Loss of CSMD1 expression disrupts mammary duct formation while enhancing proliferation, migration and invasion

The CUB and sushi multiple domains 1 (CSMD1) gene maps to chromosome 8p23, a region deleted in many cancers. Loss of CSMD1 expression is associated with poor prognosis in breast cancer suggesting that it acts as a tumour suppressor in this cancer. However, the function of CSMD1 is largely unknown. Herein, we investigated CSMD1 functions in cell line models. CSMD1 expression was suppressed in MCF10A and LNCaP cells using short hairpin RNA. Functional assays were performed focusing on the 'normal' MCF10A cell line. Suppression of CSMD1 significantly increased the proliferation, cell migration and invasiveness of MCF10A cells compared to shcontrols. shCSMD1 cells also showed significantly reduced adhesion to Matrigel and fibronectin. In a three-dimensional Matrigel model of MCF10A cells, reduced CSMD1 expression resulted in the development of larger and more poorly differentiated breast acini-like structures that displayed impaired lumen formation. Loss of CSMD1 expression disrupts a model of mammary duct formation while enhancing proliferation, migration and invasion. Our data suggest that CSMD1 is involved in the suppression of a transformed phenotype

Pre-main-sequence isochrones - III: The Cluster Collaboration isochrone server

We present an isochrone server for semi-empirical pre-main-sequence model isochrones in the following systems: Johnson–Cousins, Sloan Digital Sky Survey, Two-Micron All-Sky Survey, Isaac Newton Telescope (INT) Wide-Field Camera and INT Photometric Hα Survey (IPHAS)/UV-Excess Survey (UVEX). The server can be accessed via the Cluster Collaboration webpage http://www.astro.ex.ac.uk/people/timn/isochrones/. To achieve this, we have used the observed colours of member stars in young clusters with well-established age, distance and reddening to create fiducial loci in the colour–magnitude diagram. These empirical sequences have been used to quantify the discrepancy between the models and data arising from uncertainties in both the interior and atmospheric models, resulting in tables of semi-empirical bolometric corrections (BCs) in the various photometric systems. The model isochrones made available through the server are based on existing stellar interior models coupled with our newly derived semi-empirical BCs. As part of this analysis, we also present new cluster parameters for both the Pleiades and Praesepe, yielding ages of 135+20−11 and 665+14−7Myr as well as distances of 132 ± 2 and 184 ± 2 pc, respectively (statistical uncertainty only)

Pre-main-sequence isochrones - III. The cluster collaboration isochrone server

We present an isochrone server for semi-empirical pre-main-sequence model isochrones in the following systems: Johnson-Cousins, Sloan Digital Sky Survey, Two-Micron All-Sky Survey, Isaac Newton Telescope (INT) Wide-Field Camera and INT Photometric Ha Survey (IPHAS)/UV-Excess Survey (UVEX). The server can be accessed via the Cluster Collaboration webpage http://www.astro.ex.ac.uk/people/timn/isochrones/. To achieve this, we have used the observed colours ofmember stars in young clusters with well-established age, distance and reddening to create fiducial loci in the colour-magnitude diagram. These empirical sequences have been used to quantify the discrepancy between the models and data arising from uncertainties in both the interior and atmospheric models, resulting in tables of semi-empirical bolometric corrections (BCs) in the various photometric systems. The model isochrones made available through the server are based on existing stellar interior models coupled with our newly derived semi-empirical BCs. As part of this analysis, we also present new cluster parameters for both the Pleiades and Praesepe, yielding ages of 135+20 -11 and 665+14 -7 Myr as well as distances of 132 ± 2 and 184 ± 2 pc, respectively (statistical uncertainty only).JMR is funded by a UK Science and Technology Facilities Council (STFC) studentship. EEM acknowledges support from the National Science Foundation (NSF) Award AST-1008908. The authors would like to thank Emanuele Tognelli for the updated set of Pisa models and John Stauffer for sharing his catalogue of Kron photometric measurements of Pleiades members. The authors would also like to thank the referee for comments which have vastly improved the clarity of the manuscript. This research has made use of data obtained at the Isaac Newton Telescope, which is operated on the island of La Palma by the Isaac Newton Group (ING) in the Spanish Observatorio del Roque de los Muchachos of the Institutio de Astrofisica de Canarias. This research has made use of archival data products from the Two-Micron All-Sky Survey (2MASS), which is a joint project of the University of Massachusetts and the Infrared Processing and Analysis Center, funded by the National Aeronautics and Space Administration (NASA) and the National Science Foundation. This research has made use of public data from the SDSS. Funding for the SDSS was provided by the Alfred P. Sloan Foundation, the Participating Institutions, the National Science Foundation, the US Department of Energy, the National Aeronautics and Space Administration, the Japanese Monbukagakusho, the Max Planck Society and the Higher Education Funding Council for England. The SDSS was managed by the Astrophysical Research Consortium for the Participating Institutions

Cerebrospinal fluid and plasma neurofilament light relate to abnormal cognition

Introduction Neuroaxonal damage may contribute to cognitive changes preceding clinical dementia. Accessible biomarkers are critical for detecting such damage. Methods Plasma and cerebrospinal fluid (CSF) neurofilament light (NFL) were related to neuropsychological performance among Vanderbilt Memory & Aging Project participants (plasma n = 333, 73 ± 7 years; CSF n = 149, 72 ± 6 years) ranging from normal cognition (NC) to mild cognitive impairment (MCI). Models adjusted for age, sex, race/ethnicity, education, apolipoprotein E ε4 carriership, and Framingham Stroke Risk Profile. Results Plasma NFL was related to all domains (P values ≤ .008) except processing speed (P values ≥ .09). CSF NFL was related to memory and language (P values ≤ .04). Interactions with cognitive diagnosis revealed widespread plasma associations, particularly in MCI participants, which were further supported in head-to-head comparison models. Discussion Plasma and CSF NFL (reflecting neuroaxonal injury) relate to cognition among non-demented older adults albeit with small to medium effects. Plasma NFL shows particular promise as an accessible biomarker with relevance to cognition in MCI

Mild Cognitive Impairment Staging Yields Genetic Susceptibility, Biomarker, and Neuroimaging Differences

INTRODUCTION: While Alzheimer’s disease (AD) is divided into severity stages, mild cognitive impairment (MCI) remains a solitary construct despite clinical and prognostic heterogeneity. This study aimed to characterize differences in genetic, cerebrospinal fluid (CSF), neuroimaging, and neuropsychological markers across clinician-derived MCI stages. METHODS: Vanderbilt Memory & Aging Project participants with MCI were categorized into 3 severity subtypes at screening based on neuropsychological assessment, functional assessment, and Clinical Dementia Rating interview, including mild (n = 18, 75 ± 8 years), moderate (n = 89 72 ± 7 years), and severe subtypes (n = 18, 78 ± 8 years). At enrollment, participants underwent neuropsychological testing, 3T brain magnetic resonance imaging (MRI), and optional fasting lumbar puncture to obtain CSF. Neuropsychological testing and MRI were repeated at 18-months, 3-years, and 5-years with a mean follow-up time of 3.3 years. Ordinary least square regressions examined cross-sectional associations between MCI severity and apolipoprotein E (APOE)-ε4 status, CSF biomarkers of amyloid beta (Aβ), phosphorylated tau, total tau, and synaptic dysfunction (neurogranin), baseline neuroimaging biomarkers, and baseline neuropsychological performance. Longitudinal associations between baseline MCI severity and neuroimaging and neuropsychological trajectory were assessed using linear mixed effects models with random intercepts and slopes and a follow-up time interaction. Analyses adjusted for baseline age, sex, race/ethnicity, education, and intracranial volume for MRI models. RESULTS: Stages differed at baseline on APOE-ε4 status (early middle = late), phosphorylated and total tau (early = middle < late; p-values < 0.05), and neurogranin concentrations (early = middle < late; p-values < 0.05). MCI stage related to greater longitudinal cognitive decline, hippocampal atrophy, and inferior lateral ventricle dilation (early < late; p-values < 0.03). DISCUSSION: Clinician staging of MCI severity yielded longitudinal cognitive trajectory and structural neuroimaging differences in regions susceptible to AD neuropathology and neurodegeneration. As expected, participants with more severe MCI symptoms at study entry had greater cognitive decline and gray matter atrophy over time. Differences are likely attributable to baseline differences in amyloidosis, tau, and synaptic dysfunction. MCI staging may provide insight into underlying pathology, prognosis, and therapeutic targets

General practitioners' perceptions on home medicines reviews: A qualitative analysis

Background: Home Medicines Review (HMR) is an Australian initiative introduced in 2001 to improve quality use of medicines. Medication management services such as HMRs have the potential to reduce medication related problems. In 2011, changes to the HMR program were introduced to allow for referrals directly to accredited pharmacists in addition to the community pharmacy referral model. These changes were introduced to improve efficiency of the process. This study explored the perceptions of Western Australian general practitioners (GPs) on benefits and barriers of the HMR service and process, including their insights into the direct referral model. Methods: Purposive sampling of GPs who had experience ensured that participants had a working knowledge of the HMR service. Semi structured interviews with 24 GPs from 14 metropolitan Western Australian medical centres between March and May 2013. Transcribing and thematic analysis of data were performed. Results: Most GPs had positive attitudes towards the HMR service. Main perceived benefits of the service were poly-pharmacy reduction and education for both the GP and patient. Strategies identified to improve the service were introduction of a standard HMR report template for pharmacists and better use of technology. Whilst reliability and GPs' familiarity were the main perceived benefits of the direct referral model, a number of GPs agreed that patient unfamiliarity with the HMR pharmacist was a barrier. Conclusions: Despite recognition of the value of the HMR service participating GPs were of the opinion that there are aspects of the HMR service that could be improved. As one of the success factors of HMRs is relying on GPs to utilise this service, this study provides valuable insight into issues that need to be addressed to improve HMR uptake

Safety of anti-immunoglobulin E therapy with omalizumab in allergic patients at risk of geohelminth infection

BACKGROUND: Although the role of immunoglobulin E (IgE) in immunity against helminth parasites is unclear, there is concern that therapeutic antibodies that neutralize IgE (anti-IgE) may be unsafe in subjects at risk of helminth infection. OBJECTIVE: We conducted an exploratory study to investigate the safety of omalizumab (anti-IgE) in subjects with allergic asthma and/or perennial allergic rhinitis at high risk of intestinal helminth infection. The primary safety outcome was risk of infections with intestinal helminths during anti-IgE therapy. METHODS: A randomized, double-blind, placebo-controlled trial was conducted in 137 subjects (12–30 years) at high risk of geohelminth infection. All subjects received pre-study anthelmintic treatment, followed by 52 weeks' treatment with omalizumab or placebo. RESULTS: Of the omalizumab subjects 50% (34/68) experienced at least one intestinal geohelminth infection compared with 41% (28/69) of placebo subjects [odds ratio (OR) 1.47, 95% confidence interval (CI) 0.74–2.95, one-sided P = 0.14; OR (adjusted for study visit, baseline infection status, gender and age) 2.2 (0.94–5.15); one-sided P = 0.035], providing some evidence for a potential increased incidence of geohelminth infection in subjects receiving omalizumab. Omalizumab therapy was well tolerated, and did not appear to be associated with increased morbidity attributable to intestinal helminths as assessed by clinical and laboratory adverse events, maximal helminth infection intensities and additional anthelmintic requirements. Time to first infection (OR 1.30, 95% CI 0.79–2.15, one-sided P = 0.15) was similar between treatment groups. Infection severity and response to anthelmintics appeared to be unaffected by omalizumab therapy. CONCLUSIONS: In this exploratory study of allergic subjects at high risk of helminth infections, omalizumab therapy appeared to be safe and well tolerated, but may be associated with a modest increase in the incidence of geohelminth infection

Lower Left Ventricular Ejection Fraction Relates to Cerebrospinal Fluid Biomarker Evidence of Neurodegeneration in Older Adults

BACKGROUND: Subclinical cardiac dysfunction is associated with decreased cerebral blood flow, placing the aging brain at risk for Alzheimer's disease (AD) pathology and neurodegeneration. OBJECTIVE: This study investigates the association between subclinical cardiac dysfunction, measured by left ventricular ejection fraction (LVEF), and cerebrospinal fluid (CSF) biomarkers of AD and neurodegeneration. METHODS: Vanderbilt Memory & Aging Project participants free of dementia, stroke, and heart failure (n = 152, 72±6 years, 68% male) underwent echocardiogram to quantify LVEF and lumbar puncture to measure CSF levels of amyloid-β42 (Aβ42), phosphorylated tau (p-tau), and total tau (t-tau). Linear regressions related LVEF to CSF biomarkers, adjusting for age, sex, race/ethnicity, education, Framingham Stroke Risk Profile, cognitive diagnosis, and apolipoprotein E ɛ4 status. Secondary models tested an LVEF x cognitive diagnosis interaction and then stratified by diagnosis (normal cognitive (NC), mild cognitive impairment (MCI)). RESULTS: Higher LVEF related to decreased CSF Aβ42 levels (β= -6.50, p = 0.04) reflecting greater cerebral amyloid accumulation, but this counterintuitive result was attenuated after excluding participants with cardiovascular disease and atrial fibrillation (p = 0.07). We observed an interaction between LVEF and cognitive diagnosis on CSF t-tau (p = 0.004) and p-tau levels (p = 0.002), whereas lower LVEF was associated with increased CSF t-tau (β= -9.74, p = 0.01) and p-tau in the NC (β= -1.41, p = 0.003) but not MCI participants (p-values>0.13). CONCLUSIONS: Among cognitively normal older adults, subclinically lower LVEF relates to greater molecular evidence of tau phosphorylation and neurodegeneration. Modest age-related changes in cardiovascular function may have implications for pathophysiological changes in the brain later in life

The characteristic blue spectra of accretion disks in quasars as uncovered in the infrared

Quasars are thought to be powered by supermassive black holes accreting surrounding gas. Central to this picture is a putative accretion disk which is believed to be the source of the majority of the radiative output. It is well known, however, that the most extensively studied disk model -- an optically thick disk which is heated locally by the dissipation of gravitational binding energy -- is apparently contradicted by observations in a few major respects. In particular, the model predicts a specific blue spectral shape asymptotically from the visible to the near-infrared, but this is not generally seen in the visible wavelength region where the disk spectrum is observable. A crucial difficulty was that, toward the infrared, the disk spectrum starts to be hidden under strong hot dust emission from much larger but hitherto unresolved scales, and thus has essentially been impossible to observe. Here we report observations of polarized light interior to the dust-emiting region that enable us to uncover this near-infrared disk spectrum in several quasars. The revealed spectra show that the near-infrared disk spectrum is indeed as blue as predicted. This indicates that, at least for the outer near-infrared-emitting radii, the standard picture of the locally heated disk is approximately correct. The model problems at shorter wavelengths should then be directed toward a better understanding of the inner parts of the revealed disk. The newly uncovered disk emission at large radii, with more future measurements, will also shed totally new light on the unanswered critical question of how and where the disk ends.Comment: published in Nature, 24 July 2008 issue. Supplementary Information can be found at http://www.mpifr-bonn.mpg.de/div/ir-interferometry/suppl_info.pdf Published version can be accessed from http://www.nature.com/nature/journal/v454/n7203/pdf/nature07114.pd