Addressing obesity in the management of knee and hip osteoarthritis - weighing in from an economic perspective

BACKGROUND: Obesity is one of the only modifiable risk factors for both incidence and progression of Osteoarthritis (OA). So there is increasing interest from a public health perspective in addressing obesity in the management of OA. While evidence of the efficacy of intereventions designed to address obesity in OA populations continues to grow, little is known about their economic credentials. The aim of this study is to conduct a scoping review of: (i) the published economic evidence assessing the economic impact of obesity in OA populations; (ii) economic evaluations of interventions designed to explicitly address obesity in the prevention and management of OA in order to determine which represent value for money. Besides describing the current state of the literature, the study highlights research gaps and identifies future research priorities. METHODS: In July 2014, a search of the peer reviewed literature, published in English, was undertaken for the period January 1975 - July 2014 using Medline Complete (Ebscohost), Embase, Econlit, Global Health, Health Economics Evaluation Database (HEED), all Cochrane Library databases as well as the grey literature using Google and reference lists of relevant studies. A combination of key search terms was used to identify papers assessing the economic impact of obesity in OA or economic evaluations conducted to assess the efficiency of obesity interventions for the prevention or management of OA. RESULTS: 14 studes were identified; 13 were cost burden studies assessing the impact of obesity as a predictor for higher costs in Total Joint Arthroplasty (TJA) patients and one a cost-effectiveness study of an intervention designed to address obesity in the managment of mild to moderate OA patients. CONCLUSION: The majority of the economic studies conducted are cost burden studies. While there is some evidence of the association between severe obesity and excess hospital costs for TJA patients, heterogeneity in studies precludes definitive statements about the strength of the association. With only one economic evaluation to inform policy and practice, there is a need for future research into the cost-effectiveness of obesity interventions designed both for prevention or management of OA along the disease spectrum and over the life course

Matrix metalloproteinase-9 might affect adaptive immunity in non-ST segment elevation acute coronary syndromes by increasing CD31 cleavage on CD4+ T-cells

Aims In patients with acute coronary syndrome (ACS), the higher activity of effector T-cells suggests that mechanisms involving adaptive immunity dysregulation might play a role in coronary instability. The shedding of the functional CD31 domain 1-5 leads to uncontrolled lymphocyte activation. In experimental models, matrix metalloproteinase-9 (MMP-9) has been implicated in endothelial CD31 cleavage. Interestingly, higher serum levels of MMP-9 have been observed in ACS. We aim to investigate the mechanisms underlying CD31 dysregulation in ACS. Methods and results To assess CD31 cleavage on CD4+ T-cells, we analysed by flow cytometry CD4+ T-cells of 30 ACS, 25 stable angina (SA) patients, and 28 controls (CTRL) using two different CD31 antibodies that specifically recognize domain 1-5 or the non-functional membrane-proximal domain 6. The ratio between the domains was significantly lower in ACS than in SA and CTRL (P = 0.002 ACS vs. SA; P = 0.002 ACS vs. CTRL). After stimulation with anti-CD3/CD28, the 1-5/6 domain ratio was significantly lower in ACS than in SA (P = 0.005). ELISA of supernatants obtained from T-cell receptor-stimulated CD4+ T-cells showed higher production of MMP-9 in ACS than in SA (P < 0.001). CD31 domain 1-5 expression in activated CD4+ T-cells from ACS patients increased after treatment with a specific MMP-9 inhibitor (P = 0.042). Conclusion Our study suggest that enhanced MMP-9 release plays a key role in determining the cleavage and shedding of the functional CD31 domain 1-5 in CD4+ T-cells of ACS patients. This mechanism might represent an important therapeutic target to modulate T-cell dysregulation in ACS

Generation of human antibody fragments recognizing distinct epitopes of the nucleocapsid (N) SARS-CoV protein using a phage display approach

BACKGROUND: Severe acute respiratory syndrome (SARS)-CoV is a newly emerging virus that causes SARS with high mortality rate in infected people. Successful control of the global SARS epidemic will require rapid and sensitive diagnostic tests to monitor its spread, as well as, the development of vaccines and new antiviral compounds including neutralizing antibodies that effectively prevent or treat this disease. METHODS: The human synthetic single-chain fragment variable (scFv) ETH-2 phage antibody library was used for the isolation of scFvs against the nucleocapsid (N) protein of SARS-CoV using a bio panning-based strategy. The selected scFvs were characterized under genetics-molecular aspects and for SARS-CoV N protein detection in ELISA, western blotting and immunocytochemistry. RESULTS: Human scFv antibodies to N protein of SARS-CoV can be easily isolated by selecting the ETH-2 phage library on immunotubes coated with antigen. These in vitro selected human scFvs specifically recognize in ELISA and western blotting studies distinct epitopes in N protein domains and detect in immunohistochemistry investigations SARS-CoV particles in infected Vero cells. CONCLUSION: The human scFv antibodies isolated and described in this study represent useful reagents for rapid detection of N SARS-CoV protein and SARS virus particles in infected target cells

Specific Binding of the Pathogenic Prion Isoform: Development and Characterization of a Humanized Single-Chain Variable Antibody Fragment

Murine monoclonal antibody V5B2 which specifically recognizes the pathogenic form of the prion protein represents a potentially valuable tool in diagnostics or therapy of prion diseases. As murine antibodies elicit immune response in human, only modified forms can be used for therapeutic applications. We humanized a single-chain V5B2 antibody using variable domain resurfacing approach guided by computer modelling. Design based on sequence alignments and computer modelling resulted in a humanized version bearing 13 mutations compared to initial murine scFv. The humanized scFv was expressed in a dedicated bacterial system and purified by metal-affinity chromatography. Unaltered binding affinity to the original antigen was demonstrated by ELISA and maintained binding specificity was proved by Western blotting and immunohistochemistry. Since monoclonal antibodies against prion protein can antagonize prion propagation, humanized scFv specific for the pathogenic form of the prion protein might become a potential therapeutic reagent

One-pot synthesis of nano-crystalline MCM-22

[EN] Nano-crystalline MCM-22 zeolite was synthesized in a one-pot procedure by the use of an organosilane (dimethyl-octadecyl-(3-trimethoxysilylpropyl)-ammonium chloride, TPOAC) in the zeolite synthesis gel. This crystal growth inhibition procedure introduced mesopores in the MCM-22 crystallites. The lower mechanical stability of the nano-crystalline MCM-22 zeolite compared with bulk MCM-22 can be countered to some extent by pillaring. The increased external surface of the microporous zeolite domains resulted in increased accessibility of the Bronsted acid sites, as followed from the better performance in liquid-phase benzene alkylation with propylene as compared with bulk MCM-22. The increased accessibility of the internal acid sites in Mo-loaded hierarchical MCM-22 was also evident from the improved benzene selectivity during methane aromatization. Silylation of hierarchical Mo/MCM-22 was detrimental for the catalytic performance in MDA. The nano-crystalline MCM-22 has physico-chemical and catalytic properties intermediate between those of MCM-22 and ITQ-2 with the benefit over ITQ-2 that it can be synthesized in a single step. (C) 2015 Elsevier Inc. All rights reserved.Funding from the 7th Framework Program of the European Commission through the Collaborative Project Next-GTL (agreement no 229183) and financial support by the Spanish Government-MINECO through "Severo Ochoa" (SEV 2012-0267), Consolider Ingenio 2010-Multicat (CSD2009-00050) and MAT2012-31657 are acknowledged. Marta E. Martinez Armero thanks MINECO for economical support through pre-doctoral fellowship for doctors training (BES-2013-066800). The authors thank B. Esparcia for technical assistance.Tempelman, CHL.; Portilla Ovejero, MT.; Martínez Armero, ME.; Mezari, B.; De Caluwe, NGR.; Martínez, C.; Hensen, EJM. (2016). One-pot synthesis of nano-crystalline MCM-22. Microporous and Mesoporous Materials. 220:28-38. https://doi.org/10.1016/j.micromeso.2015.08.018S283822

Feedback Inhibition in the PhoQ/PhoP Signaling System by a Membrane Peptide

The PhoQ/PhoP signaling system responds to low magnesium and the presence of certain cationic antimicrobial peptides. It regulates genes important for growth under these conditions, as well as additional genes important for virulence in many gram-negative pathogens. PhoQ is a sensor kinase that phosphorylates and activates the transcription factor PhoP. Since feedback inhibition is a common theme in stress-response circuits, we hypothesized that some members of the PhoP regulon may play such a role in the PhoQ/PhoP pathway. We therefore screened for PhoP-regulated genes that mediate feedback in this system. We found that deletion of mgrB (yobG), which encodes a 47 amino acid peptide, results in a potent increase in PhoP-regulated transcription. In addition, over-expression of mgrB decreased transcription at both high and low concentrations of magnesium. Localization and bacterial two-hybrid studies suggest that MgrB resides in the inner-membrane and interacts directly with PhoQ. We further show that MgrB homologs from Salmonella typhimurium and Yersinia pestis also repress PhoP-regulated transcription in these organisms. In cell regulatory circuits, feedback has been associated with modulating the induction kinetics and/or the cell-to-cell variability in response to stimulus. Interestingly, we found that elimination of MgrB-mediated feedback did not have a significant effect on the kinetics of reporter protein production and did not decrease the variability in expression among cells. Our results indicate MgrB is a broadly conserved membrane peptide that is a critical mediator of negative feedback in the PhoQ/PhoP circuit. This new regulator may function as a point of control that integrates additional input signals to modulate the activity of this important signaling system

Evolution of a Bacterial Regulon Controlling Virulence and Mg2+ Homeostasis

Related organisms typically rely on orthologous regulatory proteins to respond to a given signal. However, the extent to which (or even if) the targets of shared regulatory proteins are maintained across species has remained largely unknown. This question is of particular significance in bacteria due to the widespread effects of horizontal gene transfer. Here, we address this question by investigating the regulons controlled by the DNA-binding PhoP protein, which governs virulence and Mg2+ homeostasis in several bacterial species. We establish that the ancestral PhoP protein directs largely different gene sets in ten analyzed species of the family Enterobacteriaceae, reflecting both regulation of species-specific targets and transcriptional rewiring of shared genes. The two targets directly activated by PhoP in all ten species (the most distant of which diverged >200 million years ago), and coding for the most conserved proteins are the phoPQ operon itself and the lipoprotein-encoding slyB gene, which decreases PhoP protein activity. The Mg2+-responsive PhoP protein dictates expression of Mg2+ transporters and of enzymes that modify Mg2+-binding sites in the cell envelope in most analyzed species. In contrast to the core PhoP regulon, which determines the amount of active PhoP and copes with the low Mg2+ stress, the variable members of the regulon contribute species-specific traits, a property shared with regulons controlled by dissimilar regulatory proteins and responding to different signals

Evolution of a Bacterial Regulon Controlling Virulence and Mg2+ Homeostasis

Related organisms typically rely on orthologous regulatory proteins to respond to a given signal. However, the extent to which (or even if) the targets of shared regulatory proteins are maintained across species has remained largely unknown. This question is of particular significance in bacteria due to the widespread effects of horizontal gene transfer. Here, we address this question by investigating the regulons controlled by the DNA-binding PhoP protein, which governs virulence and Mg2+ homeostasis in several bacterial species. We establish that the ancestral PhoP protein directs largely different gene sets in ten analyzed species of the family Enterobacteriaceae, reflecting both regulation of species-specific targets and transcriptional rewiring of shared genes. The two targets directly activated by PhoP in all ten species (the most distant of which diverged >200 million years ago), and coding for the most conserved proteins are the phoPQ operon itself and the lipoprotein-encoding slyB gene, which decreases PhoP protein activity. The Mg2+-responsive PhoP protein dictates expression of Mg2+ transporters and of enzymes that modify Mg2+-binding sites in the cell envelope in most analyzed species. In contrast to the core PhoP regulon, which determines the amount of active PhoP and copes with the low Mg2+ stress, the variable members of the regulon contribute species-specific traits, a property shared with regulons controlled by dissimilar regulatory proteins and responding to different signals