Fecal Dipeptidyl Peptidase-4: An Emergent Biomarker in Inflammatory Bowel Disease

INTRODUCTION: Dipeptidyl peptidase-4 (DPP-4) is a membrane-bound glycoprotein that acts as a receptor but also exists in a soluble form. It has been recognized as a mediator of inflammation and considered a biomarker in inflammatory bowel disease (IBD). METHODS: We evaluated a prospectively recruited cohort, consisting of 101 patients with IBD, using validated clinical indexes; 22 patients with ulcerative colitis (UC) underwent endoscopic evaluation. Fecal DPP-4 (fDPP-4) levels were analyzed and correlated with clinical scores, Mayo endoscopic score (in UC patients), serum DPP-4, C-reactive protein, and fecal calprotectin. Immunohistochemical staining for DPP-4 in intestinal biopsies was also performed. RESULTS: When compared with remitters, median fDPP-4 levels were higher in patients with ileal Crohn's disease (CD) (7,584 [1,464-7,816] vs 2,104 [630-2,676] ng/mL, P = 0.015) and lower in patients with UC exhibiting clinical activity (1,213 [559-1,682] vs 7,814 [2,555-7,985] ng/mL, P < 0.001). Patients with UC presenting endoscopic activity also had lower levels than remitters (939 [559-1,420] vs 7,544 [4,531-7,940] ng/mL, P = 0.006). Fecal DPP-4 discriminated clinical activity from remission with areas under the curve of 0.76 (95% confidence interval [CI] 0.58-0.94, P = 0.015) and 0.80 (95% CI 0.68-0.93, P < 0.001) in CD and UC, respectively; it allowed to differentiate endoscopic activity in patients with UC, with areas under the curve of 0.84 (95% CI 0.63-1.00, P = 0.009). Immunohistochemical analysis revealed higher DPP-4 apical expression in UC remitters, but no statistically significant differences were revealed between patients with ileal CD. DISCUSSION: Our results suggest that fDPP-4 can be used as a biomarker of IBD activity, particularly in UC. The expression profiles in intestinal tissue might represent a functional compartmentalization of DPP-4 expression

Extracellular environment contribution to astrogliosis-lessons learned from a tissue engineered 3D model of the glial scar

Glial scars are widely seen as a (bio)mechanical barrier to central nervous system regeneration. Due to the lack of a screening platform, which could allow in-vitro testing of several variables simultaneously, up to now no comprehensive study has addressed and clarified how different lesion microenvironment properties affect astrogliosis. Using astrocytes cultured in alginate gels and meningeal fibroblast conditioned medium, we have built a simple and reproducible 3D culture system of astrogliosis mimicking many features of the glial scar. Cells in this 3D culture model behave similarly to scar astrocytes, showing changes in gene expression (e.g., GFAP) and increased extra-cellular matrix production (chondroitin 4 sulfate and collagen), inhibiting neuronal outgrowth. This behavior being influenced by the hydrogel network properties. Astrocytic reactivity was found to be dependent on RhoA activity, and targeting RhoA using shRNA-mediated lentivirus reduced astrocytic reactivity. Further, we have shown that chemical inhibition of RhoA with ibuprofen or indirectly targeting RhoA by the induction of extracellular matrix composition modification with chondroitinase ABC, can diminish astrogliosis. Besides presenting the extracellular matrix as a key modulator of astrogliosis, this simple, controlled and reproducible 3D culture system constitutes a good scar-like system and offers great potential in future neurodegenerative mechanism studies, as well as in drug screenings envisaging the development of new therapeutic approaches to minimize the effects of the glial scar in the context of central nervous system disease.This work had the financial support of the Portuguese Fundação para a Ciência e Tecnologia (FCT) / Ministério da Educação e Ciência (MEC) through National Funds and, when applicable, co-financed by the FEDER via the PT2020 Partnership Agreement under the 4293 Unit I&D. DR acknowledges FCT for her PhD scholarship /SFRH/BD/64079/2009). Authors thank Dr. Michiyuki Matsuda (Kyoto University, Japan) for the RhoA FRET probe with enhanced sensitivity and Dr. Yingxiao Wang (University of California, USA) for the Src FRET probe

From sparse to dense and from assortative to disassortative in online social networks

Inspired by the analysis of several empirical online social networks, we propose a simple reaction-diffusion-like coevolving model, in which individuals are activated to create links based on their states, influenced by local dynamics and their own intention. It is shown that the model can reproduce the remarkable properties observed in empirical online social networks; in particular, the assortative coefficients are neutral or negative, and the power law exponents are smaller than 2. Moreover, we demonstrate that, under appropriate conditions, the model network naturally makes transition(s) from assortative to disassortative, and from sparse to dense in their characteristics. The model is useful in understanding the formation and evolution of online social networks.Comment: 10 pages, 7 figures and 2 table

"Detachment of the carinal hook following endobronchial intubation with a double lumen tube"

<p>Abstract</p> <p>Background</p> <p>Carinal hooks increases difficulty at endotracheal intubation. Amputation of the carinal hook during passage and malpositioning of the tube to the hook are some of the potential problems related with left-sided Carlens double lumen tube (DLT). This article reports an amputation of the hook during a difficult selective intubation and aimed at calling the attention to complications associated with DLTs and the importance of fiberoptic bronchoscopy.</p> <p>Case presentation</p> <p>A 68 year-old woman was scheduled for right-sided thoracotomy in whom blind DLT insertion was performed. Narrowed trachea causes difficulty in rotating the DLT 90° counter-clockwise. After carinal hook was noticed upon visual inspection of the DLT, fiberoptic bronchoscopy was used to remove the missing part (with the use of forceps) from the right mainstem bronchus.</p> <p>Conclusion</p> <p>Insertion of DLTs with carinal hook is associated with technical problems and potentially life-threatening hazards have discouraged their use. Fiberoptic evaluation and repositioning solves most of the problems. Although amputation of the carinal hook has not been previously reported, clinicians should be alert. This case report emphasizes the utility of the fiberoptic bronchoscopy in the operating theatre for placement, positioning and inspection of the carinal hook DLT.</p

Deciphering the contribution of biofilm to the pathogenesis of peritoneal dialysis infections: characterization and microbial behaviour on dialysis fluids

Infections are major complications in peritoneal dialysis (PD) with a multifactorial etiology that comprises patient, microbial and dialytic factors. This study aimed at investigating the contribution of microbial biofilms on PD catheters to recalcitrant infections and their interplay with PD related-factors. A prospective observational study was performed on 47 patients attending Centro Hospitalar of Porto and Vila Nova de Gaia/Espinho to whom the catheter was removed due to infectious (n = 16) and non-infectious causes (n = 31). Microbial density on the catheter was assessed by culture methods and the isolated microorganisms identified by matrix-assisted laser desorption/ionization time-of-flight intact cell mass spectrometry. The effect of conventional and three biocompatible PD solutions on 16 Coagulase Negative Staphylococci (CNS) and 10 Pseudomonas aeruginosa strains planktonic growth and biofilm formation was evaluated. Cultures were positive in 87.5% of the catheters removed due infectious and 90.3% removed due to non-infectious causes. However, microbial yields were higher on the cuffs of catheters removed due to infection vs. non-infection. Staphylococci (CNS and Staphylococcus aureus) and P. aeruginosa were the predominant species: 32% and 20% in the infection and 43.3% and 22.7% in the non-infection group, respectively. In general, PD solutions had a detrimental effect on planktonic CNS and P. aeruginosa strains growth. All strains formed biofilms in the presence of PD solutions. The solutions had a more detrimental effect on P. aeruginosa than CNS strains. No major differences were observed between conventional and biocompatible solutions, although in icodextrin solution biofilm biomass was lower than in bicarbonate/lactate solution. Overall, we show that microbial biofilm is universal in PD catheters with the subclinical menace of Staphylococci and P. aeruginosa. Cuffs colonization may significantly contribute to infection. PD solutions differentially impact microbial species. This knowledge is important for the development of infection diagnosis, treatment and preventive strategies.This work received support from a Sociedade Portuguesa de Nefrologia (http://www.spnefro.pt) research grant to AR and a Fundação para a Ciência e Tecnologia (http://www.fct.pt) post doc grant (SFRH/BPD/73663/2010) to MM. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

B cells Can Modulate the CD8 Memory T Cell after DNA Vaccination Against Experimental Tuberculosis

Abstract\ud \ud \ud \ud Background\ud \ud Although B cells are important as antigen presenting cells (APC) during the immune response, their role in DNA vaccination models is unknown.\ud \ud \ud \ud Methods\ud \ud In this study in vitro and in vivo experiments were performed to evaluate the ability of B cells to protect mice against Mycobacterium tuberculosis challenge.\ud \ud \ud \ud Results\ud \ud \ud In vitro and in vivo studies showed that B cells efficiently present antigens after naked plasmid pcDNA3 encoding M. leprae 65-kDa heat shock protein (pcDNA3-Hsp65) internalization and protect B knock-out (BKO) mice against Mycobacterium tuberculosis infection. pcDNA3-Hsp65-transfected B cells adoptively transferred into BKO mice rescued the memory phenotypes and reduced the number of CFU compared to wild-type mice.\ud \ud \ud \ud Conclusions\ud \ud These data not only suggest that B cells play an important role in the induction of CD8 T cells but also that they improve bacterial clearance in DNA vaccine model.We are thankful to Ana Paula Masson and Izaíra T Brandão for providing the DNA vaccine and recombinant protein. This study was supported by a FAPESP fellowship (05/030873) to LPA.We are thankful to Ana Paula Masson and Izaíra T Brandão for providing the DNA vaccine and recombinant protein. This study was supported by a FAPESP fellowship (05/03087-3) to LPA

A tetravalent dengue nanoparticle stimulates antibody production in mice

<p>Abstract</p> <p>Background</p> <p>Dengue is a major public health problem worldwide, especially in the tropical and subtropical regions of the world. Infection with a single <it>Dengue virus </it>(DENV) serotype causes a mild, self-limiting febrile illness called dengue fever. However, a subset of patients experiencing secondary infection with a different serotype progresses to the severe form of the disease, dengue hemorrhagic fever/dengue shock syndrome. Currently, there are no licensed vaccines or antiviral drugs to prevent or treat dengue infections. Biodegradable nanoparticles coated with proteins represent a promising method for in vivo delivery of vaccines.</p> <p>Findings</p> <p>Here, we used a murine model to evaluate the IgG production after administration of inactivated DENV corresponding to all four serotypes adsorbed to bovine serum albumin nanoparticles. This formulation induced a production of anti-DENV IgG antibodies (p < 0.001). However, plaque reduction neutralization assays with the four DENV serotypes revealed that these antibodies have no neutralizing activity in the dilutions tested.</p> <p>Conclusions</p> <p>Our results show that while the nanoparticle system induces humoral responses against DENV, further investigation with different DENV antigens will be required to improve immunogenicity, epitope specicity, and functional activity to make this platform a viable option for DENV vaccines.</p

Combining filter method and dynamically dimensioned search for constrained global optimization

In this work we present an algorithm that combines the filter technique and the dynamically dimensioned search (DDS) for solving nonlinear and nonconvex constrained global optimization problems. The DDS is a stochastic global algorithm for solving bound constrained problems that in each iteration generates a randomly trial point perturbing some coordinates of the current best point. The filter technique controls the progress related to optimality and feasibility defining a forbidden region of points refused by the algorithm. This region can be given by the flat or slanting filter rule. The proposed algorithm does not compute or approximate any derivatives of the objective and constraint functions. Preliminary experiments show that the proposed algorithm gives competitive results when compared with other methods.The first author thanks a scholarship supported by the International Cooperation Program CAPES/ COFECUB at the University of Minho. The second and third authors thanks the support given by FCT (Funda¸c˜ao para Ciˆencia e Tecnologia, Portugal) in the scope of the projects: UID/MAT/00013/2013 and UID/CEC/00319/2013. The fourth author was partially supported by CNPq-Brazil grants 308957/2014-8 and 401288/2014-5.info:eu-repo/semantics/publishedVersio

On a smoothed penalty-based algorithm for global optimization

This paper presents a coercive smoothed penalty framework for nonsmooth and nonconvex constrained global optimization problems. The properties of the smoothed penalty function are derived. Convergence to an ε -global minimizer is proved. At each iteration k, the framework requires the ε(k) -global minimizer of a subproblem, where ε(k)→ε . We show that the subproblem may be solved by well-known stochastic metaheuristics, as well as by the artificial fish swarm (AFS) algorithm. In the limit, the AFS algorithm convergence to an ε(k) -global minimum of the real-valued smoothed penalty function is guaranteed with probability one, using the limiting behavior of Markov chains. In this context, we show that the transition probability of the Markov chain produced by the AFS algorithm, when generating a population where the best fitness is in the ε(k)-neighborhood of the global minimum, is one when this property holds in the current population, and is strictly bounded from zero when the property does not hold. Preliminary numerical experiments show that the presented penalty algorithm based on the coercive smoothed penalty gives very competitive results when compared with other penalty-based methods.The authors would like to thank two anonymous referees for their valuable comments and suggestions to improve the paper. This work has been supported by COMPETE: POCI-01-0145-FEDER-007043 and FCT - Fundac¸ao para a Ci ˜ encia e Tecnologia within the projects UID/CEC/00319/2013 and ˆ UID/MAT/00013/2013.info:eu-repo/semantics/publishedVersio