Targeting the GLP-1/GLP-1R axis to treat osteoarthritis: A new opportunity?

Osteoarthritis (OA) is a degenerative joint disease affecting millions of people worldwide. In OA, chondrocytes, synovial cells and other joint cells become activated when exposed to an abnormal environment, including mechanical stress, inflammatory cytokines or disorganization of matrix proteins. Several analogues of the hormones called incretins have been developed and are used notably for treating type 2 diabetes mellitus. Data has accumulated to suggest that incretinomimetics, which bind to the glucagon-like peptide-1 receptor (GLP-1R), have beneficial pleiotropic effects such as immunomodulation, anti-inflammation and neuronal protection. Thus, because of their anti-inflammatory properties, GLP-1-based therapies could benefit OA patients. This review focuses on the GLP-1R pathway, molecular mechanisms and phenotypes related to OA pathogenesis. The translational potential of this article: The search for new therapeutic targets to treat people suffering from OA remains urgent as there is currently no disease-modifyingtherapy available for this disease. This review discusses how GLP-1 analogues could be potential DMOADs for treating OA thanks to their anti-inflammatory, immunoregulatory and differentiation properties.

Liraglutide, a glucagon-like peptide 1 receptor agonist, exerts analgesic, anti-inflammatory and anti-degradative actions in osteoarthritis.

Osteoarthritis (OA) is a common disabling disease worldwide, with no effective and safe disease-modifying drugs (DMOAD) in the market. However, studies suggest that drugs, such as liraglutide, which possess strong potential in decreasing low-grade systemic inflammation may be effective in treating OA. Therefore, the aim of this study was to examine the anti-inflammatory, analgesic, and anti-degradative effects in OA using in vitro and in vivo experiments. The results showed that intra-articular injection of liraglutide alleviated pain-related behavior in in vivo sodium monoiodoacetate OA mouse model, which was probably driven by the GLP-1R-mediated anti-inflammatory activity of liraglutide. Moreover, liraglutide treatment significantly decreased IL-6, PGE2 and nitric oxide secretion, and the expression of inflammatory genes in vitro in chondrocytes and macrophages in a dose-dependent manner. Additionally, liraglutide shifted polarized macrophage phenotype in vitro from the pro-inflammatory M1 phenotype to the M2 anti-inflammatory phenotype. Furthermore, liraglutide exerted anti-catabolic activity by significantly decreasing the activities of metalloproteinases and aggrecanases, a family of catabolic enzymes involved in cartilage breakdown in vitro. Overall, the findings of this study showed that liraglutide ameliorated OA-associated pain, possess anti-inflammatory and analgesic properties, and could constitute a novel therapeutic candidate for OA treatment.

[Single, immediate postoperative intra-vesical instillation (SI) compared to a single preoperative intra-vesical instillation of mitomycin C in non-muscle invasive bladder cancer (NMIBC). Phase II randomized trial]. / Instillation préopératoire immédiate (IPOI) de mitomycine C comparée à l'instillation postopératoire précoce (IPOP) dans les tumeurs de la vessie. Étude de phase II randomisée.

OBJECTIVE: A single immediate instillation of mitomycin C is recommended after a complete transurethral resection of the bladder (TURB) in low- and intermediate-risk patients with NMIBC. Actually, post-TURB instillation is seldom used due to logistical difficulties and surgical contraindications. Our aim was to compare patients with single pre-TURB intra-vesical instillation and patients with a single, immediate post-TURB intra-vesical instillation of mitomycin C. METHODS: We performed a multicenter randomized trial between February 17, 2014 and November 24, 2016 (registration number 2012-004341-32). Sixty patients with two or less, primary or recurrent papillary bladder tumors and a negative urinary cytology were planned. Cystoscopy was performed at 3, 6 and 12 months after TURB. Our primary endpoint was disease-free interval. Secondary endpoints were recurrence rate at 3 and 12 months, rate of patients in whom instillation could not be performed and tolerance 1 month after TURB using BCI-Fr score. RESULTS: Among 35 eligible participants, 20 were randomly assigned in the pre-TURB instillation group and 15 in the post-TURB instillation group. Follow-up was comparable: 12,3±1,6 months in the SI group and 10,2±4,5 months in the pre-TURB instillation group. In the post-TURB instillation group, 2 patients didn't have any instillation. We did not identify significant differences in disease-free interval. Tolerance at 1 month after TURB was similar in both groups. CONCLUSION: Tolerance and efficacy were not significantly different. As expected, logisitics were easier for the health providers in the pre-TURB group where all patients had their instillation conversely to the post-TURB group. These results suggest that the advantages of a single immediate pre-TURB instillation warrant further evaluation of this strategy in a phase III randomized trial.

New probiotic strains for inflammatory bowel disease management identified by combining in vitro and in vivo approaches.

Alterations in the gut microbiota composition play a key role in the development of chronic diseases such as inflammatory bowel disease (IBD). The potential use of probiotics therefore gained attention, although outcomes were sometimes conflicting and results largely strain-dependent. The present study aimed to identify new probiotic strains that have a high potential for the management of this type of pathologies. Strains were selected from a large collection by combining different in vitro and in vivo approaches, addressing both anti-inflammatory potential and ability to improve the gut barrier function. We identified six strains with an interesting anti-inflammatory profile on peripheral blood mononuclear cells and with the ability to restore the gut barrier using a gut permeability model based on Caco-2 cells sensitized with hydrogen peroxide. The in vivo evaluation in two 2,4,6-trinitrobenzene sulfonic acid-induced murine models of colitis highlighted that some of the strains exhibited beneficial activities against acute colitis while others improved chronic colitis. Bifidobacterium bifidum PI22, the strain that exhibited the most protective capacities against acute colitis was only slightly efficacious against chronic colitis, while Bifidobacterium lactis LA804 which was less efficacious in the acute model was the most protective against chronic colitis. Lactobacillus helveticus PI5 was not anti-inflammatory in vitro but the best in strengthening the epithelial barrier and as such able to significantly dampen murine acute colitis. Interestingly, Lactobacillus salivarius LA307 protected mice significantly against both types of colitis. This work provides crucial clues for selecting the best strains for more efficacious therapeutic approaches in the management of chronic inflammatory diseases. The strategy employed allowed us to identify four strains with different characteristics and a high potential for the management of inflammatory diseases, such as IBD.

Strain and Magnetic Field Induced Spin-Structure Transitions in Multiferroic BiFeO3.

The magnetic-field-dependent spin ordering of strained BiFeO3 films is determined using nuclear resonant scattering and Raman spectroscopy. The critical field required to destroy the cycloidal modulation of the Fe spins is found to be significantly lower than in the bulk, with appealing implications for field-controlled spintronic and magnonic devices.

First set of gated x-ray imaging diagnostics for the Laser Megajoule facility.

The Laser Megajoule (LMJ) facility located at CEA/CESTA started to operate in the early 2014 with two quadruplets (20 kJ at 351 nm) focused on target for the first experimental campaign. We present here the first set of gated x-ray imaging (GXI) diagnostics implemented on LMJ since mid-2014. This set consists of two imaging diagnostics with spatial, temporal, and broadband spectral resolution. These diagnostics will give basic measurements, during the entire life of the facility, such as position, structure, and balance of beams, but they will also be used to characterize gas filled target implosion symmetry and timing, to study x-ray radiography and hydrodynamic instabilities. The design requires a vulnerability approach, because components will operate in a harsh environment induced by neutron fluxes, gamma rays, debris, and shrapnel. Grazing incidence x-ray microscopes are fielded as far as possible away from the target to minimize potential damage and signal noise due to these sources. These imaging diagnostics incorporate microscopes with large source-to-optic distance and large size gated microchannel plate detectors. Microscopes include optics with grazing incidence mirrors, pinholes, and refractive lenses. Spatial, temporal, and spectral performances have been measured on x-ray tubes and UV lasers at CEA-DIF and at Physikalisch-Technische Bundesanstalt BESSY II synchrotron prior to be set on LMJ. GXI-1 and GXI-2 designs, metrology, and first experiments on LMJ are presented here.

Artificial reproduction of magnetic fields produced by a natural geomagnetic storm increases systolic blood pressure in rats.

The incidence of geomagnetic storms may be associated with changes in circulatory physiology. The way in which the natural variations of the geomagnetic field due to solar activity affects the blood pressure are poorly understood and require further study in controlled experimental designs in animal models. In the present study, we tested whether the systolic arterial pressure (AP) in adult rats is affected by simulated magnetic fields resembling the natural changes of a geomagnetic storm. We exposed adult rats to a linear magnetic profile that simulates the average changes associated to some well-known geomagnetic storm phases: the sudden commencement and principal phase. Magnetic stimulus was provided by a coil inductor and regulated by a microcontroller. The experiments were conducted in the electromagnetically isolated environment of a semi-anechoic chamber. After exposure, AP was determined with a non-invasive method through the pulse on the rat's tail. Animals were used as their own control. Our results indicate that there was no statistically significant effect in AP when the artificial profile was applied, neither in the sudden commencement nor in the principal phases. However, during the experimental period, a natural geomagnetic storm occurred, and we did observe statistically significant AP increase during the sudden commencement phase. Furthermore, when this storm phase was artificially replicated with a non-linear profile, we noticed a 7 to 9 % increase of the rats' AP in relation to a reference value. We suggested that the changes in the geomagnetic field associated with a geomagnetic storm in its first day could produce a measurable and reproducible physiological response in AP.

Effects 4.5 years after an interactive GP educational seminar on antibiotic therapy for respiratory tract infections: a randomized controlled trial.

BACKGROUND: The few studies assessing long-term effects of educational interventions on antibiotic prescription have produced conflicting results. OBJECTIVES: Our aim was to assess the effects after 4.5 years of an interactive educational seminar designed for GPs and focused on antibiotic therapy in respiratory tract infections (RTIs). The seminar was expected to decrease antibiotic prescriptions for any diagnosis. METHODS: We conducted a randomized controlled parallel-group trial in a Paris suburb (France), with GPs as the randomization unit and prescriptions as the analysis unit. The intervention occurred in September 2004 and the final assessment in March 2009. Among 203 randomized GPs, 168 completed the study, 70 in the intervention group and 98 in the control group. Intervention GPs were randomized to attending only a 2-day interactive educational seminar on evidence-based guidelines about managing RTIs or also 1 day of problem-solving training. The primary outcome was the percentage of change in the proportion of prescriptions containing an antibiotic for any diagnosis in 2009 versus 2004. An intention-to-treat sensitivity analysis was performed using multiple imputation. RESULTS: After 4.5 years, absolute changes in the primary outcome measure were -1.1% (95% confidence interval: -2.2 to 0.0) in the intervention group and +1.4% (0.3-2.6) in the control group, yielding an adjusted between-group difference of -2.2% (-2.7 to -1.7; P < 0.001). Both intervention modalities had significant effects, and multiple imputation produced similar results. CONCLUSIONS: A single, standardized and interactive educational seminar targeting GPs significantly decreased antibiotic use for RTIs after 4.5 years.

[Pathological fracture rate due to proximal femur metastasis at a referral hospital]. / Incidencia de fracturas patológicas por metástasis en el fémur proximal en un hospital de concentración.

OBJECTIVE: To report the incidence of pathological fractures secondary to metastasis at a national referral hospital during a 5-year period. METHODS: Total admissions to our center were recorded, together with the patients who met the requirement of having a proximal femur fracture in a pathological area. The potential number of beneficiaries was estimated based on official figures and the hospitals area of influence. The annual incidence rate and the incidence density were calculated using the latter data. RESULTS: 98 fractures were identified in 95 patients. The calculated incidence density was 0.70/100,000 population during the observation period. Fifty-four female patients and 41 male patients were included. Mean age was 65.3 years, with a very wide age range (18-90 years). Most patients had metastasis of solid tumors. Twenty-nine percent of patients were treated conservatively and the rest of them required surgery that included from osteosynthesis to prosthetic arthroplasty. The mean length of stay was over one week. CONCLUSIONS: The reported incidence of this type of fractures is relatively low. We found a wide variety of anatomical origins and locations. As of now, it is not possible to generalize the treatment or predict the survival.

Reportar la incidencia de fracturas en terreno patológico secundarias a metástasis que se presentaron en un hospital de referencia nacional en un período de cinco años.

Predictors of treatment dropout in self-guided web-based interventions for depression: an 'individual patient data' meta-analysis.

BACKGROUND: It is well known that web-based interventions can be effective treatments for depression. However, dropout rates in web-based interventions are typically high, especially in self-guided web-based interventions. Rigorous empirical evidence regarding factors influencing dropout in self-guided web-based interventions is lacking due to small study sample sizes. In this paper we examined predictors of dropout in an individual patient data meta-analysis to gain a better understanding of who may benefit from these interventions. METHOD: A comprehensive literature search for all randomized controlled trials (RCTs) of psychotherapy for adults with depression from 2006 to January 2013 was conducted. Next, we approached authors to collect the primary data of the selected studies. Predictors of dropout, such as socio-demographic, clinical, and intervention characteristics were examined. RESULTS: Data from 2705 participants across ten RCTs of self-guided web-based interventions for depression were analysed. The multivariate analysis indicated that male gender [relative risk (RR) 1.08], lower educational level (primary education, RR 1.26) and co-morbid anxiety symptoms (RR 1.18) significantly increased the risk of dropping out, while for every additional 4 years of age, the risk of dropping out significantly decreased (RR 0.94). CONCLUSIONS: Dropout can be predicted by several variables and is not randomly distributed. This knowledge may inform tailoring of online self-help interventions to prevent dropout in identified groups at risk.

Chronic delivery of α-melanocyte-stimulating hormone in rat hypothalamus using albumin-alginate microparticles: effects on food intake and body weight.

Chronic delivery of neuropeptides in the brain is a useful experimental approach to study their long-term effects on various biological parameters. In this work, we tested albumin-alginate microparticles, as a potential delivery system, to study if continuous release in the hypothalamus of α-melanocyte-stimulating hormone (α-MSH), an anorexigenic neuropeptide, may result in a long-term decrease in food intake and body weight. The 2-week release of α-MSH from peptide-loaded particles was confirmed by an in vitro assay. Then, daily food intake and body weight were studied for 18 days in rats injected bilaterally into the paraventricular hypothalamic nucleus with particles loaded or not with α-MSH. A decrease in body weight gain, persisting throughout the study, was found in rats injected with α-MSH-charged particles as compared with rats receiving non-charged particles and with rats injected with the same dose of α-MSH in solution. Food intake was significantly decreased for 3 days in rats receiving α-MSH-loaded particles and it was not followed by the feeding rebound effect which appears after food restriction. The presence of α-MSH-loaded particles in the hypothalamus was confirmed by immunohistochemistry. In conclusion, our study validates albumin-alginate microparticles as a new carrier system for long-term delivery of neuropeptides in the brain and demonstrates that chronic delivery of α-MSH in the hypothalamus results in a prolonged suppression of food intake and a decrease of body weight gain in rats.

Bacterial ClpB heat-shock protein, an antigen-mimetic of the anorexigenic peptide α-MSH, at the origin of eating disorders.

The molecular mechanisms at the origin of eating disorders (EDs), including anorexia nervosa (AN), bulimia and binge-eating disorder (BED), are currently unknown. Previous data indicated that immunoglobulins (Igs) or autoantibodies (auto-Abs) reactive with α-melanocyte-stimulating hormone (α-MSH) are involved in regulation of feeding and emotion; however, the origin of such auto-Abs is unknown. Here, using proteomics, we identified ClpB heat-shock disaggregation chaperone protein of commensal gut bacteria Escherichia coli as a conformational antigen mimetic of α-MSH. We show that ClpB-immunized mice produce anti-ClpB IgG crossreactive with α-MSH, influencing food intake, body weight, anxiety and melanocortin receptor 4 signaling. Furthermore, chronic intragastric delivery of E. coli in mice decreased food intake and stimulated formation of ClpB- and α-MSH-reactive antibodies, while ClpB-deficient E. coli did not affect food intake or antibody levels. Finally, we show that plasma levels of anti-ClpB IgG crossreactive with α-MSH are increased in patients with AN, bulimia and BED, and that the ED Inventory-2 scores in ED patients correlate with anti-ClpB IgG and IgM, which is similar to our previous findings for α-MSH auto-Abs. In conclusion, this work shows that the bacterial ClpB protein, which is present in several commensal and pathogenic microorganisms, can be responsible for the production of auto-Abs crossreactive with α-MSH, associated with altered feeding and emotion in humans with ED. Our data suggest that ClpB-expressing gut microorganisms might be involved in the etiology of EDs.

A minimal representation of the self-assembly of virus capsids.

Viruses are biological nanosystems with a capsid of protein-made capsomer units that encloses and protects the genetic material responsible for their replication. Here we show how the geometrical constraints of the capsomer-capsomer interaction in icosahedral capsids and the requirement of low frustration fix the form of the shortest and universal truncated multipolar expansion of the two-body interaction between capsomers. The structures of many of the icosahedral and related virus capsids are located as single lowest energy states of a potential energy surface built from this interaction. Our minimalist representation is consistent with other models known to produce a controllable and efficient self-assembly, and unveils relevant features of the natural design of the capsids. It promises to be very useful in physical virology and may also be of interest in fields of nanoscience and nanotechnology where similar hollow convex structures are relevant.

Radiation-mediated formation of complex damage to DNA: a chemical aspect overview.

During the last three decades, a considerable amount of work has been undertaken to determine the nature, the mechanism of formation and the biological consequences of radiation-induced DNA lesions. Most of the information was obtained via the development of chemical approaches, including theoretical, analytical and organic synthesis methods. Since it is not possible to present all the results obtained in this review article, we will focus on recent data dealing with the formation of complex DNA lesions produced by a single oxidation event, as these lesions may play a significant role in cellular responses to ionizing radiation and also to other sources of oxidative stress. Through the description of specific results, the contribution of different chemical disciplines in the assessment of the structure, the identification of the mechanism of formation and the biological impacts in terms of repair and mutagenicity of these complex radiation-induced DNA lesions will be highlighted.

Control of ferroelectricity and magnetism in multi-ferroic BiFeO3 by epitaxial strain.

Recently, strain engineering has been shown to be a powerful and flexible means of tailoring the properties of ABO3 perovskite thin films. The effect of epitaxial strain on the structure of the perovskite unit cell can induce a host of interesting effects, these arising from either polar cation shifts or rotation of the oxygen octahedra, or both. In the multi-ferroic perovskite bismuth ferrite (BiFeO3-BFO), both degrees of freedom exist, and thus a complex behaviour may be expected as one plays with epitaxial strain. In this paper, we review our results on the role of strain on the ferroic transition temperatures and ferroic order parameters. We find that, while the Néel temperature is almost unchanged by strain, the ferroelectric Curie temperature strongly decreases as strain increases in both the tensile and compressive ranges. Also unexpected is the very weak influence of strain on the ferroelectric polarization value. Using effective Hamiltonian calculations, we show that these peculiar behaviours arise from the competition between antiferrodistortive and polar instabilities. Finally, we present results on the magnetic order: while the cycloidal spin modulation present in the bulk survives in weakly strained films, it is destroyed at large strain and replaced by pseudo-collinear antiferromagnetic ordering. We discuss the origin of this effect and give perspectives for devices based on strain-engineered BiFeO3.

Colorectal cancer screening: factors associated with colonoscopy after a positive faecal occult blood test.

BACKGROUND: Contextual socio-economic factors, health-care access, and general practitioner (GP) involvement may influence colonoscopy uptake and its timing after positive faecal occult blood testing (FOBT). Our objectives were to identify predictors of delayed or no colonoscopy and to assess the role for GPs in colonoscopy uptake. METHODS: We included all residents of a French district with positive FOBTs (n = 2369) during one of the two screening rounds (2007-2010). Multilevel logistic regression analysis was performed to identify individual and area-level predictors of delayed colonoscopy, no colonoscopy, and no information on colonoscopy. RESULTS: A total of 998 (45.2%) individuals underwent early, 989 (44.8%) delayed, and 102 (4.6%) no colonoscopy; no information was available for 119 (5.4%) individuals. Delayed colonoscopy was independently associated with first FOBT (odds ratio, (OR)), 1.61; 95% confidence interval ((95% CI), 1.16-2.25); and no colonoscopy and no information with first FOBT (OR, 2.01; 95% CI, 1.02-3.97), FOBT kit not received from the GP (OR, 2.29; 95% CI, 1.67-3.14), and socio-economically deprived area (OR, 3.17; 95% CI, 1.98-5.08). Colonoscopy uptake varied significantly across GPs (P=0.01). CONCLUSION: Socio-economic factors, GP-related factors, and history of previous FOBT influenced colonoscopy uptake after a positive FOBT. Interventions should target GPs and individuals performing their first screening FOBT and/or living in socio-economically deprived areas.

Crafting the magnonic and spintronic response of BiFeO3 films by epitaxial strain.

Multiferroics are compounds that show ferroelectricity and magnetism. BiFeO3, by far the most studied, has outstanding ferroelectric properties, a cycloidal magnetic order in the bulk, and many unexpected virtues such as conductive domain walls or a low bandgap of interest for photovoltaics. Although this flurry of properties makes BiFeO3 a paradigmatic multifunctional material, most are related to its ferroelectric character, and its other ferroic property--antiferromagnetism--has not been investigated extensively, especially in thin films. Here we bring insight into the rich spin physics of BiFeO3 in a detailed study of the static and dynamic magnetic response of strain-engineered films. Using Mössbauer and Raman spectroscopies combined with Landau-Ginzburg theory and effective Hamiltonian calculations, we show that the bulk-like cycloidal spin modulation that exists at low compressive strain is driven towards pseudo-collinear antiferromagnetism at high strain, both tensile and compressive. For moderate tensile strain we also predict and observe indications of a new cycloid. Accordingly, we find that the magnonic response is entirely modified, with low-energy magnon modes being suppressed as strain increases. Finally, we reveal that strain progressively drives the average spin angle from in-plane to out-of-plane, a property we use to tune the exchange bias and giant-magnetoresistive response of spin valves.

Epidermolysis bullosa simplex with PLEC mutations: new phenotypes and new mutations.

BACKGROUND: Genetic mutations in the plectin gene (PLEC) cause autosomal recessive forms of epidermolysis bullosa simplex (EBS) associated with either muscular dystrophy (EBS-MD) or pyloric atresia (EBS-PA). Phenotype-genotype analysis has suggested that EBS-MD is due mostly to genetic mutations affecting the central rod domain of plectin, and EBS-PA to mutations outside this domain. OBJECTIVES: This study aimed to describe new phenotypes of patients with EBS-MD and EBS-PA, to identify novel PLEC mutations and to establish genotype-phenotype correlations. METHODS: Seven patients with a suspicion of EBS linked to PLEC mutations were included. A standardized clinical questionnaire was sent to the physicians in charge of each patient. Immunofluorescence studies of skin biopsies followed by molecular analysis of PLEC were performed in all patients. RESULTS: We report the first case of nonlethal EBS-PA improving with age, the first multisystemic involvement in a patient with lethal EBS-PA, and the first patients with EBS-MD with involvement of either the bladder or oesophagus. Eleven novel PLEC mutations are also reported. CONCLUSIONS: Our results confirm that EBS-PA is linked to mutations in the distal exons 1-30 and 32 of PLEC. Long-term survival is possible, with skin improvement, but a delayed onset of MD is probable. While EBS-MD is linked to PLEC mutations in all exons, in most cases one of the mutations affects exon 31. The precocity of MD seems to be linked to the type and localization of the PLEC mutation(s), but no correlation with mucosal involvement has been found.

Crossover from spin accumulation into interface states to spin injection in the germanium conduction band.

Electrical spin injection into semiconductors paves the way for exploring new phenomena in the area of spin physics and new generations of spintronic devices. However the exact role of interface states in the spin injection mechanism from a magnetic tunnel junction into a semiconductor is still under debate. In this Letter, we demonstrate a clear transition from spin accumulation into interface states to spin injection in the conduction band of n-Ge. We observe spin signal amplification at low temperature due to spin accumulation into interface states followed by a clear transition towards spin injection in the conduction band from 200 K up to room temperature. In this regime, the spin signal is reduced to a value compatible with the spin diffusion model. More interestingly, the observation in this regime of inverse spin Hall effect in germanium generated by spin pumping and the modulation of the spin signal by a gate voltage clearly demonstrate spin accumulation in the germanium conduction band.