Whole-body MRI of patients with polymyalgia rheumatica identifies a distinct subset with complete patient-reported response to glucocorticoids

Objectives: To determine whether whole-body MRI defines clinically-relevant subgroups within polymyalgia rheumatica (PMR) including glucocorticoid responsiveness. Methods: 22 patients with PMR and 16 with rheumatoid arthritis, untreated and diagnosed by consultant rheumatologists, underwent whole-body, multiple-joint MRI, scored by two experts. PMR patients reported whether they felt “back to normal” on glucocorticoid therapy and were followed for a median of 2 years. Results: All PMR patients were deemed to respond to glucocorticoids clinically. A characteristic pattern of symmetrical, extracapsular inflammation, adjacent to greater trochanter, acetabulum, ischial tuberosity and/or symphysis pubis, was observed in 14/22 of the PMR cases. In PMR, this pattern was associated with complete glucocorticoid response (p=0.01), higher pre-treatment C-reactive protein (CRP) and serum IL-6, and better post-treatment fatigue and function. Only 1/14 in the extracapsular group could stop glucocorticoids within 1 year, compared to 4/7 of the others. A score derived from the five sites discriminating best between PMR and RA correlated with IL-6 (p<0.002). IL-6 levels ≥16.8 pg/mL had 86% sensitivity and 86% specificity for the extracapsular MRI pattern. Conclusions: A subset of patients with rheumatologist-diagnosed PMR had a characteristic, extracapsular pattern of MRI inflammation, associated with elevated IL-6/CRP and with complete patient-reported glucocorticoid responsiveness

Structure of the X-ray Emission from the Jet of 3C 273

We present images from five observations of the quasar 3C 273 with the Chandra X-ray Observatory. The jet has at least four distinct features which are not resolved in previous observations. The first knot in the jet (A1) is very bright in X-rays. Its X-ray spectrum is well fitted with a power law with alpha = 0.60 +/- 0.05. Combining this measurement with lower frequency data shows that a pure synchrotron model can fit the spectrum of this knot from 1.647 GHz to 5 keV (over nine decades in energy) with alpha = 0.76 +/- 0.02, similar to the X-ray spectral slope. Thus, we place a lower limit on the total power radiated by this knot of 1.5e43 erg/s; substantially more power may be emitted in the hard X-ray and gamma-ray bands. Knot A2 is also detected and is somewhat blended with knot B1. Synchrotron emission may also explain the X-ray emission but a spectral bend is required near the optical band. For knots A1 and B1, the X-ray flux dominates the emitted energy. For the remaining optical knots (C through H), localized X-ray enhancements that might correspond to the optical features are not clearly resolved. The position angle of the jet ridge line follows the optical shape with distinct, aperiodic excursions of +/-1 deg from a median value of -138.0deg. Finally, we find X-ray emission from the ``inner jet'' between 5 and 10" from the core.Comment: 10 pages, 5 figures; accepted for publication in the Astrophysical Journal Letters. For the color image, see fig1.ps or http://space.mit.edu/~hermanm/papers/3c273/fig1.jp

Synthetic Lethal Targeting of PTEN-Deficient Cancer Cells Using Selective Disruption of Polynucleotide Kinase/Phosphatase

A recent screen of 6,961 siRNAs to discover possible synthetic lethal partners of the DNA repair protein polynucleotide kinase/phosphatase (PNKP) led to the identification of the potent tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN). Here, we have confirmed the PNKP/PTEN synthetic lethal partnership in a variety of different cell lines including the PC3 prostate cancer cell line, which is naturally deficient in PTEN. We provide evidence that codepletion of PTEN and PNKP induces apoptosis. In HCT116 colon cancer cells, the loss of PTEN is accompanied by an increased background level of DNA double-strand breaks, which accumulate in the presence of an inhibitor of PNKP DNA 3'-phosphatase activity. Complementation of PC3 cells with several well-characterized mutated PTEN cDNAs indicated that the critical function of PTEN required to prevent toxicity induced by an inhibitor of PNKP is most likely associated with its cytoplasmic lipid phosphatase activity. Finally, we show that modest inhibition of PNKP in a PTEN knockout background enhances cellular radiosensitivity, suggesting that such a "synthetic sickness" approach involving the combination of PNKP inhibition with radiotherapy may be applicable to PTEN-deficient tumors

Reducing the health disparities of Indigenous Australians: time to change focus

Background: Indigenous peoples have worse health than non-Indigenous, are over-represented amongst the poor and disadvantaged, have lower life expectancies, and success in improving disparities is limited. To address this, research usually focuses on disadvantaged and marginalised groups, offering only partial understanding of influences underpinning slow progress. Critical analysis is also required of those with the power to perpetuate or improve health inequities. In this paper, using Australia as a case example, we explore the effects of ‘White’, Anglo-Australian cultural dominance in health service delivery to Indigenous Australians. We address the issue using race as an organising principle, underpinned by relations of power.Methods: Interviews with non-Indigenous medical practitioners in Western Australia with extensive experience in Indigenous health encouraged reflection and articulation of their insights into factors promoting or impeding quality health care to Indigenous Australians. Interviews were audio-taped and transcribed. An inductive, exploratory analysis identified key themes that were reviewed and interrogated in light of existing literature on health care to Indigenous people, race and disadvantage. The researchers’ past experience, knowledge and understanding of health care and Indigenous health assisted with data interpretation. Informal discussions were also held with colleagues working professionally in Indigenous policy, practice and community settings.Results: Racism emerged as a key issue, leading us to more deeply interrogate the role ‘Whiteness’ plays in Indigenous health care. While Whiteness can refer to skin colour, it also represents a racialized social structure where Indigenous knowledge, beliefs and values are subjugated to the dominant western biomedical model in policy and practice. Racism towards Indigenous patients in health services was institutional and interpersonal. Internalised racism was manifest when Indigenous patients incorporated racist attitudes and beliefs into their lived experience, lowering expectations and their sense of self-worth.Conclusions: Current health policies and practices favour standardised care where the voice of those who are marginalised is often absent. Examining the effectiveness of such models in reducing health disparities requires health providers to critically reflect on whether policies and practices promote or compromise Indigenous health and wellbeing - an important step in changing the discourse that places Indigenous people at the centre of the problem

Acinetobacter baumannii Infection Inhibits Airway Eosinophilia and Lung Pathology in a Mouse Model of Allergic Asthma

Allergic asthma is a dysregulation of the immune system which leads to the development of Th2 responses to innocuous antigens (allergens). Some infections and microbial components can re-direct the immune response toward the Th1 response, or induce regulatory T cells to suppress the Th2 response, thereby inhibiting the development of allergic asthma. Since Acinetobacter baumannii infection can modulate lung cellular and cytokine responses, we studied the effect of A. baumannii in modulating airway eosinophilia in a mouse model of allergic asthma. Ovalbumin (OVA)-sensitized mice were treated with live A. baumannii or phosphate buffered saline (PBS), then intranasally challenged with OVA. Compared to PBS, A. baumannii treatment significantly reduced pulmonary Th2 cytokine and chemokine responses to OVA challenge. More importantly, the airway inflammation in A. baumannii-treated mice was strongly suppressed, as seen by the significant reduction of the proportion and the total number of eosinophils in the bronchoalveolar lavage fluid. In addition, A. baumannii-treated mice diminished lung mucus overproduction and pathology. However, A. baumannii treatment did not significantly alter systemic immune responses to OVA. Serum OVA-specific IgE, IgG1 and IgG2a levels were comparable between A. baumannii- and PBS-treated mice, and tracheobronchial lymph node cells from both treatment groups produced similar levels of Th1 and Th2 cytokines in response to in vitro OVA stimulation. Moreover, it appears that TLR-4 and IFN-γ were not directly involved in the A. baumannii-induced suppression of airway eosinophilia. Our results suggest that A. baumannii inhibits allergic airway inflammation by direct suppression of local pulmonary Th2 cytokine responses to the allergen

A review of elliptical and disc galaxy structure, and modern scaling laws

A century ago, in 1911 and 1913, Plummer and then Reynolds introduced their models to describe the radial distribution of stars in `nebulae'. This article reviews the progress since then, providing both an historical perspective and a contemporary review of the stellar structure of bulges, discs and elliptical galaxies. The quantification of galaxy nuclei, such as central mass deficits and excess nuclear light, plus the structure of dark matter halos and cD galaxy envelopes, are discussed. Issues pertaining to spiral galaxies including dust, bulge-to-disc ratios, bulgeless galaxies, bars and the identification of pseudobulges are also reviewed. An array of modern scaling relations involving sizes, luminosities, surface brightnesses and stellar concentrations are presented, many of which are shown to be curved. These 'redshift zero' relations not only quantify the behavior and nature of galaxies in the Universe today, but are the modern benchmark for evolutionary studies of galaxies, whether based on observations, N-body-simulations or semi-analytical modelling. For example, it is shown that some of the recently discovered compact elliptical galaxies at 1.5 < z < 2.5 may be the bulges of modern disc galaxies.Comment: Condensed version (due to Contract) of an invited review article to appear in "Planets, Stars and Stellar Systems"(www.springer.com/astronomy/book/978-90-481-8818-5). 500+ references incl. many somewhat forgotten, pioneer papers. Original submission to Springer: 07-June-201

LSST: from Science Drivers to Reference Design and Anticipated Data Products

(Abridged) We describe here the most ambitious survey currently planned in the optical, the Large Synoptic Survey Telescope (LSST). A vast array of science will be enabled by a single wide-deep-fast sky survey, and LSST will have unique survey capability in the faint time domain. The LSST design is driven by four main science themes: probing dark energy and dark matter, taking an inventory of the Solar System, exploring the transient optical sky, and mapping the Milky Way. LSST will be a wide-field ground-based system sited at Cerro Pach\'{o}n in northern Chile. The telescope will have an 8.4 m (6.5 m effective) primary mirror, a 9.6 deg$^2$ field of view, and a 3.2 Gigapixel camera. The standard observing sequence will consist of pairs of 15-second exposures in a given field, with two such visits in each pointing in a given night. With these repeats, the LSST system is capable of imaging about 10,000 square degrees of sky in a single filter in three nights. The typical 5$\sigma$ point-source depth in a single visit in $r$ will be $\sim 24.5$ (AB). The project is in the construction phase and will begin regular survey operations by 2022. The survey area will be contained within 30,000 deg$^2$ with $\delta<+34.5^\circ$, and will be imaged multiple times in six bands, $ugrizy$, covering the wavelength range 320--1050 nm. About 90\% of the observing time will be devoted to a deep-wide-fast survey mode which will uniformly observe a 18,000 deg$^2$ region about 800 times (summed over all six bands) during the anticipated 10 years of operations, and yield a coadded map to $r\sim27.5$. The remaining 10\% of the observing time will be allocated to projects such as a Very Deep and Fast time domain survey. The goal is to make LSST data products, including a relational database of about 32 trillion observations of 40 billion objects, available to the public and scientists around the world.Comment: 57 pages, 32 color figures, version with high-resolution figures available from https://www.lsst.org/overvie