Prolonged cholinergic enrichment influences regional cortical activation in early Alzheimer's disease

Neuroimaging studies of cholinesterase inhibitor (ChEI) treatment in Alzheimer's disease (AD) indicate that the short and long term actions of ChEIs are dissimilar. fMRI studies of the ChEI rivastigmine have focused on its short term action. In this exploratory study the effect of prolonged (20 weeks) rivastigmine treatment on regional brain activity was measured with fMRI in patients with mild AD. Eleven patients with probable AD and nine age-matched controls were assessed with a Pyramids and Palm Trees semantic association and an n-back working memory fMRI paradigm. In the patient group only, the assessment was repeated after 20 weeks of treatment. There was an increase in task-related brain activity after treatment with activations more like those of normal healthy elderly. Behaviorally, however, there were no significant differences between baseline and retest scores, with a range of performance probably reflecting variation in drug efficacy across patients. Variable patient response and drug dynamic/kinetic factors in small patient groups will inevitably bias (either way) the effect size of any relevant drug related changes in activation. Future studies should take drug response into account to provide more insight into the benefits of ChEI drugs at the individual level

Ethical Issues in Big Data Analytics: A Stakeholder Perspective

Big data analytics is a fast-evolving phenomenon shaped by interactions among individuals, organizations, and society. However, its ethical implications for these stakeholders remain empirically underexplored and not well understood. We present empirical findings from a Delphi study that identified, defined, and examined the key concepts that underlie ethical issues in big data analytics. We then analyze those concepts using stakeholder theory and discourse ethics and suggest ways to balance interactions between individuals, organizations, and society in order to promote the ethical use of big data analytics. Our findings inform practitioners and policymakers concerned with ethically using big data analytics and provide a basis for future research

LIM kinase inhibitors disrupt mitotic microtubule organization and impair tumor cell proliferation

The actin and microtubule cytoskeletons are critically important for cancer cell proliferation, and drugs that target microtubules are widely-used cancer therapies. However, their utility is compromised by toxicities due to dose and exposure. To overcome these issues, we characterized how inhibition of the actin and microtubule cytoskeleton regulatory LIM kinases could be used in drug combinations to increase efficacy. A previously-described LIMK inhibitor (LIMKi) induced dose-dependent microtubule alterations that resulted in significant mitotic defects, and increased the cytotoxic potency of microtubule polymerization inhibitors. By combining LIMKi with 366 compounds from the GSK Published Kinase Inhibitor Set, effective combinations were identified with kinase inhibitors including EGFR, p38 and Raf. These findings encouraged a drug discovery effort that led to development of CRT0105446 and CRT0105950, which potently block LIMK1 and LIMK2 activity in vitro, and inhibit cofilin phosphorylation and increase αTubulin acetylation in cells. CRT0105446 and CRT0105950 were screened against 656 cancer cell lines, and rhabdomyosarcoma, neuroblastoma and kidney cancer cells were identified as significantly sensitive to both LIMK inhibitors. These large-scale screens have identified effective LIMK inhibitor drug combinations and sensitive cancer types. In addition, the LIMK inhibitory compounds CRT0105446 and CRT0105950 will enable further development of LIMK-targeted cancer therapy

Metal-enriched, subkiloparsec gas clumps in the circumgalactic medium of a faint z = 2.5 galaxy

We report the serendipitous detection of a 0.2 L*, Lyα emitting galaxy at redshift 2.5 at an impact parameter of 50 kpc from a bright background QSO sightline. A high-resolution spectrum of the QSO reveals a partial Lyman-limit absorption system (N[subscript Hi] = 10[superscript 16.94±0.10] cm[superscript −2]) with many associated metal absorption lines at the same redshift as the foreground galaxy. Using photoionization models that carefully treat measurement errors and marginalize over uncertainties in the shape and normalization of the ionizing radiation spectrum, we derive the total hydrogen column density N[subscript H] = 10[superscript 19.4±0.3] cm[superscript −2], and show that all the absorbing clouds are metal enriched, with Z = 0.1–0.6 Z[subscript ⊙]. These metallicities and the system's large velocity width (436 km s[superscript −1]) suggest the gas is produced by an outflowing wind. Using an expanding shell model we estimate a mass outflow rate of ~5 M[subscript ⊙] yr[superscript −1]. Our photoionization model yields extremely small sizes (<100–500 pc) for the absorbing clouds, which we argue is typical of high column density absorbers in the circumgalactic medium (CGM). Given these small sizes and extreme kinematics, it is unclear how the clumps survive in the CGM without being destroyed by hydrodynamic instabilities. The small cloud sizes imply that even state-of-the-art cosmological simulations require more than a 1000-fold improvement in mass resolution to resolve the hydrodynamics relevant for cool gas in the CGM

Binary Quasars in the Sloan Digital Sky Survey: Evidence for Excess Clustering on Small Scales

We present a sample of 218 new quasar pairs with proper transverse separations R_prop < 1 Mpc/h over the redshift range 0.5 < z < 3.0, discovered from an extensive follow up campaign to find companions around the Sloan Digital Sky Survey and 2dF Quasar Redshift Survey quasars. This sample includes 26 new binary quasars with separations R_prop < 50 kpc/h (theta < 10 arcseconds), more than doubling the number of such systems known. We define a statistical sample of binaries selected with homogeneous criteria and compute its selection function, taking into account sources of incompleteness. The first measurement of the quasar correlation function on scales 10 kpc/h < R_prop < 400 kpc/h is presented. For R_prop < 40 kpc/h, we detect an order of magnitude excess clustering over the expectation from the large scale R_prop > 3 Mpc/h quasar correlation function, extrapolated down as a power law to the separations probed by our binaries. The excess grows to ~ 30 at R_prop ~ 10 kpc/h, and provides compelling evidence that the quasar autocorrelation function gets progressively steeper on sub-Mpc scales. This small scale excess can likely be attributed to dissipative interaction events which trigger quasar activity in rich environments. Recent small scale measurements of galaxy clustering and quasar-galaxy clustering are reviewed and discussed in relation to our measurement of small scale quasar clustering.Comment: 25 pages, 12 figures, 9 tables. Submitted to the Astronomical Journa

An observational study of end-tidal carbon dioxide trends in general anesthesia

PURPOSE: Despite growing evidence supporting the potential benefits of higher end-tidal carbon dioxide (ETCO METHODS: This retrospective, observational, multicentre study included 317,445 adult patients who received general anesthesia for non-cardiothoracic procedures between January 2008 and September 2016. The primary outcome was a time-weighted average area-under-the-curve (TWA-AUC) for four ETCO RESULTS: Both TWA-AUC and median ETCO CONCLUSIONS: Between 2008 and 2016, intraoperative ETC

Inflation and squeezed quantum states

The inflationary cosmology is analyzed from the point of view of squeezed quantum states. As noted by Grishchuk and Sidorov, the amplification of quantum fluctuations into macroscopic perturbations which occurs during cosmic inflation is a process of quantum squeezing. We carefully develop the squeezed state formalism and derive the equations that govern the evolution of a gaussian initial state. We derive the power spectrum of density perturbations for a simple inflationary model and discuss its features. We conclude that the squeezed state formalism provides an interesting framework within which to study the amplification process, but,in disagreement with the claims of Grishchuk and Sidorov, that it does {\em not} provide us with any new physical results.Comment: 33 pages, one section added, significant revisions, 6 figures (in uuencoded file), Imperial/TP/92-93/2

Eliminating Malaria Vectors.

Malaria vectors which predominantly feed indoors upon humans have been locally eliminated from several settings with insecticide treated nets (ITNs), indoor residual spraying or larval source management. Recent dramatic declines of An. gambiae in east Africa with imperfect ITN coverage suggest mosquito populations can rapidly collapse when forced below realistically achievable, non-zero thresholds of density and supporting resource availability. Here we explain why insecticide-based mosquito elimination strategies are feasible, desirable and can be extended to a wider variety of species by expanding the vector control arsenal to cover a broader spectrum of the resources they need to survive. The greatest advantage of eliminating mosquitoes, rather than merely controlling them, is that this precludes local selection for behavioural or physiological resistance traits. The greatest challenges are therefore to achieve high biological coverage of targeted resources rapidly enough to prevent local emergence of resistance and to then continually exclude, monitor for and respond to re-invasion from external populations

An Eye to a Kill: Using Predatory Bacteria to Control Gram-Negative Pathogens Associated with Ocular Infections

Ocular infections are a leading cause of vision loss. It has been previously suggested that predatory prokaryotes might be used as live antibiotics to control infections. In this study, Pseudomonas aeruginosa and Serratia marcescens ocular isolates were exposed to the predatory bacteria Micavibrio aeruginosavorus and Bdellovibrio bacteriovorus. All tested S. marcescens isolates were susceptible to predation by B. bacteriovorus strains 109J and HD100. Seven of the 10 P. aeruginosa isolates were susceptible to predation by B. bacteriovorus 109J with 80% being attacked by M. aeruginosavorus. All of the 19 tested isolates were found to be sensitive to at least one predator. To further investigate the effect of the predators on eukaryotic cells, human corneal-limbal epithelial (HCLE) cells were exposed to high concentrations of the predators. Cytotoxicity assays demonstrated that predatory bacteria do not damage ocular surface cells in vitro whereas the P. aeruginosa used as a positive control was highly toxic. Furthermore, no increase in the production of the proinflammatory cytokines IL-8 and TNF-alpha was measured in HCLE cells after exposure to the predators. Finally, injection of high concentration of predatory bacteria into the hemocoel of Galleria mellonella, an established model system used to study microbial pathogenesis, did not result in any measurable negative effect to the host. Our results suggest that predatory bacteria could be considered in the near future as a safe topical bio-control agent to treat ocular infections. © 2013 Shanks et al