Raloxifene for women with Alzheimer disease: A randomized controlled pilot trial

OBJECTIVE: To determine whether raloxifene, a selective estrogen receptor modulator, improves cognitive function compared with placebo in women with Alzheimer disease (AD) and to provide an estimate of cognitive effect. METHODS: This pilot study was conducted as a randomized, double-blind, placebo-controlled trial, with a planned treatment of 12 months. Women with late-onset AD of mild to moderate severity were randomly allocated to high-dose (120 mg) oral raloxifene or identical placebo provided once daily. The primary outcome compared between treatment groups at 12 months was change in the Alzheimer's Disease Assessment Scale, cognitive subscale (ADAS-cog). RESULTS: Forty-two women randomized to raloxifene or placebo were included in intent-to-treat analyses (mean age 76 years, range 68-84), and 39 women contributed 12-month outcomes. ADAS-cog change scores at 12 months did not differ significantly between treatment groups (standardized difference 0.03, 95% confidence interval -0.39 to 0.44, 2-tailed p = 0.89). Raloxifene and placebo groups did not differ significantly on secondary analyses of dementia rating, activities of daily living, behavior, or a global cognition composite score. Caregiver burden and caregiver distress were similar in both groups. CONCLUSIONS: Results on the primary outcome showed no cognitive benefits in the raloxifene-treated group. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for women with AD, raloxifene does not have a significant cognitive effect. The study lacked the precision to exclude a small effect

Role of defects in the electronic properties of amorphous/crystalline Si interface

The mechanism determining the band alignment of the amorphous/crystalline Si heterostructures is addressed with direct atomistic simulations of the interface performed using a hierarchical combination of various computational schemes ranging from classical model-potential molecular dynamics to ab-initio methods. We found that in coordination defect-free samples the band alignment is almost vanishing and independent on interface details. In defect-rich samples, instead, the band alignment is sizeably different with respect to the defect-free case, but, remarkably, almost independent on the concentration of defects. We rationalize these findings within the theory of semiconductor interfaces.Comment: 4 pages in two-column format, 2 postscript figures include

Non-traumatic Arm, Neck, and Shoulder Complaints in General Practice: Incidence, Course and Management

Non-traumatic complaints of arm, neck, and shoulder are common and can result in functional limitations in daily life and may sometimes lead to sickness absence. Reported symptoms are e.g. pain, tingling, stiffness, numbness, loss of hand coordination. When seeking medical care for these complaints, the general practitioner (GP) is usually the first person to consult. This thesis studies patients who consult their GP with a new non-traumatic complaint of arm, neck or shoulder, with a focus on incidence, course and management. The incidence study showed that a fulltime GP is consulted about 3 times every week for a new non-traumatic complaint of arm, neck, or shoulder, most frequently located at neck or shoulder. Six months after the first consultation with their GP, 46% of the patients in the cohort study reported no recovery. Next to several complaint specific variables, the psychosocial variables little social support and high score on somatization were predicitve of non-recovery at 6 months. Management upto 6 months after the first consultation most frequently consisted of prescribed analgesics and referral for physiotherapy. Specific and non-specific diagnostic subgroups differed in the frequency that corticosteroid injections were applied, and referrals to physiotherapy and to a medical specialist. In addition variables associated with five common management options within a few weeks after the first consultation were evaluated. Overall, besides diagnosis, most frequently long duration of complaints, more functional limitations but also several GP characteristics were associated with the application of a treatment option in non-traumatic arm, neck and shoulder complaints

Inclusive education in the academy: pedagogical and political imperatives in a master’s course

Many universities offer undergraduate and postgraduate courses in inclusive education. There has been much research into the impact of these courses, but little is written about their design. This article focuses on a master’s course in inclusive education in a South African university. The course positions inclusive education as a critical education project and is designed around the four propositions presented by Slee in The Irregular School (2011. Milton Park: Routledge). Using Bernsteinian ideas about pedagogising knowledge, this article accounts for the pedagogical choices made in content selection and course design. The focal questions in the course are described, together with an indication of the range of additional texts that students read. Given that Slee asserts that inclusive education is a political project, and that Allan (2010. “The Inclusive Teacher Educator: Spaces for Civic Engagement.” Discourse: Studies in the Cultural Politics of Education 31 (4): 411–422) urges inclusive teacher educators to reorientate themselves towards civic duty, I argue that producing a pedagogic discourse of inclusive education is a political task that should result in both the teacher educator and the students being oriented towards a critique of existing exclusionary arrangements and an activism that leads to change

Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis.

Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurological disturbance followed by progressive accumulation of disability. Epidemiological studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide association studies (GWAS) have enabled more than 20 additional risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the analysis of sample sizes that are beyond the numbers currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested associations and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunologically relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis

<i>Gaia</i> Data Release 1. Summary of the astrometric, photometric, and survey properties

Context. At about 1000 days after the launch of Gaia we present the first Gaia data release, Gaia DR1, consisting of astrometry and photometry for over 1 billion sources brighter than magnitude 20.7. Aims. A summary of Gaia DR1 is presented along with illustrations of the scientific quality of the data, followed by a discussion of the limitations due to the preliminary nature of this release. Methods. The raw data collected by Gaia during the first 14 months of the mission have been processed by the Gaia Data Processing and Analysis Consortium (DPAC) and turned into an astrometric and photometric catalogue. Results. Gaia DR1 consists of three components: a primary astrometric data set which contains the positions, parallaxes, and mean proper motions for about 2 million of the brightest stars in common with the HIPPARCOS and Tycho-2 catalogues – a realisation of the Tycho-Gaia Astrometric Solution (TGAS) – and a secondary astrometric data set containing the positions for an additional 1.1 billion sources. The second component is the photometric data set, consisting of mean G-band magnitudes for all sources. The G-band light curves and the characteristics of ∼3000 Cepheid and RR-Lyrae stars, observed at high cadence around the south ecliptic pole, form the third component. For the primary astrometric data set the typical uncertainty is about 0.3 mas for the positions and parallaxes, and about 1 mas yr−1 for the proper motions. A systematic component of ∼0.3 mas should be added to the parallax uncertainties. For the subset of ∼94 000 HIPPARCOS stars in the primary data set, the proper motions are much more precise at about 0.06 mas yr−1. For the secondary astrometric data set, the typical uncertainty of the positions is ∼10 mas. The median uncertainties on the mean G-band magnitudes range from the mmag level to ∼0.03 mag over the magnitude range 5 to 20.7. Conclusions. Gaia DR1 is an important milestone ahead of the next Gaia data release, which will feature five-parameter astrometry for all sources. Extensive validation shows that Gaia DR1 represents a major advance in the mapping of the heavens and the availability of basic stellar data that underpin observational astrophysics. Nevertheless, the very preliminary nature of this first Gaia data release does lead to a number of important limitations to the data quality which should be carefully considered before drawing conclusions from the data

Experiments at the margins: Ethics and transgression in cinema science

Science is a discipline defined by empiricism and reliable methodologies that result in predictable outcomes. Yet, cutting-edge experiments inevitably involve an element of the unknown, an aspect which science-fiction exploits for dramatic effect. Furthermore, fictional science is freed from the ethical constraints that regulate real-world experimentation and therefore often trangressive. Even as films capitalise on unethical practices and cutting edge scenarios for dramatic and commercial reasons, the origin of the filmmaker and/or place of production may affect a film’s content. A film is also obviously subject to legal constraints, according to the country of origin, and classification codes in its place of exhibition. Thus, while the very nature of science fiction may cause it to appear morally unbridled, there are nonetheless multiple inhibitions entrenched in such depictions. By drawing on relevant cinematic examples, including Prometheus, The Hunger Games and District 9, and scientific scenarios on which these films are based, this essay explores how the unpredictable nature of advances in science, in combination with a lack of ethics, foregrounds the dangerous dimensions of science-fiction

Genome-wide promoter analysis of histone modifications in human monocyte-derived antigen presenting cells

<p>Abstract</p> <p>Background</p> <p>Monocyte-derived macrophages and dendritic cells (DCs) are important in inflammatory processes and are often used for immunotherapeutic approaches. Blood monocytes can be differentiated into macrophages and DCs, which is accompanied with transcriptional changes in many genes, including chemokines and cell surface markers.</p> <p>Results</p> <p>To study the chromatin modifications associated with this differentiation, we performed a genome wide analysis of histone H3 trimethylation on lysine 4 (H3K4me3) and 27 (H3K27me3) as well as acetylation of H3 lysines (AcH3) in promoter regions. We report that both H3K4me3 and AcH3 marks significantly correlate with transcriptionally active genes whereas H3K27me3 mark is associated with inactive gene promoters. During differentiation, the H3K4me3 levels decreased on monocyte-specific CD14, CCR2 and CX3CR1 but increased on DC-specific TM7SF4/DC-STAMP, TREM2 and CD209/DC-SIGN genes. Genes associated with phagocytosis and antigen presentation were marked by H3K4me3 modifications. We also report that H3K4me3 levels on clustered chemokine and surface marker genes often correlate with transcriptional activity.</p> <p>Conclusion</p> <p>Our results provide a basis for further functional correlations between gene expression and histone modifications in monocyte-derived macrophages and DCs.</p

A 3D cellular context for the macromolecular world

We report the outcomes of the discussion initiated at the workshop entitled A 3D Cellular Context for the Macromolecular World and propose how data from emerging three-dimensional (3D) cellular imaging techniques—such as electron tomography, 3D scanning electron microscopy and soft X-ray tomography—should be archived, curated, validated and disseminated, to enable their interpretation and reuse by the biomedical community