microbalance with dissipation monitoring, showing that both polymers can be successfully combined to conceive nanostructured, multilayered coatings. The smart properties of the coatings are tested for their wettability by contact angle (CA) measurements as a function of external stimuli, namely temperature, pH, and ionic strength. Wettability transitions are observed from a moderate hydrophobic surface (CAs approximately from 62° to 71°) to an extremely wettable one (CA considered as 0°) as the temperature, pH, and ionic strength are raised above 50 °C, 11, and 1.25 M, respectively. Atomic force microscopy is performed at pH 7.4 and pH 11 to assess the coating topography. In the latter, the results reveal the formation of large and compact structures upon the aggregation of ELRs at the surface, which increase water affinity. Cell adhesion tests are conducted using a SaOs-2 cell line. Enhanced cell adhesion is observed in the coatings, as compared to a coating with a chitosan-ending film and a scrambled arginine-(aspartic acid)-glycine (RDG) biopolymer. The results suggest that such films could be used in the future as smart biomimetic coatings of biomaterials for different biomedical applications, including those in tissue engineering or in controlled delivery systems. Nanostructured multilayered films of chitosan and an elastin-like recombinamer are constructed. The thin films are demonstrated to possess stimuli-responsive and cyclic wettability changes from moderately hydrophobic to superhydrophilic, accompanied by the formation of spherical "micelle-like" structures. The incorporation of arginine-glycine-aspartic acid (RGD) in the recombinamer sequence improved cell adhesion. These features make of this system a promising alternative to classical layer-by-layer films with smart nature and increased functionality. © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. Source

Caridade S.G.,University of Minho | Caridade S.G.,PT Government Associate Laboratory | Caridade S.G.,CNRS Materials and Physical Engineering Laboratory | Monge C.,CNRS Materials and Physical Engineering Laboratory | And 5 more authors.

Free-standing films have increasing applications in the biomedical field as drug delivery systems for wound healing and tissue engineering. Here, we prepared free-standing membranes by the layer-by-layer assembly of chitosan and alginate, two widely used biomaterials. Our aim was to produce a thick membrane and to study the permeation of model drugs and the adhesion of muscle cells. We first defined the optimal growth conditions in terms of pH and alginate concentration. The membranes could be easily detached from polystyrene or polypropylene substrate without any postprocessing step. The dry thickness was varied over a large range from 4 to 35 μm. A 2-fold swelling was observed by confocal microscopy when they were immersed in PBS. In addition, we quantified the permeation of model drugs (fluorescent dextrans) through the free-standing membrane, which depended on the dextran molecular weight. Finally, we showed that myoblast cells exhibited a preferential adhesion on the alginate-ending membrane as compared to the chitosan-ending membrane or to the substrate side. © 2013 American Chemical Society. Source

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