Iron enhances hepatic fibrogenesis and activates TGF-β signaling in murine hepatic stellate cells

Introduction Although excess iron induces oxidative stress in the liver, it is unclear whether it directly activates the hepatic stellate cells (HSC). Methods We evaluated effects of excess iron on fibrogenesis and TGF-β signaling in murine HSC. Cells were treated with holotransferrin (0.005–5 g/L) for 24 h, with or without the iron chelator deferoxamine (10 µM). Gene expressions (α-SMA, Col1-α1, Serpine-1, TGF-β, Hif1-α, Tfrc and Slc40a1) were analyzed by qRT-PCR, while TfR1, ferroportin, ferritin, vimentin, collagen, TGF-β RII and phospho-Smad2 proteins were evaluated by immunofluorescence, western blot and ELISA. Results HSC express the iron-uptake protein TfR1, and the iron-export protein ferroportin. Holotransferrin up-regulated TfR1 expression by 1.8-fold (p<0.03) and ferritin accumulation (iron storage) by 2-fold (p<0.01), and activated HSC with 2-fold elevations (p<0.03) in α-SMA mRNA and collagen secretion, and a 1.6-fold increase (p<0.01) in vimentin protein. Moreover, holotransferrin activated the TGF-β pathway with TGF-β mRNA elevated 1.6-fold (p=0.05), and protein levels of TGF-β RII and phospho-Smad2 increased by 1.8-fold (p<0.01) and 1.6-fold (p<0.01), respectively. By contrast, iron chelation decreased ferritin levels by 30% (p<0.03), inhibited collagen secretion by 60% (p<0.01), repressed fibrogenic genes α-SMA (0.2-fold; p<0.05) and TGF-β (0.4-fold; p<0.01), and reduced levels of TGF-β RII and phospho-Smad2 proteins. Conclusion HSC express iron transport proteins. Holotransferrin (iron) activates HSC fibrogenesis and the TGF-β pathway, while iron depletion by chelation reverses this, suggesting that this could be a useful adjunct therapy for patients with fibrosis. Further studies in primary human HSC and animal models are necessary to confirm this

Haloperidol and Ziprasidone for Treatment of Delirium in Critical Illness

BACKGROUND: There are conflicting data on the effects of antipsychotic medications on delirium in patients in the intensive care unit (ICU). METHODS: In a randomized, double-blind, placebo-controlled trial, we assigned patients with acute respiratory failure or shock and hypoactive or hyperactive delirium to receive intravenous boluses of haloperidol (maximum dose, 20 mg daily), ziprasidone (maximum dose, 40 mg daily), or placebo. The volume and dose of a trial drug or placebo was halved or doubled at 12-hour intervals on the basis of the presence or absence of delirium, as detected with the use of the Confusion Assessment Method for the ICU, and of side effects of the intervention. The primary end point was the number of days alive without delirium or coma during the 14-day intervention period. Secondary end points included 30-day and 90-day survival, time to freedom from mechanical ventilation, and time to ICU and hospital discharge. Safety end points included extrapyramidal symptoms and excessive sedation. RESULTS: Written informed consent was obtained from 1183 patients or their authorized representatives. Delirium developed in 566 patients (48%), of whom 89% had hypoactive delirium and 11% had hyperactive delirium. Of the 566 patients, 184 were randomly assigned to receive placebo, 192 to receive haloperidol, and 190 to receive ziprasidone. The median duration of exposure to a trial drug or placebo was 4 days (interquartile range, 3 to 7). The median number of days alive without delirium or coma was 8.5 (95% confidence interval [CI], 5.6 to 9.9) in the placebo group, 7.9 (95% CI, 4.4 to 9.6) in the haloperidol group, and 8.7 (95% CI, 5.9 to 10.0) in the ziprasidone group (P=0.26 for overall effect across trial groups). The use of haloperidol or ziprasidone, as compared with placebo, had no significant effect on the primary end point (odds ratios, 0.88 [95% CI, 0.64 to 1.21] and 1.04 [95% CI, 0.73 to 1.48], respectively). There were no significant between-group differences with respect to the secondary end points or the frequency of extrapyramidal symptoms. CONCLUSIONS: The use of haloperidol or ziprasidone, as compared with placebo, in patients with acute respiratory failure or shock and hypoactive or hyperactive delirium in the ICU did not significantly alter the duration of delirium. (Funded by the National Institutes of Health and the VA Geriatric Research Education and Clinical Center; MIND-USA ClinicalTrials.gov number, NCT01211522 .)

Single coronary artery from the right sinus of Valsalva

We describe a case of a single coronary artery originating from the right coronary sinus and bifurcating into the left coronary artery (LCA) and right coronary artery (RCA) in a 74-year old woman, with a non-ST elevation acute myocardial infarction (NSTEMI). Diagnosis was made by coronary angiography which ruled out stenosis, and showed normal LCA and RCA branching. The connection path of LCA, with the opposite cusp, was defined retroaortic by multislice computed tomography (CT). The variants of this coronary anomaly, together with their clinical implications and pathophysiology of acute myocardial infarction (AMI) are discussed. Multislice CT is fundamental for clinical decision making

A gene regulatory network cooperatively controlled by Pdx1 and Sox9 governs lineage allocation of foregut progenitor cells

The generation of pancreas, liver, and intestine from a common pool of progenitors in the foregut endoderm requires the establishment of organ boundaries. How dorsal foregut progenitors activate pancreatic genes and evade the intestinal lineage choice remains unclear. Here, we identify Pdx1 and Sox9 as cooperative inducers of a gene regulatory network that distinguishes the pancreatic from the intestinal lineage. Genetic studies demonstrate dual and cooperative functions for Pdx1 and Sox9 in pancreatic lineage induction and repression of the intestinal lineage choice. Pdx1 and Sox9 bind to regulatory sequences near pancreatic and intestinal differentiation genes and jointly regulate their expression, revealing direct cooperative roles for Pdx1 and Sox9 in gene activation and repression. Our study identifies Pdx1 and Sox9 as important regulators of a transcription factor network that initiates pancreatic fate and sheds light on the gene regulatory circuitry that governs the development of distinct organs from multi-lineage-competent foregut progenitors

Plane-symmetric inhomogeneous magnetized viscous fluid universe with a variable Λ\Lambda

The behavior of magnetic field in plane symmetric inhomogeneous cosmological models for bulk viscous distribution is investigated. The coefficient of bulk viscosity is assumed to be a power function of mass density $(\xi =\xi_{0}\rho^{n})$. The values of cosmological constant for these models are found to be small and positive which are supported by the results from recent supernovae Ia observations. Some physical and geometric aspects of the models are also discussed.Comment: 18 pages, LaTex, no figur

Assessment of CardiOvascular Remodelling following Endovascular aortic repair through imaging and computation: the CORE prospective observational cohort study protocol

Thoracic aortic stent grafts are orders of magnitude stiffer than the native aorta. These devices have been associated with acute hypertension, elevated pulse pressure, cardiac remodelling and reduced coronary perfusion. However, a systematic assessment of such cardiovascular effects of thoracic endovascular aortic repair (TEVAR) is missing. The CardiOvascular Remodelling following Endovascular aortic repair (CORE) study aims to (1) quantify cardiovascular remodelling following TEVAR and compare echocardiography against MRI, the reference method; (2) validate computational modelling of cardiovascular haemodynamics following TEVAR using clinical measurements, and virtually assess the impact of more compliant stent grafts on cardiovascular haemodynamics; and (3) investigate diagnostic accuracy of ECG and serum biomarkers for cardiac remodelling compared to MRI

Quantum walks: a comprehensive review

Quantum walks, the quantum mechanical counterpart of classical random walks, is an advanced tool for building quantum algorithms that has been recently shown to constitute a universal model of quantum computation. Quantum walks is now a solid field of research of quantum computation full of exciting open problems for physicists, computer scientists, mathematicians and engineers. In this paper we review theoretical advances on the foundations of both discrete- and continuous-time quantum walks, together with the role that randomness plays in quantum walks, the connections between the mathematical models of coined discrete quantum walks and continuous quantum walks, the quantumness of quantum walks, a summary of papers published on discrete quantum walks and entanglement as well as a succinct review of experimental proposals and realizations of discrete-time quantum walks. Furthermore, we have reviewed several algorithms based on both discrete- and continuous-time quantum walks as well as a most important result: the computational universality of both continuous- and discrete- time quantum walks.Comment: Paper accepted for publication in Quantum Information Processing Journa

Measurement of νˉμ\bar{\nu}_{\mu} and νμ\nu_{\mu} charged current inclusive cross sections and their ratio with the T2K off-axis near detector

We report a measurement of cross section $\sigma(\nu_{\mu}+{\rm nucleus}\rightarrow\mu^{-}+X)$ and the first measurements of the cross section $\sigma(\bar{\nu}_{\mu}+{\rm nucleus}\rightarrow\mu^{+}+X)$ and their ratio $R(\frac{\sigma(\bar \nu)}{\sigma(\nu)})$ at (anti-)neutrino energies below 1.5 GeV. We determine the single momentum bin cross section measurements, averaged over the T2K $\bar{\nu}/\nu$-flux, for the detector target material (mainly Carbon, Oxygen, Hydrogen and Copper) with phase space restricted laboratory frame kinematics of $\theta_{\mu}$500 MeV/c. The results are $\sigma(\bar{\nu})=\left( 0.900\pm0.029{\rm (stat.)}\pm0.088{\rm (syst.)}\right)\times10^{-39}$ and $\sigma(\nu)=\left( 2.41\ \pm0.022{\rm{(stat.)}}\pm0.231{\rm (syst.)}\ \right)\times10^{-39}$in units of cm$^{2}$/nucleon and$R\left(\frac{\sigma(\bar{\nu})}{\sigma(\nu)}\right)= 0.373\pm0.012{\rm (stat.)}\pm0.015{\rm (syst.)}$.Comment: 18 pages, 8 figure

Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector

A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results