A 4% Geometric Distance to the Galaxy NGC4258 from Orbital Motions in a Nuclear Gas Disk

The water maser in the mildly active nucleus in the nearby galaxy NGC4258 traces a thin, nearly edge-on, subparsec-scale Keplerian disk. Using the technique of very long baseline interferometry, we have detected the proper motions of these masers as they sweep in front of the central black hole at an orbital velocity of about 1100 km/s. The average maser proper motion of 31.5 microarcseconds per year is used in conjunction with the observed acceleration of the masers to derive a purely geometric distance to the galaxy of 7.2 +- 0.3 Mpc. This is the most precise extragalactic distance measured to date, and, being independent of all other distance indicators, is likely to play an important role in calibrating the extragalactic distance scale.Comment: 11 pages, 3 figures. Accepted for publication in Natur

Glial sulfatides and neuronal complex gangliosides are functionally interdependent in maintaining myelinating axon integrity

Sulfatides and gangliosides are raft-associated glycolipids essential for maintaining myelinated nerve integrity. Mice deficient in sulfatide (cerebroside sulfotransferase knockout, CST-/- ) or complex gangliosides (β-1,4-N-acetylegalactosaminyltransferase1 knockout, GalNAc-T-/- ) display prominent disorganization of proteins at the node of Ranvier (NoR) in early life, and age-dependent neurodegeneration. Loss of neuronal rather than glial complex gangliosides underpins the GalNAc-T-/- phenotype, as shown by neuron or glial-specific rescue, whereas sulfatide is principally expressed and functional in glial membranes. The similarities in NoR phenotype of CST-/- , GalNAc-T-/- and axo-glial protein deficient mice suggests these glycolipids stabilise membrane proteins including neurofascin155 (NF155) and myelin-associated glycoprotein (MAG) at axo-glial junctions. To assess the functional interactions between sulfatide and gangliosides, CST-/- and GalNAc-T-/- genotypes were interbred. CST-/- x GalNAc-T-/- mice develop normally to P10, but all die between P20-P25, coinciding with peak myelination. Ultrastructural, immunohistological and biochemical analysis of either sex reveals widespread axonal degeneration and disruption to the axo-glial junction at the NoR. In addition to sulfatide-dependent loss of NF155, CST-/-x GalNAc-T-/- mice exhibited a major reduction in MAG protein levels in CNS myelin, compared to wild type and single lipid deficient mice. The CST-/- x GalNAc-T-/- phenotype was fully restored to that of CST-/- mice by neuron-specific expression of complex gangliosides, but not by their glial-specific expression nor by the global expression of a-series gangliosides. These data indicate that sulfatide and complex b-series gangliosides on the glial and neuronal membranes respectively act in concert to promote NF155 and MAG in maintaining the stable axo-glial interactions essential for normal nerve function.SIGNIFICANCE STATEMENTSulfatides and complex gangliosides are membrane glycolipids with important roles in maintaining nervous system integrity. Node of Ranvier maintenance in particular requires stable compartmentalisation of multiple membrane proteins. The axo-glial adhesion molecules neurofascin 155 and myelin-associated glycoprotein require membrane microdomains containing either sulfatides or complex gangliosides to localise and function effectively. The co-operative roles of these microdomains and associated proteins are unknown. Here we show vital interdependent roles for sulfatides and complex gangliosides as double (but not single) deficiency causes a rapidly lethal phenotype in early age. These findings suggests that sulfatides and complex gangliosides on opposing axo-glial membranes are responsible for essential tethering of the axo-glial junction proteins, neurofascin155 and myelin-associated glycoprotein that interact to maintain the nodal complex

Dietary garlic and hip osteoarthritis: evidence of a protective effect and putative mechanism of action

Background Patterns of food intake and prevalent osteoarthritis of the hand, hip, and knee were studied using the twin design to limit the effect of confounding factors. Compounds found in associated food groups were further studied in vitro. Methods Cross-sectional study conducted in a large population-based volunteer cohort of twins. Food intake was evaluated using the Food Frequency Questionnaire; OA was determined using plain radiographs. Analyses were adjusted for age, BMI and physical activity. Subsequent in vitro studies examined the effects of allium-derived compounds on the expression of matrix-degrading proteases in SW1353 chondrosarcoma cells. Results Data were available, depending on phenotype, for 654-1082 of 1086 female twins (median age 58.9 years; range 46-77). Trends in dietary analysis revealed a specific pattern of dietary intake, that high in fruit and vegetables, showed an inverse association with hip OA (p = 0.022). Consumption of 'non-citrus fruit' (p = 0.015) and 'alliums' (p = 0.029) had the strongest protective effect. Alliums contain diallyl disulphide which was shown to abrogate cytokine-induced matrix metalloproteinase expression. Conclusions Studies of diet are notorious for their confounding by lifestyle effects. While taking account of BMI, the data show an independent effect of a diet high in fruit and vegetables, suggesting it to be protective against radiographic hip OA. Furthermore, diallyl disulphide, a compound found in garlic and other alliums, represses the expression of matrix-degrading proteases in chondrocyte-like cells, providing a potential mechanism of action

Plugging a hole and lightening the burden: A process evaluation of a practice education team

Aim: To investigate the perceptions of clinical and senior managers about the role of Practice Educators employed in one acute hospital in the UK. Background: Producing nurses who are fit for practice, purpose and academic award is a key issue for nurse education partnership providers in the UK. Various new models for practice learning support structures and new roles within health care institutions have been established. To sustain funding and policy support for these models, there is a need for evaluation research. Design: A process evaluation methodology was employed to determine the current value of a practice education team and to provide information to guide future direction. Methods: Data were collected through semi-structured telephone interviews using a previously designed schedule. All senior nurse managers (N=5) and a purposive sample of clinical managers (n=13) who had personal experience of and perceptions about the role of practice educators provided the data. Interview notes were transcribed, coded and a thematic framework devised to present the results. Results: A number of key themes emerged including: qualities needed for being a successful practice educator; visibility and presence of practice educators; providing a link with the university; ‘plugging a hole’ in supporting learning needs; providing relief to practitioners in dealing with ‘the burden of students’; alleviating the ‘plight of students’; and effects on student attrition. Conclusions: Findings provided evidence for the continued funding of the practice educator role with improvements to be made in dealing with stakeholder expectations and outcomes. Relevance to clinical practice: In the UK, there still remain concerns about the fitness for practice of newly registered nurses, prompting a recent national consultation by the professional regulating body. Despite fiscal pressures, recommendations for further strengthening of all systems that will support the quality of practice learning may continue to sustain practice learning support roles

Recommendations for the treatment of epilepsy in adult patients in general practice in Belgium: an update

In 2008, a group of Belgian epilepsy experts published recommendations for antiepileptic drug (AED) treatment of epilepsies in adults and children. Selection of compounds was based on the registration and reimbursement status in Belgium, the level of evidence for efficacy, common daily practice and the personal views and experiences of the authors. In November 2011 the validity of these recommendations was reviewed by the same group of Belgian epilepsy experts who contributed to the preparation of the original paper. The recommendations made in 2008 for initial monotherapy in paediatric patients were still considered to be valid, except for the first choice treatment for childhood absence epilepsy. This update therefore focuses on the treatment recommendations for initial monotherapy and add-on treatment in adult patients. Several other relevant aspects of treatment with AEDs are addressed, including considerations for optimal combination of AEDs (rational polytherapy), pharmacokinetic properties, pharmacodynamic and pharmacokinetic interaction profile, adverse effects, comorbidity, treatment of elderly patients, AED treatment during pregnancy, and generic substitution of AEDs

Early, Goal-Directed Therapy for Septic Shock - A Patient-Level Meta-Analysis

BACKGROUND: After a single-center trial and observational studies suggesting that early, goal-directed therapy (EGDT) reduced mortality from septic shock, three multicenter trials (ProCESS, ARISE, and ProMISe) showed no benefit. This meta-analysis of individual patient data from the three recent trials was designed prospectively to improve statistical power and explore heterogeneity of treatment effect of EGDT. METHODS: We harmonized entry criteria, intervention protocols, outcomes, resource-use measures, and data collection across the trials and specified all analyses before unblinding. After completion of the trials, we pooled data, excluding the protocol-based standard-therapy group from the ProCESS trial, and resolved residual differences. The primary outcome was 90-day mortality. Secondary outcomes included 1-year survival, organ support, and hospitalization costs. We tested for treatment-by-subgroup interactions for 16 patient characteristics and 6 care-delivery characteristics. RESULTS: We studied 3723 patients at 138 hospitals in seven countries. Mortality at 90 days was similar for EGDT (462 of 1852 patients [24.9%]) and usual care (475 of 1871 patients [25.4%]); the adjusted odds ratio was 0.97 (95% confidence interval, 0.82 to 1.14; P=0.68). EGDT was associated with greater mean (±SD) use of intensive care (5.3±7.1 vs. 4.9±7.0 days, P=0.04) and cardiovascular support (1.9±3.7 vs. 1.6±2.9 days, P=0.01) than was usual care; other outcomes did not differ significantly, although average costs were higher with EGDT. Subgroup analyses showed no benefit from EGDT for patients with worse shock (higher serum lactate level, combined hypotension and hyperlactatemia, or higher predicted risk of death) or for hospitals with a lower propensity to use vasopressors or fluids during usual resuscitation. CONCLUSIONS: In this meta-analysis of individual patient data, EGDT did not result in better outcomes than usual care and was associated with higher hospitalization costs across a broad range of patient and hospital characteristics. (Funded by the National Institute of General Medical Sciences and others; PRISM ClinicalTrials.gov number, NCT02030158.

Extragalactic Results from the Infrared Space Observatory

More than a decade ago the IRAS satellite opened the realm of external galaxies for studies in the 10 to 100 micron band and discovered emission from tens of thousands of normal and active galaxies. With the 1995-1998 mission of the Infrared Space Observatory the next major steps in extragalactic infrared astronomy became possible: detailed imaging, spectroscopy and spectro-photometry of many galaxies detected by IRAS, as well as deep surveys in the mid- and far- IR. The spectroscopic data reveal a wealth of detail about the nature of the energy source(s) and about the physical conditions in galaxies. ISO's surveys for the first time explore the infrared emission of distant, high-redshift galaxies. ISO's main theme in extragalactic astronomy is the role of star formation in the activity and evolution of galaxies.Comment: 106 pages, including 17 figures. Ann.Rev.Astron.Astrophys. (in press), a gzip'd pdf file (667kB) is also available at http://www.mpe.mpg.de/www_ir/preprint/annrev2000.pdf.g