1,720,995 research outputs found
The role of Preptin in the response of bone tissues to a high fat diet
No full textBackground: Obesity has a detrimental role in overall health. Obesity can be driven by consuming a high-fat diet (HFD), resulting in dysregulation in bone metabolism. Preptin is a novel peptide hormone derived from pro-IGF-2. Preptin is co-secreted with insulin, from pancreatic β-cells and increases glucose-stimulated insulin secretion. Preptin also has effects on osteoblasts. We tested the hypothesis that HFD negatively affects bone microarchitecture, and preptin deficiency worsens this phenotype using a preptin knockout (KO) mouse fed HFD.
Methods: Wild type (WT) and KO C57BL/6J mice were placed onto either control diet or HFD for 14 weeks at 8 weeks of age. Metabolic phenotypes were evaluated by weekly fasted blood glucose measurements at 10, 17 and 21 weeks of age. An oral glucose tolerance test was performed at 13 weeks of study (n=12-15/sex/genotype). Femurs were excised at 23 weeks of age and analysed using micro-computed tomography.
Results: Bodyweights of preptin KO mice were different in both females and males at 23 weeks of age. Male preptin KO in both CD and HFD had increased blood glucose concentration at 30- and 60- minutes post-glucose during glucose tolerance test (GTT) compared to WT mice. There were no metabolic differences in females. HFD affected both cortical and trabecular indices with no differences between genotypes. HFD decreased trabecular bone volume fraction (BV/TV) in WT and KO male mice by 40% and 29%, respectively, and in female mice by 51% and 44%, respectively. Cortical bone area was decreased in WT and KO male mice by 13% and 6%, respectively, and in female mice by 7% and 9%, respectively.
Discussion: The findings gathered from the results indicate that deletion of preptin did not elicit an overall deleterious effect on trabecular and cortical bone. The introduction of HFD contributed to weight gain, and metabolic disturbance resulting in glucose intolerance and compromises bone health in the trabecular and cortical bones in both sexes. Despite the removal of the gene encoding preptin, the effects of HFD on bone microarchitecture had no other further detrimental effects on bone health
Characterisation of skeletal stem and progenitor cells in the periosteum
No full textTissue-resident stem and progenitor cells are essential for skeletal healing and regeneration throughout life. The periosteum is a major source of adult skeletal stem and progenitor cells (SSPCs) that contribute to fracture healing. Human skeletal stem cells (SSCs) have been identified in embryos, fetuses, or adult bone marrow, but freshly isolated periosteal SSPCs have been less well-characterised. In mice, fracture studies involve the injury response from multiple tissues, but the independent role of periosteum is yet to be fully determined. The overall hypothesis of this thesis is that periosteum is enriched for adult SSPCs compared to other skeletal tissue compartments, and periosteal cells efficiently contribute to local healing.
Marker expression was compared in matched skeletal tissues by multi-colour flow cytometry. Sex, age, and osteoarthritis minimally affected human SSPC (hSSPC) phenotype. Periosteum and articular cartilage were enriched for most putative hSSPC markers compared to marrow compartments. In mice, periosteum was also enriched for adult mouse SSPC (mSSPC) markers and populations compared to matched bone marrow and endosteum. After sorting, haematopoietic lineage negative (Lin-) cells from the periosteum showed efficient CFU-F formation compared with Lin- cells from the marrow compartments in both humans and mice. In humans, freshly isolated periosteal CD90+CD34+ cells contained SSPCs with clonal self-renewal and multipotent differentiation capacity in vitro.
We designed a murine periosteum scratch injury model which successfully mimicked fracture healing process without breaking the bone. Following local injury, many mSSPC markers and populations rapidly expanded during the early stages of healing. We identified a group of osteoprogenitors labelled by Sca1-CD51+, which expanded and contributed to bone and cartilage upon transplantation. Histologically, these cells mainly resided in the cambium layer of the periosteum and expanded with local injury. CD51+ and CD34+ cells expanded in a model of enhanced healing.
In summary, the periosteum is enriched with adult SSPCs and contains unique SSPC populations compared to the bone marrow compartment. We have defined adult SSPCs in the periosteum of humans and mice, although these populations are still heterogeneous. In conclusion, periosteum is a rich source of adult SSPCs, which are primarily quiescent but rapidly respond to injury
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
Understanding and Optimising Outcomes of Unicompartmental Knee Arthroplasty: Risk, Reasons, and Predictors of Revision
No full textBackground : Knee arthroplasty is the only effective long-term treatment for end-stage osteoarthritis (OA), which is a degenerative joint disease with significant impact on patient quality of life. For those with the right indications, unicompartmental knee arthroplasty (UKA) has surgical and clinical benefits over total knee arthroplasty (TKA), however UKA also has a higher risk of revision. A better understanding of UKA survivorship and revision is needed to optimise patient outcomes following knee arthroplasty.
Aims :
This thesis aims to improve understanding of clinical and biological factors affecting UKA survivorship with two overarching aims: 1) investigate revision following UKA, and 2) develop models of prediction for UKA patients at risk of revision.
Methods :
Systematic reviews of the literature identified the main reasons for UKA revision in a global context. Five retrospective studies were performed to investigate the risk, risk factors, and reasons for revision of UKA in New Zealand, with comparison to TKA. A prospective cohort study was carried out to characterise the inflammatory profile of UKA patients and identify associations between inflammatory markers and post-operative patient-reported outcomes.
Findings :
The main reasons for UKA revision were OA progression, aseptic loosening and bearing dislocation. Higher risk of UKA revision was associated with younger age, females, higher American Society of Anesthesiologists status and cemented mobile-bearing implants. Compared with TKA, the higher risk of UKA revision was associated with a lower clinical threshold for revision, and two modes of failure almost exclusive to UKA: OA progression and bearing dislocation. Poor post-operative Oxford Knee Scores, particularly for questions on ‘overall pain’, ‘limping when walking’ and ‘knee giving way’, were associated with higher risk of UKA and TKA revision. The inflammatory profile of UKA patients included synovitis, and inflammatory markers (IL-5, IL-6, IL-8, MCP-1, MIP-1β, TNFα, VEGFA). Lower levels of synovitis, and higher levels of VEGFA and IL-6 were associated with better post-surgical patient-reported outcomes.
Conclusions :
This thesis improves understanding of UKA survivorship and revision, and identifies post-operative scores and molecular biomarkers as useful clinical tools for predicting post-operative outcomes. These findings are informative for optimising patient selection, risk counselling and aftercare for improved outcomes following UKA
Supporting bone regeneration: Evaluation of endocrine peptides and delivery systems for local application of lactoferrin
No full textIntroduction
Fractures, especially in elderly people, have devastating outcomes and can drastically reduce the quality of life. Targeted delivery of growth factors directly to the site of fracture or other skeletal defects has been recognised as a strategy that could improve healing and lead to better clinical outcomes. Delivery systems that can enhance bone formation, accelerate regeneration and healing, and ultimately restore bone integrity and strength, are still largely missing.
Aim
We aimed to evaluate the myokine irisin and the neuropeptide orexin as potential bone anabolic factors and to develop a clinically suitable drug delivery system for the optimal delivery of the bone anabolic factor lactoferrin (LF).
Methods
We developed an ex vivo osteocyte culture system, and investigated the effects of irisin and orexin on bone cells at different stages of development in vitro: on bone marrow stromal cells, osteoblasts, osteocytes, and osteoclasts.
In vitro studies were conducted with three different delivery systems to assess their ability to deliver anabolic factor LF and their cytocompatibility with osteoblasts. Drug delivery systems demonstrating potential were tested in vivo using a rat calvarial defect model.
Results
Firstly, we validated our osteocyte-rich ex vivo bone tube system. The osteocytes in bone tubes were responsive to rhPTH(1-34) and decreased expression of Sost. Both irisin and orexin enhanced bone marrow stromal cell differentiation into adipocytes, and orexin also increased osteoblast proliferation. Irisin and orexin did not affect matrix mineralisation by osteoblasts, osteocyte function or osteoclastogenesis. Secondly, we found LF delivered in the commercial INFUSE® ACS and the current formulation of LF/poloxamers did not increase bone regeneration in a rat calvarial defect model. We developed a novel self-assembling peptide that is cytocompatible with osteoblasts and has potential to be used for sustained delivery of LF.
Conclusion
In conclusion, the present study suggests there is not enough evidence to demonstrate that irisin and orexin have potential as anabolic factors for local bone regeneration. While this study has not yet found a suitable delivery system for LF, we demonstrated that synthetic self-assembling peptide hydrogels have the potential to be further examined for local delivery of LF in vivo
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