Transplantation of Ciliary Neurotrophic Factor-Expressing Adult Oligodendrocyte Precursor Cells Promotes Remyelination and Functional Recovery after SpinalCord Injury

Demyelination contributes to the dysfunction after traumatic spinal cord injury (SCI). We explored whether the combination of neurotrophic factors and transplantation of adult rat spinal cord oligodendrocyte precursor cells (OPCs) could enhance remyelination and functional recovery after SCI. Ciliary neurotrophic factor (CNTF) was the most effective neurotrophic factor to promote oligodendrocyte (OL) differentiation and survival of OPCs in vitro. OPCs were infected with retroviruses expressing enhanced green fluorescent protein (EGFP) or CNTF and transplanted into the contused adult thoracic spinal cord 9 d after injury. Seven weeks after transplantation, the grafted OPCs survived and integrated into the injured spinal cord. The survival of grafted CNTF-OPCs increased fourfold compared with EGFP-OPCs. The grafted OPCs differentiated into adenomatus polyposis coli (APC+) OLs, and CNTF significantly increased the percentage of APC+ OLs from grafted OPCs. Immunofluorescent and immunoelectron microscopic analyses showed that the grafted OPCs formed central myelin sheaths around the axons in the injured spinal cord. The number of OL-remyelinated axons in ventrolateral funiculus (VLF) or lateral funiculus (LF) at the injured epicenter was significantly increased in animals that received CNTF-OPC grafts compared with all other groups. Importantly, 75% of rats receiving CNTF-OPC grafts recovered transcranial magnetic motor-evoked potential and magnetic interenlargement reflex responses, indicating that conduction through the demyelinated axons in VLF or LF, respectively, was partially restored. More importantly, recovery of hindlimb locomotor function was significantly enhanced in animals receiving grafts of CNTF-OPCs. Thus, combined treatment with OPC grafts expressing CNTF can enhance remyelination and facilitate functional recovery after traumatic SCI

Systems analysis of metabolism in the pathogenic trypanosomatid Leishmania major

Systems analyses have facilitated the characterization of metabolic networks of several organisms. We have reconstructed the metabolic network of Leishmania major, a poorly characterized organism that causes cutaneous leishmaniasis in mammalian hosts. This network reconstruction accounts for 560 genes, 1112 reactions, 1101 metabolites and 8 unique subcellular localizations. Using a systems-based approach, we hypothesized a comprehensive set of lethal single and double gene deletions, some of which were validated using published data with approximately 70% accuracy. Additionally, we generated hypothetical annotations to dozens of previously uncharacterized genes in the L. major genome and proposed a minimal medium for growth. We further demonstrated the utility of a network reconstruction with two proof-of-concept examples that yielded insight into robustness of the network in the presence of enzymatic inhibitors and delineation of promastigote/amastigote stage-specific metabolism. This reconstruction and the associated network analyses of L. major is the first of its kind for a protozoan. It can serve as a tool for clarifying discrepancies between data sources, generating hypotheses that can be experimentally validated and identifying ideal therapeutic targets

Anonymisation of geographical distance matrices via Lipschitz embedding

BACKGROUND: Anonymisation of spatially referenced data has received increasing attention in recent years. Whereas the research focus has been on the anonymisation of point locations, the disclosure risk arising from the publishing of inter-point distances and corresponding anonymisation methods have not been studied systematically. METHODS: We propose a new anonymisation method for the release of geographical distances between records of a microdata file-for example patients in a medical database. We discuss a data release scheme in which microdata without coordinates and an additional distance matrix between the corresponding rows of the microdata set are released. In contrast to most other approaches this method preserves small distances better than larger distances. The distances are modified by a variant of Lipschitz embedding. RESULTS: The effects of the embedding parameters on the risk of data disclosure are evaluated by linkage experiments using simulated data. The results indicate small disclosure risks for appropriate embedding parameters. CONCLUSION: The proposed method is useful if published distance information might be misused for the re-identification of records. The method can be used for publishing scientific-use-files and as an additional tool for record-linkage studies

Impact of technology-based interventions for children and young people with type 1 diabetes on key diabetes self-management behaviours and prerequisites: A systematic review

Background The role of technology in the self-management of type 1 diabetes mellitus (T1DM) among children and young people is not well understood. Interventions should aim to improve key diabetes self-management behaviours (self-management of blood glucose, insulin administration, physical activity and dietary behaviours) and prerequisites (psychological outcomes and HbA1c) highlighted in the UK guidelines of the National Institute for Health and Care Excellence (NICE) for management of T1DM. The purpose was to identify evidence to assess the effectiveness of technological tools in promoting aspects of these guidelines amongst children and young people. Methods A systematic review of English language articles was conducted using the following databases: Web of Science, PubMed, Scopus, NUSearch, SAGE Journals, SpringerLink, Google Scholar, Science Direct, Sport Discus, Embase, Psychinfo and Cochrane Trials. Search terms included paediatric, type one diabetes, technology, intervention and various synonyms. Included studies examined interventions which supplemented usual care with a health care strategy primarily delivered through a technology-based medium (e.g. mobile phone, website, activity monitor) with the aim of engaging children and young people with T1DM directly in their diabetes healthcare. Studies did not need to include a comparator condition and could be randomised, non-randomised or cohort studies but not single-case studies. Results Of 30 included studies (21 RCTs), the majority measured self-monitoring of blood glucose monitoring (SMBG) frequency, clinical indicators of diabetes self-management (e.g. HbA1c) and/or psychological or cognitive outcomes. The most positive findings were associated with technology-based health interventions targeting SMBG as a behavioural outcome, with some benefits found for clinical and/or psychological diabetes self-management outcomes. Technological interventions were well accepted by children and young people. For the majority of included outcomes, clinical relevance was deemed to be little or none. Conclusions More research is required to assess which elements of interventions are most likely to produce beneficial behavioural outcomes. To produce clinically relevant outcomes, interventions may need to be delivered for at least 1 year and should consider targeting individuals with poorly managed diabetes. It is not possible to determine the impact of technology-based interventions on insulin administration, dietary habits and/or physical activity behaviour due to lack of evidence

A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes

In computing the probability that a woman is a BRCA1 or BRCA2 carrier for genetic counselling purposes, it is important to allow for the fact that other breast cancer susceptibility genes may exist. We used data from both a population based series of breast cancer cases and high risk families in the UK, with information on BRCA1 and BRCA2 mutation status, to investigate the genetic models that can best explain familial breast cancer outside BRCA1 and BRCA2 families. We also evaluated the evidence for risk modifiers in BRCA1 and BRCA2 carriers. We estimated the simultaneous effects of BRCA1, BRCA2, a third hypothetical gene ‘BRCA3’, and a polygenic effect using segregation analysis. The hypergeometric polygenic model was used to approximate polygenic inheritance and the effect of risk modifiers. BRCA1 and BRCA2 could not explain all the observed familial clustering. The best fitting model for the residual familial breast cancer was the polygenic, although a model with a single recessive allele produced a similar fit. There was also significant evidence for a modifying effect of other genes on the risks of breast cancer in BRCA1 and BRCA2 mutation carriers. Under this model, the frequency of BRCA1 was estimated to be 0.051% (95% CI: 0.021–0.125%) and of BRCA2 0.068% (95% CI: 0.033–0.141%). The breast cancer risk by age 70 years, based on the average incidence over all modifiers was estimated to be 35.3% for BRCA1 and 50.3% for BRCA2. The corresponding ovarian cancer risks were 25.9% for BRCA1 and 9.1% for BRCA2. The findings suggest that several common, low penetrance genes with multiplicative effects on risk may account for the residual non-BRCA1/2 familial aggregation of breast cancer. The modifying effect may explain the previously reported differences between population based estimates for BRCA1/2 penetrance and estimates based on high-risk families

Oral contraceptive use and ovarian cancer risk among carriers of BRCA1 or BRCA2 mutations

Women with mutations of the genes BRCA1 or BRCA2 are at increased risk of ovarian cancer. Oral contraceptives protect against ovarian cancer in general, but it is not known whether they protect against the disease in carriers of these mutations. We obtained self-reported lifetime histories of oral contraceptive use from 451 women who carried mutations of BRCA1 or BRCA2. We used conditional logistic regression to estimate the odds ratios associated with oral contraceptive use, comparing the histories of 147 women with ovarian cancer (cases) to those of 304 women without ovarian cancer (controls) who were matched to cases on year of birth, country of residence and gene (BRCA1 vs BRCA2). Reference ages for controls had to exceed the ages at diagnosis of their matched cases. After adjusting for parity, the odds-ratio for ovarian cancer associated with use of oral contraceptives for at least 1 year was 0.85 (95 percent confidence interval, 0.53-1.36). The risk decreased by 5% (1-9%) with each year of use (P for trend=0.01). Use for 6 or more years was associated with an odds-ratio of 0.62 (0.35-1.09). These data support the hypothesis that long-term oral contraceptive use reduces the risk of ovarian cancer among women who carry mutations of BRCA1 or BRCA2