Shallow Dark Matter Cusps in Galaxy Clusters

We study the evolution of the stellar and dark matter components in a galaxy cluster of $10^{15} \, \rm{M_{\odot}}$ from $z=3$ to the present epoch using the high-resolution collisionless simulations of Ruszkowski & Springel (2009). At $z=3$ the dominant progenitor halos were populated with spherical model galaxies with and without accounting for adiabatic contraction. We apply a weighting scheme which allows us to change the relative amount of dark and stellar material assigned to each simulation particle in order to produce luminous properties which agree better with abundance matching arguments and observed bulge sizes at $z=3$. This permits the study of the effect of initial compactness on the evolution of the mass-size relation. We find that for more compact initial stellar distributions the size of the final Brightest Cluster Galaxy grows with mass according to $r\propto M^{2}$, whereas for more extended initial distributions, $r\propto M$. Our results show that collisionless mergers in a cosmological context can reduce the strength of inner dark matter cusps with changes in logarithmic slope of 0.3 to 0.5 at fixed radius. Shallow cusps such as those found recently in several strong lensing clusters thus do not necessarily conflict with CDM, but may rather reflect on the initial structure of the progenitor galaxies, which was shaped at high redshift by their formation process.Comment: 8 pages, 4 figures, submitted to MNRA

Natalizumab affects T-cell phenotype in multiple sclerosis: implications for JCV reactivation

The anti-CD49d monoclonal antibody natalizumab is currently an effective therapy against the relapsing-remitting form of multiple sclerosis (RRMS). Natalizumab therapeutic efficacy is limited by the reactivation of the John Cunningham polyomavirus (JCV) and development of progressive multifocal leukoencephalopathy (PML). To correlate natalizumab-induced phenotypic modifications of peripheral blood T-lymphocytes with JCV reactivation, JCV-specific antibodies (serum), JCV-DNA (blood and urine), CD49d expression and relative abundance of peripheral blood T-lymphocyte subsets were longitudinally assessed in 26 natalizumab-treated RRMS patients. Statistical analyses were performed using GraphPad Prism and R. Natalizumab treatment reduced CD49d expression on memory and effector subsets of peripheral blood T-lymphocytes. Moreover, accumulation of peripheral blood CD8+ memory and effector cells was observed after 12 and 24 months of treatment. CD4+ and CD8+ T-lymphocyte immune-activation was increased after 24 months of treatment. Higher percentages of CD8+ effectors were observed in subjects with detectable JCV-DNA. Natalizumab reduces CD49d expression on CD8+ T-lymphocyte memory and effector subsets, limiting their migration to the central nervous system and determining their accumulation in peripheral blood. Impairment of central nervous system immune surveillance and reactivation of latent JCV, can explain the increased risk of PML development in natalizumab-treated RRMS subjects

Pharmacogenomics of Interferon-ß Therapy in Multiple Sclerosis: Baseline IFN Signature Determines Pharmacological Differences between Patients

Multiple sclerosis (MS) is a heterogeneous disease. In order to understand the partial responsiveness to IFNbeta in Relapsing Remitting MS (RRMS) we studied the pharmacological effects of IFNbeta therapy. Large scale gene expression profiling was performed on peripheral blood of 16 RRMS patients at baseline and one month after the start of IFNbeta therapy. Differential gene expression was analyzed by Significance Analysis of Microarrays. Subsequent expression analyses on specific genes were performed after three and six months of treatment. Peripheral blood mononuclear cells (PBMC) were isolated and stimulated in vitro with IFNbeta. Genes of interest were measured and validated by quantitative realtime PCR. An independent group of 30 RRMS patients was used for validation. Pharmacogenomics revealed a marked variation in the pharmacological response to IFNbeta between patients. A total of 126 genes were upregulated in a subset of patients whereas in other patients these genes were downregulated or unchanged after one month of IFNbeta therapy. Most interestingly, we observed that the extent of the pharmacological response correlates negatively with the baseline expression of a specific set of 15 IFN response genes (R = -0.7208; p = 0.0016). The negative correlation was maintained after three (R = -0.7363; p = 0.0027) and six (R = -0.8154; p = 0.0004) months of treatment, as determined by gene expression levels of the most significant correlating gene. Similar results were obtained in an independent group of patients (n = 30; R = -0.4719; p = 0.0085). Moreover, the ex vivo results could be confirmed by in vitro stimulation of purified PBMCs at baseline with IFNbeta indicating that differential responsiveness to IFNbeta is an intrinsic feature of peripheral blood cells at baseline. These data imply that the expression levels of IFN response genes in the peripheral blood of MS patients prior to treatment could serve a role as biomarker for the differential clinical response to IFNbet

Rasch analysis of the Multiple Sclerosis Impact Scale (MSIS-29)

<p>Abstract</p> <p>Background</p> <p>Multiple Sclerosis (MS) is a degenerative neurological disease that causes impairments, including spasticity, pain, fatigue, and bladder dysfunction, which negatively impact on quality of life. The Multiple Sclerosis Impact Scale (MSIS-29) is a disease-specific health-related quality of life (HRQoL) instrument, developed using the patient's perspective on disease impact. It consists of two subscales assessing the physical (MSIS-29-PHYS) and psychological (MSIS-29-PSYCH) impact of MS. Although previous studies have found support for the psychometric properties of the MSIS-29 using traditional methods of scale evaluation, the scale has not been subjected to a detailed Rasch analysis. Therefore, the objective of this study was to use Rasch analysis to assess the internal validity of the scale, and its response format, item fit, targeting, internal consistency and dimensionality.</p> <p>Methods</p> <p>Ninety-two persons with definite MS residing in the community were recruited from a tertiary hospital database. Patients completed the MSIS-29 as part of a larger study. Rasch analysis was undertaken to assess the psychometric properties of the MSIS-29.</p> <p>Results</p> <p>Rasch analysis showed overall support for the psychometric properties of the two MSIS-29 subscales, however it was necessary to reduce the response format of the MSIS-29-PHYS to a 3-point response scale. Both subscales were unidimensional, had good internal consistency, and were free from item bias for sex and age. Dimensionality testing indicated it was not appropriate to combine the two subscales to form a total MSIS score.</p> <p>Conclusion</p> <p>In this first study to use Rasch analysis to fully assess the psychometric properties of the MSIS-29 support was found for the two subscales but not for the use of the total scale. Further use of Rasch analysis on the MSIS-29 in larger and broader samples is recommended to confirm these findings.</p

Activated Human CD4+CD45RO+ Memory T-Cells Indirectly Inhibit NLRP3 Inflammasome Activation through Downregulation of P2X7R Signalling

Inflammasomes are multi-protein complexes that control the production of pro-inflammatory cytokines such as IL-1β. Inflammasomes play an important role in the control of immunity to tumors and infections, and also in autoimmune diseases, but the mechanisms controlling the activation of human inflammasomes are largely unknown. We found that human activated CD4+CD45RO+ memory T-cells specifically suppress P2X7R-mediated NLRP3 inflammasome activation, without affecting P2X7R-independent NLRP3 or NLRP1 inflammasome activation. The concomitant increase in pro-IL-1β production induced by activated memory T-cells concealed this effect. Priming with IFNβ decreased pro-IL-1β production in addition to NLRP3 inflammasome inhibition and thus unmasked the inhibitory effect on NLRP3 inflammasome activation. IFNβ suppresses NLRP3 inflammasome activation through an indirect mechanism involving decreased P2X7R signaling. The inhibition of pro-IL-1β production and suppression of NLRP3 inflammasome activation by IFNβ-primed human CD4+CD45RO+ memory T-cells is partly mediated by soluble FasL and is associated with down-regulated P2X7R mRNA expression and reduced response to ATP in monocytes. CD4+CD45RO+ memory T-cells from multiple sclerosis (MS) patients showed a reduced ability to suppress NLRP3 inflammasome activation, however their suppressive ability was recovered following in vivo treatment with IFNβ. Thus, our data demonstrate that human P2X7R-mediated NLRP3 inflammasome activation is regulated by activated CD4+CD45RO+ memory T cells, and provide new information on the mechanisms mediating the therapeutic effects of IFNβ in MS

Intracluster light in clusters of galaxies at redshifts 0.4<z<0.8

The study of intracluster light can help us to understand the mechanisms taking place in galaxy clusters, and to place constraints on the cluster formation history and physical properties. However, owing to the intrinsic faintness of ICL emission, most searches and detailed studies of ICL have been limited to redshifts z<0.4.We search for ICL in a subsample of ten clusters detected by the ESO Distant Cluster Survey (EDisCS), at redshifts 0.4<z<0.8, that are also part of our DAFT/FADA Survey. We analyze the ICL by applying the OV WAV package, a wavelet-based technique, to deep HST ACS images in the F814W filter and to V-band VLT/FORS2 images of three clusters. Detection levels are assessed as a function of the diffuse light source surface brightness using simulations. In the F814W filter images, we detect diffuse light sources in all the clusters, with typical sizes of a few tens of kpc (assuming that they are at the cluster redshifts). The ICL detected by stacking the ten F814W images shows an 8sigma detection in the source center extending over a ~50x50kpc2 area, with a total absolute magnitude of -21.6 in the F814W filter, equivalent to about two L* galaxies per cluster. We find a weak correlation between the total F814W absolute magnitude of the ICL and the cluster velocity dispersion and mass. There is no apparent correlation between the cluster mass-to-light ratio (M/L) and the amount of ICL, and no evidence for any preferential orientation in the ICL source distribution. We find no strong variation in the amount of ICL between z=0 and z=0.8. In addition, we find wavelet-detected compact objects (WDCOs) in the three clusters for which data in two bands are available; these objects are probably very faint compact galaxies that in some cases are members of the respective clusters. We have shown that ICL is important in clusters at least up to z=0.8.Comment: Accepted in A&A. Six figures in jpg format. Paper still to be improved by A&A english correcto

Cerebral atrophy as outcome measure in short-term phase 2 clinical trials in multiple sclerosis

Cerebral atrophy is a compound measure of the neurodegenerative component of multiple sclerosis (MS) and a conceivable outcome measure for clinical trials monitoring the effect of neuroprotective agents. In this study, we evaluate the rate of cerebral atrophy in a 6-month period, investigate the predictive and explanatory value of other magnetic resonance imaging (MRI) measures in relation to cerebral atrophy, and determine sample sizes for future short-term clinical trials using cerebral atrophy as primary outcome measure

Diffuse stellar emission in X-ray luminous galaxy clusters at z~0.3 I. Is the diffuse optical light boosted and rejuvenated in merging clusters?

[Abridged] We searched for diffuse stellar emission around BCGs in three of the most X-ray luminous clusters found at z~0.3 in the REFLEX cluster survey and observed with XMM-Newton. These systems (RXCJ0014.3-3022, RXCJ0232.2-4420, and RXCJ2308.3-0211) are in different dynamical states, as witnessed by their X-ray morphology and optical appearence (e.g. multiplicity of BCGs). [Abridged] Diffuse stellar emission is robustly detected down to a surface brightness of 26 R-mag/arcsec^2 (observed frame) around a total of seven BCGs, extending up to galactocentric distances of ~100 kpc. In particular, it surrounds a pair of BCGs in RXCJ0232.2-4420, while it bridges two BCGs associated with the minor subcomponent of the merging cluster RXCJ0014.3-3022. The diffuse light detected at the greatest distances from the BCGs of the rather regular clusters RXCJ0232.2-4420 and RXCJ2308.3-0211 follows the ICM distribution. Its B-R colour is consistent with the colours measured within the BCG effective radii. The diffuse light around the two pairs of BCGs in RXCJ0014.3-3022 exhibits bluer colours than the BCG central regions by up to 0.5 mag. If the contribution of the intracluster light (ICL) to the detected diffuse light around BCGs is not negligible, ICL and BCGs have similar stellar populations in relatively relaxed clusters. Merging on a cluster scale eventually adds gravitational stresses to BCGs and other galaxies in subcluster cores. This event may affect the properties of the diffuse stellar emission around BCGs. Shredding of star-forming, low-metallicity dwarf galaxies is favoured as the cause of the bluer B-R colours of the diffuse stellar component around the two pairs of BCGs in the merging cluster RXCJ0014.3-3022.Comment: 20 pages including 3 tables and 11 low-resolution colour figures, accepted for publication in A&

The potential of urinary metabolites for diagnosing multiple sclerosis

A definitive diagnostic test for multiple sclerosis (MS) does not exist; instead physicians use a combination of medical history, magnetic resonance imaging, and cerebrospinal fluid analysis (CSF). Significant effort has been employed to identify biomarkers from CSF to facilitate MS diagnosis; however none of the proposed biomarkers have been successful to date. Urine is a proven source of metabolite biomarkers and has the potential to be a rapid, non-invasive, inexpensive, and efficient diagnostic tool for various human diseases. Nevertheless, urinary metabolites have not been extensively explored as a source of biomarkers for MS. Instead, we demonstrate that urinary metabolites have significant promise for monitoring disease-progression, and response to treatment in MS patients. NMR analysis of urine permitted the identification of metabolites that differentiate experimental autoimmune encephalomyelitis (EAE)-mice (prototypic disease model for MS) from healthy and MS drug-treated EAE mice