Behavioral, Hormonal, Inflammatory, and Metabolic Effects Associated with FGF21-Pathway Activation in an ALS Mouse Model.

In amyotrophic lateral sclerosis (ALS), motor neuron degeneration occurs simultaneously with systemic metabolic dysfunction and neuro-inflammation. The fibroblast growth factor 21 (FGF21) plays an important role in the regulation of both phenomena and is a major hormone of energetic homeostasis. In this study, we aimed to determine the relevance of FGF21 pathway stimulation in a male mouse model of ALS (mutated SOD1-G93A mice) by using a pharmacological agonist of FGF21, R1Mab1. Mice (SOD1-WT and mutant SOD1-G93A) were treated with R1Mab1 or vehicle. Longitudinal data about clinical status (motor function, body weight) and biological parameters (including hormonal, immunological, and metabolomics profiles) were collected from the first symptoms to euthanasia at week 20. Multivariate models were performed to identify the main parameters associated with R1Mab1 treatment and to link them with clinical status, and metabolic pathways involving the discriminant metabolites were also determined. A beneficial clinical effect of R1Mab1 was revealed on slow rotarod (p = 0.032), despite a significant decrease in body weight of ALS mice (p < 0.001). We observed a decrease in serum TNF-α, MCP-1, and insulin levels (p = 0.0059, p = 0.003, and p = 0.01, respectively). At 16 weeks, metabolomics analyses revealed a clear discrimination (CV-ANOVA = 0.0086) according to the treatment and the most discriminant pathways, including sphingolipid metabolism, butanoate metabolism, pantothenate and CoA biosynthesis, and the metabolism of amino acids like tyrosine, arginine, proline, glycine, serine, alanine, aspartate, and glutamate. Mice treated with R1Mab1 had mildly higher performance on slow rotarod despite a decrease on body weight and could be linked with the anti-inflammatory effect of R1Mab1. These results indicate that FGF21 pathway is an interesting target in ALS, with a slight improvement in motor function combined with metabolic and anti-inflammatory effects.

Multicolor particle shadow accelerometry.

This paper describes the extension of multicolor particle shadow velocimetry (CPSV) to the measurement of local acceleration in an Eulerian frame of reference. A validation experiment was conducted on a pendulous disk undergoing unsteady rigid body rotation. Angular velocity and acceleration profiles by CPSA are presented along with a comparison to recordings by an accelerometer mounted on the pendulum. CPSA is also demonstrated in a fully-developed turbulent pipe flow. Profiles of standard deviation of the local acceleration in the near wall region (0< y + <75) are compared to similar measurements by Christensen and Adrian. A favorable comparison is found between CPSA and particle image accelerometry (PIA). The effect of acceleration time delay, or the time between two velocity estimates, on local acceleration estimates is discussed.

Correcting for color crosstalk and chromatic aberration in multicolor particle shadow velocimetry.

Color crosstalk and chromatic aberration can bias estimates of fluid velocity measured by color particle shadow velocimetry (CPSV), using multicolor illumination and a color camera. This article describes corrections to remove these bias errors, and their evaluation. Color crosstalk removal is demonstrated with linear unmixing. It is also shown that chromatic aberrations may be removed using either scale calibration, or by processing an image illuminated by all colors simultaneously. CPSV measurements of a fully developed turbulent pipe flow of glycerin were conducted. Corrected velocity statistics from these measurements were compared to both single-color PSV and LDV measurements and showed excellent agreement to fourth-order, to well into the viscous sublayer. Recommendations for practical assessment and correction of color aberration and color crosstalk are discussed.

Artificially-induced organelles are optimal targets for optical trapping experiments in living cells.

Optical trapping supplies information on the structural, kinetic or rheological properties of inner constituents of the cell. However, the application of significant forces to intracellular objects is notoriously difficult due to a combination of factors, such as the small difference between the refractive indices of the target structures and the cytoplasm. Here we discuss the possibility of artificially inducing the formation of spherical organelles in the endoplasmic reticulum, which would contain densely packed engineered proteins, to be used as optimized targets for optical trapping experiments. The high index of refraction and large size of our organelles provide a firm grip for optical trapping and thereby allow us to exert large forces easily within safe irradiation limits. This has clear advantages over alternative probes, such as subcellular organelles or internalized synthetic beads.

Shifting mountain snow patterns in a changing climate from remote sensing retrieval.

Observed climate change has already led to a wide range of impacts on environmental systems and society. In this context, many mountain regions seem to be particularly sensitive to a changing climate, through increases in temperature coupled with changes in precipitation regimes that are often larger than the global average (EEA, 2012). In mid-latitude mountains, these driving factors strongly influence the variability of the mountain snow-pack, through a decrease in seasonal reserves and earlier melting of the snow pack. These in turn impact on hydrological systems in different watersheds and, ultimately, have consequences for water management. Snow monitoring from remote sensing provides a unique opportunity to address the question of snow cover regime changes at the regional scale. This study outlines the results retrieved from the MODIS satellite images over a time period of 10 hydrological years (2000-2010) and applied to two case studies of the EU FP7 ACQWA project, namely the upper Rhone and Po in Europe and the headwaters of the Syr Darya in Kyrgyzstan (Central Asia). The satellite data were provided by the MODIS Terra MOD-09 reflectance images (NASA) and MOD-10 snow products (NSIDC). Daily snow maps were retrieved over that decade and the results presented here focus on the temporal and spatial changes in snow cover. This paper highlights the statistical bias observed in some specific regions, expressed by the standard deviation values (STD) of annual snow duration. This bias is linked to the response of snow cover to changes in elevation and can be used as a signal of strong instability in regions sensitive to climate change: with alternations of heavy snowfalls and rapid snow melting processes. The interest of the study is to compare the methodology between the medium scales (Europe) and the large scales (Central Asia) in order to overcome the limits of the applied methodologies and to improve their performances. Results show that the yearly snow cover duration increases by 4-5 days per 100 m elevation during the accumulation period, depending of the watershed, while during the melting season the snow depletion rate is 0.3% per day of surface loss for the upper Rhone catchment, 0.4%/day for the Syr Darya headwater basins, and 0.6%/day for the upper Po, respectively. Then, the annual STD maps of snow cover indicate higher values (more than 45 days difference compared to the mean values) for (i) the Po foothill region at medium elevation (SE orientation) and (ii) the Kyrgyzstan high plateaux (permafrost areas). These observations cover only a time-period of 10 years, but exhibit a signal under current climate that is already consistent with the expected decline in snow in these regions in the course of the 21st century.

Target charging in short-pulse-laser-plasma experiments.

Interaction of high-intensity laser pulses with solid targets results in generation of large quantities of energetic electrons that are the origin of various effects such as intense x-ray emission, ion acceleration, and so on. Some of these electrons are escaping the target, leaving behind a significant positive electric charge and creating a strong electromagnetic pulse long after the end of the laser pulse. We propose here a detailed model of the target electric polarization induced by a short and intense laser pulse and an escaping electron bunch. A specially designed experiment provides direct measurements of the target polarization and the discharge current in the function of the laser energy, pulse duration, and target size. Large-scale numerical simulations describe the energetic electron generation and their emission from the target. The model, experiment, and numerical simulations demonstrate that the hot-electron ejection may continue long after the laser pulse ends, enhancing significantly the polarization charge.

Mosquito salivary gland protein preservation in the field for immunological and biochemical analysis.

Mosquito salivary proteins are involved in several biological processes that facilitate their blood feeding and have also been reported to elicit an IgG response in vertebrates. A growing number of studies have focused on this immunological response for its potential use as a biological marker of exposure to arthropod bites. As mosquito saliva collection is extremely laborious and inefficient, most research groups prefer to work on mosquito salivary glands (SGs). Thus, SG protein integrity is a critical factor in obtaining meaningful data from immunological and biochemical analysis. Current methodologies rely on an immediate freezing of SGs after their collection. However, the maintenance of samples in a frozen environment can be hard to achieve in field conditions. In this study, SG proteins from two mosquito species (Aedes aegypti and Anopheles gambiae s.s.) stored in different media for 5 days at either +4°C or room temperature (RT) were evaluated at the quantitative (i.e., ELISA) and qualitative (i.e., SDS-PAGE and immunoblotting) levels. Our results indicated that PBS medium supplemented with an anti-protease cocktail seems to be the best buffer to preserve SG antigens for 5 days at +4°C for ELISA analysis. Conversely, cell-lysis buffer (Urea-Thiourea-CHAPS-Tris) was best at preventing protein degradation both at +4°C and RT for further qualitative analysis. These convenient storage methods provide an alternative to freezing and are expected to be applicable to other biological samples collected in the field.

Hot electrons transverse refluxing in ultraintense laser-solid interactions.

We have analyzed the coupling of ultraintense lasers (at ∼2×10{19} W/cm{2}) with solid foils of limited transverse extent (∼10 s of µm) by monitoring the electrons and ions emitted from the target. We observe that reducing the target surface area allows electrons at the target surface to be reflected from the target edges during or shortly after the laser pulse. This transverse refluxing can maintain a hotter, denser and more homogeneous electron sheath around the target for a longer time. Consequently, when transverse refluxing takes places within the acceleration time of associated ions, we observe increased maximum proton energies (up to threefold), increased laser-to-ion conversion efficiency (up to a factor 30), and reduced divergence which bodes well for a number of applications.

[Post-transplant renal tumors: a report of three cases]. / Diagnostic des tumeurs du greffon rénal: à propos de trois cas.

We report three cases of primary renal tumors occurring on post-transplant kidneys, after a delay of 4, 8 and 12 years respectively following transplantation in a population of 1134 post kidney transplant followed at our institution. All three tumors underwent early detection because of the yearly ultrasound evaluation recommended for all post kidney transplant patients. The diagnosis was suggested by CT in all three cases but confirmed by preoperative percutaneous biopsy in two cases. The final pathology results confirmed two cases of clear cell renal carcinomas and one case of oncocytoma. Tumorectomy was undertaken for all three patients with successful results in two cases and return to hemodialysis in the third patient with a 4 cm tumor with mass effect on the collecting system.

Sialome individuality between Aedes aegypti colonies.

Aedes aegypti is responsible for the transmission of arboviruses. The Yellow Fever, Dengue and Chikungunya viruses are transmitted to the vertebrate host by injection of infected saliva during the blood meal of its vectors. Saliva contains different components with various biochemical activities; anti-hemostatic, angiogenic, inflammatory, and immunomodulatory. This work compares the sialomes of three Ae. aegypti colonies (Rockefeller, PAEA, and Formosus), where the repertoire of salivary proteins from these colonies was analyzed by a proteomic approach. This study indicated that major proteins were detectable in the three colonies. However, differences in the abundance of some saliva proteins have been observed between the three Ae. aegypti colonies.

[Proteomic analysis and parasitosis: principles and applications]. / Analyses protéomiques et parasitoses: principes et applications.

O'Farrel described a method allowing two-dimensional (2D) protein separation more than 30 years ago. Since then the original technique has made enormous progress. This progress has been accompanied by advances in mass spectrometry technology as well as various genome-sequencing programs. Today 2D electrophoresis has become the workhorse of proteomics, allowing resolution of complex structures containing thousands of proteins and providing a global view of the state of a proteome. This article presents the different steps and limitations of proteomic analysis: preparation of biological material, 2D electrophoresis, protein detection systems, and available tools for protein identification. Alternative proteomic approaches to 2D electrophoresis are also presented. A few applications are described as examples to illustrate the utility of proteomic analysis for studying the mechanisms underlying virulence, resistance to antimalarial therapies and immune response against pathologic agents.

PCBs and PCDD/FS in fish and fish products and their impact on the human body burden in Belgium.

The concentrations of marker PCBs (28, 52, 101, 118, 138, 153, 180) in fish have been assessed with GC-MS: an average concentration of 540 ng-PCB g(-1) fat (5.02 ng-PCB g(-1) wet weight) was observed. The average concentration of PCDD/Fs, assessed with the CALUX bioassay, amounted to 64 pg-CALUX-TEQ g(-1) fat (0.58 pg-CALUX-TEQ g(-1) wet weight) and that of PCDD/Fs + dioxin-like PCBs amounted to 131 pg-CALUX-TEQ g(-1) fat (1.18 pg-CALUX-TEQ g(-1) wet weight). Results of the PCB congeners analyses show that PCB-153 is the most abundant congener in almost all samples, with also main contributions of the 138- and 180-congeners. For some species such as the sand sole and lemon sole, a fairly constant PCB content, independent of the fat percentage, was observed. For a second group of species such as whelks, cod, and whiting, a positive correlation was observed between their PCB concentration (ng g(-1) fat) and their % of fat. The relationship between marker PCBs and PCDD/Fs concentrations, when plotted on a log scale, fits a straight line (correlation coefficient r = 0.83). With our results on fish and literature data for other food products, intake of marker PCBs and PCDD/Fs could be calculated for the adult population in Belgium (19-60 years old). The Total Daily Intake (TDI) of marker PCBs (ng-PCB day(-1)) ranges between 1690 and 2210. The TDI of PCDD/Fs (pg-CALUX day(-1)) ranges between 80.5 and 122, that of PCDD/Fs + dioxin-like PCBs amounts to 151. When PCDD/Fs in fish are assessed with GC-HRMS, the TDI can be lower. The relative importance of fish regarding marker PCB intake amounts to 15-19%, while regarding PCDD/Fs intake it amounts to 34-51%. Using TDI, the body burden evolution of marker PCBs and PCDD/Fs, with age has been calculated.

Effectiveness of written guidelines on the appropriateness of thromboprophylaxis prescriptions for medical patients: a prospective randomized study.

OBJECTIVE: To assess the effectiveness of providing doctors with written thromboprophylaxis prescription aids based on current recommendations. DESIGN: A prospective trial of specific anticoagulant prescription forms: a 1-day survey before and after the intervention in each centre. SETTING: 30 Internal Medicine departments of Assistance Publique-Hôpitaux de Paris. SUBJECTS: All inpatients were included, except those who were either admitted or discharged on the day of the survey, and those receiving curative anticoagulant treatment. INTERVENTIONS: The study included three parts: (i) a 1-day baseline survey; (ii) over the following 3-month period, departments were randomized into two groups: all practitioners in wards allocated to the intervention group were required to systematically use specific anticoagulant prescription forms, whilst doctors in the control group continued prescribing according to their usual practices and (iii) a 1-day postintervention survey. MAIN OUTCOME MEASURE: The proportion of prescriptions in accordance with the recommendations. RESULTS: 1,469 patients were included. The intervention produced a significant reduction in the frequency of over-prescriptions, from 25% to 14% of the patients who did not meet the guideline criteria (adjusted OR: 0.3; 95% CI: 0.1-0.8). Using specific forms did not improve under-prescription of anticoagulants. A little over 60% of the patients who met guideline criteria for thromboprophylaxis were prescribed anticoagulants in both intervention and control wards, either at baseline or after intervention. CONCLUSIONS: Multitargeted interventions using a variety of means and strategies should still be considered to improve prescriptions that may have a significant impact on health expenses and, most importantly, on patients outcomes.

[Pigment dispersion and Artisan implants: crystalline lens rise as a safety criterion]. / Migrations pigmentaires après implant Artisan: importance de la flèche cristallinienne comme critère de sécurité

PURPOSE: To validate the theoretical notion of a crystalline lens rise as a safety criterion for ARTISAN implants in order to prevent the development of pigment dispersion in the implanted eye. MATERIAL AND METHOD: Crystalline lens rise is defined by the distance between the crystalline lens's anterior pole and the horizontal plane joining the opposite iridocorneal recesses. We analyzed the biometric measurements of 87 eyes with an Artisan implant. A comparative analysis of the crystalline lens rise was carried out on the nine eyes having developed pigment dispersion and 78 eyes with no problems. Among the modern anterior segment imaging devices (Artemis, Scheimpflug photography, optical coherence tomography, radiology exploration, magnetic resonance imaging, TDM), an anterior chamber optical coherence tomography (AC-OCT) prototype was used. RESULTS: This working hypothesis was confirmed by this study: the crystalline lens rise must be considered as a new safety criterion for implanting Artisan phakic lenses. Indeed, the higher the crystalline lens's rise, the greater the risk of developing pigment dispersion in the pupil area. This complication is more frequent in hyperopes than in myopes. We can consider that there is little or no risk of pigment dispersion if the rise is below 600 microm; however, at 600 microm or greater, there is a 67% rate of pupillary pigment dispersion. In certain cases, when the implant was loosely fixed, there was no traction on the iris root. This is a complication that can be avoided or delayed. CONCLUSIONS: The crystalline lens rise must be part of new safety criteria to be taken into consideration when inserting an Artisan implant. This notion must also be applied to other types of phakic implants. The distance remaining between the crystalline lens rise and a 600-micromm theoretical safety level allows one to calculate a safety time interval.

[Multifocal phakic intraocular lens implant to correct presbyopia]. / Lentille intraoculaire réfractive multifocale pour la correction de la presbytie chez le sujet phaque.

INTRODUCTION: Presbyopic surgery is considered as the new frontier in refractive surgery. Different solutions are proposed: myopization of one eye, insertion of an accommodative crystalline lens, scleral surgery, the effects of which are still unknown, and finally multifocal phakic implants. We therefore decided to undertake a prospective study under the Huriet law to determine its efficacy and specify the conditions required for an anterior chamber multifocal phakic implant. MATERIAL AND METHOD: Fifty-five eyes of 33 patients received an anterior chamber foldable multifocal phakic implant. Twenty-one females and 12 males underwent surgery. Initial refraction was between -5D and +5D. The implant's single addition was +2.50. Recuperating a distant uncorrected visual acuity of 0.6 or better and near uncorrected vision of Parinaud 3 or better can be considered a very good postoperative result. RESULTS: Average follow-up was 42.6+/-18 weeks. Mean postoperative refraction was -0.12+/-0.51 D. Mean postoperative uncorrected visual acuity was 0.78+/-0.20. Postoperative uncorrected visual acuity was Parinaud 2.3+/-0.6. Eighty-four percent of eyes operated on recuperated 0.6 or better without correction and Parinaud 3 or better without correction. Lenses in four eyes were explanted for different reasons, essentially optical, and no severe anatomical complications were observed. CONCLUSIONS: Placing an anterior chamber multifocal phakic implant to correct presbyopia is an effective technique with good predictability and has the advantage of being reversible in case of intolerance, optical parasite effects or undesired complications. Considering the particularity of this surgery, it is imperative to respect very strict inclusion criteria: anterior chamber depth equal to or above 3.1 mm, open angle, endothelial cell count equal to or above 2000 cells/mm2, absence of an incipient cataract or the slightest evidence of macular alteration.

Current requirements and emerging trends for labelling as a tool for communicating pharmacovigilance findings.

The labelling of prescription drugs is expected to ensure the safe use of medicines and effect changes in use if such changes are required by new safety information. However, withdrawal of drugs from the market and data about medication errors have demonstrated the limitations of labelling as a tool for risk management. Regulatory initiatives in many countries aim at increasing the usefulness and use of labelling by healthcare professionals and patients. These changes in regulations and guidelines, which parallel changes in the approach to premarketing risk assessment and pharmacovigilance, will result in a more relevant and extensive characterisation of a product's safety profile and better international labelling consistency. But despite improvements in the format of labelling in some countries, labelling overall continues to be bound to conventional layout and restricted in its ability to meet the heterogeneous needs of its intended audience. Technological developments such as electronic prescribing and the availability of electronic decision support systems can effectively implement compliance with labelled conditions of use and safety precautions in the prescription process. It will be one of the major challenges to make labelling easily available and suitable for use in such systems. This technology, bar coding of medicines, and preventive evaluation of labelling and packaging for clarity, readability and potential confusion can also help reduce medication errors.

TEQ-value determinations of animal feed; emphasis on the CALUX bioassay validation.

Polyhalogenated aromatic hydrocarbons, such as polychlorinated dibenzo-p-dioxins are a large and diverse group of environmental pollutants. Their tendency to accumulate in the food chain and their toxicity make monitoring necessary. The reference analysis method is laborious and very expensive, therefore cheap and rapid bioassays have been developed. The chemical-activated luciferase bioassay (CALUX) bioassay uses a recombinant cell line, which responds to dioxins and dioxin-like molecules with Ah receptor (AhR)-dependent induction of firefly luciferase in a dose related response. The CALUX was tested for its use in the screening of feed. Aliquots of 20g of enriched feed were extracted with a toluene:methanol mixture (20:4 v/v) and extracts were defatted on 33% H(2)SO(4) silica columns and purified on carbon columns. Only the dioxin and furan fraction was analysed, the PCB fraction was discarded. The precision of the method is acceptable and in compliance with an R.S.D. <30% as suggested for cell-based bioassays in the Commission Directive 2002/70/EC of July 2002. The results evidence good agreement between TEQ-values obtained by either CALUX or GC-HRMS. The method is now routinely in use for a feed screening programme designed by the Federal Agency for the Safety of the Food chain. Approximately, 25 samples are analysed weekly. From the obtained results approximately 10% was confirmed by GC-HRMS. The false positive ratio is 1% and no false negatives were found, making the use of the CALUX technology advantageous.