Liver progenitor cells (LPCs) represent the cell compartment facilitating hepatic regeneration during chronic injury while hepatocyte‐mediated repair mechanisms are compromised. LPC proliferation is ...frequently observed in human chronic liver diseases such as hereditary hemochromatosis, fatty liver disease, and chronic hepatitis. In vivo studies have suggested that a tumor necrosis factor family member, tumor necrosis factor–like weak inducer of apoptosis (TWEAK), is promitotic for LPCs; whether it acts directly is not known. In our murine choline‐deficient, ethionine‐supplemented (CDE) model of chronic liver injury, TWEAK receptor fibroblast growth factor‐inducible 14 (Fn14) expression in the whole liver is massively upregulated. We therefore set out to investigate whether TWEAK/Fn14 signaling promotes the regenerative response in CDE‐induced chronic liver injury by mitotic stimulation of LPCs. Fn14 knockout (KO) mice showed significantly reduced LPC numbers and attenuated inflammation and cytokine production after 2 weeks of CDE feeding. The close association between LPC proliferation and activation of hepatic stellate cells in chronic liver injury prompted us to investigate whether fibrogenesis was also modulated in Fn14 KO animals. Collagen deposition and expression of key fibrogenesis mediators were reduced after 2 weeks of injury, and this correlated with LPC numbers. Furthermore, the injection of 2‐week‐CDE‐treated wildtype animals with TWEAK led to increased proliferation of nonparenchymal pan cytokeratin–positive cells. Stimulation of an Fn14‐positive LPC line with TWEAK led to nuclear factor kappa light chain enhancer of activated B cells (NFκB) activation and dose‐dependent proliferation, which was diminished after targeting of the p50 NFκB subunit by RNA interference. Conclusion: TWEAK acts directly and stimulates LPC mitosis in an Fn14‐dependent and NFκB‐dependent fashion, and signaling via this pathway mediates the LPC response to CDE‐induced injury and regeneration. (HEPATOLOGY 2010)
The Integrated Science Investigation of the Sun (ISIS) is a complete science investigation on the Solar Probe Plus (SPP) mission, which flies to within nine solar radii of the Sun’s surface. ISIS ...comprises a two-instrument suite to measure energetic particles over a very broad energy range, as well as coordinated management, science operations, data processing, and scientific analysis. Together, ISIS observations allow us to explore the mechanisms of energetic particles dynamics, including their: (1) Origins—defining the seed populations and physical conditions necessary for energetic particle acceleration; (2) Acceleration—determining the roles of shocks, reconnection, waves, and turbulence in accelerating energetic particles; and (3) Transport—revealing how energetic particles propagate from the corona out into the heliosphere. The two ISIS Energetic Particle Instruments measure lower (EPI-Lo) and higher (EPI-Hi) energy particles. EPI-Lo measures ions and ion composition from ∼20 keV/nucleon–15 MeV total energy and electrons from ∼25–1000 keV. EPI-Hi measures ions from ∼1–200 MeV/nucleon and electrons from ∼0.5–6 MeV. EPI-Lo comprises 80 tiny apertures with fields-of-view (FOVs) that sample over nearly a complete hemisphere, while EPI-Hi combines three telescopes that together provide five large-FOV apertures. ISIS observes continuously inside of 0.25 AU with a high data collection rate and burst data (EPI-Lo) coordinated with the rest of the SPP payload; outside of 0.25 AU, ISIS runs in low-rate science mode whenever feasible to capture as complete a record as possible of the solar energetic particle environment and provide calibration and continuity for measurements closer in to the Sun. The ISIS Science Operations Center plans and executes commanding, receives and analyzes all ISIS data, and coordinates science observations and analyses with the rest of the SPP science investigations. Together, ISIS’ unique observations on SPP will enable the discovery, untangling, and understanding of the important physical processes that govern energetic particles in the innermost regions of our heliosphere, for the first time. This paper summarizes the ISIS investigation at the time of the SPP mission Preliminary Design Review in January 2014.
Here we report multiple lines of evidence for a comprehensive model of energy metabolism in the vertebrate eye. Metabolic flux, locations of key enzymes, and our finding that glucose enters mouse and ...zebrafish retinas mostly through photoreceptors support a conceptually new model for retinal metabolism. In this model, glucose from the choroidal blood passes through the retinal pigment epithelium to the retina where photoreceptors convert it to lactate. Photoreceptors then export the lactate as fuel for the retinal pigment epithelium and for neighboring Müller glial cells. We used human retinal epithelial cells to show that lactate can suppress consumption of glucose by the retinal pigment epithelium. Suppression of glucose consumption in the retinal pigment epithelium can increase the amount of glucose that reaches the retina. This framework for understanding metabolic relationships in the vertebrate retina provides new insights into the underlying causes of retinal disease and age-related vision loss.
We made new estimates of the Galactic escape speed at various Galactocentric radii using the latest data release of the RAdial Velocity Experiment (RAVE DR4). Compared to previous studies we have a ...database that is larger by a factor of 10, as well as reliable distance estimates for almost all stars. Our analysis is based on statistical analysis of a rigorously selected sample of 90 high-velocity halo stars from RAVE and a previously published data set. We calibrated and extensively tested our method using a suite of cosmological simulations of the formation of Milky Way-sized galaxies. Our best estimate of the local Galactic escape speed, which we define as the minimum speed required to reach three virial radii R340, is 533+54-41 km s-1 (90% confidence), with an additional 4% systematic uncertainty, where R340 is the Galactocentric radius encompassing a mean overdensity of 340 times the critical density for closure in the Universe. From the escape speed we further derived estimates of the mass of the Galaxy using a simple mass model with two options for the mass profile of the dark matter halo: an unaltered and an adiabatically contracted Navarro, Frenk & White (NFW) sphere. If we fix the local circular velocity, the latter profile yields a significantly higher mass than the uncontracted halo, but if we instead use the statistics for halo concentration parameters in large cosmological simulations as a constraint, we find very similar masses for both models. Our best estimate for M340, the mass interiorto R340 (dark matter and baryons), is 1.3+0.4-0.3 × 1012 M⊙ (corresponds to M200 = 1.6+0.5-0.4 × 1012 M⊙). This estimate is in good agreement with recently published, independent mass estimates based on the kinematics of more distant halo stars and the satellite galaxy Leo I.
Abstract
Difficulties with tracheal intubation commonly arise and impact patient safety. This systematic review evaluates whether videolaryngoscopes reduce intubation failure and complications ...compared with direct laryngoscopy in adults. We searched CENTRAL, MEDLINE, Embase and clinicaltrials.gov up to February 2015, and conducted forward and backward citation tracking. We included randomized controlled trials that compared adult patients undergoing laryngoscopy with videolaryngoscopy or Macintosh laryngoscopy. We did not primarily intend to compare individual videolaryngoscopes. Sixty-four studies (7044 participants) were included. Moderate quality evidence showed that videolaryngoscopy reduced failed intubations (Odds Ratio (OR) 0.35, 95% Confidence Interval (CI) 0.19-0.65) including in participants with anticipated difficult airways (OR 0.28, 95% CI 0.15-0.55). There was no evidence of reduction in hypoxia or mortality, but few studies reported these outcomes. Videolaryngoscopes reduced laryngeal/airway trauma (OR 0.68, 95% CI 0.48-0.96) and hoarseness (OR 0.57, 95% CI 0.36-0.88). Videolaryngoscopy increased easy laryngeal views (OR 6.77, 95% CI 4.17-10.98) and reduced difficult views (OR 0.18, 95% CI 0.13-0.27) and intubation difficulty, typically using an 'intubation difficulty score' (OR 7.13, 95% CI 3.12-16.31). Failed intubations were reduced with experienced operators (OR 0.32, 95% CI 0.13-0.75) but not with inexperienced users. We identified no difference in number of first attempts and incidence of sore throat. Heterogeneity around time for intubation data prevented meta-analysis. We found evidence of differential performance between different videolaryngoscope designs. Lack of data prevented analysis of impact of obesity or clinical location on failed intubation rates. Videolaryngoscopes may reduce the number of failed intubations, particularly among patients presenting with a difficult airway. They improve the glottic view and may reduce laryngeal/airway trauma. Currently, no evidence indicates that use of a videolaryngoscope reduces the number of intubation attempts or the incidence of hypoxia or respiratory complications, and no evidence indicates that use of a videolaryngoscope affects time required for intubation.
Metabolic stress due to nutrient excess and lipid accumulation is at the root of many age-associated disorders and the identification of therapeutic targets that mimic the beneficial effects of ...calorie restriction has clinical importance. Here, using C. elegans as a model organism, we study the roles of a recently discovered enzyme at the heart of metabolism in mammalian cells, glycerol-3-phosphate phosphatase (G3PP) (gene name Pgp) that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol. We identify three Pgp homologues in C. elegans (pgph) and demonstrate in vivo that their protein products have G3PP activity, essential for glycerol synthesis. We demonstrate that PGPH/G3PP regulates the adaptation to various stresses, in particular hyperosmolarity and glucotoxicity. Enhanced G3PP activity reduces fat accumulation, promotes healthy aging and acts as a calorie restriction mimetic at normal food intake without altering fertility. Thus, PGP/G3PP can be considered as a target for age-related metabolic disorders.
Neoadjuvant therapy is increasingly the standard of care in the management of locally advanced adenocarcinoma of the oesophagus and junction (AEG). In randomised controlled trials (RCTs), the MAGIC ...regimen of pre- and postoperative chemotherapy, and the CROSS regimen of preoperative chemotherapy combined with radiation, were superior to surgery only in RCTs that included AEG but were not powered on this cohort. No completed RCT has directly compared neoadjuvant or perioperative chemotherapy and neoadjuvant chemoradiation. The Neo-AEGIS trial, uniquely powered on AEG, and including comprehensive modern staging, compares both these regimens.
This open label, multicentre, phase III RCT randomises patients (cT2-3, N0-3, M0) in a 1:1 fashion to receive CROSS protocol (Carboplatin and Paclitaxel with concurrent radiotherapy, 41.4Gy/23Fr, over 5 weeks). The power calculation is a 10% difference in favour of CROSS, powered at 80%, two-sided alpha level of 0.05, requiring 540 patients to be evaluable, 594 to be recruited if a 10% dropout is included (297 in each group). The primary endpoint is overall survival, with a minimum 3-year follow up. Secondary endpoints include: disease free survival, recurrence rates, clinical and pathological response rates, toxicities of induction regimens, post-operative pathology and tumour regression grade, operative in-hospital complications, and health-related quality of life. The trial also affords opportunities for establishing a bio-resource of pre-treatment and resected tumour, and translational research.
This RCT directly compares two established treatment regimens, and addresses whether radiation therapy positively impacts on overall survival compared with a standard perioperative chemotherapy regimen Sponsor: Irish Clinical Research Group (ICORG).
NCT01726452 . Protocol 10-14. Date of registration 06/11/2012.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background
Enhanced recovery programmes (ERPs) have been developed over the past 10 years to improve patient outcomes and to accelerate recovery after surgery. The existing literature focuses on ...specific specialties, mainly colorectal surgery. The aim of this review was to investigate whether the effect of ERPs on patient outcomes varies across surgical specialties or with the design of individual programmes.
Methods
MEDLINE, Embase, CINAHL and the Cochrane Central Register of Controlled Trials were searched from inception to January 2013 for randomized or quasi‐randomized trials comparing ERPs with standard care in adult elective surgical patients.
Results
Thirty‐eight trials were included in the review, with a total of 5099 participants. Study design and quality was poor. Meta‐analyses showed that ERPs reduced the primary length of stay (standardized mean difference −1·14 (95 per cent confidence interval −1·45 to −0·85)) and reduced the risk of all complications within 30 days (risk ratio (RR) 0·71, 95 per cent c.i. 0·60 to 0·86). There was no evidence of a reduction in mortality (RR 0·69, 95 per cent c.i. 0·34 to 1·39), major complications (RR 0·95, 0·69 to 1·31) or readmission rates (RR 0·96, 0·59 to 1·58). The impact of ERPs was similar across specialties and there was no consistent evidence that elements included within ERPs affected patient outcomes.
Conclusion
ERPs are effective in reducing length of hospital stay and overall complication rates across surgical specialties. It was not possible to identify individual components that improved outcome. Qualitative synthesis may be more appropriate to investigate the determinants of success.
Effective components of ERPs not identifiable
The initial multiplicity of stellar systems is highly uncertain. A number of mechanisms have been proposed to explain the origin of binary and multiple star systems, including core fragmentation, ...disk fragmentation and stellar capture. Observations show that protostellar and pre-main-sequence multiplicity is higher than the multiplicity found in field stars, which suggests that dynamical interactions occur early, splitting up multiple systems and modifying the initial stellar separations. Without direct, high-resolution observations of forming systems, however, it is difficult to determine the true initial multiplicity and the dominant binary formation mechanism. Here we report observations of a wide-separation (greater than 1,000 astronomical units) quadruple system composed of a young protostar and three gravitationally bound dense gas condensations. These condensations are the result of fragmentation of dense gas filaments, and each condensation is expected to form a star on a timescale of 40,000 years. We determine that the closest pair will form a bound binary, while the quadruple stellar system itself is bound but unstable on timescales of 500,000 years (comparable to the lifetime of the embedded protostellar phase). These observations suggest that filament fragmentation on length scales of about 5,000 astronomical units offers a viable pathway to the formation of multiple systems.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Obesity is a major risk factor underlying the development of metabolic disease and a growing public health concern globally. Strategies to promote skeletal muscle metabolism can be effective to limit ...the progression of metabolic disease. Here, we demonstrate that the levels of the Hippo pathway transcriptional co-activator YAP are decreased in muscle biopsies from obese, insulin-resistant humans and mice. Targeted disruption of Yap in adult skeletal muscle resulted in incomplete oxidation of fatty acids and lipotoxicity. Integrated 'omics analysis from isolated adult muscle nuclei revealed that Yap regulates a transcriptional profile associated with metabolic substrate utilisation. In line with these findings, increasing Yap abundance in the striated muscle of obese (db/db) mice enhanced energy expenditure and attenuated adiposity. Our results demonstrate a vital role for Yap as a mediator of skeletal muscle metabolism. Strategies to enhance Yap activity in skeletal muscle warrant consideration as part of comprehensive approaches to treat metabolic disease.
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