307 research outputs found
P2x7 deficiency suppresses development of experimental autoimmune encephalomyelitis
<p>Abstract</p> <p>Background</p> <p>The purinergic receptor P2x7 is expressed on myeloid cells as well as on CNS glial cells, and P2x7 activation has been shown to increase both glial and T-cell activation. These properties suggest a role in the development of autoimmune disease including multiple sclerosis.</p> <p>Methods</p> <p>The animal model of MS, experimental autoimmune encephalomyelitis (EAE) using myelin oligodendrocyte glycoprotein (MOG) peptide residues 35–55 was induced in wildtype C57BL6 mice and in P2x7 deficient mice ('P2x7 mice') that were backcrossed to C57BL6 mice. Disease progression was monitored by appearance of clinical signs, immunocytochemical staining to assess brain inflammation and neuronal damage, and by measurement of Tcell cytokine production.</p> <p>Results</p> <p>The incidence of EAE disease in P2x7 mice was reduced 4-fold compared to the wildtype mice; however the P2x7 mice that became ill had similar days of onset and clinical scores as the wildtype mice. Splenic T-cells isolated from P2x7 null mice produced greater IFNγ and IL-17 (from 3 to 12 fold greater levels) than wildtype cells, however cytokine production from P2x7 derived cells was not increased by a selective P2x7 agonist as was cytokine production from wildtype cells. Although infiltrating cells were detected in brains of both the P2x7 and wildtype mice, astroglial activation and axonal damage was reduced versus wildtype mice, and the distribution of astroglial activation was markedly distinct in the two strains. In contrast, microglial activation was similar in the two strains.</p> <p>Conclusion</p> <p>P2x7 deficiency resulted in compensatory changes leading to increased T-cell cytokine production, and activated T-cells were detected in the brains of P2x7 null mice with no clinical signs. However, the greatly reduced incidence of disease suggests that an initiating event is absent in these mice, and points to a role for astroglial P2x7 in development of EAE disease.</p
The anti-inflammatory effects of dimethyl fumarate in astrocytes involve glutathione and haem oxygenase-1
DMF (dimethyl fumarate) exerts anti-inflammatory and pro-metabolic effects in a variety of cell types, and a formulation (BG-12) is being evaluated for monotherapy in multiple sclerosis patients. DMF modifies glutathione (GSH) levels that can induce expression of the anti-inflammatory protein HO-1 (haem oxygenase-1). In primary astrocytes and C6 glioma cells, BG-12 dose-dependently suppressed nitrite production induced by either LI [LPS (lipopolysaccharide) at 1 \u3bcg/ml plus IFN\u3b3 (interferon \u3b3) at 20 units/ml] or a mixture of pro-inflammatory cytokines, with greater efficacy in C6 cells. BG-12 reduced NOS2 (nitric oxide synthase 2) mRNA levels and activation of a NOS2 promoter, reduced nuclear levels of NF-\u3baB (nuclear factor \u3baB) p65 subunit and attenuated loss of I\u3baB\u3b1 (inhibitory \u3baB\u3b1) in both cell types, although with greater effects in astrocytes. In astrocytes, LI decreased mRNA levels for GSHr (GSH reductase) and GCL (c-glutamylcysteine synthetase), and slightly suppressed GSHs (GSH synthetase) mRNAs. Co-treatment with BG-12 prevented those decreased and increased levels above control values. In contrast, LI reduced GSHp (GSH peroxidase) and GCL in C6 cells, and BG-12 had no effect on those levels. BG-12 increased nuclear levels of Nrf2 (nuclear factor-erythroid 2 p45 subunit-related factor 2), an inducer of GSH-related enzymes, in astrocytes but not C6 cells. In astrocytes, GSH was decreased by BG-12 at 2 h and increased at 24 h. Prior depletion of GSH using buthionine-sulfoximine increased the ability of BG-12 to reduce nitrites. In astrocytes, BG-12 increased HO-1 mRNA levels and effects on nitrite levels were blocked by an HO-1 inhibitor. These results demonstrate that BG-12 suppresses inflammatory activation in astrocytes and C6 glioma cells, but with distinct mechanisms, different dependence on GSH and different effects on transcription factor activation
Regulation of oligodendrocyte progenitor cell maturation by PPARδ: effects on bone morphogenetic proteins
In EAE (experimental autoimmune encephalomyelitis), agonists of PPARs (peroxisome proliferator-activated receptors) provide clinical benefit and reduce damage. In contrast with PPARγ, agonists of PPARδ are more effective when given at later stages of EAE and increase myelin gene expression, suggesting effects on OL (oligodendrocyte) maturation. In the present study we examined effects of the PPARδ agonist GW0742 on OPCs (OL progenitor cells), and tested whether the effects involve modulation of BMPs (bone morphogenetic proteins). We show that effects of GW0742 are mediated through PPARδ since no amelioration of EAE clinical scores was observed in PPARδ-null mice. In OPCs derived from E13 mice (where E is embryonic day), GW0742, but not the PPARγ agonist pioglitazone, increased the number of myelin-producing OLs. This was due to activation of PPARδ since process formation was reduced in PPARδ-null compared with wild-type OPCs. In both OPCs and enriched astrocyte cultures, GW0742 increased noggin protein expression; however, noggin mRNA was only increased in astrocytes. In contrast, GW0742 reduced BMP2 and BMP4 mRNA levels in OPCs, with lesser effects in astrocytes. These findings demonstrate that PPARδ plays a role in OPC maturation, mediated, in part, by regulation of BMP and BMP antagonists
Fast Photon Detection for Particle Identification with COMPASS RICH-1
Particle identification at high rates is an important challenge for many
current and future high-energy physics experiments. The upgrade of the COMPASS
RICH-1 detector requires a new technique for Cherenkov photon detection at
count rates of several per channel in the central detector region, and a
read-out system allowing for trigger rates of up to 100 kHz. To cope with these
requirements, the photon detectors in the central region have been replaced
with the detection system described in this paper. In the peripheral regions,
the existing multi-wire proportional chambers with CsI photocathode are now
read out via a new system employing APV pre-amplifiers and flash ADC chips. The
new detection system consists of multi-anode photomultiplier tubes (MAPMT) and
fast read-out electronics based on the MAD4 discriminator and the F1-TDC chip.
The RICH-1 is in operation in its upgraded version for the 2006 CERN SPS run.
We present the photon detection design, constructive aspects and the first
Cherenkov light in the detector.Comment: Proceedings of the Imaging 2006 conference, Stockholm, Sweden, 27-30
June 2006, 5 pages, 6 figures, to appear in NIM A; corrected typo in caption
of Fig.
Fast photon detection for the COMPASS RICH detector
The COMPASS experiment at the SPS accelerator at CERN uses a large scale Ring
Imaging CHerenkov detector (RICH) to identify pions, kaons and protons in a
wide momentum range. For the data taking in 2006, the COMPASS RICH has been
upgraded in the central photon detection area (25% of the surface) with a new
technology to detect Cherenkov photons at very high count rates of several 10^6
per second and channel and a new dead-time free read-out system, which allows
trigger rates up to 100 kHz. The Cherenkov photons are detected by an array of
576 visible and ultra-violet sensitive multi-anode photomultipliers with 16
channels each. The upgraded detector showed an excellent performance during the
2006 data taking.Comment: Proceeding of the IPRD06 conference (Siena, Okt. 06
The Fast Read-out System for the MAPMTs of COMPASS RICH-1
A fast readout system for the upgrade of the COMPASS RICH detector has been
developed and successfully used for data taking in 2006 and 2007. The new
readout system for the multi-anode PMTs in the central part of the photon
detector of the RICH is based on the high-sensitivity MAD4
preamplifier-discriminator and the dead-time free F1-TDC chip characterized by
high-resolution. The readout electronics has been designed taking into account
the high photon flux in the central part of the detector and the requirement to
run at high trigger rates of up to 100 kHz with negligible dead-time. The
system is designed as a very compact setup and is mounted directly behind the
multi-anode photomultipliers. The data are digitized on the frontend boards and
transferred via optical links to the readout system. The read-out electronics
system is described in detail together with its measured performances.Comment: Proceeding of RICH2007 Conference, Trieste, Oct. 2007. v2: minor
change
Continuously improving the practice of cardiology
Guidelines for the management of patients with
cardiovascular disease are designed to assist
cardiologists and other physicans in their practice.
Surveys are conducted to assess whether guidelines
are followed in practice. The results of surveys on
acute coronary syndromes, coronary revascularisation,
secondary prevention, valvular heart disease
and heart failure are presented. Comparing surveys
conducted between 1995 and 2002, a gradual improvement
in use ofsecondary preventive therapy
is observed. Nevertheless, important deviations
from established guidelines are noted, with a
significant variation among different hospitals in
the Netherlands and in other European countries.
Measures for fiuther improvement of clinical
practice indude more rapid treatment of patients
with evolving myocardial infarction, more frequent
use of clopidogrel and glycoprotein IIb/IIIa
receptor blockers in patients with acute coronary
syndromes, more frequent use of 5-blockers in
patients with heart failure and more intense
measures to encourage patients to stop smoking.
Targets for the proportion ofpatients who might
receive specific therapies are presented
Economic Integration and FDI: An Empirical Analysis of Foreign Investment in the EU and in Central and Eastern Europe
Low-dose aspirin does not improve ovarian stimulation, endometrial response, or pregnancy rates for in vitro fertilization
BACKGROUND: The purpose of this study is to determine if low-dose aspirin improved ovarian stimulation, endometrial response, or IVF pregnancy rates in our program. METHODS: Retrospective analysis of 316 consecutive IVF cycles from 1995 through 2001. Aspirin 80 mg daily was initiated at the start of luteal leuprolide in 72 cycles. The 244 controls received no aspirin during treatment. RESULTS: The live birth rate in aspirin users was 29%, slightly lower compared to 41% in the no aspirin control group (p = 0.07). Implantation rates were 21% with aspirin and 30% in the control population (p = 0.01). There was no difference in the maximal endometrial thickness between aspirin and non-aspirin groups. The two groups were similar regarding age, gonadotropin ampules, embryos, number of embryos transferred, prior parity, diagnosis, use of intracytoplasmic sperm injection, and stimulation protocol. CONCLUSION: Low-dose aspirin was not beneficial to IVF patients in our program. Aspirin does not enhance endometrial thickness, augment the ovarian response, or improve pregnancy rates
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