Bioavailability, Antipsoriatic Efficacy and Tolerability of a New Light Cream with Mometasone Furoate 0.1%

Mometasone furoate, a potent glucocorticoid (class III) with a favorable benefit/risk ratio, has emerged as a standard medication for the treatment of inflammatory skin disorders. The purpose of the investigation presented here was to determine the noninferiority of a topical mometasone formulation, a light cream (O/W 60/40 emulsion) with mometasone furoate 0.1% (water content of 33%) versus marketed comparators. Using the vasoconstrictor assay, a strong blanching effect of the new cream (called Mometasone cream) comparable to that of a mometasone comparator, a fatty cream with mometasone furoate 0.1%, could be demonstrated. Thus, the topical bioavailability of the active ingredient mometasone furoate (0.1%) was regarded to be similar for Mometasone cream and the mometasone comparator. Using the psoriasis plaque test, a strong antipsoriatic effect comparable to that of the mometasone comparator was found for Mometasone cream after 12 days of occlusive treatment. A nearly identical reduction in the mean infiltrate thickness and similar mean AUC values were noted with both formulations confirmed by clinical assessment data. The noninferiority of Mometasone cream to its active comparator with re-spect to the AUC of change to baseline in infiltrate thickness was demonstrated. Both medications were well tolerated. Overall, Mometasone cream and the mometasone comparator showed similar efficacy and tolerability. Mometasone cream, in addition to its high potency and good tolerability, provides the properties of a light cream, which might make this new medication particularly suitable for application on acutely inflamed and sensitive skin. Copyright (C) 2012 S. Karger AG, Base

Hawking emission from quantum gravity black holes

We address the issue of modelling quantum gravity effects in the evaporation of higher dimensional black holes in order to go beyond the usual semi-classical approximation. After reviewing the existing six families of quantum gravity corrected black hole geometries, we focus our work on non-commutative geometry inspired black holes, which encode model independent characteristics, are unaffected by the quantum back reaction and have an analytical form compact enough for numerical simulations. We consider the higher dimensional, spherically symmetric case and we proceed with a complete analysis of the brane/bulk emission for scalar fields. The key feature which makes the evaporation of non-commutative black holes so peculiar is the possibility of having a maximum temperature. Contrary to what happens with classical Schwarzschild black holes, the emission is dominated by low frequency field modes on the brane. This is a distinctive and potentially testable signature which might disclose further features about the nature of quantum gravity.Comment: 36 pages, 18 figures, v2: updated reference list, minor corrections, version matching that published on JHE

Identification of Key Residues for pH Dependent Activation of Violaxanthin De-Epoxidase from Arabidopsis thaliana

Plants are often exposed to saturating light conditions, which can lead to oxidative stress. The carotenoid zeaxanthin, synthesized from violaxanthin by Violaxanthin De-Epoxidase (VDE) plays a major role in the protection from excess illumination. VDE activation is triggered by a pH reduction in the thylakoids lumen occurring under saturating light. In this work the mechanism of the VDE activation was investigated on a molecular level using multi conformer continuum electrostatic calculations, site directed mutagenesis and molecular dynamics. The pKa values of residues of the inactive VDE were determined to identify target residues that could be implicated in the activation. Five such target residues were investigated closer by site directed mutagenesis, whereas variants in four residues (D98, D117, H168 and D206) caused a reduction in enzymatic activity indicating a role in the activation of VDE while D86 mutants did not show any alteration. The analysis of the VDE sequence showed that the four putative activation residues are all conserved in plants but not in diatoms, explaining why VDE in these algae is already activated at higher pH. Molecular dynamics showed that the VDE structure was coherent at pH 7 with a low amount of water penetrating the hydrophobic barrel. Simulations carried out with the candidate residues locked into their protonated state showed instead an increased amount of water penetrating the barrel and the rupture of the H121–Y214 hydrogen bond at the end of the barrel, which is essential for VDE activation. These results suggest that VDE activation relies on a robust and redundant network, in which the four residues identified in this study play a major role

Clinical risk stratification of paediatric renal transplant recipients using C1q and C3d fixing of de novo donor-specific antibodies

Introduction: We have previously shown that children who developed de novo donor-specific human leukocyte antigen (HLA) antibodies (DSA) had greater decline in allograft function. We hypothesised that patients with complement-activating DSA would have poorer renal allograft outcomes. Methods: A total of 75 children developed DSA in the original study. The first positive DSA sample was subsequently tested for C1q and C3d fixing. The primary event was defined as 50% reduction from baseline estimated glomerular filtration rate and was analysed using the Kaplan–Meier estimator. Results: Of 65 patients tested, 32 (49%) and 23 (35%) tested positive for C1q and C3d fixing, respectively. Of the 32 C1q-positive (c1q+) patients, 13 (41%) did not show concomitant C3d fixing. The mean fluorescence intensity values of the original immunoglobulin G DSA correlated poorly with complement-fixing positivity (C1q: adjusted R2 0.072; C3d: adjusted R2 0.11; p < 0.05). C1q+ antibodies were associated with acute tubulitis [0.75 ± 0.18 (C1q+) vs. 0.25 ± 0.08 (C1q−) episodes per patient (mean ± standard error of the mean; p < 0.05] but not with worse long-term renal allograft dysfunction (median time to primary event 5.9 (C1q+) vs. 6.4 (C1q−) years; hazard ratio (HR) 0.74; 95% confidence ratio (CI) 0.30–1.81; p = 0.58]. C3d-positive (C3d+) antibodies were associated with positive C4d histological staining [47% (C3d+) vs. 20% (C3d−); p = 0.04] and with significantly worse long-term allograft dysfunction [median time to primary event: 5.6 (C3d+) vs. 6.5 (C3d−) years; HR 0.38; 95% CI 0.15–0.97; p = 0.04]. Conclusion: Assessment of C3d fixing as part of prospective HLA monitoring can potentially aid stratification of patients at the highest risk of long-term renal allograft dysfunction

Patterns of multimorbidity in working Australians

Background: Multimorbidity is becoming more prevalent. Previously-used methods of assessing multimorbidity relied on counting the number of health conditions, often in relation to an index condition (comorbidity), or grouping conditions based on body or organ systems. Recent refinements in statistical approaches have resulted in improved methods to capture patterns of multimorbidity, allowing for the identification of nonrandomly occurring clusters of multimorbid health conditions. This paper aims to identify nonrandom clusters of multimorbidity.Methods: The Australian Work Outcomes Research Cost-benefit (WORC) study cross-sectional screening dataset (approximately 78,000 working Australians) was used to explore patterns of multimorbidity. Exploratory factor analysis was used to identify nonrandomly occurring clusters of multimorbid health conditions.Results: Six clinically-meaningful groups of multimorbid health conditions were identified. These were: factor 1: arthritis, osteoporosis, other chronic pain, bladder problems, and irritable bowel; factor 2: asthma, chronic obstructive pulmonary disease, and allergies; factor 3: back/neck pain, migraine, other chronic pain, and arthritis; factor 4: high blood pressure, high cholesterol, obesity, diabetes, and fatigue; factor 5: cardiovascular disease, diabetes, fatigue, high blood pressure, high cholesterol, and arthritis; and factor 6: irritable bowel, ulcer, heartburn, and other chronic pain. These clusters do not fall neatly into organ or body systems, and some conditions appear in more than one cluster.Conclusions: Considerably more research is needed with large population-based datasets and a comprehensive set of reliable health diagnoses to better understand the complex nature and composition of multimorbid health conditions

Correcting for Mortality Among Patients Lost to Follow Up on Antiretroviral Therapy in South Africa: A Cohort Analysis

Loss to follow-up (LTF) challenges the reporting of antiretroviral treatment (ART) programmes, since it encompasses patients alive but lost to programme and deaths misclassified as LTF. We describe LTF before and after correction for mortality in a primary care ART programme with linkages to the national vital registration system

Synthesis and Magnetic Properties of Maghemite (γ-Fe2O3) Short-Nanotubes

We report a rational synthesis of maghemite (γ-Fe2O3) short-nanotubes (SNTs) by a convenient hydrothermal method and subsequent annealing process. The structure, shape, and magnetic properties of the SNTs were investigated. Room-temperature and low-temperature magnetic measurements show that the as-fabricated γ-Fe2O3 SNTs are ferromagnetic, and its coercivity is nonzero when the temperature above blocking temperature (TB). The hysteresis loop was operated to show that the magnetic properties of γ-Fe2O3 SNTs are strongly influenced by the morphology of the crystal. The unique magnetic behaviors were interpreted by the competition of the demagnetization energy of quasi-one-dimensional nanostructures and the magnetocrystalline anisotropy energy of particles in SNTs

Search for new phenomena in final states with an energetic jet and large missing transverse momentum in pp collisions at √ s = 8 TeV with the ATLAS detector

Results of a search for new phenomena in final states with an energetic jet and large missing transverse momentum are reported. The search uses 20.3 fb−1 of √ s = 8 TeV data collected in 2012 with the ATLAS detector at the LHC. Events are required to have at least one jet with pT > 120 GeV and no leptons. Nine signal regions are considered with increasing missing transverse momentum requirements between Emiss T > 150 GeV and Emiss T > 700 GeV. Good agreement is observed between the number of events in data and Standard Model expectations. The results are translated into exclusion limits on models with either large extra spatial dimensions, pair production of weakly interacting dark matter candidates, or production of very light gravitinos in a gauge-mediated supersymmetric model. In addition, limits on the production of an invisibly decaying Higgs-like boson leading to similar topologies in the final state are presente

Multimorbidity Patterns in the Elderly: A New Approach of Disease Clustering Identifies Complex Interrelations between Chronic Conditions

Objective: Multimorbidity is a common problem in the elderly that is significantly associated with higher mortality, increased disability and functional decline. Information about interactions of chronic diseases can help to facilitate diagnosis, amend prevention and enhance the patients ’ quality of life. The aim of this study was to increase the knowledge of specific processes of multimorbidity in an unselected elderly population by identifying patterns of statistically significantly associated comorbidity. Methods: Multimorbidity patterns were identified by exploratory tetrachoric factor analysis based on claims data of 63,104 males and 86,176 females in the age group 65+. Analyses were based on 46 diagnosis groups incorporating all ICD-10 diagnoses of chronic diseases with a prevalence $ 1%. Both genders were analyzed separately. Persons were assigned to multimorbidity patterns if they had at least three diagnosis groups with a factor loading of 0.25 on the corresponding pattern. Results: Three multimorbidity patterns were found: 1) cardiovascular/metabolic disorders [prevalence female: 30%; male: 39%], 2) anxiety/depression/somatoform disorders and pain [34%; 22%], and 3) neuropsychiatric disorders [6%; 0.8%]. The sampling adequacy was meritorious (Kaiser-Meyer-Olkin measure: 0.85 and 0.84, respectively) and the factors explained a large part of the variance (cumulative percent: 78 % and 75%, respectively). The patterns were largely age-dependent an

Modelling credit spreads with time volatility, skewness, and kurtosis

This paper seeks to identify the macroeconomic and financial factors that drive credit spreads on bond indices in the US credit market. To overcome the idiosyncratic nature of credit spread data reflected in time varying volatility, skewness and thick tails, it proposes asymmetric GARCH models with alternative probability density functions. The results show that credit spread changes are mainly explained by the interest rate and interest rate volatility, the slope of the yield curve, stock market returns and volatility, the state of liquidity in the corporate bond market and, a heretofore overlooked variable, the foreign exchange rate. They also confirm that the asymmetric GARCH models and Student-t distributions are systematically superior to the conventional GARCH model and the normal distribution in in-sample and out-of-sample testing