Effects of 1,25 Dihydroxyvitamin D3 and Calcium on Growth and Differentiation and on c-fos and p53 Gene Expression in Normal Human Keratinocytes

Calcium enhances keratinocyte differentiation, and 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) is both antiproliferative and prodifferentiative in many cell types, including normal human keratinocytes. In the present study, we examined the combined effects of calcium and 1,25(OH)2D3 on parameters of growth and differentiation and on c-fos and p53 gene expression in normal human keratinocytes. Exposure of normal human keratinocytes to 1,25(OH)2D3 markedly reduced [3H] thymidine incorporation and cell number at low and high medium Ca++ concentrations. Simultaneously, cells in the G0/G1 phase of the cell cycle increased significantly and those in the S phase fell precipitously. l,25(OH)2D3 and calcium also induced keratinocyte differentiation independently, as assessed by iminuno- cytochemistry and by induction of involucrin mRNA. Both Ca++ and 1,25(OH)2D3 were shown, by nuclear run-on assays, to increase involucrin gene transcription. A rapid, transient elevation in c-fos protooncogene expression preceded these effects when epidermal growth factor was present alone. When 1,25(OH)2D3 was added to quiescent keratinocytes, there was a marked augmentation of c-fos mRNA accumulation at low and high medium Ca++ concentrations. Varying medium Ca++ concentrations had no effect on c-fos mRNA levels. Increasing medium Ca++ concentrations from 0.15 to 2.0mM produced marked elevations of p53 mRNA accumulation and of the rate of p53 gene transcription, whereas 1,25(OH)2D3 had no effect.These results, therefore, suggest that 1,25(OH)2D3 and calcium act in concert to modulate the expression of two important cell-cycle-associated genes, which may be important components in the initial programming of growth and differentiation of normal human keratinocytes

Does it measure up? A comparison of pollution exposure assessment techniques applied across hospitals in England

Weighted averages of air pollution measurements from monitoring stations are commonly assigned as air pollution exposures to specific locations. However, monitoring networks are spatially sparse and fail to adequately capture the spatial variability. This may introduce bias and exposure misclassification. Advanced methods of exposure assessment are rarely practicable in estimating daily concentrations over large geographical areas. We propose an accessible method using temporally adjusted land use regression models (daily LUR). We applied this to produce daily concentration estimates for nitrogen dioxide, ozone, and particulate matter in a healthcare setting across England and compared them against geographically extrapolated measurements (inverse distance weighting) from air pollution monitors. The daily LUR estimates outperformed IDW. The precision gains varied across air pollutants, suggesting that, for nitrogen dioxide and particulate matter, the health effects may be underestimated. The results emphasised the importance of spatial heterogeneity in investigating the societal impacts of air pollution, illustrating improvements achievable at a lower computational cost

Targeting the Oxytocin System: New Pharmacotherapeutic Approaches

Deficits in social behavioral domains, such as interpersonal communication, emotion recognition, and empathy, are a characteristic symptom in several neuropsychiatric disorders, including schizophrenia and autism spectrum disorder (ASD). The neuropeptide oxytocin (OT) has emerged as a key regulator of diverse social behaviors in vertebrates and, thus, has been identified as a potential therapeutic target for improving social dysfunction. In recent years, the field of OT research has seen an explosion of scientific inquiry, producing a more comprehensive picture of oxytocinergic signaling and the pathways that regulate its release and degradation in the brain. In this review, we provide an analysis of how this information is being exploited to accelerate the discovery of novel oxytocinergic therapeutics

Demography, baseline disease characteristics and treatment history of patients with psoriasis enrolled in a multicentre, prospective, disease-based registry (PSOLAR)*

Summary Background: Psoriasis is associated with several comorbidities and behavioural risk factors. Objectives: To evaluate demographic and disease characteristics in patients enrolled in the Psoriasis Longitudinal Assessment and Registry (PSOLAR). Methods: PSOLAR is a global, prospective, longitudinal, disease-based registry that includes a postmarketing commitment to evaluate safety in patients with psoriasis. Enrolled patients had to be receiving, or be eligible to receive, conventional systemic or biological agents. Demographic/disease characteristics, medical histories, lifestyle risk factors and previous treatments are collected at enrolment. Efficacy and safety data are collected every 6 months for 8 years, and data are extracted annually. Selected parameters are evaluated by age quartile using post hoc analyses. Results: As of 23 August 2012, 11 900 patients were enrolled at 301 sites in North America, Europe and Latin America. Over half of the PSOLAR population (54·7%) is male, with a mean age of 48·6 years and mean body mass index of 30·9 kg m−2 at enrolment. Mean duration of disease at enrolment was 17·5 years, and mean Physician's Global Assessment score was 2·0. Psoriatic arthritis (35·5%) and cardiovascular diseases (38·2%) were highly prevalent. Diabetes mellitus type II was reported in 11·4% of patients. Depression and anxiety were noted in 14·7% and 11·1% of patients, respectively; 79·0% reported any alcohol use and 56·7% reported smoking or a history of smoking. The occurrence of most comorbidities, including cardiovascular disease and risk factors, increased with age. Conclusions: In the PSOLAR population, multiple and age-appropriate comorbidities are associated with psoriasis and may affect the selection of psoriasis treatments. What's already known about this topic? Psoriasis is a complicated disorder, often accompanied by multiple comorbidities. Demographic and disease characteristics of patients with psoriasis reported from large claims datasets may be affected by misclassification bias or coding errors. In clinical trials, many patients are excluded owing to strict inclusion criteria. What does this study add? Data collected by the Psoriasis Longitudinal Assessment and Registry reveal that the demographics and disease characteristics of patients with psoriasis who are receiving, or are candidates for, systemic therapy in actual clinical care resemble those reported in clinical trials. Most comorbidities occur more frequently in older patients, who, in turn, may require more comprehensive overall medical care

Mulsemedia: State of the art, perspectives, and challenges

Mulsemedia-multiple sensorial media-captures a wide variety of research efforts and applications. This article presents a historic perspective on mulsemedia work and reviews current developments in the area. These take place across the traditional multimedia spectrum-from virtual reality applications to computer games-as well as efforts in the arts, gastronomy, and therapy, to mention a few. We also describe standardization efforts, via the MPEG-V standard, and identify future developments and exciting challenges the community needs to overcome

Using environmental tracers to evaluate the preservation of palaeoclimate signals in aquifers of the London Basin, UK

The concept of aquifer basins as palaeoclimate archives has existed for some decades, yet few detailed studies comparing aquifer types have been carried out. To assess the potential of a particular aquifer as an archive, its hydrogeochemical characteristics must be thoroughly investigated, ideally in comparison to an adjacent aquifer which can be shown to substantially preserve its ice-age endowment at depth. The London Basin (UK) presents such an opportunity, containing two main aquifers of contrasting type: the Chalk, a fractured microporous limestone, and the Lower Greensand, a porous sandstone. Despite intensive exploitation of both, evidence for Devensian (late-glacial) water remains at depth, though this differs between aquifer type. To understand the reasons for this, a suite of environmental tracers has been applied. In addition to hydrochemistry, stable isotopes (δ18O, δ2H), carbon isotopes (δ13C-DIC, 14C-DIC) and noble gases (He, Ne, Ar, Kr and Xe), two tracers new to the basin (CFCs and 14C-DOC) have been used. In effect the Lower Greensand appears to be the ‘reference aquifer’, preserving recharge from prior to the Last Glacial Maximum (LGM), while the Chalk contains mixed water, with no remaining trace of the undiluted pre-LGM end member even at depth in remote parts of the confined basin. Whereas both aquifers had in the past given maximum 14C-DIC model ages ≥ 30 kyr (the effective limit of that method), in the present study the use of 14C-DOC has reduced this to 23.4 kyr (Lower Greensand) and 17.2 kyr (Chalk). Similar contrasts in maximum stable isotope depletions (−8.2 ‰ and −7.8 ‰ δ18O) and noble-gas-derived recharge temperature minima (2.6° and 4.1 °C) were also observed. CFCs were found at all Chalk sites, with traces detectable even at 40 km from outcrop, so some climate signal degradation appears inevitable throughout the Chalk aquifer of the basin. A correlation between 14C activity and excess 4He suggests that deep saline water in the Lower Greensand could be ≥ 50 kyr old. The use of 14C-DOC in particular appears to be key to understanding how reliable these individual aquifers are as palaeoarchives

The HgMn Binary Star Phi Herculis: Detection and Properties of the Secondary and Revision of the Elemental Abundances of the Primary

Observations of the Mercury-Manganese star Phi Herculis with the Navy Prototype Optical Interferometer (NPOI) conclusively reveal the previously unseen companion in this single-lined binary system. The NPOI data were used to predict a spectral type of A8V for the secondary star Phi Her B. This prediction was subsequently confirmed by spectroscopic observations obtained at the Dominion Astrophysical Observatory. Phi Her B is rotating at 50 +/-3 km/sec, in contrast to the 8 km/sec lines of Phi Her A. Recognizing the lines from the secondary permits one to separate them from those of the primary. The abundance analysis of Phi Her A shows an abundance pattern similar to those of other HgMn stars with Al being very underabundant and Sc, Cr, Mn, Zn, Ga, Sr, Y, Zr, Ba, Ce, and Hg being very overabundant.Comment: Accepted to ApJ, 45 pages, 11 figure

First evidence of pulsations in Vega? Results of today's most extensive spectroscopic search

The impact of rapid rotation on stellar evolution theory remains poorly understood as of today. Vega is a special object in this context as spectroscopic and interferometric studies have shown that it is a rapid rotator seen nearly pole one, a rare orientation particularly interesting for seismic studies. In this paper we present a first systematic search for pulsations in Vega. The goal of the present work is to detect for the first time pulsations in a rapidly rotating star seen nearly pole-on. Vega was monitored in quasi-continuous high-resolution echelle spectroscopy. A total of 4478 spectra were obtained within 3 individual runs in 2008, 2009 and 2010 at high resolution. This data set should represent the most extensive high S/N, high resolution quasi-continuous survey obtained on Vega as of today. Equivalent photospheric absorption profiles were calculated for the stellar spectrum, but also for the telluric lines acting as a radial velocity reference. Residual velocities were analysed and periodic low amplitude variations, potentially indicative of stellar pulsations, detected. All three data sets revealed the presence of residual periodic variations: 5.32 and 9.19 c/d, (A approx 6 m/s) in 2008, 12.71 and 13.25 c/d, (A approx 8 m/s) in 2009 and 5.42 and 10.82 c/d, (A approx 3-4 m/s) in 2010. A Lomb-Scargle periodogram of each velocity bin of the equivalent profile was performed for the 2010 run, not showing the presence of any higher order nrp mode. It is too early to conclude that the variations are due to stellar pulsations, and a confirmation of the detection with a highly stable spectrograph is a necessary next step. If pulsations are confirmed, their very small amplitudes show that the star would belong to a category of very "quiet" pulsators

Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial

Objective: Assess ustekinumab efficacy (week 24/week 52) and safety (week 16/week 24/week 60) in patients with active psoriatic arthritis (PsA) despite treatment with conventional and/or biological anti-tumour necrosis factor (TNF) agents. Methods: In this phase 3, multicentre, placebo-controlled trial, 312 adults with active PsA were randomised (stratified by site, weight (≤100 kg/>100 kg), methotrexate use) to ustekinumab 45 mg or 90 mg at week 0, week 4, q12 weeks or placebo at week 0, week 4, week 16 and crossover to ustekinumab 45 mg at week 24, week 28 and week 40. At week 16, patients with <5% improvement in tender/swollen joint counts entered blinded early escape (placebo→45 mg, 45 mg→90 mg, 90 mg→90 mg). The primary endpoint was ≥20% improvement in American College of Rheumatology (ACR20) criteria at week 24. Secondary endpoints included week 24 Health Assessment Questionnaire-Disability Index (HAQ-DI) improvement, ACR50, ACR70 and ≥75% improvement in Psoriasis Area and Severity Index (PASI75). Efficacy was assessed in all patients, anti-TNF-naïve (n=132) patients and anti-TNF-experienced (n=180) patients. Results: More ustekinumab-treated (43.8% combined) than placebo-treated (20.2%) patients achieved ACR20 at week 24 (p<0.001). Significant treatment differences were observed for week 24 HAQ-DI improvement (p<0.001), ACR50 (p≤0.05) and PASI75 (p<0.001); all benefits were sustained through week 52. Among patients previously treated with ≥1 TNF inhibitor, sustained ustekinumab efficacy was also observed (week 24 combined vs placebo: ACR20 35.6% vs 14.5%, PASI75 47.1% vs 2.0%, median HAQ-DI change −0.13 vs 0.0; week 52 ustekinumab-treated: ACR20 38.9%, PASI75 43.4%, median HAQ-DI change −0.13). No unexpected adverse events were observed through week 60. Conclusions: The interleukin-12/23 inhibitor ustekinumab (45/90 mg q12 weeks) yielded significant and sustained improvements in PsA signs/symptoms in a diverse population of patients with active PsA, including anti-TNF-experienced PsA patients

Genesis and development of an interfluvial peatland in the central Congo Basin since the Late Pleistocene

The central Congo Basin contains the largest known peatland complex in the tropics. Here we present a detailed multi-proxy record from a peat core, CEN-17.4, from the centre of a 45 km wide interfluvial peatland (Ekolongouma), the first record of its kind from the central Congo peatlands. We use pollen, charcoal, sedimentological and geochemical data to reconstruct the site's history from the late Pleistocene to the present day. Peat began accumulating at the centre of the peatland ∼19,600 cal BP (∼17,500–20,400 cal BP, 95% confidence interval), and between ∼9500 (9430–9535 cal BP) and 10,500 (10,310–10,660 cal BP) cal BP towards the margins. Pollen data from the peatland centre show that an initial grass- and sedge-dominated vegetation, which burned frequently, was replaced by a Manilkara-type dominated flooded forest at ∼12,640 cal BP, replaced in turn by a more mixed swamp forest at ∼9670 cal BP. Mixed swamp forest vegetation has persisted to the present day, with variations in composition and canopy openness likely caused at least in part by changes in palaeo-precipitation. Stable isotope data (δDn-C29-v&icecorr) indicate a large reduction in precipitation beginning ∼5000 and peaking ∼2000 cal BP, associated with the near-complete mineralization of several metres of previously accumulated peat and with a transition to a drier, more heliophilic swamp forest assemblage, likely with a more open canopy. Although the peatland and associated vegetation recovered from this perturbation, the strong response to this climatic event underlines the ecosystem's sensitivity to changes in precipitation. We find no conclusive evidence for anthropogenic activity in our record; charcoal is abundant only in the Pleistocene part of the record and may reflect natural rather than anthropogenic fires. We conclude that autogenic succession and variation in the amount and seasonality of precipitation have been the most important drivers of ecological change in this peatland since the late Pleistocene