Circadian Activity of Topical 0.05% Betamethasone Dipropionate in Human Skin In Vivo

The influence of treatment duration, vehicle, and time of day of application on topical 0.05% betamethasone dipropionate uptake into human stratum corneum and the resulting skin- blanching response was investigated in human subjects. Drug uptake into stratum corneum and the resulting skin color changes measured with a chromameter demonstrate an equilibrium delay. Maximal drug uptake occurred at 2 h, whereas maximal skin color changes occurred 6h after a single application. Extent of decreased skin color was dependent on vehicle, treatment duration, and time of day of application. Time of maximal decreased skin color occurred at midnight independent of vehicle, treatment duration, or time of day of application. This time of maximal drug activity coincides with the well-known time period of lowest circulating cortisol concentrations (2000-0400 h). Application of a single 2- or 6-h dose of the 0.05% cream at 1600h produced more extensive and prolonged changes in skin color over 24h than a 0900-h application in the same subject. These data demonstrate that the extent and duration of topical corticosteroid activity in human skin is influenced by vehicle, treatment duration, and time of day of application. The prolonged changes in skin color measured with a single dose applied at 1600h suggest that a once-a-day dosing regimen in the late afternoon may be sufficient for dermatologic therapy. Elucidation of these circadian responses with topical corticosteroids may provide a rational basis for the future re-evaluation of the appropriate therapeutic regimen with this class of drugs in dermatologic medicine

Simplifying transformations for nonlinear systems: Part I, an optimisation-based variant of normal form analysis

This paper introduces the idea of a ‘simplifying transformation’ for nonlinear structural dynamic systems. The idea simply stated; is to bring under one heading, those transformations which ‘simplify’ structural dynamic systems or responses in some sense. The equations of motion may be cast in a simpler form or decoupled (and in this sense, nonlinear modal analysis is encompassed) or the responses may be modified in order to isolate and remove certain components. It is the latter sense of simplification which is considered in this paper. One can regard normal form analysis in a way as the removal of superharmonic content from nonlinear system response. In the current paper, this problem is cast in an optimisation form and the differential evolution algorithm is used

Ammonia (J,K) = (1,1) to (4,4) and (6,6) inversion lines detected in the Seyfert 2 galaxy NGC 1068

We present the detection of the ammonia (NH3) (J,K) = (1,1) to (4,4) and (6,6) inversion lines toward the prototypical Seyfert 2 galaxy NGC 1068, made with the Green Bank Telescope (GBT). This is the first detection of ammonia in a Seyfert galaxy. The ortho-to-para-NH3 abundance ratio suggests that the molecule was formed in a warm medium of at least 20 K. For the NH3 column density and fractional abundance, we find (1.09\pm0.23)\times10^14 cm^-2 and (2.9\pm0.6)\times10^-8, respectively, from the inner 1.2 kpc of NGC 1068. The kinetic temperature can be constrained to 80\pm20 K for the bulk of the molecular gas, while some fraction has an even higher temperature of 140\pm30 K.Comment: 5 pages, 3 figures, accepted by A&

Resolving the complex structure of the dust torus in the active nucleus of the Circinus galaxy

To test the dust torus model for active galactic nuclei directly, we study the extent and morphology of the nuclear dust distribution in the Circinus galaxy using high resolution interferometric observations in the mid-infrared with the MIDI instrument at the Very Large Telescope Interferometer. We find that the dust distribution in the nucleus of Circinus can be explained by two components, a dense and warm disk-like component of 0.4 pc size and a slightly cooler, geometrically thick torus component with a size of 2.0 pc. The disk component is oriented perpendicular to the ionisation cone and outflow and seems to show the silicate feature at 10 micron in emission. It coincides with a nuclear maser disk in orientation and size. From the energy needed to heat the dust, we infer a luminosity of the accretion disk corresponding to 20% of the Eddington luminosity of the nuclear black hole. We find that the interferometric data are inconsistent with a simple, smooth and axisymmetric dust emission. The irregular behaviour of the visibilities and the shallow decrease of the dust temperature with radius provide strong evidence for a clumpy or filamentary dust structure. We see no evidence for dust reprocessing, as the silicate absorption profile is consistent with that of standard galactic dust. We argue that the collimation of the ionising radiation must originate in the geometrically thick torus component. Our findings confirm the presence of a geometrically thick, torus-like dust distribution in the nucleus of Circinus, as required in unified schemes of Seyfert galaxies. Several aspects of our data require that this torus is irregular, or "clumpy".Comment: 20 pages, 16 figures, accepted for publication by A&

Influence of total sugar intake on metabolic blood markers at 8 years of age in the Childhood Obesity Project

PURPOSE We aimed to characterize the association of dietary sugar intake with blood lipids and glucose-related markers in childhood. METHODS Data from the multicentric European Childhood Obesity Project Trial were used. Three-day weighed dietary records were obtained at 8~years of age along with serum concentrations of triglycerides, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol (HDL-C), glucose, and insulin. Total sugar intake comprised all mono- and disaccharides; different sugar sources were defined. Linear regression models were applied to investigate the cross-sectional association of total sugar intake with blood lipids and glucose-related markers with adjustment for total energy intake using the residual method. RESULTS Data were available for 325 children. Children consumed on average 332~kcal (SD 110) and 21% (SD 6) of energy from total sugar. In an energy-adjusted model, an increase of 100~kcal from total sugar per day was significantly associated with a z score HDL-C decrease (-~0.14; 95% CI -~0.01, -~0.27; p value = 0.031). Concerning different food groups of total sugar intake, 100~kcal total sugar from sweetened beverages was negatively associated with z score HDL-C (-~1.67; 95% CI -~0.42, -~2.91; p value = 0.009), while total sugar from milk products was positively related to z score HDL-C (1.38, 95% CI 0.03, 2.72; p value = 0.045). None of the other blood lipids or glucose-related markers showed a significant relationship with total sugar intake. CONCLUSION Increasing dietary total sugar intake in children, especially from sweetened beverages, was associated with unfavorable effects on HDL-C, which might increase the long-term risk for dyslipidemia and cardiovascular disease. CLINICAL TRIAL REGISTRY ClinicalTrials.gov Identifier: NCT00338689; Registered: June 19, 2006. URL: https://clinicaltrials.gov/ct2/show/NCT00338689?term=NCT00338689&rank=1

Parsec-scale dust distributions in Seyfert galaxies - Results of the MIDI AGN snapshot survey

The emission of warm dust dominates the mid-infrared spectra of active galactic nuclei (AGN). Only interferometric observations provide the necessary angular resolution to resolve the nuclear dust and to study its distribution and properties. The investigation of dust in AGN cores is hence one of the main science goals for the MID-infrared Interferometric instrument MIDI at the VLTI. As the first step, the feasibility of AGN observations was verified and the most promising sources for detailed studies were identified. This was carried out in a "snapshot survey" with MIDI using Guaranteed Time Observations. In the survey, observations were attempted for 13 of the brightest AGN in the mid-infrared which are visible from Paranal. The results of the three brightest, best studied sources have been published in separate papers. Here we present the interferometric observations for the remaining 10, fainter AGN. For 8 of these, interferometric measurements could be carried out. Size estimates or limits on the spatial extent of the AGN-heated dust were derived from the interferometric data of 7 AGN. These indicate that the dust distributions are compact, with sizes on the order of a few parsec. The derived sizes roughly scale with the square root of the luminosity in the mid-infrared, s ~ sqrt(L), with no clear distinction between type 1 and type 2 objects. This is in agreement with a model of nearly optically thick dust structures heated to T ~ 300 K. For three sources, the 10 micron feature due to silicates is tentatively detected either in emission or in absorption. Based on the results for all AGN studied with MIDI so far, we conclude that in the mid-infrared the differences between individual galactic nuclei are greater than the generic differences between type 1 and type 2 objects.Comment: 18 pages, 8 figures, updated to version published in A&A 502, 67-8

Mental performance in 8-year-old children fed reduced protein content formula during the 1st year of life: safety analysis of a randomised clinical trial

In humans, maximum brain development occurs between the third trimester of gestation and 2 years of life. Nutrition during these critical windows of rapid brain development might be essential for later cognitive functioning and behaviour. In the last few years, trends on protein recommendations during infancy and childhood have tended to be lower than that in the past. It remains to be demonstrated that lower protein intakes among healthy infants, a part of being able to reduce obesity risk, is safe in terms of mental performance achievement. Secondary analyses of the EU CHOP, a clinical trial in which infants from five European countries were randomised to be fed a higher or a lower protein content formula during the 1st year of life. Children were assessed at the age of 8 years with a neuropsychological battery of tests that included assessments of memory (visual and verbal), attention (visual, selective, focused and sustained), visual-perceptual integration, processing speed, visual-motor coordination, verbal fluency and comprehension, impulsivity/inhibition, flexibility/shifting, working memory, reasoning, visual-spatial skills and decision making. Internalising, externalising and total behaviour problems were assessed using the Child Behaviour Checklist 4\u201318. Adjusted analyses considering factors that could influence neurodevelopment, such as parental education level, maternal smoking, child\u2019s gestational age at birth and head circumference, showed no differences between feeding groups in any of the assessed neuropsychological domains and behaviour. In summary, herewith we report on the safety of lower protein content in infant formulae (closer to the content of human milk) according to long-term mental performance

Gas dynamics of the central few parsec region of NGC 1068 fuelled by the evolving nuclear star cluster

High resolution observations with the NIR adaptive optics integral field spectrograph SINFONI at the VLT proved the existence of massive and young nuclear star clusters in the centres of a sample of Seyfert galaxies. With the help of three-dimensional high resolution hydrodynamical simulations with the Pluto code, we follow the evolution of such clusters, focusing on stellar mass loss. This leads to clumpy or filamentary inflow of gas on large scales (tens of parsec), whereas a turbulent and very dense disc builds up on the parsec scale. In order to capture the relevant physics in the inner region, we treat this disc separately by viscously evolving the radial surface density distribution. This enables us to link the tens of parsec scale region (accessible via SINFONI observations) to the (sub-)parsec scale region (observable with the MIDI instrument and via water maser emission). In this work, we concentrate on the effects of a parametrised turbulent viscosity to generate angular momentum and mass transfer in the disc and additionally take star formation into account. Input parameters are constrained by observations of the nearby Seyfert 2 galaxy NGC 1068. At the current age of its nuclear starburst of 250 Myr, our simulations yield disc sizes of the order of 0.8 to 0.9 pc, gas masses of 1.0e6 solar masses and mass transfer rates of 0.025 solar masses per year through the inner rim of the disc. This shows that our large scale torus model is able to approximately account for the disc size as inferred from interferometric observations in the mid-infrared and compares well to the extent and mass of a rotating disc structure as inferred from water maser observations. Several other observational constraints are discussed as well.Comment: 13 pages, 11 figures, accepted for publication in MNRAS, updated author list and reference

Cardiosphere-derived cells suppress allogeneic lymphocytes by production of PGE2 acting via the EP4 receptor

derived cells (CDCs) are a cardiac progenitor cell population, which have been shown to possess cardiac regenerative properties and can improve heart function in a variety of cardiac diseases. Studies in large animal models have predominantly focussed on using autologous cells for safety, however allogeneic cell banks would allow for a practical, cost-effective and efficient use in a clinical setting. The aim of this work was to determine the immunomodulatory status of these cells using CDCs and lymphocytes from 5 dogs. CDCs expressed MHC I but not MHC II molecules and in mixed lymphocyte reactions demonstrated a lack of lymphocyte proliferation in response to MHC-mismatched CDCs. Furthermore, MHC-mismatched CDCs suppressed lymphocyte proliferation and activation in response to Concanavalin A. Transwell experiments demonstrated that this was predominantly due to direct cell-cell contact in addition to soluble mediators whereby CDCs produced high levels of PGE2 under inflammatory conditions. This led to down-regulation of CD25 expression on lymphocytes via the EP4 receptor. Blocking prostaglandin synthesis restored both, proliferation and activation (measured via CD25 expression) of stimulated lymphocytes. We demonstrated for the first time in a large animal model that CDCs inhibit proliferation in allo-reactive lymphocytes and have potent immunosuppressive activity mediated via PGE2

Modulation of transforming growth factor beta signalling pathway genes by transforming growth factor beta in human osteoarthritic chondrocytes: involvement of Sp1 in both early and late response cells to transforming growth factor beta

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