Determining a low disease activity threshold for decision to maintain disease-modifying antirheumatic drug treatment unchanged in rheumatoid arthritis patients

Introduction

The aim of this study was to determine a low disease activity threshold - a 28-joint disease activity score (DAS28) value - for the decision to maintain unchanged disease-modifying antirheumatic drug (DMARD) treatment in rheumatoid arthritis patients, based on expert opinion.

Methods

Nine hundred and sixty-seven case scenarios with various levels for each component of the DAS28 (resulting in a disease activity score between 2 and 3.2) were presented to 44 panelists. For each scenario, panelists had to decide whether or not DMARD treatment (excluding steroids) could be maintained unchanged. In each scenario, for decision, the participants were given the DAS28 parameters, without knowledge of the resultant DAS28. The relationship between panelists' decision, DAS28 value, and components of the score were analysed by multiple logistic regression analysis. Each panelist analysed 160 randomised scenarios. Intra-rater and inter-rater reproducibility were assessed.

Results

Forty-four panelists participated in the study. Inter-panelist agreement was good (κ = 0.63; 95% confidence interval = 0.61 to 0.65). Intra-panelist agreement was excellent (κ = 0.87; 95% confidence interval = 0.82 to 0.92). Quasi-perfect agreement was observed for DAS28 ≤ 2.4, less pronounced between 2.5 and 2.9, and almost no agreement for DAS28 > 3.0. For values below 2.5, panelists agreed to maintain unchanged DMARDs; for values above 2.5, discrepancies occurred more frequently as the DAS28 value increased. Multivariate analysis confirmed the relationship between panelist's decision, DAS28 value and components of the DAS28. Between DAS28 of 2.4 and 3.2, a major determinant for panelists' decision was swollen joint count. Female and public practice physicians decided more often to maintain treatment unchanged.

Conclusions

As a conclusion, panelists suggested that in clinical practice there is no need to change DMARD treatment in rheumatoid arthritis patients with DAS28 ≤ 2.4.     

Asymmetric lipid bilayer formation stabilized by DNA at the air/water interface

The lipid bis(guanidinium)-tren-cholesterol (BGTC) is a cationic cholesterol derivative bearing guanidinium polar headgroups used for gene transfection either alone or formulated as liposomes with the zwitterionic lipid 1,2-di-[cis-9-octadecenoyl]-sn-glycero-3-phosphoethanolamine (DOPE). Previous investigations have shown its ability to strongly interact with DNA and form asymmetric lipid bilayers at the air/water interface when mixed with DOPE. Here, with a view to further investigate its physicochemical behavior, we studied the interactions of mixtures of BGTC with another zwitterionic lipid, 1,2-Dimyristoyl-sn-Glycero-3-Phosphocholine, (DMPC), with DNA at the air/water interface by using the Langmuir monolayer technique coupled with Brewster Angle Microscopy (BAM) and Polarization Modulation Infra Red Reflexion Absorption (PMIRRAS) spectroscopy and we investigate DNA–BGTC/DMPC interactions. We demonstrate that when DNA is injected into the subphase in excess compared to the positive charges of BGTC, it adsorbs to BGTC/DMPC monolayers at 20 mN/m whatever the lipid monolayer composition (1/5, 2/3 or 3/2 BGTC/DMPC molar ratio) and forms an incomplete monolayer of either isotropic or anisotropic double strands depending on the BGTC content in the monolayer. Compression beyond the collapse of some mixed DNA–BGTC/DMPC (2/3 and 3/2 molar ratio) systems leads to the formation of DNA monolayers underneath asymmetric lipid bilayers characterized by a bottom layer of BGTC in contact with DNA and a top layer mainly constituted of DMPC.     

Differential assay for high-throughput screening of antibacterial compounds

The previously described Bacillus subtilis reporter strain BAU-102 is capable of detecting cell wall synthesis inhibitors that act at all stages of the cell wall synthesis pathway. In addition, this strain is capable of detecting compounds with hydrophobic/surfactant activity and alternative mechanisms of cell wall disruption. BAU-102 sequesters preformed beta-gal in the periplasm, suggesting leakage of beta-gal as the means by which this assay detects compound activities. A model is proposed according to which beta-gal release by BAU-102 reflects activation of pathways leading to autolysis. The authors also report a simplified high-throughput assay using BAU-102 combined with the fluorogenic substrate N-methylumbelliferyl-beta-D-galactoside as a single reagent. Cell wall inhibitors release beta-gal consistently only after 60 min of incubation, whereas compounds with surfactant activity show an almost immediate release. A high-throughput screen of a 480-compound library of known bioactives yielded 8 compounds that cause beta-gal release. These results validate the BAU-102 assay as an effective tool in antimicrobial drug discovery.     

Complex recombination patterns arising during geminivirus coinfections preserve and demarcate biologically important intra-genome interaction networks

Genetic recombination is an important process during the evolution of many virus species and occurs particularly frequently amongst begomoviruses in the single stranded DNA virus family, Geminiviridae. As in many other recombining viruses it is apparent that non-random recombination breakpoint distributions observable within begomovirus genomes sampled from nature are the product of variations both in basal recombination rates across genomes and in the over-all viability of different recombinant genomes. Whereas factors influencing basal recombination rates might include local degrees of sequence similarity between recombining genomes, nucleic acid secondary structures and genomic sensitivity to nuclease attack or breakage, the viability of recombinant genomes could be influenced by the degree to which their co-evolved protein-protein and protein-nucleotide and nucleotide-nucleotide interactions are disreputable by recombination. Here we investigate patterns of recombination that occur over 120 day long experimental infections of tomato plants with the begomoviruses Tomato yellow leaf curl virus and Tomato leaf curl Comoros virus. We show that patterns of sequence exchange between these viruses can be extraordinarily complex and present clear evidence that factors such as local degrees of sequence similarity but not genomic secondary structure strongly influence where recombination breakpoints occur. It is also apparent from our experiment that over-all patterns of recombination are strongly influenced by selection against individual recombinants displaying disrupted intra-genomic interactions such as those required for proper protein and nucleic acid folding. Crucially, we find that selection favoring the preservation of co-evolved longer-range protein-protein and protein DNA interactions is so strong that its imprint can even be used to identify the exact sequence tracts involved in these interactions.     

Towards biocompatible vaccine delivery systems: interactions of colloidal PECs based on polysaccharides with HIV-1 p24 antigen

This work reports on the interactions of a model protein (p24, the capside protein of HIV-1 virus) with colloids obtained from polyelectrolyte complexes (PECs) involving two polysaccharides: chitosan and dextran sulfate (DS). The PECs were elaborated by a one-shot addition of default amounts of one counterpart to the polymer in excess. Depending on the nature of the excess polyelectrolyte, the submicrometric colloid was either positively or negatively charged. HIV-1 capsid p24 protein was chosen as antigen, the ultrapure form, lipopolysaccharide-free (endotoxin-, vaccine grade) was used in most experiments, as the level of purity of the protein had a great impact on the immobilization process. p24 sorption kinetics, isotherms, and loading capacities were investigated for positively and negatively charged particles of chitosans and dextran sulfates differing in degrees of polymerization (DP) or acetylation (DA). Compared with the positive particles, negatively charged colloids had higher binding capacities, faster kinetics, and a better stability of the adsorbed p24. Capacities up to 600 mg x g(-1) (protein-colloid) were obtained, suggesting that the protein interacted within the shell of the particles. Small-angle X-rays scattering experiments confirmed this hypothesis. Finally, the immunogenicity of the p24-covered particles was assessed for vaccine purposes in mice. The antibody titers obtained with immobilized p24 was dose dependent and in the same range as for Freund's adjuvant, a gold standard for humoral responses.     

CD200: a putative therapeutic target in cancer

CD200 was recently described as a new prognosis factor in multiple myeloma and acute myeloid leukemia. CD200 is a membrane glycoprotein that imparts an immunoregulatory signal through CD200R, leading to the suppression of T-cell-mediated immune responses. We investigated the expression of CD200 in cancer using publicly available gene expression data. CD200 gene expression in normal or malignant human tissues or cell lines was obtained from the Oncomine Cancer Microarray database, Amazonia database and the ITTACA database. We found significant overexpression of CD200 in renal carcinoma, head and neck carcinoma, testicular cancer, malignant mesothelioma, colon carcinoma, MGUS/smoldering myeloma, and in chronic lymphocytic leukemia compared to their normal cells or their tissue counterparts. Moreover, we show that CD200 expression is associated with tumor progression in various cancers. Taken together, these data suggest that CD200 is a potential therapeutic target and prognostic factor for a large array of malignancies.     

Progenitor cells of the distal lung and their potential role in neonatal lung disease

Bronchopulmonary dysplasia (BPD) is the most common adverse outcome in extreme preterm neonates (born before 28 weeks gestation). BPD is characterized by interrupted lung growth and may predispose to early‐onset emphysema and poor lung function in later life. At present, there is no treatment for BPD. Recent advances in stem/progenitor cell biology have enabled the exploration of endogenous lung progenitor populations in health and disease. In parallel, exogenous stem/progenitor cell administration has shown promise in protecting the lung from injury in the experimental setting. This review will provide an outline of the progenitor populations that have currently been identified in all tissue compartments of the distal lung and how they may be affected in BPD. A thorough understanding of the lung's endogenous progenitor populations during normal development, injury and repair may one day allow us to harness their regenerative capacity. Birth Defects Research (Part A) 100:217–226, 2014. © 2014 Wiley Periodicals, Inc.     

Foxl2 gene and the development of the ovary: a story about goat, mouse, fish and woman

In this review, we describe recent results concerning the genetics of sex determination in mammals. Particularly, we developed the study of the FOXL2 gene and its implication in genetic anomalies in goats (PIS mutation) and humans (BPES). We present the expression of FOXL2 in the ovaries of different species.