Physical map and cosmid contig encompassing a new interstitial deletion of the X-linked lymphoproliferative syndrome region

The X-linked lymphoproliferative syndrome (XLP) is an inherited immuno-deficiency to Epstein-Barr virus infection that has been mapped to chromosome Xq25. Molecular analysis of XLP patients from ten different families identified a small interstitial constitutional deletion in 1 patient (XLP-D). This deletion, initially defined by a single marker, DF83, known to map to interval Xq24-q26.1, is nested within a previously reported and much larger deletion in another XLP patient (XLP-739). A cosmid minilibrary was constructed from a single mega-YAC and used to establish a contig encompassing the whole XLP-D deletion and a portion of the XLP-739 deletion. Based on this contig, the size of the XLP-D deletion can be estimated at 130 kb. The identification of this minimal deletion, within which at least a portion of the XLP gene is likely to reside, should greatly facilitate efforts in isolating the gene.

A systematic review and meta-analysis of the survival of feldspathic porcelain veneers over 5 and 10 years

PURPOSE: This systematic review reports on the survival of feldspathic porcelain veneers.

MATERIALS AND METHODS: The Cochrane Library, MEDLINE (OVID), Embase, Web of Knowledge, selected journals, clinical trials registers, and conference proceedings were searched independently by two reviewers. Academic colleagues were also contacted to identify relevant research. Inclusion criteria were human cohort studies (prospective and retrospective) and controlled trials assessing outcomes of feldspathic porcelain veneers in more than 15 patients and with at least some of the veneers in situ for 5 years. Of 4,294 articles identified, 116 studies underwent full-text screenings and 69 were further reviewed for eligibility. Of these, 11 were included in the qualitative analysis and 6 (5 cohorts) were included in meta-analyses. Estimated cumulative survival and standard error for each study were assessed and used for meta-, sensitivity, and post hoc analyses. The I2 statistic and the Cochran Q test and its associated P value were used to evaluate statistical heterogeneity, with a random-effects meta-analysis used when the P value for heterogeneity was less than .1. Galbraith, forest, and funnel plots explored heterogeneity, publication patterns, and small study biases.

RESULTS: The estimated cumulative survival for feldspathic porcelain veneers was 95.7% (95% confidence interval [CI]: 92.9% to 98.4%) at 5 years and ranged from 64% to 95% at 10 years across three studies. A post hoc meta-analysis indicated that the 10-year best estimate may approach 95.6% (95% CI: 93.8% to 97.5%). High levels of statistical heterogeneity were found.

CONCLUSIONS: When bonded to enamel substrate, feldspathic porcelain veneers have a very high 10-year survival rate that may approach 95%. Clinical heterogeneity is associated with differences in reported survival rates. Use of clinically relevant survival definitions and careful reporting of tooth characteristics, censorship, clustering, and precise results in future research would improve metaanalytic estimates and aid treatment decisions.

Glacial cirques as palaeoenvironmental indicators: their potential and limitations

Glacial cirques are armchair-shaped erosional hollows, typified by steep headwalls and, often, overdeepened floors. They reflect former regions of glacier initiation, and their distribution is, therefore, linked to palaeoclimate. Because of this association, cirques can be analysed for the information they provide about past environments, an approach that has a strong heritage, and has seen resurgence over recent years. This paper provides a critical assessment of what cirques can tell us about past environments, and considers their reliability as palaeoenvironmental proxies. Specific focus is placed on information that can be obtained from consideration of cirque distribution, aspect, altitude, and morphometry. The paper highlights the fact that cirques potentially provide information about the style, duration and intensity of former glaciation, as well as information about past temperatures, precipitation gradients, cloud-cover and wind directions. In all, cirques are considered a valuable source of palaeoenvironmental information (if used judiciously), particularly as they are ubiquitous within formerly glaciated mountain ranges globally, thus making regional or even global scale studies possible. Furthermore, cirques often occupy remote and inaccessible regions where other palaeoenvironmental proxies may be limited or lacking.

People with intellectual disabilities: promoting quality end of life care

Background: Internationally concerns have been highlighted about the quality of palliative care that people with intellectual disability receive. It has also been evidenced that people with intellectual disabilities are seldom referred to hospice and palliative care services. 

Aims: This study aimed to explore the experience of health and social care professionals in providing palliative care to people with intellectual disabilities. 

Methods An exploratory, qualitative design was used. A purposive sample of thirty health and social care professionals, working in intellectual disability and palliative care services, who had provided end-of-life care to adults with intellectual disabilities, were recruited to the study following informed consent. They were asked to reflect on a case scenario of a person with intellectual disability to whom they had provided end of life care. A semi-structured interview technique, with open questions and prompts, was used to explore their experiences and insights. The narrative from the case scenarios were content analysed using a recognised framework. 

Results: Three themes emerged from the data within the case scenarios: Identifying end of life care needs, meeting support needs and empowerment in partnership. Examples of good practice and issues in practice were apparent. 

Conclusion/ Discussion: This study contributes to the developing international evidence base to enhance end of life care for people with intellectual disabilities and provides further insights into this area of practice. Funder: HSC Research and Development Doctoral Fellowship Scheme

Green Space Attachment and Health: A Comparative Study in Two Urban Neighborhoods

The positive relationships between urban green space and health have been well documented. Little is known, however, about the role of residents’ emotional attachment to local green spaces in these relationships, and how attachment to green spaces and health may be promoted by the availability of accessible and usable green spaces. The present research aimed to examine the links between self-reported health, attachment to green space, and the availability of accessible and usable green spaces. Data were collected via paper-mailed surveys in two neighborhoods (n = 223) of a medium-sized Dutch city in the Netherlands. These neighborhoods differ in the perceived and objectively measured accessibility and usability of green spaces, but are matched in the physically available amount of urban green space, as well as in demographic and socio-economic status, and housing conditions. Four dimensions of green space attachment were identified through confirmatory factor analysis: place dependence, affective attachment, place identity and social bonding. The results show greater attachment to local green space and better self-reported mental health in the neighborhood with higher availability of accessible and usable green spaces. The two neighborhoods did not differ, however, in physical and general health. Structural Equation Modelling confirmed the neighborhood differences in green space attachment and mental health, and also revealed a positive path from green space attachment to mental health. These findings convey the message that we should make green places, instead of green spaces.

Glycosylation of Vitamin D Binding Protein Reduced in Juvenile Idiopathic Arthritis Patients At Risk of Disease Extension.

Background/Purpose:Juvenile idiopathic arthritis (JIA) comprises a poorly understood group of chronic, childhood onset, autoimmune diseases with variable clinical outcomes. We investigated whether profiling of the synovial fluid (SF) proteome by a fluorescent dye based, two-dimensional gel (DIGE) approach could distinguish the subset of patients in whom inflammation extends to affect a large number of joints, early in the disease process. The post-translational modifications to candidate protein markers were verified by a novel deglycosylation strategy.Methods:SF samples from 57 patients were obtained around time of initial diagnosis of JIA. At 1 year from inclusion patients were categorized according to ILAR criteria as oligoarticular arthritis (n=26), extended oligoarticular (n=8) and polyarticular disease (n=18). SF samples were labeled with Cy dyes and separated by two-dimensional electrophoresis. Multivariate analyses were used to isolate a panel of proteins which distinguish patient subgroups. Proteins were identified using MALDI-TOF mass spectrometry with vitamin D binding protein (VDBP) expression and siaylation further verified by immunohistochemistry, ELISA test and immunoprecipitation. Candidate biomarkers were compared to conventional inflammation measure C-reactive protein (CRP). Sialic acid residues were enzymatically cleaved from immunopurified SF VDBP, enriched by hydrophilic interaction liquid chromatography (HILIC) and analysed by mass spectrometry.Results:Hierarchical clustering based on the expression levels of a set of 23 proteins segregated the extended-to-be oligoarticular from the oligoarticular patients. A cleaved isoform of VDBP, spot 873, is present at significantly reduced levels in the SF of oligoarticular patients at risk of disease extension, relative to other subgroups (p<0.05). Conversely total levels of vitamin D binding protein are elevated in plasma and ROC curves indicate an improved diagnostic sensitivity to detect patients at risk of disease extension, over both spot 873 and CRP levels. Sialysed forms of intact immunopurified VDBP were more prevalent in persistent oligoarticular patient synovial fluids.Conclusion:The data indicate that a subset of the synovial fluid proteome may be used to stratify patients to determine risk of disease extension. Reduced conversion of VDBP to a macrophage activation factor may represent a novel pathway contributing to increased risk of disease extension in JIA patients.

A Molecular Mechanism for Sequential Activation of a G Protein-Coupled Receptor

Ligands targeting G protein-coupled receptors (GPCRs) are currently classified as either orthosteric, allosteric, or dualsteric/bitopic. Here, we introduce a new pharmacological concept for GPCR functional modulation: sequential receptor activation. A hallmark feature of this is a stepwise ligand binding mode with transient activation of a first receptor site followed by sustained activation of a second topographically distinct site. We identify 4-CMTB (2-(4-chlorophenyl)-3-methyl-N-(thiazol-2-yl)butanamide), previously classified as a pure allosteric agonist of the free fatty acid receptor 2, as the first sequential activator and corroborate its two-step activation in living cells by tracking integrated responses with innovative label-free biosensors that visualize multiple signaling inputs in real time. We validate this unique pharmacology with traditional cellular readouts, including mutational and pharmacological perturbations along with computational methods, and propose a kinetic model applicable to the analysis of sequential receptor activation. We envision this form of dynamic agonism as a common principle of nature to spatiotemporally encode cellular information.

Rapid glacial retreat on the Kamchatka Peninsula during the early 21st Century

Monitoring glacier fluctuations provides insights into changing glacial environments and recent climate change. The availability of satellite imagery offers the opportunity to view these changes for remote and inaccessible regions. Gaining an understanding of the ongoing changes in such regions is vital if a complete picture of glacial fluctuations globally is to be established. Here, satellite imagery (Landsat 7, 8 and ASTER) is used to conduct a multi-annual remote sensing survey of glacier fluctuations on the Kamchatka Peninsula (eastern Russia) over the 2000–2014 period. Glacier margins were digitised manually and reveal that, in 2000, the peninsula was occupied by 673 glaciers, with a total glacier surface area of 775.7 ± 27.9 km2 . By 2014, the number of glaciers had increased to 738 (reflecting the fragmentation of larger glaciers), but their surface area had decreased to 592.9 ± 20.4 km2 . This represents a ∼ 24 % decline in total glacier surface area between 2000 and 2014 and a notable acceleration in the rate of area loss since the late 20th century. Analysis of possible controls indicates that these glacier fluctuations were likely governed by variations in climate (particularly rising summer temperatures), though the response of individual glaciers was modulated by other (non-climatic) factors, principally glacier size, local shading and debris cover.

Addiction to Runx1 is partially attenuated by loss of p53 in the Eµ-Myc lymphoma model

The Runx genes function as dominant oncogenes that collaborate potently with Myc or loss of p53 to induce lymphoma when over-expressed. Here we examined the requirement for basal Runx1 activity for tumor maintenance in the Eµ-Myc model of Burkitt's lymphoma. While normal Runx1fl/fl lymphoid cells permit mono-allelic deletion, primary Eµ-Myc lymphomas showed selection for retention of both alleles and attempts to enforce deletion in vivo led to compensatory expansion of p53null blasts retaining Runx1. Surprisingly, Runx1 could be excised completely from established Eµ-Myc lymphoma cell lines in vitro without obvious effects on cell phenotype. Established lines lacked functional p53, and were sensitive to death induced by introduction of a temperature-sensitive p53 (Val135) allele. Transcriptome analysis of Runx1-deleted cells revealed a gene signature associated with lymphoid proliferation, survival and differentiation, and included strong de-repression of recombination-activating (Rag) genes, an observation that was mirrored in a panel of human acute leukemias where RUNX1 and RAG1,2 mRNA expression were negatively correlated. Notably, despite their continued growth and tumorigenic potential, Runx1null lymphoma cells displayed impaired proliferation and markedly increased sensitivity to DNA damage and dexamethasone-induced apoptosis, validating Runx1 function as a potential therapeutic target in Myc-driven lymphomas regardless of their p53 status.