1,029 research outputs found
Endothelin-1 Drives Epithelial-Mesenchymal Transition In Hypertensive Nephroangiosclerosis
BACKGROUND: Tubulointerstitial fibrosis, the final outcome of most kidney diseases, involves activation of epithelial mesenchymal transition (EMT). Endothelinâ1 (ETâ1) activates EMT in cancer cells, but it is not known whether it drives EMT in the kidney. We therefore tested the hypothesis that tubulointerstitial fibrosis involves EMT driven by ETâ1. METHODS AND RESULTS: Transgenic TG[mRen2]27 (TGRen2) rats developing fulminant angiotensin IIâdependent hypertension with prominent cardiovascular and renal damage were submitted to drug treatments targeted to ETâ1 and/or angiotensin II receptor or left untreated (controls). Expressional changes of Eâcadherin and αâsmooth muscle actin (αSMA) were examined as markers of renal EMT. In human kidney HKâ2 proximal tubular cells expressing the ET(B) receptor subtype, the effects of ETâ1 with or without ETâ1 antagonists were also investigated. The occurrence of renal fibrosis was associated with EMT in control TGRen2 rats, as evidenced by decreased Eâcadherin and increased αSMA expression. Irbesartan and the mixed ETâ1 receptor antagonist bosentan prevented these changes in a blood pressureâindependent fashion (P < 0.001 for both versus controls). In HKâ2 cells ETâ1 blunted Eâcadherin expression, increased αSMA expression (both P < 0.01), collagen synthesis, and metalloproteinase activity (P < 0.005, all versus untreated cells). All changes were prevented by the selective ET(B) receptor antagonist BQâ788. Evidence for involvement of the Rhoâkinase signaling pathway and dephosphorylation of Yesâassociated protein in EMT was also found. CONCLUSIONS: In angiotensin IIâdependent hypertension, ETâ1 acting via ET(B) receptors and the Rhoâkinase and Yesâassociated protein induces EMT and thereby renal fibrosis
Expression and Functional Role of Urotensin-II and Its Receptor in the Adrenal Cortex and Medulla: Novel Insights for the Pathophysiology of Primary Aldosteronism
Abstract
Context: The involvement of urotensin II, a vasoactive peptide acting via the G protein-coupled urotensin II receptor, in arterial hypertension remains contentious.
Objective: We investigated the expression of urotensin II and urotensin II receptor in adrenocortical and adrenomedullary tumors and the functional effects of urotensin II receptor activation.
Design: The expression of urotensin II and urotensin II receptor was measured by real time RT-PCR in aldosterone-producing adenoma (n = 22) and pheochromocytoma (n = 10), using histologically normal adrenocortical (n = 6) and normal adrenomedullary (n = 5) tissue as control. Urotensin II peptide and urotensin II receptor protein were investigated with immunohistochemistry and immunoblotting. To identify urotensin II-related and urotensin II receptor-related pathways, a whole transcriptome analysis was used. The adrenocortical effects of urotensin II receptor activation were also assessed by urotensin II infusion with/without the urotensin II receptor antagonist palosuran in rats.
Results: Urotensin II was more expressed in pheochromocytoma than in aldosterone-producing adenoma tissue; the opposite was seen for the urotensin II receptor expression. Urotensin II receptor activation in vivo in rats enhanced (by 182 ± 9%; P < 0.007) the adrenocortical expression of immunoreactive aldosterone synthase.
Conclusions: Urotensin II is a putative mediator of the effects of the adrenal medulla and pheochromocytoma on the adrenocortical zona glomerulosa. This pathophysiological link might account for the reported causal relationship between pheochromocytoma and primary aldosteronism
Bayesian analysis of weak gravitational lensing and Sunyaev-Zel'dovich data for six galaxy clusters
We present an analysis of observations made with the Arcminute Microkelvin
Imager (AMI) and the Canada-France-Hawaii Telescope (CFHT) of six galaxy
clusters in a redshift range of 0.16--0.41. The cluster gas is modelled using
the Sunyaev--Zel'dovich (SZ) data provided by AMI, while the total mass is
modelled using the lensing data from the CFHT. In this paper, we: i) find very
good agreement between SZ measurements (assuming large-scale virialisation and
a gas-fraction prior) and lensing measurements of the total cluster masses out
to r_200; ii) perform the first multiple-component weak-lensing analysis of
A115; iii) confirm the unusual separation between the gas and mass components
in A1914; iv) jointly analyse the SZ and lensing data for the relaxed cluster
A611, confirming our use of a simulation-derived mass-temperature relation for
parameterizing measurements of the SZ effect.Comment: 22 pages, 12 figures, 12 tables, published by MNRA
Prognostic Value of [18F]-Fluoro-Deoxy-Glucose PET/CT, S100 or MIA for Assessment of Cancer-Associated Mortality in Patients with High Risk Melanoma
PURPOSE: To assess the prognostic value of FDG PET/CT compared to the tumor markers S100B and melanoma inhibitory activity (MIA) in patients with high risk melanoma. METHODS: Retrospective study in 125 consecutive patients with high risk melanoma that underwent FDG PET/CT for re-staging. Diagnostic accuracy and prognostic value was determined for FDG PET/CT as well as for S100B and MIA. As standard of reference, cytological, histological, PET/CT or MRI follow-up findings as well as clinical follow-up were used. RESULTS: Of 125 patients, FDG PET/CT was positive in 62 patients. 37 (29.6%) patients had elevated S100B (>100 pg/ml) and 24 (20.2%) had elevated MIA (>10 pg/ml) values. Overall specificities for FDG PET/CT, S100B and MIA were 96.8% (95% CI, 89.1% to 99.1%), 85.7% (75.0% to 92.3%), and 95.2% (86.9% to 98.4%), corresponding sensitivities were 96.8% (89.0% to 99.1%), 45.2% (33.4% to 55.5%), and 36.1% (25.2% to 48.6%), respectively. The negative predictive values (NPV) for PET/CT, S100B, and MIA were 96.8% (89.1% to 99.1%), 61.4% (50.9% to 70.9%), and 60.6% (50.8% to 69.7%). The positive predictive values (PPV) were 96.7% (89.0% to 99.1%), 75.7% (59.9% to 86.6%), and 88.0% (70.0% to 95.8%). Patients with elevated S100B- or MIA values or PET/CT positive findings showed a significantly (p<0.001 each, univariate Cox regression models) higher risk of melanoma associated death which was increased 4.2-, 6.5- or 17.2-fold, respectively. CONCLUSION: PET/CT has a higher prognostic power in the assessment of cancer-associated mortality in melanoma patients compared with S100 and MIA
ALMS1-Deficient Fibroblasts Over-Express Extra-Cellular Matrix Components, Display Cell Cycle Delay and Are Resistant to Apoptosis
Alström Syndrome (ALMS) is a rare genetic disorder (483 living cases), characterized by many clinical manifestations, including blindness, obesity, type 2 diabetes and cardiomyopathy. ALMS is caused by mutations in the ALMS1 gene, encoding for a large protein with implicated roles in ciliary function, cellular quiescence and intracellular transport. Patients with ALMS have extensive fibrosis in nearly all tissues resulting in a progressive organ failure which is often the ultimate cause of death. To focus on the role of ALMS1 mutations in the generation and maintenance of this pathological fibrosis, we performed gene expression analysis, ultrastructural characterization and functional assays in 4 dermal fibroblast cultures from ALMS patients. Using a genome-wide gene expression analysis we found alterations in genes belonging to specific categories (cell cycle, extracellular matrix (ECM) and fibrosis, cellular architecture/motility and apoptosis). ALMS fibroblasts display cytoskeleton abnormalities and migration impairment, up-regulate the expression and production of collagens and despite the increase in the cell cycle length are more resistant to apoptosis. Therefore ALMS1-deficient fibroblasts showed a constitutively activated myofibroblast phenotype even if they do not derive from a fibrotic lesion. Our results support a genetic basis for the fibrosis observed in ALMS and show that both an excessive ECM production and a failure to eliminate myofibroblasts are key mechanisms. Furthermore, our findings suggest new roles for ALMS1 in both intra- and extra-cellular events which are essential not only for the normal cellular function but also for cell-cell and ECM-cell interactions
Current patch test results with the European baseline series and extensions to it from the 'European Surveillance System on Contact Allergy' network, 2007-2008
BACKGROUND: The pattern of contact sensitization to the supposedly most important allergens assembled in the baseline series differs between countries, presumably at least partly because of exposure differences. Objectives. To describe the prevalence of contact sensitization to allergens tested in consecutive patients in the years 2007 and 2008, and to discuss possible differences. METHODS: Data from the 39 departments in 11 European countries comprising the European Surveillance System on Contact Allergy network (www.essca-dc.org) in this period have been pooled and analysed according to common standards. RESULTS: Patch test results with the European baseline series, and country-specific or department-specific additions to it, obtained in 25 181 patients, showed marked international variation. Metals and fragrances are still the most frequent allergens across Europe. Some allergens tested nationally may be useful future additions to the European baseline series, for example methylisothiazolinone, whereas a few long-term components of the European baseline series, namely primin and clioquinol, no longer warrant routine testing. CONCLUSIONS: The present analysis points to 'excess' prevalences of specific contact sensitization in some countries, although interpretation must be cautious if only few, and possibly specialized, centres are representing one country. A comparison as presented may help to target in-depth research into possible causes of 'excess' exposure, and/or consideration of methodological issues, including modifications to the baseline series
NuSTAR and Chandra observations of new X-ray transients in the central parsec of the Galaxy
We report NuSTAR and Chandra observations of two X-ray transients, SWIFT
J174540.7290015 (T15) and SWIFT J174540.2290037 (T37), which were
discovered by the Neil Gehrels Swift Observatory in 2016 within pc of
Sgr A*. NuSTAR detected bright X-ray outbursts from T15 and T37, likely in the
soft and hard states, with 3-79~keV luminosities of and
erg/s, respectively. No X-ray outbursts have previously been
detected from the two transients and our Chandra ACIS analysis puts an upper
limit of erg/s on their quiescent 2-8 keV
luminosities. No pulsations, significant QPOs, or type I X-ray bursts were
detected in the NuSTAR data. While T15 exhibited no significant red noise, the
T37 power density spectra are well characterized by three Lorentzian
components. The declining variability of T37 above Hz is typical
of black hole (BH) transients in the hard state. NuSTAR spectra of both
transients exhibit a thermal disk blackbody, X-ray reflection with broadened Fe
atomic features, and a continuum component well described by Comptonization
models. Their X-ray reflection spectra are most consistent with high BH spin
() and large disk density ( cm).
Based on the best-fit ionization parameters and disk densities, we found that
X-ray reflection occurred near the inner disk radius, which was derived from
the relativistic broadening and thermal disk component. These X-ray
characteristics suggest the outbursting BH-LMXB scenario for both transients
and yield the first BH spin measurements from X-ray transients in the central
100 pc region.Comment: 15 pages, 7 figures, accepted for publication in Ap
Search for standard model production of four top quarks in the lepton + jets channel in pp collisions at âs = 8 TeV
Open Access, Copyright CERN, for the benefit of the CMS Collaboration. Article funded by SCOAP3.Abstract: A search is presented for standard model (SM) production of four top quarks (Formula presented.) in pp collisions in the lepton + jets channel. The data correspond to an integrated luminosity of 19.6 fbâ1 recorded at a centre-of-mass energy of 8 TeV with the CMS detector at the CERN LHC. The expected cross section for SM (Formula presented.) production is (Formula presented.). A combination of kinematic reconstruction and multivariate techniques is used to distinguish between the small signal and large background. The data are consistent with expectations of the SM, and an upper limit of 32 fb is set at a 95% confidence level on the cross section for producing four top quarks in the SM, where a limit of 32 ± 17 fb is expected
Study of Z boson production in pPb collisions at âsNN=5.02 TeV
The production of Z bosons in pPb collisions at root S-NN = 5.02 TeV is studied by the CMS experiment via the electron and muon decay channels. The inclusive cross section is compared to pp collision predictions, and found to scale with the number of elementary nucleon-nucleon collisions. The differential cross sections as a function of the Z boson rapidity and transverse momentum are measured. Though they are found to be consistent within uncertainty with theoretical predictions both with and without nuclear effects, the forward-backward asymmetry suggests the presence of nuclear effects at large rapidities. These results provide new data for constraining nuclear parton distribution functions
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