On the quasi-steady state assumption applied to Michaelis-Menten and suicide substrate reactions with diffusion

We consider a recent extension to the validity of the quasi-steady-state assumption (QSSA) which includes the case where the ratio of the initial enzyme to substrate concentration is not necessarily small. We extend the analysis to include diffusion of substrate, in which case the initial enzyme to substrate ratio is spatially dependent and no longer constant. We show that the region in which the QSSA holds depends on the nature of the enzyme-substrate reaction: if the enzyme is inactivated by the substrate then the QSSA holds in a growing disc; if the enzyme is unchanged after reaction then the QSSA holds in a ring travelling through space

A comparison of the effect of age on levator ani and obturator internus muscle cross‐sectional areas and volumes in nulliparous women

Aims Functional tests have demonstrated minimal loss of vaginal closure force with age. So we tested the null hypotheses that age neither affects the maximum cross‐sectional area (CSA) nor the volume of the levator muscle. Corresponding hypotheses were also tested in the adjacent obturator internus muscle, which served as a control for the effect of age on appendicular muscle in these women. Methods Magnetic resonance images of 15 healthy younger (aged 21–25 years) and 12 healthy older nulliparous women (aged >63 years) were selected to avoid the confounding effect of childbirth. Models were created from tracing outlines of the levator ani muscle in the coronal plane, and obturator internus in the axial plane using 3D Slicer v. 3.4. Muscle volumes were calculated using Slicer, while CSA was measured using Imageware™ at nine locations. The hypotheses were tested using repeated measures analysis of variance with P  < 0.05 being considered significant. Results The effect of age did not reach statistical significance for the decrease in levator ani muscle maximum CSA or the decrease in volume (4.3%, P  = 0.62 and 10.9%, 0.12, respectively). However, age did significantly adversely decrease obturator internus muscle maximum CSA and volume (24.5% and 28.2%, P  < 0.001, respectively). Significant local age‐related changes were observed dorsally in both muscles. Conclusions Unlike the adjacent appendicular muscle, obturator internus, the levator ani muscle in healthy nullipara does not show evidence of significant age‐related atrophy. Neurourol. Urodynam. 31:481–486, 2012. © 2012 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91125/1/21208_ftp.pd

A comparison of the effect of age on levator ani and obturator internus muscle cross‐sectional areas and volumes in nulliparous women

Aims Functional tests have demonstrated minimal loss of vaginal closure force with age. So we tested the null hypotheses that age neither affects the maximum cross‐sectional area (CSA) nor the volume of the levator muscle. Corresponding hypotheses were also tested in the adjacent obturator internus muscle, which served as a control for the effect of age on appendicular muscle in these women. Methods Magnetic resonance images of 15 healthy younger (aged 21–25 years) and 12 healthy older nulliparous women (aged >63 years) were selected to avoid the confounding effect of childbirth. Models were created from tracing outlines of the levator ani muscle in the coronal plane, and obturator internus in the axial plane using 3D Slicer v. 3.4. Muscle volumes were calculated using Slicer, while CSA was measured using Imageware™ at nine locations. The hypotheses were tested using repeated measures analysis of variance with P  < 0.05 being considered significant. Results The effect of age did not reach statistical significance for the decrease in levator ani muscle maximum CSA or the decrease in volume (4.3%, P  = 0.62 and 10.9%, 0.12, respectively). However, age did significantly adversely decrease obturator internus muscle maximum CSA and volume (24.5% and 28.2%, P  < 0.001, respectively). Significant local age‐related changes were observed dorsally in both muscles. Conclusions Unlike the adjacent appendicular muscle, obturator internus, the levator ani muscle in healthy nullipara does not show evidence of significant age‐related atrophy. Neurourol. Urodynam. 31:481–486, 2012. © 2012 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/91125/1/21208_ftp.pd

Risk of Mortality (including Sudden Cardiac Death) and Major Cardiovascular Events in Users of Olanzapine and Other Antipsychotics: A Study with the General Practice Research Database.

Objective. Assess risk of cardiac events and mortality among users of olanzapine and other antipsychotics relative to nonusers. Methods. The General Practice Research Database was used to identify cohorts of antipsychotic users and nonusers with psychiatric illness. Outcomes included cardiac mortality, sudden cardiac death (SCD), all-cause mortality (excluding suicide), coronary heart disease (CHD), and ventricular arrhythmias (VA). Results. 183,392 antipsychotic users (including 20,954 olanzapine users) and 193,920 psychiatric nonusers were identified. There was a significantly higher rate of cardiac mortality (adjusted RR [aRR]: 1.53, CI, 1.12-2.09) in olanzapine users relative to psychiatric nonusers, consistent with findings for both atypical and typical antipsychotics. Relative to psychiatric nonusers, no increased risk of all-cause mortality was observed among olanzapine users (aRR: 1.04, CI, 0.93-1.17), but elevated all-cause mortality risk was observed when compared to all antipsychotic users (aRR: 1.75, CI, 1.64-1.87). There was no increased risk of CHD or VA among olanzapine users relative to psychiatric nonusers, consistent with findings for atypical but not typical antipsychotics. SCD cases were uncommon. Conclusions. Use of antipsychotic agents was associated with increased risk of all-cause and cardiac mortality. Patients treated with olanzapine were found to be at increased risk of cardiac mortality versus psychiatric nonusers

IL-10-conditioned dendritic cells, decommissioned for recruitment of adaptive immunity, elicit innate inflammatory gene products in response to danger signals

Dendritic cells (DCs) are the professional APCs of the immune system, enabling T cells to perceive and respond appropriately to potentially dangerous microbes, while also being able to maintain T cell tolerance toward self. In part, such tolerance can be determined by IL-10 released from certain types of regulatory T cells. IL-10 has previously been shown to render DCs unable to activate T cells and it has been assumed that this process represents a general block in maturation. Using serial analysis of gene expression, we show that IL-10 pretreatment of murine bone marrow-derived DCs alone causes significant changes in gene expression. Furthermore, these cells retain the ability to respond to Toll-like receptor agonists, but in a manner skewed toward the selective induction of mediators known to enhance local inflammation and innate immunity, among which we highlight a novel CXCR2 ligand, DC inflammatory protein-1. These data suggest that, while the presence of a protolerogenic and purportedly anti-inflammatory agent such as IL-10 precludes DCs from acquiring their potential as initiators of adaptive immunity, their ability to act as initiators of innate immunity in response to Toll-like receptor signaling is enhanced

Risk of mortality (including sudden cardiac death) and major cardiovascular events in atypical and typical antipsychotic users: a study with the general practice research database.

Objective. Antipsychotics have been associated with increased cardiac events including mortality. This study assessed cardiac events including mortality among antipsychotic users relative to nonusers. Methods. The General Practice Research Database (GPRD) was used to identify antipsychotic users, matched general population controls, and psychiatric diseased nonusers. Outcomes included cardiac mortality, sudden cardiac death (SCD), all-cause mortality (excluding suicide), coronary heart disease (CHD), and ventricular arrhythmias (VA). Sensitivity analyses were conducted for age, dose, duration, antipsychotic type, and psychiatric disease. Results. 183,392 antipsychotic users (115,491 typical and 67,901 atypical), 544,726 general population controls, and 193,920 psychiatric nonusers were identified. Nonusers with schizophrenia, dementia, or bipolar disorder had increased risks of all-cause mortality compared to general population controls, while nonusers with major depression had comparable risks. Relative to psychiatric nonusers, the adjusted relative ratios (aRR) of all-cause mortality in antipsychotic users was 1.75 (95% CI: 1.64-1.87); cardiac mortality 1.72 (95% CI: 1.42-2.07); SCD primary definition 5.76 (95% CI: 2.90-11.45); SCD secondary definition 2.15 (95% CI: 1.64-2.81); CHD 1.16 (95% CI: 0.94-1.44); and VA 1.16 (95% CI: 1.02-1.31). aRRs of the various outcomes were lower for atypical versus typical antipsychotics (all-cause mortality 0.83 (95% CI: 0.80-0.85); cardiac mortality 0.89 (95% CI: 0.82-0.97); and SCD secondary definition 0.76 (95% CI: 0.55-1.04). Conclusions. Antipsychotic users had an increased risk of cardiac mortality, all-cause mortality, and SCD compared to a psychiatric nonuser cohort

Structural basis of synthetic agonist activation of the nuclear receptor REV-ERB

The nuclear receptor REV-ERB plays an important role in a range of physiological processes. REV-ERB behaves as a ligand-dependent transcriptional repressor and heme has been identified as a physiological agonist. Our current understanding of how ligands bind to and regulate transcriptional repression by REV-ERB is based on the structure of heme bound to REV-ERB. However, porphyrin (heme) analogues have been avoided as a source of synthetic agonists due to the wide range of heme binding proteins and potential pleotropic effects. How non-porphyrin synthetic agonists bind to and regulate REV-ERB has not yet been defined. Here, we characterize a high affinity synthetic REV-ERB agonist, STL1267, and describe its mechanism of binding to REV-ERB as well as the method by which it recruits transcriptional corepressor both of which are unique and distinct from that of heme-bound REV-ERB

Does the Swiss Car Market Reward Fuel Efficient Cars? Evidence from Hedonic Pricing Regressions, Matching and a Regression Discontinuity Design

To correct market failures due to the presence of negative externalities associated with energy consumption, governments have adopted a variety of policies, including taxes, subsidies, regulations and standards, and information-based policies. For example, labels that clearly convey energy consumption rates, associated costs, and emissions of conventional pollutants and CO2, have been devised and used in the last two decades in several countries. In 2003, Switzerland introduced a system of fuel economy labels, based on grades ranging from A to G, where is A best and G is worst, to assist consumers in making decisions that improve the fleet s fuel economy and lower emissions. We use a dataset documenting all passenger cars approved for sale in Switzerland each year from 2000 to 2011 to answer three key research questions. First, what is the willingness to pay for fuel economy? Second, do Swiss drivers - or Swiss auto importers on their behalf - appear to do a one-to-one tradeoff between car purchase price and savings on fuel costs over the lifetime of the car? Third, does the label have an additional effect on price, all else the same, above and beyond that of fuel efficiency alone? Hedonic pricing regressions that exploit the variation in fuel economy across make-models, and over time within make-models, suggest that there is a (modest) capitalization of fuel economy into car prices. The diesel premium, however, exceeds the future fuel cost savings made possible by diesel cars, even at zero discount rates. An alternate calculation suggests that the fuel economy premium is consistent with a very low discount rate (2.5%). We use a sharp regression discontinuity design (RDD) based on the mechanism used by the Swiss Federal Office of Energy to assign cars to the fuel economy label to see if the label has an independent effect on price, above and beyond that of the fuel economy. The RDD approach estimates the effect to be 6-11%. To broaden the fuel economy range over which we assess the effect of the A label, we also deploy matching estimators, and find that the effect of an A label on car price is approximately 5%