Design and stability study of a paediatric oral solution of methotrexate 2mg/ml

Oral paediatric forms development by pharmaceutical industry is still insufficient. The present study was performed to propose an adapted and pleasant formulation of liquid oral formulation of MTX. The solution is composed of injectable methotrexate, water, Ora Sweet(®) and sodium bicarbonate. After 120 days storage, pH remained stable at about 8 in all formulations, insuring no risk of MTX precipitation. MTX content in solution formulation, determined by high performance liquid chromatography measurements, remained in the specifications of >90% of the initial concentration when stored at 4 and 25°C. Forced degradation of MTX by heat and acidic conditions allowed formation and detection of degradation products by the analytical method. Microbial study of the preparation shows that the solution remains in the specifications during all the storage, or after one sample each week during one month, eventually indicating the microbial properties are not affected by patient use. To conclude, we here propose a new MTX liquid formulation stable for at least 120 days

The Conserved nhaAR Operon Is Drastically Divergent between B2 and Non-B2 Escherichia coli and Is Involved in Extra-Intestinal Virulence

The Escherichia coli species is divided in phylogenetic groups that differ in their virulence and commensal distribution. Strains belonging to the B2 group are involved in extra-intestinal pathologies but also appear to be more prevalent as commensals among human occidental populations. To investigate the genetic specificities of B2 sub-group, we used 128 sequenced genomes and identified genes of the core genome that showed marked difference between B2 and non-B2 genomes. We focused on the gene and its surrounding region with the strongest divergence between B2 and non-B2, the antiporter gene nhaA. This gene is part of the nhaAR operon, which is in the core genome but flanked by mobile regions, and is involved in growth at high pH and high sodium concentrations. Consistently, we found that a panel of non-B2 strains grew faster than B2 at high pH and high sodium concentrations. However, we could not identify differences in expression of the nhaAR operon using fluorescence reporter plasmids. Furthermore, the operon deletion had no differential impact between B2 and non-B2 strains, and did not result in a fitness modification in a murine model of gut colonization. Nevertheless, sequence analysis and experiments in a murine model of septicemia revealed that recombination in nhaA among B2 strains was observed in strains with low virulence. Finally, nhaA and nhaAR operon deletions drastically decreased virulence in one B2 strain. This effect of nhaAR deletion appeared to be stronger than deletion of all pathogenicity islands. Thus, a population genetic approach allowed us to identify an operon in the core genome without strong effect in commensalism but with an important role in extra-intestinal virulence, a landmark of the B2 strains

Beyond universality: parametrizing ultracold complex-mediated reactions using statistical assumptions

We have calculated accurate quantum reactive and elastic cross-sections for the prototypical barrierless reaction D$^{+}$ + H$_2$($v$=0, $j$=0) using the hyperspherical scattering method. The considered kinetic energy ranges from the ultracold to the Langevin regimes. The availability of accurate results for this system allows to test the quantum theory by Jachymski et al. [Phys. Rev. Lett. 110, 213202 (2013)] in a nonuniversal case. The short range reaction probability is rationalized using statistical model assumptions and related to a statistical factor. This provides a means to estimate one of the parameters that characterizes ultracold processes from first principles. Possible limitations of the statistical model are considered

Atomic Diagnostics of X-ray Irradiated Protoplanetary Disks

We study atomic line diagnostics of the inner regions of protoplanetary disks with our model of X-ray irradiated disk atmospheres which was previously used to predict observable levels of the NeII and NeIII fine-structure transitions at 12.81 and 15.55mum. We extend the X-ray ionization theory to sulfur and calculate the fraction of sulfur in S, S+, S2+ and sulfur molecules. For the D'Alessio generic T Tauri star disk, we find that the SI fine-structure line at 25.55mum is below the detection level of the Spitzer Infrared Spectrometer (IRS), in large part due to X-ray ionization of atomic S at the top of the atmosphere and to its incorporation into molecules close to the mid-plane. We predict that observable fluxes of the SII 6718/6732AA forbidden transitions are produced in the upper atmosphere at somewhat shallower depths and smaller radii than the neon fine-structure lines. This and other forbidden line transitions, such as the OI 6300/6363AA and the CI 9826/9852AA lines, serve as complementary diagnostics of X-ray irradiated disk atmospheres. We have also analyzed the potential role of the low-excitation fine-structure lines of CI, CII, and OI, which should be observable by SOFIA and Herschel.Comment: Accepted by Ap

Infrared Spectroscopy of Molecular Supernova Remnants

We present Infrared Space Observatory spectroscopy of sites in the supernova remnants W28, W44, and 3C391, where blast waves are impacting molecular clouds. Atomic fine-structure lines were detected from C, N, O, Si, P, and Fe. The S(3) and S(9) lines of H2 were detected for all three remnants. The observations require both shocks into gas with moderate (~ 100 /cm3) and high (~10,000 /cm3) pre-shock densities, with the moderate density shocks producing the ionic lines and the high density shock producing the molecular lines. No single shock model can account for all of the observed lines, even at the order of magnitude level. We find that the principal coolants of radiative supernova shocks in moderate-density gas are the far-infrared continuum from dust grains surviving the shock, followed by collisionally-excited [O I] 63.2 and [Si II] 34.8 micron lines. The principal coolant of the high-density shocks is collisionally-excited H2 rotational and ro-vibrational line emission. We systematically examine the ground-state fine structure of all cosmically abundant elements, to explain the presence or lack of all atomic fine lines in our spectra in terms of the atomic structure, interstellar abundances, and a moderate-density, partially-ionized plasma. The [P II] line at 60.6 microns is the first known astronomical detection. There is one bright unidentified line in our spectra, at 74.26 microns. The presence of bright [Si II] and [Fe II] lines requires partial destruction of the dust. The required gas-phase abundance of Fe suggests 15-30% of the Fe-bearing grains were destroyed. The infrared continuum brightness requires ~1 Msun of dust survives the shock, suggesting about 1/3 of the dust mass was destroyed, in agreement with the depletion estimate and with theoretical models for dust destruction.Comment: 40 pages; 10 figures; accepted by ApJ July 11, 200

High-excitation OH and H_2O lines in Markarian 231: the molecular signatures of compact far-infrared continuum sources

The ISO/LWS far-infrared spectrum of the ultraluminous galaxy Mkn 231 shows OH and H_2O lines in absorption from energy levels up to 300 K above the ground state, and emission in the [O I] 63 micron and [C II] 158 micron lines. Our analysis shows that OH and H_2O are radiatively pumped by the far-infrared continuum emission of the galaxy. The absorptions in the high-excitation lines require high far-infrared radiation densities, allowing us to constrain the properties of the underlying continuum source. The bulk of the far-infrared continuum arises from a warm (T_dust=70-100 K), optically thick (tau_100micron=1-2) medium of effective diameter 200-400 pc. In our best-fit model of total luminosity L_IR, the observed OH and H2O high-lying lines arise from a luminous (L/L_IR~0.56) region with radius ~100 pc. The high surface brightness of this component suggests that its infrared emission is dominated by the AGN. The derived column densities N(OH)>~10^{17} cm^{-2} and N(H_2O)>~6x10^{16} cm^{-2} may indicate XDR chemistry, although significant starburst chemistry cannot be ruled out. The lower-lying OH, [C II] 158 micron, and [O I] 63 micron lines arise from a more extended (~350 pc) starburst region. We show that the [C II] deficit in Mkn 231 is compatible with a high average abundance of C+ because of an extreme overall luminosity to gas mass ratio. Therefore, a [C II] deficit may indicate a significant contribution to the luminosity by an AGN, and/or by extremely efficient star formation.Comment: 16 pages, 6 figures, accepted for publication in The Astrophysical Journa

Space exploration by dendritic cells requires maintenance of myosin II activity by IP3 receptor 1

Dendritic cells (DCs) patrol the interstitial space of peripheral tissues. The mechanisms that regulate their migration in such constrained environment remain unknown. We here investigated the role of calcium in immature DCs migrating in confinement. We found that they displayed calcium oscillations that were independent of extracellular calcium and more frequently observed in DCs undergoing strong speed fluctuations. In these cells, calcium spikes were associated with fast motility phases. IP3 receptors (IP(3)Rs) channels, which allow calcium release from the endoplasmic reticulum, were identified as required for immature DCs to migrate at fast speed. The IP(3)R1 isoform was further shown to specifically regulate the locomotion persistence of immature DCs, that is, their capacity to maintain directional migration. This function of IP(3)R1 results from its ability to control the phosphorylation levels of myosin II regulatory light chain (MLC) and the back/front polarization of the motor protein. We propose that by upholding myosin II activity, constitutive calcium release from the ER through IP(3)R1 maintains DC polarity during migration in confinement, facilitating the exploration of their environment

A rare presentation of atypical demyelination: tumefactive multiple sclerosis causing Gerstmann's syndrome

r. KS has been supported by a Higher Education Funding Council for England (HEFCE) Clinical Senior Lectureshi