Exome sequencing identifies a missense variant in EFEMP1 co-segregating in a family with autosomal dominant primary open-angle glaucoma

Primary open-angle glaucoma (POAG) is a clinically important and genetically heterogeneous cause of progressive vision loss as a result of retinal ganglion cell death. Here we have utilized trio-based, whole-exome sequencing to identify the genetic defect underlying an autosomal dominant form of adult-onset POAG segregating in an African-American family. Exome sequencing identified a novel missense variant (c.418C>T, p.Arg140Trp) in exon-5 of the gene coding for epidermal growth factor (EGF) containing fibulin-like extracellular matrix protein 1 (EFEMP1) that co-segregated with disease in the family. Linkage and haplotype analyses with microsatellite markers indicated that the disease interval overlapped a known POAG locus (GLC1H) on chromosome 2p. The p.Arg140Trp substitution was predicted in silico to have damaging effects on protein function and transient expression studies in cultured cells revealed that the Trp140-mutant protein exhibited increased intracellular accumulation compared with wild-type EFEMP1. In situ hybridization of the mouse eye with oligonucleotide probes detected the highest levels of EFEMP1 transcripts in the ciliary body, cornea, inner nuclear layer of the retina, and the optic nerve head. The recent finding that a common variant near EFEMP1 was associated with optic nerve-head morphology supports the possibility that the EFEMP1 variant identified in this POAG family may be pathogenic

Exome sequencing identifies novel and recurrent mutations in GJA8 and CRYGD associated with inherited cataract

BACKGROUND: Inherited cataract is a clinically important and genetically heterogeneous cause of visual impairment. Typically, it presents at an early age with or without other ocular/systemic signs and lacks clear phenotype-genotype correlation rendering both clinical classification and molecular diagnosis challenging. Here we have utilized trio-based whole exome sequencing to discover mutations in candidate genes underlying autosomal dominant cataract segregating in three nuclear families. RESULTS: In family A, we identified a recurrent heterozygous mutation in exon-2 of the gene encoding γD-crystallin (CRYGD; c.70C > A, p.Pro24Thr) that co-segregated with ‘coralliform’ lens opacities. Families B and C were found to harbor different novel variants in exon-2 of the gene coding for gap-junction protein α8 (GJA8; c.20T > C, p.Leu7Pro and c.293A > C, p.His98Pro). Each novel variant co-segregated with disease and was predicted in silico to have damaging effects on protein function. CONCLUSIONS: Exome sequencing facilitates concurrent mutation-profiling of the burgeoning list of candidate genes for inherited cataract, and the results can provide enhanced clinical diagnosis and genetic counseling for affected families. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s40246-014-0019-6) contains supplementary material, which is available to authorized users

The Next WHO Director-General’s Highest Priority: a Global Treaty on the Human Right to Health

Amidst the many challenges facing the next WHO Director-General, the new WHO head should find WHO’s foremost priority in its most important constitutional pillar: the right to health. The centerpiece of this endeavor should be leadership on the Framework Convention on Global Health (FCGH), the proposed global treaty based in the right to health and aimed at national and global health equity. The treaty would reform global governance for health to enhance accountability, transparency, and civil society participation and protect the right to health in trade, investment, climate change, and other international regimes, while catalyzing governments to institutionalize the right to health at community through to national levels. It would usher in a new era of global health with justice – vast improvements in health outcomes, equitably distributed. With the Framework Convention on Tobacco Control having served as a proof of concept, the FCGH would be an innovative treaty finding solutions to overcome global health failings in accountability, equality, financing, and inter-sectoral coherence. It would include a global health accountability framework, encompassing, civil society engagement, independent monitoring, and plans for redress, while catalyzing national health accountability strategies, accountability mechanisms, disaggregated data, and community participation. National health equity strategies, pro-poor pathways to universal health coverage, and robust non-discrimination provisions could elevate the voices, priorities, and ultimately power of marginalized populations. The FCGH would include a national and global health financing framework, while reaching beyond the health sector with right to health assessments, public health participation in developing international agreements, and responsibility for all sectors for improving health outcomes. The FCGH would reinvigorate WHO’s global health leadership, breathing new life into its founding principles. It could become the platform for reforming WHO as a rights-based 21st century institution, with badly-needed reforms, such as community participation, new priorities favouring social determinants of health, and a culture of transparency and accountability. The next Director-General should launch a historic effort to align national and global governance for with human rights through the FCGH, bringing the world closer to global health with justice

The non-evolving internal structure of early-type galaxies: the case study SDSS J0728+3835 at z = 0.206

We study the internal dynamical structure of the early-type lens galaxy SDSS J0728+3835 at z = 0.206. The analysis is based on two-dimensional kinematic maps extending out to 1.7 effective radii obtained from Keck spectroscopy, on lensing geometry and on stellar mass estimates obtained from multiband Hubble Space Telescope imaging. The data are modelled under the assumptions of axial symmetry supported by a two-integral distribution function (DF), by applying the combined gravitational lensing and stellar dynamics code CAULDRON, and yielding high-quality constraints for an early-type galaxy at cosmological redshifts. Modelling the total density profile as a power-law of the form rho_tot ~ 1/r^{gamma}, we find that it is nearly isothermal (logarithmic slope gamma = 2.08^{+0.04}_{-0.02}), and quite flattened (axial ratio q = 0.60^{+0.08}_{-0.03}). The galaxy is mildly anisotropic (delta = 0.08 +/- 0.02) and shows a fair amount of rotational support, in particular towards the outer regions. We determine a dark matter fraction lower limit of 28 per cent within the effective radius. The stellar contribution to the total mass distribution is close to maximal for a Chabrier initial mass function (IMF), whereas for a Salpeter IMF the stellar mass exceeds the total mass within the galaxy inner regions. We find that the combination of a NFW dark matter halo with the maximally rescaled luminous profile provides a remarkably good fit to the total mass distribution over a broad radial range. Our results confirm and expand the findings of the SLACS survey for early-type galaxies of comparable velocity dispersion (sigma_SDSS = 214 +/- 11 km/s). The internal structure of J0728 is consistent with that of local early-type galaxies of comparable velocity dispersion as measured by the SAURON project, suggesting lack of evolution in the past two billion years.Comment: 13 pages, 10 figures. MNRAS in press. Revised to match accepted versio

Dyslexia-friendly schools and parent partnership: inclusion and home-school relationships

This is a postprint of an article whose final and definitive form has been published in the European Journal of Special Needs Education© 2005 Copyright Taylor & Francis; European Journal of Special Needs Education is available online at http://www.informaworld.comThis paper summarizes an action research project in five local areas in the south-west of England which aimed to support parents of children with dyslexic difficulties who were experiencing problems in obtaining appropriate provision in mainstream schools. It was based on the importance of effective parental partnership and quality inclusive practice for children having dyslexic difficulties. A development officer worked over two years in the five participating LEAs that were selected to represent a range of professional practice with a mix of urban and rural populations. As part of the evaluation, the authors also examined longitudinally the educational experiences of a sample of parents. The paper includes a conceptual framework of parental agency in this field in terms of knowledge, identity and parental strategies, and the conditions under which parents escalate their strategies to secure appropriate provision for their children. The support provided by the development officer is analysed in terms of the kinds of support requests received, the kinds of support offered and qualitative evidence of the impact of this support. This research is theorized in terms of current ideas about parent-partnership and theories about parent-teacher relations in terms of the diversity of parents. It highlights the significance of thinking about inclusive schooling and parent-school relations in terms of the interconnections between general systems for all, for those with special educational needs and those with specific difficulties. The policy and practice implications are interpreted in terms of the importance of a system of extended professionalism, which is inclusive of parents with learning difficulties and disabilities.The research project this paper summarises was funded by the British Dyslexia Association (BDA) and the Buttle Trust

Two-dimensional kinematics of SLACS lenses: III. Mass structure and dynamics of early-type lens galaxies beyond z ~ 0.1

We combine in a self-consistent way the constraints from both gravitational lensing and stellar kinematics to perform a detailed investigation of the internal mass distribution, amount of dark matter, and dynamical structure of the 16 early-type lens galaxies from the SLACS Survey, at z = 0.08 - 0.33, for which both HST/ACS and NICMOS high-resolution imaging and VLT VIMOS IFU spectroscopy are available. Based on this data set, we analyze the inner regions of the galaxies, i.e. typically within one (3D) effective radius r_e, under the assumption of axial symmetry and by constructing dynamical models supported by two-integral stellar DFs. For all systems, the total mass density distribution is found to be well approximated by a simple power-law: this profile is on average slightly super-isothermal, with a logarithmic slope = 2.074^{+0.043}_{-0.041} (68% CL) and an intrinsic scatter 0.144^{+0.055}_{-0.014}, and is fairly round, with an average axial ratio = 0.77+/-0.04. The lower limit for the dark matter fraction (fDM) inside r_e ranges, in individual systems, from nearly zero to almost a half, with a median value of 12%. By including stellar masses derived from SPS models with a Salpeter IMF, we obtain an average fDM = 31%. The fDM rises to 61% if, instead, a Chabrier IMF is assumed. For both IMFs, the dark matter fraction increases with the total mass of the galaxy (3-sigma correlation). Based on the intrinsic angular momentum parameter calculated from our models, we find that the galaxies can be divided into two dynamically distinct groups, which are shown to correspond to the usual classes of the slow and fast rotators. Overall, the SLACS systems are structurally and dynamically very similar to their nearby counterparts, indicating that the inner regions of early-type galaxies have undergone little, if any, evolution since redshift z ~ 0.35. (Abridged)Comment: 27 pages, 34 figures. MNRAS, in pres

Socioeconomic differentials in the immediate mortality effects of the national Irish smoking ban

This article has been made available through the Brunel Open Access Publishing Fund.Background: Consistent evidence has demonstrated that smoking ban policies save lives, but impacts on health inequalities are uncertain as few studies have assessed post-ban effects by socioeconomic status (SES) and findings have been inconsistent. The aim of this study was to assess the effects of the national Irish smoking ban on ischemic heart disease (IHD), stroke, and chronic obstructive pulmonary disease (COPD) mortality by discrete and composite SES indicators to determine impacts on inequalities. Methods: Census data were used to assign frequencies of structural and material SES indicators to 34 local authorities across Ireland with a 2000–2010 study period. Discrete indicators were jointly analysed through principal component analysis to generate a composite index, with sensitivity analyses conducted by varying the included indicators. Poisson regression with interrupted time-series analysis was conducted to examine monthly age and gender-standardised mortality rates in the Irish population, ages ≥35 years, stratified by tertiles of SES indicators. All models were adjusted for time trend, season, influenza, and smoking prevalence. Results: Post-ban mortality reductions by structural SES indicators were concentrated in the most deprived tertile for all causes of death, while reductions by material SES indicators were more equitable across SES tertiles. The composite indices mirrored the results of the discrete indicators, demonstrating that post-ban mortality decreases were either greater or similar in the most deprived when compared to the least deprived for all causes of death. Conclusions: Overall findings indicated that the national Irish smoking ban reduced inequalities in smoking-related mortality. Due to the higher rates of smoking-related mortality in the most deprived group, even equitable reductions across SES tertiles resulted in decreases in inequalities. The choice of SES indicator was influential in the measurement of effects, underscoring that a differentiated analytical approach aided in understanding the complexities in which structural and material factors influence mortality

Comparing families of dynamic causal models

Mathematical models of scientific data can be formally compared using Bayesian model evidence. Previous applications in the biological sciences have mainly focussed on model selection in which one first selects the model with the highest evidence and then makes inferences based on the parameters of that model. This “best model” approach is very useful but can become brittle if there are a large number of models to compare, and if different subjects use different models. To overcome this shortcoming we propose the combination of two further approaches: (i) family level inference and (ii) Bayesian model averaging within families. Family level inference removes uncertainty about aspects of model structure other than the characteristic of interest. For example: What are the inputs to the system? Is processing serial or parallel? Is it linear or nonlinear? Is it mediated by a single, crucial connection? We apply Bayesian model averaging within families to provide inferences about parameters that are independent of further assumptions about model structure. We illustrate the methods using Dynamic Causal Models of brain imaging data

EMQN best practice guidelines for the molecular genetic testing and reporting of chromosome 11p15 imprinting disorders: Silver–Russell and Beckwith–Wiedemann syndrome

Molecular genetic testing for the 11p15-associated imprinting disorders Silver–Russell and Beckwith–Wiedemann syndrome (SRS, BWS) is challenging because of the molecular heterogeneity and complexity of the affected imprinted regions. With the growing knowledge on the molecular basis of these disorders and the demand for molecular testing, it turned out that there is an urgent need for a standardized molecular diagnostic testing and reporting strategy. Based on the results from the first external pilot quality assessment schemes organized by the European Molecular Quality Network (EMQN) in 2014 and in context with activities of the European Network of Imprinting Disorders (EUCID.net) towards a consensus in diagnostics and management of SRS and BWS, best practice guidelines have now been developed. Members of institutions working in the field of SRS and BWS diagnostics were invited to comment, and in the light of their feedback amendments were made. The final document was ratified in the course of an EMQN best practice guideline meeting and is in accordance with the general SRS and BWS consensus guidelines, which are in preparation. These guidelines are based on the knowledge acquired from peer-reviewed and published data, as well as observations of the authors in their practice. However, these guidelines can only provide a snapshot of current knowledge at the time of manuscript submission and readers are advised to keep up with the literature