Significant receptor affinities of metabolites and a degradation product of mometasone furoate

Mometasone furoate (MF) is a highly potent glucocorticoid used topically to treat inflammation in the lung, nose and on the skin. However, so far no information has been published on the human glucocorticoid receptor activity of the metabolites or degradation products of MF. We have now determined the relative receptor binding affinities of the known metabolite 6β-OH MF and the degradation product 9,11-epoxy MF to understand their possible contribution to undesirable systemic side effects. In competition experiments with human lung glucocorticoid receptors we have determined the relative receptor affinities (RRA) of these substances with reference to dexamethasone (RRA = 100). We have discovered that 6β-OH MF and 9,11-epoxy MF display RRAs of 206 ± 15 and 220 ± 22, respectively. This level of activity is similar to that of the clinically used inhaled corticosteroid flunisolide (RRA 180 ± 11). Furthermore we observed that 9,11-epoxy MF is a chemically reactive metabolite. In recovery experiments with human plasma and lung tissue we found a time dependent decrease in extractability of the compound. Hence, we provide data that might contribute to the understanding of the pharmacokinetics as well as the clinical effects of MF

A numerical study on the evolution of portfolio rules

In this paper we test computationally the performance of CAPM in an evolutionary setting. In particular we study the stability of distribution of wealth in a financial market where some traders invest as prescribed by CAPM and others behave according to different portfolio rules. Our study is motivated by recent analytical results that show that, whenever a logarithmic utility maximiser enters the market, CAPM traders vanish in the long run. Our analysis provides further insights and extends these results. We simulate a sequence of trades in a financial market and: first, we address the issue of how long is the long run in different parametric settings; second, we study the effect of heterogeneous savings behaviour on asymptotic wealth shares. We find that CAPM is particularly “unfit” for highly risky environments

Incidence and drug treatment of emotional distress after cancer diagnosis : a matched primary care case-control study

Notes This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License.Peer reviewedPublisher PD

Management of major depression in outpatients attending a cancer centre: a preliminary evaluation of a multicomponent cancer nurse-delivered intervention

A novel nurse-delivered multicomponent intervention for major depressive disorder (MDD) in cancer outpatients was compared with usual care alone in a nonrandomised matched group design (n=30 per group). At the final 6-month outcome, 38.5% (95% CI, 5.4-57%) fewer patients in the intervention group still met the criteria for MDD

Stabilizing the Complex Structure in Heterotic Calabi-Yau Vacua

In this paper, we show that the presence of gauge fields in heterotic Calabi-Yau compacitifications causes the stabilisation of some, or all, of the complex structure moduli of the Calabi-Yau manifold while maintaining a Minkowski vacuum. Certain deformations of the Calabi-Yau complex structure, with all other moduli held fixed, can lead to the gauge bundle becoming non-holomorphic and, hence, non-supersymmetric. This leads to an F-term potential which stabilizes the corresponding complex structure moduli. We use 10- and 4-dimensional field theory arguments as well as a derivation based purely on algebraic geometry to show that this picture is indeed correct. An explicit example is presented in which a large subset of complex structure moduli is fixed. We demonstrate that this type of theory can serve as the hidden sector in heterotic vacua and can co-exist with realistic particle physics.Comment: 17 pages, Late

Psychiatric misdiagnoses in patients with chronic fatigue syndrome

OBJECTIVES: The aim of this study was to examine the accuracy of doctors at diagnosing co-morbid psychiatric disorders in patients with chronic fatigue syndrome (CFS). DESIGN: Case series comparing clinical diagnoses with a standardized structured psychiatric interview. SETTING: Secondary care specialist chronic fatigue syndrome clinic. PARTICIPANTS: One hundred and thirty-five participants of a randomized controlled trial of non-pharmacological treatments at one centre in the PACE trial. MAIN OUTCOME MEASURES: Current psychiatric diagnoses made by CFS specialist doctors, compared with current psychiatric diagnoses made independently using a structured psychiatric interview. RESULTS: Clinicians identified 59 (44%, 95% CI 39-56%) of patients as suffering from a co-morbid psychiatric disorder compared to 76 (56%, CI 53-69%) by structured interview. Depressive and anxiety disorders were most common. Clinicians were twice as likely to miss diagnoses (30 patients, 22%) than misdiagnose them (13, 10%). Psychiatrists were less likely to miss diagnoses than other clinicians, but were as likely to misdiagnose them. CONCLUSIONS: Doctors assessing patients in a chronic fatigue syndrome clinic miss psychiatric diagnoses more often than misdiagnosing them. Missed diagnoses are common. CFS clinic doctors should be trained to diagnose psychiatric disorders.East London Foundation Trust, Queen Mary University of London,and the Medical Research Counci

Numerical Hermitian Yang-Mills Connections and Vector Bundle Stability in Heterotic Theories

A numerical algorithm is presented for explicitly computing the gauge connection on slope-stable holomorphic vector bundles on Calabi-Yau manifolds. To illustrate this algorithm, we calculate the connections on stable monad bundles defined on the K3 twofold and Quintic threefold. An error measure is introduced to determine how closely our algorithmic connection approximates a solution to the Hermitian Yang-Mills equations. We then extend our results by investigating the behavior of non slope-stable bundles. In a variety of examples, it is shown that the failure of these bundles to satisfy the Hermitian Yang-Mills equations, including field-strength singularities, can be accurately reproduced numerically. These results make it possible to numerically determine whether or not a vector bundle is slope-stable, thus providing an important new tool in the exploration of heterotic vacua.Comment: 52 pages, 15 figures. LaTex formatting of figures corrected in version 2

Numerical Hermitian Yang-Mills Connections and Kahler Cone Substructure

We further develop the numerical algorithm for computing the gauge connection of slope-stable holomorphic vector bundles on Calabi-Yau manifolds. In particular, recent work on the generalized Donaldson algorithm is extended to bundles with Kahler cone substructure on manifolds with h^{1,1}>1. Since the computation depends only on a one-dimensional ray in the Kahler moduli space, it can probe slope-stability regardless of the size of h^{1,1}. Suitably normalized error measures are introduced to quantitatively compare results for different directions in Kahler moduli space. A significantly improved numerical integration procedure based on adaptive refinements is described and implemented. Finally, an efficient numerical check is proposed for determining whether or not a vector bundle is slope-stable without computing its full connection.Comment: 38 pages, 10 figure

Yukawa Textures From Heterotic Stability Walls

A holomorphic vector bundle on a Calabi-Yau threefold, X, with h^{1,1}(X)>1 can have regions of its Kahler cone where it is slope-stable, that is, where the four-dimensional theory is N=1 supersymmetric, bounded by "walls of stability". On these walls the bundle becomes poly-stable, decomposing into a direct sum, and the low energy gauge group is enhanced by at least one anomalous U(1) gauge factor. In this paper, we show that these additional symmetries can strongly constrain the superpotential in the stable region, leading to non-trivial textures of Yukawa interactions and restrictions on allowed masses for vector-like pairs of matter multiplets. The Yukawa textures exhibit a hierarchy; large couplings arise on the stability wall and some suppressed interactions "grow back" off the wall, where the extended U(1) symmetries are spontaneously broken. A number of explicit examples are presented involving both one and two stability walls, with different decompositions of the bundle structure group. A three family standard-like model with no vector-like pairs is given as an example of a class of SU(4) bundles that has a naturally heavy third quark/lepton family. Finally, we present the complete set of Yukawa textures that can arise for any holomorphic bundle with one stability wall where the structure group breaks into two factors.Comment: 53 pages, 4 figures and 13 table

Heterotic Line Bundle Standard Models

In a previous publication, arXiv:1106.4804, we have found 200 models from heterotic Calabi-Yau compactifications with line bundles, which lead to standard models after taking appropriate quotients by a discrete symmetry and introducing Wilson lines. In this paper, we construct the resulting standard models explicitly, compute their spectrum including Higgs multiplets, and analyze some of their basic properties. After removing redundancies we find about 400 downstairs models, each with the precise matter spectrum of the supersymmetric standard model, with one, two or three pairs of Higgs doublets and no exotics of any kind. In addition to the standard model gauge group, up to four Green-Schwarz anomalous U(1) symmetries are present in these models, which constrain the allowed operators in the four-dimensional effective supergravity. The vector bosons associated to these anomalous U(1) symmetries are massive. We explicitly compute the spectrum of allowed operators for each model and present the results, together with the defining data of the models, in a database of standard models accessible at http://www-thphys.physics.ox.ac.uk/projects/CalabiYau/linebundlemodels/index.html. Based on these results we analyze elementary phenomenological properties. For example, for about 200 models all dimension four and five proton decay violating operators are forbidden by the additional U(1) symmetries.Comment: 55 pages, Latex, 3 pdf figure