2,953 research outputs found
Clinical and functional characterisation of a novel TNFRSF1A c.605T > A/V173D cleavage site mutation associated with tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), cardiovascular complications and excellent response to etanercept treatment.
Objectives: To study the clinical outcome, treatment
response, T-cell subsets and functional consequences of a
novel tumour necrosis factor (TNF) receptor type 1
(TNFRSF1A) mutation affecting the receptor
cleavage site.
Methods: Patients with symptoms suggestive of tumour
necrosis factor receptor-associated periodic syndrome
(TRAPS) and 22 healthy controls (HC) were screened for
mutations in the TNFRSF1A gene. Soluble TNFRSF1A and
inflammatory cytokines were measured by ELISAs.
TNFRSF1A shedding was examined by stimulation of
peripheral blood mononuclear cells (PBMCs) with phorbol
12-myristate 13-acetate followed by flow cytometric
analysis (FACS). Apoptosis of PBMCs was studied by
stimulation with TNFa in the presence of cycloheximide
and annexin V staining. T cell phenotypes were monitored
by FACS.
Results: TNFRSF1A sequencing disclosed a novel V173D/
p.Val202Asp substitution encoded by exon 6 in one
family, the c.194â14G.A splice variant in another and
the R92Q/p.Arg121Gln substitution in two families.
Cardiovascular complications (lethal heart attack and
peripheral arterial thrombosis) developed in two V173D
patients. Subsequent etanercept treatment of the V173D
carriers was highly effective over an 18-month follow-up
period. Serum TNFRSF1A levels did not differ between
TRAPS patients and HC, while TNFRSF1A cleavage from
monocytes was significantly reduced in V173D and R92Q
patients. TNFa-induced apoptosis of PBMCs and T-cell
senescence were comparable between V173D patients
and HC.
Conclusions: The TNFRSF1A V173D cleavage site
mutation may be associated with an increased risk for
cardiovascular complications and shows a strong
response to etanercept. T-cell senescence does not seem
to have a pathogenetic role in affected patients
Unstable states in QED of strong magnetic fields
We question the use of stable asymptotic scattering states in QED of strong
magnetic fields. To correctly describe excited Landau states and photons above
the pair creation threshold the asymptotic fields are chosen as generalized
Licht fields. In this way the off-shell behavior of unstable particles is
automatically taken into account, and the resonant divergences that occur in
scattering cross sections in the presence of a strong external magnetic field
are avoided. While in a limiting case the conventional electron propagator with
Breit-Wigner form is obtained, in this formalism it is also possible to
calculate -matrix elements with external unstable particles.Comment: Revtex, 7 pages. To appear in Phys. Rev. D53(2
Les bulles « robustes »:Pourquoi il faut construire des logements en région parisienne
« Bulle » ou « pas bulle » ? La question taraude les observateurs et les acteurs du marchĂ© immobilier français. Nous examinons dans cet article les Ă©lĂ©ments empiriques et thĂ©oriques qui expliquent la hausse des prix rĂ©cente et sa rĂ©sistance aux retournements conjoncturels. En combinant la notion de bulle Ă©conomique, les arguments de lâĂ©conomie spatiale et une analyse dâĂ©conomie politique, nous suggĂ©rons que la valorisation importante de lâimmobilier en France est le rĂ©sultat dâune logique rationnelle et conforte les intĂ©rĂȘts des acteurs locaux. DĂšs lors, la forte valorisation peut ĂȘtre considĂ©rĂ©e comme une « bulle robuste », Ă mĂȘme de rĂ©sister Ă des chocs importants. Cette bulle organise un transfert intergĂ©nĂ©rationnel et peut avoir des effets positifs. Elle peut Ă©galement renforcer la sĂ©grĂ©gation spatiale, alimenter les inĂ©galitĂ©s territoriales et empĂȘcher dâexploiter les Ă©conomies dâagglomĂ©ration possibles. Lâanalyse est dĂ©taillĂ©e sur la rĂ©gion Ile-de-France oĂč ces phĂ©nomĂšnes sont particuliĂšrement marquĂ©s
RUNX1/ETO blocks selectin-mediated adhesion via epigenetic silencing of PSGL-1
RUNX1/ETO (RE),the t(8;21)-derived leukemic transcription factor associated with acute myeloid leukemia (AML) development, deregulates genes involved in differentiation, self-renewal and proliferation. In addition, these cells show differences in cellular adhesion behavior whose molecular basis is not well understood. Here, we demonstrate that RE epigenetically silences the gene encoding P-Selectin Glycoprotein Ligand-1 (PSGL-1) and downregulates PSGL-1 expression in human CD34+ and murine lin-hematopoietic progenitor cells. Levels of PSGL-1 inversely and dose-dependently correlate with RE oncogene levels. However, a DNA-binding defective mutant fails to downregulate PSGL-1. We show by ChIP experiments that the PSGL-1 promoter is a direct target of RE and binding is accompanied by high levels of the repressive chromatin mark histone H3K27me3. In t(8;21)+ Kasumi-1 cells, PSGL-1 expression is completely restored at both the mRNA and cell surface protein levels following RE downregulation with short hairpin RNA (shRNA) or RE inhibition with tetramerization-blocking peptides, and at the promoter H3K27me3 is replaced by the activating chromatin mark H3K9ac as well as by RNA polymerase II. Upregulation of PSGL-1 restores the binding of cells to P- and E-selectin and re-establishes myeloid-specific cellular adhesion while it fails to bind to lymphocyte-specific L-selectin. Overall, our data suggest that the RE oncoprotein epigenetically represses PSGL-1 via binding to its promoter region and thus affects the adhesive behavior of t(8;21)+ AML cells
Innovative methods in European road freight transport statistics: A pilot study
By using innovative methods, such as the automated transfer of corporate electronic data to National Statistical Institutions, official transport data can be significantly improved in terms of reliability, costs and the burden on respondents. In this paper, we show that the automated compilation of statistical reports is possible and feasible. Based on previous findings, a new method and tool were developed in cooperation with two business partners from the logistics sector in Austria. The results show that the prototype could successfully be implemented at the partner companies. Improved data quality can lead to more reliable analyses in various fields. Compared to actual volumes of investments into transport, the costs of transport statistics are limited. By using the new and innovative data collection techniques, these costs can even be reduced in the long run; at the same time, the risk of bad investments and wrong decisions caused by analyses relying on poor data quality can be reduced. This results in a substantial value for business, research, the economy and the society
Compton Scattering in Ultra-Strong Magnetic Fields: Numerical and Analytical Behavior in the Relativistic Regime
This paper explores the effects of strong magnetic fields on the Compton
scattering of relativistic electrons. Recent studies of upscattering and energy
loss by relativistic electrons that have used the non-relativistic, magnetic
Thomson cross section for resonant scattering or the Klein-Nishina cross
section for non-resonant scattering do not account for the relativistic quantum
effects of strong fields ( G). We have derived a
simplified expression for the exact QED scattering cross section for the
broadly-applicable case where relativistic electrons move along the magnetic
field. To facilitate applications to astrophysical models, we have also
developed compact approximate expressions for both the differential and total
polarization-dependent cross sections, with the latter representing well the
exact total QED cross section even at the high fields believed to be present in
environments near the stellar surfaces of Soft Gamma-Ray Repeaters and
Anomalous X-Ray Pulsars. We find that strong magnetic fields significantly
lower the Compton scattering cross section below and at the resonance, when the
incident photon energy exceeds in the electron rest frame. The cross
section is strongly dependent on the polarization of the final scattered
photon. Below the cyclotron fundamental, mostly photons of perpendicular
polarization are produced in scatterings, a situation that also arises above
this resonance for sub-critical fields. However, an interesting discovery is
that for super-critical fields, a preponderance of photons of parallel
polarization results from scatterings above the cyclotron fundamental. This
characteristic is both a relativistic and magnetic effect not present in the
Thomson or Klein-Nishina limits.Comment: AASTeX format, 31 pages included 7 embedded figures, accepted for
publication in The Astrophysical Journa
Depressive disorders are associated with increased peripheral blood cell deformability: a cross-sectional case-control study (Mood-Morph)
Pathophysiological landmarks of depressive disorders are chronic low-grade inflammation and elevated glucocorticoid output. Both can potentially interfere with cytoskeleton organization, cell membrane bending and cell function, suggesting altered cell morpho-rheological properties like cell deformability and other cell mechanical features in depressive disorders. We performed a cross-sectional case-control study using the image-based morpho-rheological characterization of unmanipulated blood samples facilitating real-time deformability cytometry (RT-DC). Sixty-nine pre-screened individuals at high risk for depressive disorders and 70 matched healthy controls were included and clinically evaluated by Composite International Diagnostic Interview leading to lifetime and 12-month diagnoses. Facilitating deep learning on blood cell images, major blood cell types were classified and morpho-rheological parameters such as cell size and cell deformability of every individual cell was quantified. We found peripheral blood cells to be more deformable in patients with depressive disorders compared to controls, while cell size was not affected. Lifetime persistent depressive disorder was associated with increased cell deformability in monocytes and neutrophils, while in 12-month persistent depressive disorder erythrocytes deformed more. Lymphocytes were more deformable in 12-month major depressive disorder, while for lifetime major depressive disorder no differences could be identified. After correction for multiple testing, only associations for lifetime persistent depressive disorder remained significant. This is the first study analyzing morpho-rheological properties of entire blood cells and highlighting depressive disorders and in particular persistent depressive disorders to be associated with increased blood cell deformability. While all major blood cells tend to be more deformable, lymphocytes, monocytes, and neutrophils are mostly affected. This indicates that immune cell mechanical changes occur in depressive disorders, which might be predictive of persistent immune response
Equation of state of a strongly magnetized hydrogen plasma
The influence of a constant uniform magnetic field on the thermodynamic
properties of a partially ionized hydrogen plasma is studied. Using the method
of Green' s function various interaction contributions to the thermodynamic
functions are calculated. The equation of state of a quantum magnetized plasma
is presented within the framework of a low density expansion up to the order
e^4 n^2 and, additionally, including ladder type contributions via the bound
states in the case of strong magnetic fields (2.35*10^{5} T << B << 2.35*10^{9}
T). We show that for high densities (n=10^{27-30} m^{-3}) and temperatures
T=10^5 - 10^6 K typical for the surface of neutron stars nonideality effects
as, e.g., Debye screening must be taken into account.Comment: 12 pages, 2 Postscript figures. uses revtex, to appear in Phys. Rev.
Power grip, pinch grip, manual muscle testing or thenar atrophy - which should be assessed as a motor outcome after carpal tunnel decompression? A systematic review
<p>Abstract</p> <p>Background</p> <p>Objective assessment of motor function is frequently used to evaluate outcome after surgical treatment of carpal tunnel syndrome (CTS). However a range of outcome measures are used and there appears to be no consensus on which measure of motor function effectively captures change. The purpose of this systematic review was to identify the methods used to assess motor function in randomized controlled trials of surgical interventions for CTS. A secondary aim was to evaluate which instruments reflect clinical change and are psychometrically robust.</p> <p>Methods</p> <p>The bibliographic databases Medline, AMED and CINAHL were searched for randomized controlled trials of surgical interventions for CTS. Data on instruments used, methods of assessment and results of tests of motor function was extracted by two independent reviewers.</p> <p>Results</p> <p>Twenty-two studies were retrieved which included performance based assessments of motor function. Nineteen studies assessed power grip dynamometry, fourteen studies used both power and pinch grip dynamometry, eight used manual muscle testing and five assessed the presence or absence of thenar atrophy. Several studies used multiple tests of motor function. Two studies included both power and pinch strength and reported descriptive statistics enabling calculation of effect sizes to compare the relative responsiveness of grip and pinch strength within study samples. The study findings suggest that tip pinch is more responsive than lateral pinch or power grip up to 12 weeks following surgery for CTS.</p> <p>Conclusion</p> <p>Although used most frequently and known to be reliable, power and key pinch dynamometry are not the most valid or responsive tools for assessing motor outcome up to 12 weeks following surgery for CTS. Tip pinch dynamometry more specifically targets the thenar musculature and appears to be more responsive. Manual muscle testing, which in theory is most specific to the thenar musculature, may be more sensitive if assessed using a hand held dynamometer â the Rotterdam Intrinsic Handheld Myometer. However further research is needed to evaluate its reliability and responsiveness and establish the most efficient and psychometrically robust method of evaluating motor function following surgery for CTS.</p
Biological and technical variables affecting immunoassay recovery of cytokines from human serum and simulated vaginal fluid: A multicenter study
The increase of proinflammatory cytokines in vaginal secretions may serve as a surrogate marker of unwanted inflammatory reaction to microbicide products topically applied for the prevention of sexually transmitted diseases, including HIV-1. Interleukin (IL)-1ÎČ and IL-6 have been proposed as indicators of inflammation and increased risk of HIV-1 transmission; however, the lack of information regarding detection platforms optimal for vaginal fluids and interlaboratory variation limit their use for microbicide evaluation and other clinical applications. This study examines fluid matrix variants relevant to vaginal sampling techniques and proposes a model for interlaboratory comparisons across current cytokine detection technologies. IL-1ÎČ and IL-6 standards were measured by 12 laboratories in four countries, using 14 immunoassays and four detection platforms based on absorbance, chemiluminescence, electrochemiluminescence, and fluorescence. International reference preparations of cytokines with defined biological activity were spiked into (1) a defined medium simulating the composition of human vaginal fluid at pH 4.5 and 7.2, (2) physiologic salt solutions (phosphate-buffered saline and saline) commonly used for vaginal lavage sampling in clinical studies of cytokines, and (3) human blood serum. Assays were assessed for reproducibility, linearity, accuracy, and significantly detectable fold difference in cytokine level. Factors with significant impact on cytokine recovery were determined by KruskalâWallis analysis of variance with Dunnâs multiple comparison test and multiple regression models. All assays showed acceptable intra-assay reproducibility; however, most were associated with significant interlaboratory variation. The smallest reliably detectable cytokine differences (P < 0.05) derived from pooled interlaboratory data varied from 1.5- to 26-fold depending on assay, cytokine, and matrix type. IL-6 but not IL-1ÎČ determinations were lower in both saline and phosphate-buffered saline as compared to vaginal fluid matrix, with no significant effect of pH. The (electro)chemiluminescence-based assays were most discriminative and consistently detected <2-fold differences within each matrix type. The Luminex-based assays were less discriminative with lower reproducibility between laboratories. These results suggest the need for uniform vaginal sampling techniques and a better understanding of immunoassay platform differences and cross-validation before the biological significance of cytokine variations can be validated in clinical trials. This investigation provides the first standardized analytic approach for assessing differences in mucosal cytokine levels and may improve strategies for monitoring immune responses at the vaginal mucosal interface
- âŠ