Chronic kidney disease (CKD) and NAFLD: Time for awareness and screening

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Are the physicochemical properties of antibacterial compounds really different from other drugs?

Background: It is now widely recognized that there is an urgent need for new antibacterial drugs, with novel mechanisms of action, to combat the rise of multi-drug resistant bacteria. However, few new compounds are reaching the market. Antibacterial drug discovery projects often succeed in identifying potent molecules in biochemical assays but have been beset by difficulties in obtaining antibacterial activity. A commonly held view, based on analysis of marketed antibacterial compounds, is that antibacterial drugs possess very different physicochemical properties to other drugs, and that this profile is required for antibacterial activity. Results: We have re-examined this issue by performing a cheminformatics analysis of the literature data available in the ChEMBL database. The physicochemical properties of compounds with a recorded activity in an antibacterial assay were calculated and compared to two other datasets extracted from ChEMBL, marketed antibacterials and drugs marketed for other therapeutic indications. The chemical class of the compounds and Gram-negative/Grampositive profile were also investigated. This analysis shows that compounds with antibacterial activity have physicochemical property profiles very similar to other drug classes. Conclusions: The observation that many current antibacterial drugs lie in regions of physicochemical property space far from conventional small molecule therapeutics is correct. However, the inference that a compound must lie in one of these “outlier” regions in order to possess antibacterial activity is not supported by our analysis

Results of Monitoring the Dramatically Variable C IV Mini-BAL System in the Quasar HS 1603+3820

We present six new and two previously published high-resolution spectra of the quasar HS 1603+3820 (z_em = 2.542) taken over an interval of 4.2 years (1.2 years in the quasar rest frame). The observations were made with the High-Dispersion Spectrograph on the Subaru telescope and Medium-Resolution Spectrograph on the Hobby-Eberly Telescope. The purpose was to study the narrow absorption lines (NALs). We use time variability as well as coverage fraction analysis to separate intrinsic absorption lines, which are physically related to the quasar, from intervening absorption lines. By fitting models to the line profiles, we derive the parameters of the respective absorbers as a function of time. Only the mini-BAL system at z_abs ~ 2.43 (v_off ~ 9,500 km/s) shows both partial coverage and time variability, although two NAL systems possibly show evidence of partial coverage. We find that all the troughs of the mini-BAL system vary in concert and its total equivalent width variations resemble those of the coverage fraction. However, no other correlations are seen between the variations of different model parameters. Thus, the observed variations cannot be reproduced by a simple change of ionization state nor by motion of a homogeneous parcel of gas across the cylinder of sight. We propose that the observed variations are a result of rapid continuum fluctuations, coupled with coverage fraction fluctuations caused by a clumpy screen of variable optical depth located between the continuum source and the mini-BAL gas. An alternative explanation is that the observed partial coverage signature is the result of scattering of continuum photons around the absorber, thus the equivalent width of the mini-BAL can vary as the intensity of the scattered continuum changes.Comment: 29 pages, including 17 figures; accepted for publication in the Astrophysical Journa

Quantifying the improvement of surrogate indices of hepatic insulin resistance using complex measurement techniques

We evaluated the ability of simple and complex surrogate-indices to identify individuals from an overweight/obese cohort with hepatic insulin-resistance (HEP-IR). Five indices, one previously defined and four newly generated through step-wise linear regression, were created against a single-cohort sample of 77 extensively characterised participants with the metabolic syndrome (age 55.6±1.0 years, BMI 31.5±0.4 kg/m2; 30 males). HEP-IR was defined by measuring endogenous-glucose-production (EGP) with [6–62H2] glucose during fasting and euglycemic-hyperinsulinemic clamps and expressed as EGP*fasting plasma insulin. Complex measures were incorporated into the model, including various non-standard biomarkers and the measurement of body-fat distribution and liver-fat, to further improve the predictive capability of the index. Validation was performed against a data set of the same subjects after an isoenergetic dietary intervention (4 arms, diets varying in protein and fiber content versus control). All five indices produced comparable prediction of HEP-IR, explaining 39–56% of the variance, depending on regression variable combination. The validation of the regression equations showed little variation between the different proposed indices (r2 = 27–32%) on a matched dataset. New complex indices encompassing advanced measurement techniques offered an improved correlation (r = 0.75, P<0.001). However, when validated against the alternative dataset all indices performed comparably with the standard homeostasis model assessment for insulin resistance (HOMA-IR) (r = 0.54, P<0.001). Thus, simple estimates of HEP-IR performed comparable to more complex indices and could be an efficient and cost effective approach in large epidemiological investigations

A minimal model to diagnose the contribution of the stratosphere to tropospheric forecast skill

Many recent studies have confirmed that variability in the stratosphere is a significant source of surface sub-seasonal prediction skill during Northern Hemisphere winter. It may be beneficial, therefore, to think about times in which there might be windows-of-opportunity for skillful sub-seasonal predictions based on the initial or predicted state of the stratosphere. In this study, we propose a simple, minimal model that can be used to understand the impact of the stratosphere on tropospheric predictability. Our model purposefully excludes state dependent predictability in either the stratosphere or troposphere or in the coupling between the two. Model parameters are set up to broadly represent current sub-seasonal prediction systems by comparison with four dynamical models from the Sub-Seasonal to Seasonal Prediction Project database. The model can reproduce the increases in correlation skill in sub-sets of forecasts for weak and strong lower stratospheric polar vortex states over neutral states despite the lack of dependence of coupling or predictability on the stratospheric state. We demonstrate why different forecast skill diagnostics can give a very different impression of the relative skill in the three sub-sets. Forecasts with large stratospheric signals and low amounts of noise are demonstrated to also be windows-of-opportunity for skillful tropospheric forecasts, but we show that these windows can be obscured by the presence of unrelated tropospheric signals

Report of the first international liver transplantation society expert panel consensus conference on renal insufficiency in liver transplantation

No abstract.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/64330/1/21877_ftp.pd

Impaired decisional impulsivity in pathological videogamers

Abstract Background Pathological gaming is an emerging and poorly understood problem. Impulsivity is commonly impaired in disorders of behavioural and substance addiction, hence we sought to systematically investigate the different subtypes of decisional and motor impulsivity in a well-defined pathological gaming cohort. Methods Fifty-two pathological gaming subjects and age-, gender- and IQ-matched healthy volunteers were tested on decisional impulsivity (Information Sampling Task testing reflection impulsivity and delay discounting questionnaire testing impulsive choice), and motor impulsivity (Stop Signal Task testing motor response inhibition, and the premature responding task). We used stringent diagnostic criteria highlighting functional impairment. Results In the Information Sampling Task, pathological gaming participants sampled less evidence prior to making a decision and scored fewer points compared with healthy volunteers. Gaming severity was also negatively correlated with evidence gathered and positively correlated with sampling error and points acquired. In the delay discounting task, pathological gamers made more impulsive choices, preferring smaller immediate over larger delayed rewards. Pathological gamers made more premature responses related to comorbid nicotine use. Greater number of hours played also correlated with a Motivational Index. Greater frequency of role playing games was associated with impaired motor response inhibition and strategy games with faster Go reaction time. Conclusions We show that pathological gaming is associated with impaired decisional impulsivity with negative consequences in task performance. Decisional impulsivity may be a potential target in therapeutic management

Examining the predictability of the Stratospheric Sudden Warming of January 2013 using multiple NWP systems

The first multi-model study to estimate the predictability of a boreal Sudden Stratospheric Warming (SSW) is performed using five NWP systems. During the 2012-2013 boreal winter, anomalous upward propagating planetary wave activity was observed towards the end of December, which followed by a rapid deceleration of the westerly circulation around 2 January 2013, and on 7 January 2013 the zonal mean zonal wind at 60°N and 10 hPa reversed to easterly. This stratospheric dynamical activity was followed by an equatorward shift of the tropospheric jet stream and by a high pressure anomaly over the North Atlantic, which resulted in severe cold conditions in the UK and Northern Europe. In most of the five models, the SSW event was predicted 10 days in advance. However, only some ensemble members in most of the models predicted weakening of westerly wind when the models were initialized 15 days in advance of the SSW. Further dynamical analysis of the SSW shows that this event was characterized by the anomalous planetary wave-1 amplification followed by the anomalous wave-2 amplification in the stratosphere, which resulted in a split vortex occurring between 6 January 2013 and 8 January 2013. The models have some success in reproducing wave-1 activity when initialized 15 days in advance, they but generally failed to produce the wave-2 activity during the final days of the event. Detailed analysis shows that models have reasonably good skill in forecasting tropospheric blocking features that stimulate wave-2 amplification in the troposphere, but they have limited skill in reproducing wave-2 amplification in the stratosphere

Ubiquitous outflows in DEEP2 spectra of star-forming galaxies at z=1.4

Galactic winds are a prime suspect for the metal enrichment of the intergalactic medium and may have a strong influence on the chemical evolution of galaxies and the nature of QSO absorption line systems. We use a sample of 1406 galaxy spectra at z~1.4 from the DEEP2 redshift survey to show that blueshifted Mg II 2796, 2803 A absorption is ubiquitous in starforming galaxies at this epoch. This is the first detection of frequent outflowing galactic winds at z~1. The presence and depth of absorption are independent of AGN spectral signatures or galaxy morphology; major mergers are not a prerequisite for driving a galactic wind from massive galaxies. Outflows are found in coadded spectra of galaxies spanning a range of 30x in stellar mass and 10x in star formation rate (SFR), calibrated from K-band and from MIPS IR fluxes. The outflows have column densities of order N_H ~ 10^20 cm^-2 and characteristic velocities of ~ 300-500 km/sec, with absorption seen out to 1000 km/sec in the most massive, highest SFR galaxies. The velocities suggest that the outflowing gas can escape into the IGM and that massive galaxies can produce cosmologically and chemically significant outflows. Both the Mg II equivalent width and the outflow velocity are larger for galaxies of higher stellar mass and SFR, with V_wind ~ SFR^0.3, similar to the scaling in low redshift IR-luminous galaxies. The high frequency of outflows in the star-forming galaxy population at z~1 indicates that galactic winds occur in the progenitors of massive spirals as well as those of ellipticals. The increase of outflow velocity with mass and SFR constrains theoretical models of galaxy evolution that include feedback from galactic winds, and may favor momentum-driven models for the wind physics.Comment: Accepted by ApJ. 25 pages, 17 figures. Revised to add discussions of intervening absorbers and AGN-driven outflows; conclusions unchange