Interleukin-9 regulates macrophage activation in the progressive multiple sclerosis brain.

BACKGROUND: Multiple sclerosis (MS) is an immune-mediated, chronic inflammatory, and demyelinating disease of the central nervous system (CNS). Several cytokines are thought to be involved in the regulation of MS pathogenesis. We recently identified interleukin (IL)-9 as a cytokine reducing inflammation and protecting from neurodegeneration in relapsing-remitting MS patients. However, the expression of IL-9 in CNS, and the mechanisms underlying the effect of IL-9 on CNS infiltrating immune cells have never been investigated. METHODS: To address this question, we first analyzed the expression levels of IL-9 in post-mortem cerebrospinal fluid of MS patients and the in situ expression of IL-9 in post-mortem MS brain samples by immunohistochemistry. A complementary investigation focused on identifying which immune cells express IL-9 receptor (IL-9R) by flow cytometry, western blot, and immunohistochemistry. Finally, we explored the effect of IL-9 on IL-9-responsive cells, analyzing the induced signaling pathways and functional properties. RESULTS: We found that macrophages, microglia, and CD4 T lymphocytes were the cells expressing the highest levels of IL-9 in the MS brain. Of the immune cells circulating in the blood, monocytes/macrophages were the most responsive to IL-9. We validated the expression of IL-9R by macrophages/microglia in post-mortem brain sections of MS patients. IL-9 induced activation of signal transducer and activator of transcription (STAT)1, STAT3, and STAT5 and reduced the expression of activation markers, such as CD45, CD14, CD68, and CD11b in inflammatory macrophages stimulated in vitro with lipopolysaccharide and interferon (IFN)-γ. Similarly, in situ the number of activated CD68+ macrophages was significantly reduced in areas with high levels of IL-9. Moreover, in the same conditions, IL-9 increased the secretion of the anti-inflammatory cytokine, transforming growth factor (TGF)-β. CONCLUSIONS: These results reveal a new cytokine expressed in the CNS, with a role in the context of MS. We have demonstrated that IL-9 and its receptor are both expressed in CNS. Moreover, we found that IL-9 decreases the activation state and promotes the anti-inflammatory properties of human macrophages. This mechanism may contribute to the beneficial effects of IL-9 that are observed in MS, and may be therapeutically potentiated by modulating IL-9 expression in MS

Serologic evidence of human orthopoxvirus infections in Sierra Leone

<p>Abstract</p> <p>Background</p> <p>Orthopoxviruses, including variola virus, vaccinia virus, and monkeypox virus, have previously been documented in humans in West Africa, however, no cases of human orthopoxvirus infection have been reported in the region since 1986. We conducted a serosurvey to determine whether human exposure to orthopoxviruses continues to occur in eastern Sierra Leone.</p> <p>Findings</p> <p>To examine evidence of exposure to orthopoxviruses in the Kenema District of Sierra Leone, we collected and tested sera from 1596 persons by IgG ELISA and a subset of 313 by IgM capture ELISA. Eleven persons born after the cessation of smallpox vaccination had high orthopoxvirus-specific IgG values, and an additional 6 persons had positive IgM responses. No geographic clustering was noted.</p> <p>Conclusions</p> <p>These data suggest that orthopoxviruses continue to circulate in Sierra Leone. Studies aimed at obtaining orthopoxvirus isolates and/or genetic sequences from rodents and symptomatic humans in the area are indicated.</p

Cosmic ray diffusion near the Bohm limit in the Cassiopeia A supernova remnant

Supernova remnants (SNRs) are believed to be the primary location of the acceleration of Galactic cosmic rays, via diffusive shock (Fermi) acceleration. Despite considerable theoretical work the precise details are still unknown, in part because of the difficulty in directly observing nucleons that are accelerated to TeV energies in, and affect the structure of, the SNR shocks. However, for the last ten years, X-ray observatories ASCA, and more recently Chandra, XMM-Newton, and Suzaku have made it possible to image the synchrotron emission at keV energies produced by cosmic-ray electrons accelerated in the SNR shocks. In this article, we describe a spatially-resolved spectroscopic analysis of Chandra observations of the Galactic SNR Cassiopeia A to map the cutoff frequencies of electrons accelerated in the forward shock. We set upper limits on the electron diffusion coefficient and find locations where particles appear to be accelerated nearly as fast as theoretically possible (the Bohm limit).Comment: 18 pages, 5 figures. Accepted for publication in Nature Physics (DOI below), final version available week of August 28, 2006 at http://www.nature.com/nphy

Does publication bias inflate the apparent efficacy of psychological treatment for major depressive disorder? A systematic review and meta-analysis of US national institutes of health-funded trials

Background The efficacy of antidepressant medication has been shown empirically to be overestimated due to publication bias, but this has only been inferred statistically with regard to psychological treatment for depression. We assessed directly the extent of study publication bias in trials examining the efficacy of psychological treatment for depression. Methods and Findings We identified US National Institutes of Health grants awarded to fund randomized clinical trials comparing psychological treatment to control conditions or other treatments in patients diagnosed with major depressive disorder for the period 1972–2008, and we determined whether those grants led to publications. For studies that were not published, data were requested from investigators and included in the meta-analyses. Thirteen (23.6%) of the 55 funded grants that began trials did not result in publications, and two others never started. Among comparisons to control conditions, adding unpublished studies (Hedges’ g = 0.20; CI95% -0.11~0.51; k = 6) to published studies (g = 0.52; 0.37~0.68; k = 20) reduced the psychotherapy effect size point estimate (g = 0.39; 0.08~0.70) by 25%. Moreover, these findings may overestimate the "true" effect of psychological treatment for depression as outcome reporting bias could not be examined quantitatively. Conclusion The efficacy of psychological interventions for depression has been overestimated in the published literature, just as it has been for pharmacotherapy. Both are efficacious but not to the extent that the published literature would suggest. Funding agencies and journals should archive both original protocols and raw data from treatment trials to allow the detection and correction of outcome reporting bias. Clinicians, guidelines developers, and decision makers should be aware that the published literature overestimates the effects of the predominant treatments for depression

An Initial Step of GAS-Containing Autophagosome-Like Vacuoles Formation Requires Rab7

Group A streptococcus (GAS; Streptococcus pyogenes) is a common pathogen that invades non-phagocytic human cells via endocytosis. Once taken up by cells, it escapes from the endocytic pathway to the cytoplasm, but here it is contained within a membrane-bound structure termed GAS-containing autophagosome-like vacuoles (GcAVs). The autophagosome marker GFP-LC3 associates with GcAVs, and other components of the autophagosomal pathway are involved in GcAV formation. However, the mechanistic relationship between GcAV and canonical autophagy is largely unknown. Here, we morphologically analyzed GcAV formation in detail. Initially, a small, GFP-LC3-positive GcAV sequesters each streptococcal chain, and these then coalesce into a single, large GcAV. Expression of a dominant-negative form of Rab7 or RNAi-mediated knockdown of Rab7 prevented the initial formation of small GcAV structures. Our results demonstrate that mechanisms of GcAV formation includes not only the common machinery of autophagy, but also Rab7 as an additional component, which is dispensable in canonical autophagosome formation

Endogenous cholinergic inputs and local circuit mechanisms govern the phasic mesolimbic dopamine response to nicotine

Nicotine exerts its reinforcing action by stimulating nicotinic acetylcholine receptors (nAChRs) and boosting dopamine (DA) output from the ventral tegmental area (VTA). Recent data have led to a debate about the principal pathway of nicotine action: direct stimulation of the DAergic cells through nAChR activation, or disinhibition mediated through desensitization of nAChRs on GABAergic interneurons. We use a computational model of the VTA circuitry and nAChR function to shed light on this issue. Our model illustrates that the α4β2-containing nAChRs either on DA or GABA cells can mediate the acute effects of nicotine. We account for in vitro as well as in vivo data, and predict the conditions necessary for either direct stimulation or disinhibition to be at the origin of DA activity increases. We propose key experiments to disentangle the contribution of both mechanisms. We show that the rate of endogenous acetylcholine input crucially determines the evoked DA response for both mechanisms. Together our results delineate the mechanisms by which the VTA mediates the acute rewarding properties of nicotine and suggest an acetylcholine dependence hypothesis for nicotine reinforcement.Peer reviewe

X-ray emission from isolated neutron stars

X-ray emission is a common feature of all varieties of isolated neutron stars (INS) and, thanks to the advent of sensitive instruments with good spectroscopic, timing, and imaging capabilities, X-ray observations have become an essential tool in the study of these objects. Non-thermal X-rays from young, energetic radio pulsars have been detected since the beginning of X-ray astronomy, and the long-sought thermal emission from cooling neutron star's surfaces can now be studied in detail in many pulsars spanning different ages, magnetic fields, and, possibly, surface compositions. In addition, other different manifestations of INS have been discovered with X-ray observations. These new classes of high-energy sources, comprising the nearby X-ray Dim Isolated Neutron Stars, the Central Compact Objects in supernova remnants, the Anomalous X-ray Pulsars, and the Soft Gamma-ray Repeaters, now add up to several tens of confirmed members, plus many candidates, and allow us to study a variety of phenomena unobservable in "standard'' radio pulsars.Comment: Chapter to be published in the book of proceedings of the 1st Sant Cugat Forum on Astrophysics, "ICREA Workshop on the high-energy emission from pulsars and their systems", held in April, 201