Imaging muscle as a potential biomarker of denervation in motor neuron disease

Objective To assess clinical, electrophysiological and whole-body muscle MRI measurements of progression in patients with motor neuron disease (MND), as tools for future clinical trials, and to probe pathophysiological mechanisms in vivo. Methods A prospective longitudinal observational clinico-electrophysiological and radiological cohort study was performed. Twenty-nine MND patients and 22 age and gender-matched healthy controls were assessed with clinical measures, electrophysiological motor unit number index (MUNIX) and T2-weighted whole-body muscle MRI, at first clinic presentation and four months later. Between-group differences and associations were assessed using age and gender-adjusted multivariable regression models. Within-subject longitudinal changes were assessed using paired t-tests. Patterns of disease spread were modelled using mixed-effects multivariable regression, assessing associations between muscle relative T2 signal and anatomical adjacency to site of clinical onset. Results MND patients had 30% higher relative T2 muscle signal than controls at baseline (all-regions mean, 95%CI 15%, 45%, p<0.001). Higher T2 signal was associated with greater overall disability (coefficient -0.009, 95%CI -0.017, -0.001, p=0.023), and with clinical weakness and lower MUNIX in multiple individual muscles. Relative T2 signal in bilateral tibialis anterior increased over four months in MND patients (right: 10.2%, 95%CI 2.0%, 18.4%, p=0.017; left: 14.1%, 95%CI 3.4%, 24.9%, p=0.013). Anatomically contiguous disease spread on MRI was not apparent in this model. Conclusions Whole-body muscle MRI offers a new approach to objective assessment of denervation over short timescales in MND, and enables investigation of patterns of disease spread in vivo. Muscles inaccessible to conventional clinical and electrophysiological assessment may be investigated using this methodology

Thirty Years After Michael E. Porter: What Do We Know About Business Exit?

Although a business exit is an important corporate change initiative, the buyer’s side seems to be more appealing to management researchers than the seller’s because acquisitions imply growth, i.e., success. Yet from an optimistic viewpoint, business exit can effectively create value for the selling company. In this paper we attempt to bring the relevance of the seller’s side back into our consciousness by asking: What do we know about business exit? We start our exploration with Porter (1976), focusing on literature that investigates the antecedents of, barriers to, and outcomes of business exit. We also include studies from related fields such as finance and economics.1 Through this research we determine three clusters of findings: factors promoting business exit, exit barriers, and exit outcomes. Overall, it is the intention of this paper to highlight the importance of business exit for research and practice. Knowing what we know about business exits and their high financial value we should bear in mind that exit need not mean failure but a new beginning for a corporation

Imaging denervation in motor neuron disease for future clinical trials: a longitudinal cohort study

A key area-of-need in motor neuron disease/amyotrophic lateral sclerosis (MND/ALS) translational research is a tool to objectively track disease progression over short timescales, to reduce duration and cost of clinical trials. Previous studies have focused on the central nervous system

Space Telescope and Optical Reverberation Mapping Project. VII. Understanding the Ultraviolet Anomaly in NGC 5548 with X-Ray Spectroscopy

During the Space Telescope and Optical Reverberation Mapping Project observations of NGC 5548, the continuum and emission-line variability became decorrelated during the second half of the six-month-long observing campaign. Here we present Swift and Chandra X-ray spectra of NGC 5548 obtained as part of the campaign. The Swift spectra show that excess flux (relative to a power-law continuum) in the soft X-ray band appears before the start of the anomalous emission-line behavior, peaks during the period of the anomaly, and then declines. This is a model-independent result suggesting that the soft excess is related to the anomaly. We divide the Swift data into on- and off-anomaly spectra to characterize the soft excess via spectral fitting. The cause of the spectral differences is likely due to a change in the intrinsic spectrum rather than to variable obscuration or partial covering. The Chandra spectra have lower signal-to-noise ratios, but are consistent with the Swift data. Our preferred model of the soft excess is emission from an optically thick, warm Comptonizing corona, the effective optical depth of which increases during the anomaly. This model simultaneously explains all three observations: the UV emission-line flux decrease, the soft-excess increase, and the emission-line anomaly

Space Telescope and Optical Reverberation Mapping Project. XII. Broad-line Region Modeling of NGC 5548

We present geometric and dynamical modeling of the broad line region (BLR) for the multi-wavelength reverberation mapping campaign focused on NGC 5548 in 2014. The data set includes photometric and spectroscopic monitoring in the optical and ultraviolet, covering the Hβ, C iv, and Ly broad emission lines. We find an extended disk-like Hβ BLR with a mixture of near-circular and outflowing gas trajectories, while the C iv and Ly BLRs are much less extended and resemble shell-like structures. There is clear radial structure in the BLR, with C iv and Ly emission arising at smaller radii than the Hβ emission. Using the three lines, we make three independent black hole mass measurements, all of which are consistent. Combining these results gives a joint inference of . We examine the effect of using the V band instead of the UV continuum light curve on the results and find a size difference that is consistent with the measured UV-optical time lag, but the other structural and kinematic parameters remain unchanged, suggesting that the V band is a suitable proxy for the ionizing continuum when exploring the BLR structure and kinematics. Finally, we compare the Hβ results to similar models of data obtained in 2008 when the active galactic nucleus was at a lower luminosity state. We find that the size of the emitting region increased during this time period, but the geometry and black hole mass remained unchanged, which confirms that the BLR kinematics suitably gauge the gravitational field of the central black hole

The evolution of cellular deficiency in GATA2 mutation.

To access publisher's full text version of this article click on the hyperlink at the bottom of the pageConstitutive heterozygous GATA2 mutation is associated with deafness, lymphedema, mononuclear cytopenias, infection, myelodysplasia (MDS), and acute myeloid leukemia. In this study, we describe a cross-sectional analysis of 24 patients and 6 relatives with 14 different frameshift or substitution mutations of GATA2. A pattern of dendritic cell, monocyte, B, and natural killer (NK) lymphoid deficiency (DCML deficiency) with elevated Fms-like tyrosine kinase 3 ligand (Flt3L) was observed in all 20 patients phenotyped, including patients with Emberger syndrome, monocytopenia with Mycobacterium avium complex (MonoMAC), and MDS. Four unaffected relatives had a normal phenotype indicating that cellular deficiency may evolve over time or is incompletely penetrant, while 2 developed subclinical cytopenias or elevated Flt3L. Patients with GATA2 mutation maintained higher hemoglobin, neutrophils, and platelets and were younger than controls with acquired MDS and wild-type GATA2. Frameshift mutations were associated with earlier age of clinical presentation than substitution mutations. Elevated Flt3L, loss of bone marrow progenitors, and clonal myelopoiesis were early signs of disease evolution. Clinical progression was associated with increasingly elevated Flt3L, depletion of transitional B cells, CD56(bright) NK cells, naïve T cells, and accumulation of terminally differentiated NK and CD8(+) memory T cells. These studies provide a framework for clinical and laboratory monitoring of patients with GATA2 mutation and may inform therapeutic decision-making.Lymphoma and Leukaemia Research British Society of Hematology Bright Red George Walker Trust Wellcome Trus

Space Telescope and Optical Reverberation Mapping Project. V. Optical Spectroscopic Campaign and Emission-line Analysis for NGC 5548

We present the results of an optical spectroscopic monitoring program targeting NGC 5548 as part of a larger multiwavelength reverberation mapping campaign. The campaign spanned 6 months and achieved an almost daily cadence with observations from five ground-based telescopes. The Hβ and He ii λ4686 broad emission-line light curves lag that of the 5100 +-optical continuum by 4.17+0.36-0.36 and 0.79+0.35-0.34 days, respectively. The Hβ lag relative to the 1158 ultraviolet continuum light curve measured by the Hubble Space Telescope is ∼50% longer than that measured against the optical continuum, and the lag difference is consistent with the observed lag between the optical and ultraviolet continua. This suggests that the characteristic radius of the broad-line region is ∼50% larger than the value inferred from optical data alone. We also measured velocity-resolved emission-line lags for Hβ and found a complex velocity-lag structure with shorter lags in the line wings, indicative of a broad-line region dominated by Keplerian motion. The responses of both the Hβ and He ii emission lines to the driving continuum changed significantly halfway through the campaign, a phenomenon also observed for C iv, Lyα, He ii(+O iii]), and Si iv(+O iv]) during the same monitoring period. Finally, given the optical luminosity of NGC 5548 during our campaign, the measured Hβ lag is a factor of five shorter than the expected value implied by the R BLR-L AGN relation based on the past behavior of NGC 5548

The Microphenotron: a robotic miniaturized plant phenotyping platform with diverse applications in chemical biology

Background Chemical genetics provides a powerful alternative to conventional genetics for understanding gene function. However, its application to plants has been limited by the lack of a technology that allows detailed phenotyping of whole-seedling development in the context of a high-throughput chemical screen. We have therefore sought to develop an automated micro-phenotyping platform that would allow both root and shoot development to be monitored under conditions where the phenotypic effects of large numbers of small molecules can be assessed. Results The ‘Microphenotron’ platform uses 96-well microtitre plates to deliver chemical treatments to seedlings of Arabidopsis thaliana L. and is based around four components: (a) the ‘Phytostrip’, a novel seedling growth device that enables chemical treatments to be combined with the automated capture of images of developing roots and shoots; (b) an illuminated robotic platform that uses a commercially available robotic manipulator to capture images of developing shoots and roots; (c) software to control the sequence of robotic movements and integrate these with the image capture process; (d) purpose-made image analysis software for automated extraction of quantitative phenotypic data. Imaging of each plate (representing 80 separate assays) takes 4 min and can easily be performed daily for time-course studies. As currently configured, the Microphenotron has a capacity of 54 microtitre plates in a growth room footprint of 2.1 m², giving a potential throughput of up to 4320 chemical treatments in a typical 10 days experiment. The Microphenotron has been validated by using it to screen a collection of 800 natural compounds for qualitative effects on root development and to perform a quantitative analysis of the effects of a range of concentrations of nitrate and ammonium on seedling development. Conclusions The Microphenotron is an automated screening platform that for the first time is able to combine large numbers of individual chemical treatments with a detailed analysis of whole-seedling development, and particularly root system development. The Microphenotron should provide a powerful new tool for chemical genetics and for wider chemical biology applications, including the development of natural and synthetic chemical products for improved agricultural sustainability

Sodium-Dependent Vitamin C Transporter 2 (SVCT2) Expression and Activity in Brain Capillary Endothelial Cells after Transient Ischemia in Mice

Expression and transport activity of Sodium-dependent Vitamin C Transporter 2 (SVCT2) was shown in various tissues and organs. Vitamin C was shown to be cerebroprotective in several animal models of stroke. Data on expression, localization and transport activity of SVCT2 after cerebral ischemia, however, has been scarce so far. Thus, we studied the expression of SVCT2 after middle cerebral artery occlusion (MCAO) in mice by immunohistochemistry. We found an upregulation of SVCT2 after stroke. Co-stainings with Occludin, Von-Willebrand Factor and CD34 demonstrated localization of SVCT2 in brain capillary endothelial cells in the ischemic area after stroke. Time-course analyses of SVCT2 expression by immunohistochemistry and western blots showed upregulation in the subacute phase of 2–5 days. Radioactive uptake assays using 14C-labelled ascorbic acid showed a significant increase of ascorbic acid uptake into the brain after stroke. Taken together, these results provide evidence for the expression and transport activity of SVCT2 in brain capillary endothelial cells after transient ischemia in mice. These results may lead to the development of novel neuroprotective strategies in stroke therapy