Optimising metadata workflows in a distributed information environment

The different purposes present within a distributed information environment create the potential for repositories to enhance their metadata by capitalising on the diversity of metadata available for any given object. This paper presents three conceptual reference models required to achieve this optimisation of metadata workflow: the ecology of repositories, the object lifecycle model, and the metadata lifecycle model. It suggests a methodology for developing the metadata lifecycle model, and illustrates how it might be used to enhance metadata within a network of repositories and services

Quality assurance for digital learning object repositories: issues for the metadata creation process

Metadata enables users to find the resources they require, therefore it is an important component of any digital learning object repository. Much work has already been done within the learning technology community to assure metadata quality, focused on the development of metadata standards, specifications and vocabularies and their implementation within repositories. The metadata creation process has thus far been largely overlooked. There has been an assumption that metadata creation will be straightforward and that where machines cannot generate metadata effectively, authors of learning materials will be the most appropriate metadata creators. However, repositories are reporting difficulties in obtaining good quality metadata from their contributors, and it is becoming apparent that the issue of metadata creation warrants attention. This paper surveys the growing body of evidence, including three UK-based case studies, scopes the issues surrounding human-generated metadata creation and identifies questions for further investigation. Collaborative creation of metadata by resource authors and metadata specialists, and the design of tools and processes, are emerging as key areas for deeper research. Research is also needed into how end users will search learning object repositories

The use of novel techniques to study the roles of cytokines in joint pain and inflammation

Rheumatoid arthritis (RA) is a common, chronic, autoimmune, inflammatory disease characterized by persistent synovitis that results in the progressive destruction ofjoints. The cellular and molecular basis of the inflammation is complex and multifactorial. During the progression of the disease many types of cells are activated, which in turn secrete a variety of mediators, including cytokines, which initiate and perpetuate the disease.Rat adjuvant-induced unilateral arthritis is a well established RA disease model and use of this model has facilitated the understanding of the pathology of joint inflammation. The model closely mimics the pathology of human RA, including histopathological changes, cell infiltration, as well as hypersensitivity and swelling of the joint. Measurements of spontaneous pain and hypersensitivity states are assessed in this model. However, no objective measure ofjoint hypersensitivity is used to assess experimental arthritic joint pain in laboratory rodents. To that end, the pressure application device (PAD) was developed to align pre-clinical measures to those used clinically and help the translation of animal studies to human conditions. PAD was able to detect FCA-induced hypersensitivity in mice and rats, observed as a decrease in limb withdrawal thresholds (LWTs) of around 60% and 40% respectively, compared with basal levels in normal joints. PAD subsequently detected prednisolone analgesia in both species, which was abolished after dosing ceased. PAD also showed significant reversal of evoked mechanical hypersensitivity in arthritic animals treated with morphine or celecoxib, which was comparable to that measured by the weight distribution readout. PAD provides a novel, accurate behavioural tool for detecting localised primary mechanical hypersensitivity in two animal models of chronic inflammatory joint pain.The infiltration of cells and release of inflammatory proteins in the synovial tissue and joint space is a key characteristic of synovitis. Measuring the levels of these in the synovial fluid can provide information about the underlying pathophysiology of joint v disease. Furthermore changes occurring in the synovial fluid can be used as biomarkers of disease; therefore the joint perfusion method was developed to evaluate the inflammatory protein and cell content of rat knee joints, to further validate the adjuvant-induced arthritis model, as well as to determine the effects of inflammatory insults or the effect of anti¬ inflammatory, analgesic or anti-rheumatic drugs. This technique proved to be reliable and consistent when perfusing the joint cavity, and regular volumes of sample were easily collected. This technique is therefore a valuable addition to protocols which use homogenates of entire joints to assess inflammatory mediator content.The temporal expression patterns of cytokines and inflammatory cells in the knee joints of rats following induction of arthritis were determined using the novel perfusion technique. Cytokine expression altered over time as arthritis progressed from the acute to the more "chronic" phase. The proportion of inflamed joints that contained detectable levels of each mediator measured was significantly increased during the study. This suggests that it may be the presence of the protein, even at low levels, that is important for the development and maintenance of joint inflammation and hypersensitivity. In addition, significant correlations between measures ofjoint swelling or mechanical hypersensitivity and levels of cytokines in inflamed joints were seen. Prednisolone did not affect the absolute levels of cytokines in inflamed joints, although it reduced the percentage of inflamed joints that contained detectable levels of ILla and IL6. This suggests that the steroid appears to have an all-or-none effect in terms of cytokine expression levels in this study.The roles of ILip and IL6 in joint pain and inflammation were assessed. The contribution of the activity of primary afferent fibres to joint pain and hypersensitivity after administration of intra-articular ILip or IL6 was investigated by recording action potentials from primary afferent nerves innervating the knee joint. IL1 p caused a transient increase in the frequency of basal neural discharge by 88% within three hours. It also decreased the threshold of mechanical stimulation required to evoke neural activity by 50% between one and four hours after injection. In contrast, IL6 did not affect the frequency of basal neural discharge or the mechanical threshold. Neither ILiß nor IL6 affected the neural discharge frequency to mechanical stimulation above the threshold. The induction of basal neural activity resembles the occurrence of spontaneous pain during inflammation, such as that measured by the incapacitance tester as a result of intra-articular IL1ß or IL6. A reduction in the LWT, measured by PAD, following ILiß or IL6 occurred within a few hours, similar to the decrease in the mechanical threshold to von Frey hairs in primary afferents after ILiß, as a result of neuronal sensitization. Although ILiß or IL6 did not cause swelling of the joint, they did induce mechanical hypersensitivity within a couple of hours, which lasted for up to four days. Intra-articular IL1ß or IL6 had no effect on joint structure, bone or cartilage. ILiß and IL6 evoked increases in the expression of ILip, IL6 and TNFa within the first eight hours, and additionally elevated levels of ILla, IL2, IL4 (IL6-treated only) and IL10 (ILiß-treated only) from day one post administration. ILiß also resulted in recruitment of inflammatory cells into the synovial cavity one day after administration.In conclusion, this study has developed and validated two novel techniques to study experimental joint pain and inflammation in rodents; the behavioural measure of joint mechanical hypersensitivity, PAD; and the joint perfusion technique to assess inflammatory mediator and cell content of synovial fluid. These methods have been used alongside other techniques to show the temporal cytokine expression patterns during adjuvant-induced arthritis and the relationship of these to swelling and hypersensitivity of the joint. The roles of ILip and IL6 in evoking joint pain and hypersensitivity were also investigated. This data supports the hypothesis that ILip and IL6 are directly involved in the development of joint pain, but cannot alone elicit swelling or joint damage at doses sufficient to evoke hypersensitivity. Furthermore, similarities between this animal model of joint disease and human RA have been demonstrated that further validate the model as a valuable pre-clinical tool to study the inflammatory process of human RA. Moreover, consolidation of these similarities helps improve the confidence of novel drug screening using this model prior to use in the clinic

Commentary on "Genetic linkage and transmission disequilibrium of marker haplotypes at chromosome 1q41 in human systemic lupus erythematosus", by RR Graham et al.

Genome-wide linkage analysis studies in families with systemic lupus erythematosus (SLE) have revealed consistent evidence of linkage to several regions of the genome. In a previous issue of this journal, Graham and colleagues described their approach to following up the linkage data for one of these regions, 1q41–42. Using methods based on the transmission disequilibrium test, the region likely to harbour a SLE disease gene was refined to 2.3 Mb. This commentary discusses their approach and identifies lessons that may be applicable to the investigation of other complex diseases

Characterisation of the genomic architecture of human chromosome 17q and evaluation of different methods for haplotype block definition

BACKGROUND: The selection of markers in association studies can be informed through the use of haplotype blocks. Recent reports have determined the genomic architecture of chromosomal segments through different haplotype block definitions based on linkage disequilibrium (LD) measures or haplotype diversity criteria. The relative applicability of distinct block definitions to association studies, however, remains unclear. We compared different block definitions in 6.1 Mb of chromosome 17q in 189 unrelated healthy individuals. Using 137 single nucleotide polymorphisms (SNPs), at a median spacing of 15.5 kb, we constructed haplotype block maps using published methods and additional methods we have developed. Haplotype tagging SNPs (htSNPs) were identified for each map. RESULTS: Blocks were found to be shorter and coverage of the region limited with methods based on LD measures, compared to the method based on haplotype diversity. Although the distribution of blocks was highly variable, the number of SNPs that needed to be typed in order to capture the maximum number of haplotypes was consistent. CONCLUSION: For the marker spacing used in this study, choice of block definition is not important when used as an initial screen of the region to identify htSNPs. However, choice of block definition has consequences for the downstream interpretation of association study results

Carbon capture and storage: Designing the legal and regulatory framework for New Zealand

The purpose of this Report is to identify the best possible legal framework for carbon capture and storage (CCS) in New Zealand. The Report is of a study funded by the Ministry of Business, Innovation and Employment under research contract UOWX1204. The aim of the research was to provide a comprehensive framework for the development of law and policy to govern CCS in New Zealand. The methodology involved an analysis of the existing law and policy as it applies to CCS, assessment of any barriers, and a comparison with law in selected other jurisdictions. That analysis was followed by discussion of different policy options and evaluation of the possibility of addressing CCS in the existing legal framework. Recommendations were made for law reform on each aspect of the subject. The Report is concerned with the legal framework for geological storage or sequestration of carbon dioxide (CO₂). It does not address biosequestration, where CO₂ is accumulated, temporarily or permanently, in forests or other vegetation. Nor is it concerned with the sequestration of CO₂ in oceans, or with climate engineering

Estimating loss in quality of life associated with asthma-related crisis events (ESQUARE): a cohort, observational study

Background: Evidence of quality of life implications of asthma attacks are limited,particularly when measured on a utility scale, which enables calculating Quality-Adjusted Life-Years (QALYs) and comparisons with other health conditions andservices. Therefore, this study sought to estimate the utility loss associated with anasthma-related crisis event (accident and emergency (A&E) attendance or hospitaladmission).Methods: Participants were recruited in a cohort study from A&E and hospitaladmissions at three UK hospitals. They completed the EuroQol-5 Dimensions 5-Level(EQ-5D-5L), Asthma Quality of Life Questionnaire (AQLQ), Time trade-off (TTO), andpeak flow and symptom diary over 8 weeks, where three different methods (EQ-5D-5L,AQLQ, and TTO), were used to estimate utilities. The mean difference between twotime points were estimated using the Wilcoxon signed rank test.Results: From baseline to week 8, mean increases (95% CI) were estimated to be0.086 (0.019-0.153), 0.154 (0.112-0.196) and 0.132 (0.063-0.201) for EQ-5D-5L, AQL-5D (preference-based measure derived from AQLQ), and TTO respectively over 8weeks (p<0.01).Conclusion: Asthma crisis events are estimated to be associated with a mean utilityloss of between 0.086 and 0.132. The utility decrement can be used to assign valuesto asthma-related crisis events, which can enhance economic evaluations

Fine mapping of genes within the IDDM8 region in rheumatoid arthritis

The IDDM8 region on chromosome 6q27, first identified as a susceptibility locus for type 1 diabetes, has previously been linked and associated with rheumatoid arthritis (RA). The region contains a number of potential candidate genes, including programmed cell death 2 (PDCD2), the proteosome subunit beta type 1 (PSMB1), delta-like ligand 1 (DLL-1) and TATA box-binding protein (TBP) amongst others. The aim of this study was to fine map the IDDM8 region on chromosome 6q27, focusing on the genes in the region, to identify polymorphisms that may contribute to susceptibility to RA and potentially to other autoimmune diseases. Validated single nucleotide polymorphisms (SNPs; n = 65) were selected from public databases from the 330 kb region of IDDM8. These were genotyped using Sequenom MassArray genotyping technology in two datasets; the test dataset comprised 180 RA cases and 180 controls. We tested 50 SNPs for association with RA and any significant associations were genotyped in a second dataset of 174 RA cases and 192 controls, and the datasets were combined before analysis. Association analysis was performed by chi-square test implemented in Stata software and linkage disequilibrium and haplotype analysis was performed using Helix tree version 4.1. There was initial weak evidence of association, with RA, of a number of SNPs around the loc154449 putative gene and within the KIAA1838 gene; however, these associations were not significant in the combined dataset. Our study has failed to detect evidence of association with any of the known genes mapping to the IDDM8 locus with RA