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1
Wedin, Rikard. "Metastatic bone disease /". Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-3829-6/.
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2
Putman, Melissa. "Cystic Fibrosis Related Bone Disease". Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17613728.
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Over the past several decades, life expectancy for patients with cystic fibrosis (CF) has increased significantly. As patients live longer, other nonpulmonary co-morbidities related to CF have become increasingly prevalent, including CF-related bone disease. Because CF related bone disease has only recently emerged as a clinical problem, and the underlying bone alterations and pathogenesis of this condition have not been established.
This thesis explores the underlying bone micro-architecture and strength alterations found in adults with CF using state-of-the-art bone imaging techniques and explores whether improvements in the treatment of patients with CF over the past 15 years has led to similar improvements in bone health.
3
Goodyear, Simon R. "Physicochemical methods for measuring the properties of bone and their application to mouse models of disease". Thesis, University of Aberdeen, 2009. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=133992.
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This thesis describes a toolbox of complementary techniques that together measure and mechanical properties of bone. Three-point bending is used to measure the mechanical properties of bone; micro computed tomography provides cortical geometry and parameters describing trabecular bone. The material properties, elastic modulus and density, are measured directly using ultrasound and Archimedes’ principle, while composition and bone chemistry are investigated by ashing and Raman microscopy. These methods are used to characterise bone from the naturally occurring Gunmetal mouse and the engineered neuronal nitric oxide synthase (nNOS) knockout mouse. Comparison was also made between femora and tibiae and cortical and trabecular bone from wild type mice. Gunmetal mice had inferior mechanical properties, but unaffected material and chemical properties. Cortical area but not second moment of area was also reduced. nNOS knockouts had superior bone mechanically, due to increased mineralisation and geometrical parameters. Femora and tibiae had different mechanical and material properties that were not linked to the size or shape of the bones. Cortical bone had characteristics of older bone compared to trabecular material, possibly due to the lower turnover rate. These results show the necessity for measuring material properties directly, rather than inferring them from mechanical and geometrical properties. The differences in femora and tibiae suggest testing only femur or tibia may result in the risk of missing important results. Application of this toolbox of methods provides a comprehensive description of bone’s overall fitness for purpose and an understanding of the origin of any defect or enhancement in its properties.
4
Abdelhadi, Mohamed Mohamed. "Posttransplantation bone disease : the effect of immunosuppressive drugs on bone: clinical and experimental studies /". Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-384-8/.
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Nixon, Matthew Frank. "Metabolic bone disease and arthroplasty loosening". Thesis, University of Leicester, 2009. http://hdl.handle.net/2381/8448.
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Joint degeneration requiring arthroplasty surgery and the consequences of osteoporosis are the two fundamental pathologies in orthopaedics. There are around 44,000 Medline-indexed journals about osteoporosis, and around 30,000 concerned with arthroplasty. However despite both typically occurring in a similar elderly population, only 350 (less than 0.5%) are cross-indexed. Aseptic loosening is the commonest cause of hip arthroplasty failure, with revision surgery being the only current treatment. Recent work has increased the understanding of the aetiology of aseptic loosening and studies suggest that this process may be inhibited by the use of drugs that are normally used to treat osteoporosis, such as the bisphosphonates. It has also been shown that the occult incidence of metabolic bone disease may be as high as 40% in patients undergoing primary hip arthroplasty. This study is a progression of similar work on the aetiology and control of aseptic loosening done in the same department over the proceeding few years. In the first instance a cellular model of aseptic loosening was investigated by Ong and Taylor [published in 2003]. This laboratory based project used mouse bone, and exposing it to interface membrane tissue sampled at the time of revision arthroplasty surgery. This model was described by Reynolds and Dingle in 1970, and shown to activate osteoclasts. Ong and Taylor demonstrated that osteoclast activation could be inhibited with doxycycline, suggesting that matrix metalloproteinases may be important in the pathophysiology of aseptic loosening, and that the process is potentially preventable. The work was progressed further by Ibrahim and Taylor [2004] who developed a live model of particle induced osteolysis. They measured radio-labelled calcium uptake in mouse femora following implantation of ceramic particles, sham surgery and in controls. This was shown to be a useful model of quantifying osteolysis, although they did not find a difference between the controls and those exposed to ceramic particles. The original aim of this work was to follow on from the previous work and demonstrate that osteolysis could be inhibited or reversed using pharmacological agents. Ideally this would be done in a human clinical model, and a number of drugs were considered, including doxycycline, bisphosphonates and statins. Such a project would have involved recruiting patients to a clinical trial, followed by either randomisation to treatment or control groups before commencing treatment on participants. The ideal end-point would be revision for aseptic loosening (although radiological development of loosening would be an alternative). Because hip arthroplasty is such a successful operation these end-points are both rare and often not seen for many years. Even if we assume a rather optimistic reduction in loosening of 50% using our agent, we would have to recruit several hundred participants and wait at least 10 years to get meaningful results. We therefore have had to sacrifice some of the principles of strong research in favour of a project that could be completed with a limited time-frame and a limited budget. We studied patients that had already had an arthroplasty in situ for a number of years, and in view of the multi-factorial nature of loosening (as discussed below), limited this to one type of arthroplasty. The hypothesis of this study is that patients who have an underlying disorder of bone metabolism (such as osteoporosis or vitamin D deficiency) are more likely to develop aseptic loosening. In addition we hypothesise that there are measurable clinical, radiographic and biochemical markers that help predict those likely to develop loosening. This hypothesis was investigated in 127 patients (78 patients with a loose cemented total hip replacement matched by age, gender, race, prosthesis and time from surgery with 49 patients with a well-fixed stable hip replacement)/ We then conducted four connected studies involving, clinical, radiological, DEXA and biochemical assessment for markers of loosening. The aims are detailed below, but were principally to see whether patients with loosening are more likely to markers of osteoporosis or poor bone health. Unfortunately, this study takes us no further forward with regard to whether aseptic loosening can be inhibited by specific therapeutic agents, but hopefully it helps us to better understand the pathophysiological processes involved with arthroplasty failure. These can be used in future research to help improve arthroplasty function and longevity.
6
Lucas, Gavin J. A. "Genetics of Paget's disease of bone". Thesis, University of Aberdeen, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.430978.
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Chapter 3 describes the results of mutation screening of a candidate gene, SQSTM1, from one of the linkage regions implicated in the pathogenesis of PDB in families of mainly British descent. Seven mutations that segregated with the disease were identified and all clustered in the ubiquitin-associated (UBA) domain of the protein. In Chapter 4, an association study and haplotype analysis was conducted in PDB families using SNPs in SQSTM1. This revealed that the most common SQSTM1 mutation was predominantly carried on one of two common haplotype backgrounds, suggesting that a strong founder effect exists in this population. The P392L mutations occurred on the same haplotype background in sporadic cases as in the PDB families, indicating that many ‘sporadic’ PDB cases may have occult familial PDB. A syndrome of PDB associated with inclusion body myopathy and dementia has recently been shown to be caused by mutations that cluster in the CDC48 domain of the VCP gene. In Chapter 5, the VCP gene was screened for mutations in familial PDB and an association study was conducted in patients with sporadic PDB. No mutations in this gene were found in the PDB families. Haplotype analysis of a region spanning this gene also failed to support the involvement of polymorphisms in this gene in determining risk of sporadic PDB. In Chapter 6, genome-wide linkage analysis was conducted in PDB families without SQSTM1 mutations. This revealed significant evidence of linkage at a locus on chromosome 10p13 (PDB6). All families involved in this analysis were found to have a high likelihood of linkage at this locus.
7
Hocking, Lynne J. "Genetics of Paget's disease of bone". Thesis, University of Aberdeen, 2002. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU160239.
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In Chapter 4, I investigated the roles of the RANK signalling partners RANK ligand (RANKL) and osteoprotegerin (OPG) in the pathogenesis of sporadic and familial PDB. One polymorphism in the RANK gene and five polymorphisms in the OPG gene were examined in sporadic PDB cases and in sex- and age-matched controls. No allele-disease or genotype-disease association was observed for the RANKL polymorphism, suggesting RANKL is not directly involved in susceptibility to sporadic PDB. Genotypes at two OPG polymorphisms did significantly predict disease status in individuals affected with sporadic PDB, suggesting a role for OPG in the pathogenesis of sporadic PDB. The five OPG polymorphisms were also examined in families affected with PDB. No evidence was found to either suggest or exclude the involvement of any of the OPG polymorphisms in familial PDB. In Chapter 5, I performed a genome-wide search for PDB susceptibility loci in families with inherited PDB. Three regions of potential linkage were identified at 2q36, 5q35 and 10p11. Fine mapping was performed for the candidate region on chromosome 5q35, and eight families with a high probability of linkage to 5q35 were identified. In seven of the families, a shared haplotype transmitted only with affected family members was present. The shared haplotype varied between families and no common allele existed in the seven families for any of the nine markers studied. However, one area of shared haplotype occurred in all seven families across three of the markers, supporting evidence for a susceptibility gene for PDB on 5q35 in these families and narrowing the candidate region. In summary, this study has further highlighted the importance of genetic heterogeneity in the pathogenesis of PDB, excluding the previously identified PDB2 susceptibility locus and identifying three novel regions potentially harbouring susceptibility loci in the families studied. This study has also further defined the role of members of the RANK signalling pathway in the pathogenesis of familial and sporadic PDB.
8
Haarhaus, Mathias. "Bone alkaline phosphatase isoforms in chronic kidney disease : mineral and bone disorder". Doctoral thesis, Linköpings universitet, Avdelningen för mikrobiologi och molekylär medicin, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-111870.
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Chronic kidney disease (CKD) is associated with increased mortality and cardiovascular complications. Disturbances in mineral metabolism occur early <luring the course of CKD and several components of the CKD-mineral and bone disorder (CKD-MBD) are independent predictors of mortality. Alkaline phosphatase (ALP) is necessary for skeletal mineralization and is also involved in the process of vascular calcification. In recent years, ALP has evolved as a strong predictor of mortality in the CKD population. The significant role of ALP in the mineralization process renders it a putative target for the treatment and prevention of vascular calcification. Three circulating isoforms of bone ALP (BALP) have been identified (B/I, B 1, and B2). A fourth isoform, Blx, has been identified exclusively in serum from patients with CKD. The aim of the present thesis was to further elucidate the role ofthe BALP isoforms in CKD with respect to bone abnormalities and vascular calcification. In study I we identified the novel BALP isoform Blx in 20% of patients with mild to moderate CKD. Blx was associated with lower glomerular filtration rate and higher serum phosphate and calcium x phosphate product, which are risk factors for cardiovascular mortality in CKD. We also identified the BALP isoforms B/I, Bl and B2 as predictors of total hip bone mineral density. Study II was an experimental study, investigating the role of the BALP isoforms in phosphate induced calcification of human aortic smooth muscle cells (HASMCs). We found that the ALP expressed in HASMCs is exclusively BALP. Phosphate induced calcification of HASMCs was associated with increased BALP isoforms B/I, Blx, and B2 activities, which implies functional differences between the BALP isoforms in HASMC calcification. In study III we investigated the association of BALP isoforms in serum and histomorphometric parameters of bone in patients on chronic hemodialysis. W e identified the BALP isoform Blx as a novel marker for reduced osteoblastic activity. Study IV was a prospective cohort study of the association of serum BALP isoforms with aortic calcification and vascular stiffness in prevalent chronic dialysis patients. Blx was associated with baseline and time varying vascular stiffness, determined by pulse wave velocity, but not with calcification of the abdominal aorta. We also found an association of Blx with better event-free survival. In conclusion, these studies demonstrate that the BALP isoforms, especially isoform Blx, are involved in different aspects of CKD-MBD. This opens up for further research to identify the BALP isoforms as diagnostic markers and possible treatment targets in CKD-MBD.
9
Porter, Ryan Michael. "Examination of Glucocorticoid Treatment on Bone Marrow Stroma: Implications for Bone Disease and Applied Bone Regeneration". Thesis, Virginia Tech, 2002. http://hdl.handle.net/10919/36365.
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Long-term exposure to pharmacological doses of glucocorticoids has been associated with the development of osteopenia and avascular necrosis. Bone loss may be partially attributed to a steroid-induced decrease in the osteoblastic differentiation of multipotent progenitor cells found in the bone marrow. In order to determine if there is a change in the osteogenic potential of the bone marrow stroma following glucocorticoid treatment, Sprague-Dawley rats were administered methylprednisolone for up to six weeks, then sacrificed at 0, 2, 4, or 6 weeks during treatment or 4 weeks after cessation of treatment. Femurs were collected and analyzed for evidence of steroid-induced osteopenia and bone marrow adipogenesis. Although glucocorticoid treatment did inhibit bone growth, differences in ultimate shear stress and mineral content were not detected. The volume of marrow fat increased with increasing duration of treatment, but returned to near control levels after cessation of treatment. Marrow stromal cells were isolated from tibias, cultured in the presence of osteogenic supplements, and analyzed for their capacity to differentiate into osteoblast-like cells in vitro. Glucocorticoid treatment diminished the absolute number of isolated stromal cells, but did not inhibit the relative levels of bone-like mineral deposition or osteocalcin expression and secretion.
Although pharmacological glucocorticoid levels induce bone loss in vivo, physiologically equivalent concentrations have been shown to enhance the formation of bone-like tissue in vitro. However, glucocorticoids have also been reported to inhibit proliferation and type I collagen synthesis in marrow stromal cell cultures. In order to assess the effects of intermittent dexamethasone treatment on the progression of osteogenesis in rat marrow stromal cell culture, this synthetic glucocorticoid was removed from the culture medium after a variable period of initial supplementation. Cell layers were analyzed for total cell number, collagen synthesis, phenotypic marker expression, and matrix mineralization. Prolonged supplementation with dexamethasone decreased proliferation, but did not significantly affect collagen synthesis. Furthermore, increased treatment duration was found to increase bone sialoprotein expression and mineral deposition. The duration of glucocorticoid treatment may be a key factor for controlling the extent of differentiation in vitro.Master of Science
10
Good, David Andrew, i n/a. "Genetic Loci for Paget's Disease of Bone". Griffith University. School of Biomolecular and Biomedical Science, 2003. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20040319.125358.
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Paget's disease of the bone is a skeletal disorder of unknown cause. This disease is characterised by excessive and abnormal bone remodelling brought about by increased bone resorption followed by disorganised bone formation. Increased bone turnover results in a disorganised mosaic of woven and lamellar bone at affected skeletal sites. This produces bone that is expanded in size, less compact, more vascular, and more susceptible to deformity or fracture than normal bone. Symptoms of Paget's disease may include bone pain, bone deformity, excessive warmth over bone from hypervascularity, secondary arthritis, and a variety of neurologic complications caused in most instances by compression of the neural tissues adjacent to pagetic bone. Genetic factors play a role in the pathogenesis of Paget's disease but the molecular basis remains largely unknown. The identification of the molecular basis of Paget's disease is fundamental for an understanding of the cause of the disease, for identifying subjects at risk at a preclinical stage, and for the development of more effective preventive and therapeutic strategies for the management of the condition. With this in mind, the aim of this project is to identify genetic loci, in a large pedigree, that may harbour genes responsible for Paget's disease of bone. A large Australian family with evidence of Paget's disease was recruited for these studies (Chapter 3). This pedigree has characterised over 250 individuals, with 49 informative individuals affected with Paget's disease of bone, 31 of whom are available for genotypic analysis. The pattern of disease in these individuals is polystotic, with sites of involvement including the spine, pelvis, skull and femur. Although the affected individuals have a severe early-onset form of the disease, the clinical features of the pedigree suggest that the affected family members have Paget's disease and not familial expansile osteolysis (a disease with some similarities to Paget's disease), as our patients have extensive skull and axial skeletal involvement. The disease is inherited as an autosomal dominant trait in the pedigree with high penetrance by the sixth decade. Due to the large size of this family and multiple affected members, this pedigree is a unique resource for the detection of the susceptibility gene in Paget's disease. The first susceptibility loci for Paget's disease of bone have been mapped by other investigators to chromosome 6p21 (PDB1) and 18q21.1-q22 (PDB2) in different pedigrees. Linkage analysis of the Australian pedigree in these studies was performed with markers at PDB1: these data showed significant exclusion of linkage, with LOD scores < - 2 in this region (Chapter 4). Linkage analysis of microsatellite markers from the PDB2 region excluded linkage with this region also, with a 30 cM exclusion region (LOD score < -2.0) centred on D18S42 (Chapter 4). This locus on chromosome 18q21.1-q22 contains a serine protease (serpin) cluster with similarities to chromosome 6p21. Linkage analysis of this region also failed to provide evidence of linkage to this locus (Chapter 4). These data are consistent with genetic heterogeneity of Paget's disease of bone. A gene essential for osteoclast formation encoding receptor activator of nuclear factor-kB (RANK), TNFRSF11A, has been previously mapped to the PDB2 region. Mutations in the TNFRSF11A gene have been identified segregating in pedigrees with Familial Expansile Osteolysis and early onset familial Paget's disease, however, linkage studies and mutation screening have excluded the involvement of RANK in the majority of Paget's disease patients. For the Australian pedigree, mutation screening at the TNFRSF11A locus revealed no mutations segregating with affected individuals with Paget's disease (Chapter 4). Based on these findings, our hypothesis is that a novel susceptibility gene relevant to the pathogenesis of Paget's disease of bone lies elsewhere in the genome in the affected members of this pedigree; this gene should be identifiable using a microsatellite genome-wide scan followed by positional cloning. A genome-wide scan of the Australian pedigree was carried out, followed by fine mapping and multipoint analysis in regions of interest (Chapter 5). The peak 2-point LOD scores from the genome-wide scan were LOD = 2.75 at D7S507 and LOD = 1.76 at D18S70. Two additional regions were also considered for fine mapping: chromosome 19p11-q13.1 with a LOD of 1.58 and chromosome 5q35-qter with a LOD of 1.57. Multipoint and haplotype analysis of markers flanking D7S507 did not support linkage to this region (Chapter 5). Similarly, fine mapping of chromosome 19p11-q13.1 failed to support linkage to this region (Chapter 5). Linkage analysis with additional markers in the region on chromosome 5q35-qter revealed a peak multipoint LOD score of 6.77 (Chapter 5). A distinct haplotype was shown to segregate with all members of the family, except the offspring of III-5 and III-6. Haplotype analysis of markers flanking D18S70 demonstrated a haplotype segregating with Paget's disease in a large sub-pedigree (descendants of III-3 and III-4) (Chapter 5). This sub-pedigree had a significantly lower age at diagnosis than the rest of the pedigree (51.2 + 8.5 vs. 64.2 + 9.7 years, p = 0.0012). Linkage analysis of this sub-pedigree demonstrated a peak two-point LOD score of 4.23 at marker D18S1390 (q = 0.00), and a peak multipoint LOD score of 4.71, at marker D18S70. An implication of these data is that 18q23 harbours a novel modifier gene for reducing the age of onset of Paget's disease of bone. A number of candidate Paget's genes have previously been identified on chromosome 18q23, including the nuclear factor of activated T cells (NFATc1), membrane-associated guanylated kinase (MAGUK) and a zinc finger protein. Candidate gene sequencing of these genes in these studies has failed to identify mutations segregating with affected family members in the sub-pedigree linked to chromosome 18q23 (Chapter 6). More recently, a mutation in the gene encoding the ubiquitin-binding protein sequestosome 1 (SQSTM/p62) has been shown to segregate with affected members of Paget's disease families of French-Canadian origin. In this study, a single base pair deletion (1215delC) was identified as segregating with the majority of affected members in the pedigree (Chapter 6). This deletion introduces a stop codon at amino acid position 392 which potentially results in early termination of the protein and loss of the ubiquitin binding domain. The three affected members of the family that do not share the affected haplotype do not carry a mutation in the coding region of SQSTM/p62. Screening of affected members from 10 further Paget's disease families identified the previously reported P392L mutation in 2 (20%) families. No SQSTM1/p62 coding mutations have been found in the remaining 8 families or in 113 aged matched controls. In conclusion, this project has identified genetic loci and mutations that segregate with individuals affected with Paget's disease. Further investigation of the functional significance of the genetic changes at these loci is expected to lead to a better understanding of the molecular basis of this disease.
11
Amofah, Eunice. "Bone marrow stem cells in liver disease". Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.497234.
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Najat, Dereen. "SQSTM1 mutations and Paget's disease of bone". Thesis, University of Nottingham, 2010. http://eprints.nottingham.ac.uk/11118/.
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Mutations affecting the p62 signalling adapter protein are commonly found in patients with the skeletal disorder Paget‟s disease of bone (PDB). We have extended previous in vitro functional analyses of PDB-mutant p62 proteins (Cavey et al., 2006) to study the effects of several uncharacterised PDB-associated mutations on the ubiquitin-binding properties of p62. These include mutations which affect regions of p62 outside of the ubiquitin-binding UBA domain (A381V, D335E and a mutant equivalent to a predicted product of the G1205C splice-site mutation which lacks amino acids 351-388), as well as a double mutation involving the P392L and S399P changes on the same allele. In accordance with previous findings, both of the non-UBA domain mutations (A381V, ∆351-388) showed deleterious effects on ubiquitin-binding by p62 in pull-down assays, further emphasising the important role of non-UBA domain sequences in mediating ubiquitin-recognition, as well as in PDB aetiology. The D335E mutant retained its ubiquitin-binding function in vitro. The P392L/S399P double mutant showed a more severe effect on ubiquitin-binding than either of the single P392L or S399P missense mutations alone; as this double mutation is associated with a particularly severe phenotype, our findings are supportive of the proposal that disease severity in PDB with p62 mutations may be directly related to the effects of the mutations on the ubiquitin-binding function of the p62 protein. Since the in vitro pull-down assays are semi-quantitative at best, we sought to investigate if a more quantitative biophysical approach, two dimensional Heteronuclear Single Quantum Coherence (2D-HSQC) protein NMR, might be applied to investigate the effects of PDB-associated mutations on protein (ubiquitin-binding) function. Our results showed that protein NMR was not optimal to quantitatively assess the effects of the mutations on the interaction between p62 and ubiquitin in vitro. Using confocal microscopy, co-transfection of U20S cells showed that the selected PDB-associated p62 mutants (A381V, P392L, G425R) co-localised with ubiquitin with a cellular phenotype indistinguishable from wild type, as each PDB mutant formed cytoplasmic bodies with an area ranging from the detection limit of the microscope to 40μm2 or higher; in contrast the E396X truncating mutant did not form cytoplasmic bodies nor co-localise with ubiquitin. In addition to interacting with ubiquitin, p62 also interacts with the LC3 (an autophagic marker) through its LC3 interacting region (LIR) to mediate the formation of autophagosomes. By co-transfecting p62 constructs with LC3 We found that some of the p62-positive cytoplasmic bodies were autophagosomes, and that the D335E mutation of p62 (which lies within the LIR) did not appear to affect the formation of autophagosomes. The effects of the wild type and PDB-mutant p62 proteins on NF-κB signalling were assessed in HEK293 cells co-transfected with an NF-κB luciferase reporter construct. A381V mutant p62 produced a level of activation of NF-κB signalling greater than wildtype and similar to that of UBA domain mutants, indicating that non-UBA and UBA domain mutations may exert their effects through a common mechanism involving dysregulated NF-κB signalling. To further examine the function of p62 in the regulation of NF-κB signalling, we went on to determine possible effects of PDB-associated mutations on p62-CYLD (a DUB enzyme) interactions. Unexpectedly we found that CYLD expression appears to abrogate the formation of the p62 cytoplasmic bodies previously shown to be ubiquitin-positive. Finally, we went on to study the interaction of p62 (and its PDB mutants) with another important regulator of NF-κB signalling, IKKγ/NEMO. We concluded that wild type and PDB-mutant p62 proteins are capable of recruiting NEMO to cytoplasmic bodies which may represent autophagosomes, but do not appear to accelerate its degradation.
13
Birch, Mark Andrew. "Investigations of bone cells in Paget's disease". Thesis, University of Liverpool, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.333632.
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14
Good, David Andrew. "Genetic Loci for Paget's Disease of Bone". Thesis, Griffith University, 2003. http://hdl.handle.net/10072/365759.
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Paget's disease of the bone is a skeletal disorder of unknown cause. This disease is characterised by excessive and abnormal bone remodelling brought about by increased bone resorption followed by disorganised bone formation. Increased bone turnover results in a disorganised mosaic of woven and lamellar bone at affected skeletal sites. This produces bone that is expanded in size, less compact, more vascular, and more susceptible to deformity or fracture than normal bone. Symptoms of Paget's disease may include bone pain, bone deformity, excessive warmth over bone from hypervascularity, secondary arthritis, and a variety of neurologic complications caused in most instances by compression of the neural tissues adjacent to pagetic bone. Genetic factors play a role in the pathogenesis of Paget's disease but the molecular basis remains largely unknown. The identification of the molecular basis of Paget's disease is fundamental for an understanding of the cause of the disease, for identifying subjects at risk at a preclinical stage, and for the development of more effective preventive and therapeutic strategies for the management of the condition. With this in mind, the aim of this project is to identify genetic loci, in a large pedigree, that may harbour genes responsible for Paget's disease of bone. A large Australian family with evidence of Paget's disease was recruited for these studies (Chapter 3). This pedigree has characterised over 250 individuals, with 49 informative individuals affected with Paget's disease of bone, 31 of whom are available for genotypic analysis. The pattern of disease in these individuals is polystotic, with sites of involvement including the spine, pelvis, skull and femur. Although the affected individuals have a severe early-onset form of the disease, the clinical features of the pedigree suggest that the affected family members have Paget's disease and not familial expansile osteolysis (a disease with some similarities to Paget's disease), as our patients have extensive skull and axial skeletal involvement. The disease is inherited as an autosomal dominant trait in the pedigree with high penetrance by the sixth decade. Due to the large size of this family and multiple affected members, this pedigree is a unique resource for the detection of the susceptibility gene in Paget's disease. The first susceptibility loci for Paget's disease of bone have been mapped by other investigators to chromosome 6p21 (PDB1) and 18q21.1-q22 (PDB2) in different pedigrees. Linkage analysis of the Australian pedigree in these studies was performed with markers at PDB1: these data showed significant exclusion of linkage, with LOD scores < - 2 in this region (Chapter 4). Linkage analysis of microsatellite markers from the PDB2 region excluded linkage with this region also, with a 30 cM exclusion region (LOD score < -2.0) centred on D18S42 (Chapter 4). This locus on chromosome 18q21.1-q22 contains a serine protease (serpin) cluster with similarities to chromosome 6p21. Linkage analysis of this region also failed to provide evidence of linkage to this locus (Chapter 4). These data are consistent with genetic heterogeneity of Paget's disease of bone. A gene essential for osteoclast formation encoding receptor activator of nuclear factor-kB (RANK), TNFRSF11A, has been previously mapped to the PDB2 region. Mutations in the TNFRSF11A gene have been identified segregating in pedigrees with Familial Expansile Osteolysis and early onset familial Paget's disease, however, linkage studies and mutation screening have excluded the involvement of RANK in the majority of Paget's disease patients. For the Australian pedigree, mutation screening at the TNFRSF11A locus revealed no mutations segregating with affected individuals with Paget's disease (Chapter 4). Based on these findings, our hypothesis is that a novel susceptibility gene relevant to the pathogenesis of Paget's disease of bone lies elsewhere in the genome in the affected members of this pedigree; this gene should be identifiable using a microsatellite genome-wide scan followed by positional cloning. A genome-wide scan of the Australian pedigree was carried out, followed by fine mapping and multipoint analysis in regions of interest (Chapter 5). The peak 2-point LOD scores from the genome-wide scan were LOD = 2.75 at D7S507 and LOD = 1.76 at D18S70. Two additional regions were also considered for fine mapping: chromosome 19p11-q13.1 with a LOD of 1.58 and chromosome 5q35-qter with a LOD of 1.57. Multipoint and haplotype analysis of markers flanking D7S507 did not support linkage to this region (Chapter 5). Similarly, fine mapping of chromosome 19p11-q13.1 failed to support linkage to this region (Chapter 5). Linkage analysis with additional markers in the region on chromosome 5q35-qter revealed a peak multipoint LOD score of 6.77 (Chapter 5). A distinct haplotype was shown to segregate with all members of the family, except the offspring of III-5 and III-6. Haplotype analysis of markers flanking D18S70 demonstrated a haplotype segregating with Paget's disease in a large sub-pedigree (descendants of III-3 and III-4) (Chapter 5). This sub-pedigree had a significantly lower age at diagnosis than the rest of the pedigree (51.2 + 8.5 vs. 64.2 + 9.7 years, p = 0.0012). Linkage analysis of this sub-pedigree demonstrated a peak two-point LOD score of 4.23 at marker D18S1390 (q = 0.00), and a peak multipoint LOD score of 4.71, at marker D18S70. An implication of these data is that 18q23 harbours a novel modifier gene for reducing the age of onset of Paget's disease of bone. A number of candidate Paget's genes have previously been identified on chromosome 18q23, including the nuclear factor of activated T cells (NFATc1), membrane-associated guanylated kinase (MAGUK) and a zinc finger protein. Candidate gene sequencing of these genes in these studies has failed to identify mutations segregating with affected family members in the sub-pedigree linked to chromosome 18q23 (Chapter 6). More recently, a mutation in the gene encoding the ubiquitin-binding protein sequestosome 1 (SQSTM/p62) has been shown to segregate with affected members of Paget's disease families of French-Canadian origin. In this study, a single base pair deletion (1215delC) was identified as segregating with the majority of affected members in the pedigree (Chapter 6). This deletion introduces a stop codon at amino acid position 392 which potentially results in early termination of the protein and loss of the ubiquitin binding domain. The three affected members of the family that do not share the affected haplotype do not carry a mutation in the coding region of SQSTM/p62. Screening of affected members from 10 further Paget's disease families identified the previously reported P392L mutation in 2 (20%) families. No SQSTM1/p62 coding mutations have been found in the remaining 8 families or in 113 aged matched controls. In conclusion, this project has identified genetic loci and mutations that segregate with individuals affected with Paget's disease. Further investigation of the functional significance of the genetic changes at these loci is expected to lead to a better understanding of the molecular basis of this disease.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Biomedical Sciences
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Obaid, Rami Abdulhadi Abdulmajeed. "Investigating the role of optineurin in bone biology and Paget's disease of bone". Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/23419.
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Paget’s disease of bone (PDB) is a common disease with a strong genetic component. Approaches such as linkage analysis and candidate gene studies have shown that mutations in Sequestosome 1 (SQSTM1) explain up to 40% of familial cases and 10% of sporadic cases, however the majority of PDB patients have no mutations in this gene. Genome-wide association studies (GWAS) have recently identified new susceptibility loci for PDB including variants at CSF1, TNFRSF11A, OPTN, TM7SF4, PML, NUP205 and RIN3 loci. These loci were confirmed to be associated with PDB in various European populations. OPTN encodes optineurin, a widely expressed protein involved in many cellular processes but its role in bone metabolism is yet unknown. The aim of this PhD thesis was to investigate the role of OPTN in bone metabolism and PDB using in vitro and in vivo studies. In chapter 3, the OPTN rs1561570 identified by previous GWAS was examined for its association with the severity and clinical outcome of PDB in patients without SQSTM1 mutations. The results showed that rs1561570 was significantly associated with total disease severity score so that carriers of the risk allele “T” had higher severity score compared to non-carriers (P < 0.05). A trend for reduced quality of life physical scores (SF36) was also associated with the rs1561570 risk allele, but the relationship was not statistically significant. In order to identify functional variants within OPTN, the coding regions as well as the exon-intron boundaries were sequenced in 24 familial PDB cases and 19 controls. No mutation was found that could be predicted as pathogenic suggesting that disease susceptibility could be mediated by regulatory polymorphisms that influence gene expression. In chapter 4, the role of OPTN was investigated in osteoclast development using in vitro knockdown experiments. Optn was expressed in mouse bone marrow derived macrophages (BMDMs) as well as all stages of osteoclast development and it was significantly increased three days post RANKL treatment. Optn expression was knocked down in BMDMs and cells were induced to form osteoclast in the presence of RANKL and M-CSF. Compared to non-targeted cells, Optn depleted cells formed significantly more and larger osteoclasts (P< 0.05). Optn knockdown was also found to enhance osteoclast survival as well as RANKL-induced NFκB activation. In chapter 5, the role of OPTN was investigated in vitro from cells obtained from knock in mice with a loss-of-function mutation in Optn (OptnD477N/D477N). In agreement with the in vitro knockdown experiments, osteoclasts were significantly higher and larger in mutant mice compared to WT and the NF-B activity measured by luciferase reporter assay was significantly higher in cells from OptnD477N/D477N compared to WT during most stages of osteoclast development. OPTN from mutant and WT mice was co-precipitated with its CYLD binding-partner, which acts as a negative regulator to RANK signalling by inhibiting the TRAF6 downstream signalling. The data from this immunoprecipitation (IP) experiment revealed that defective OPTN interacted less with CYLD from mutant mice compared to WT. This study also showed that OPTN was expressed in osteoblasts and the expression rate did not change during osteoblast development. The data obtained from the mineralization assay revealed no significant difference between OptnD477N/D477N and WT. In chapter 6, I investigated the effect of the D477N loss of function mutation in Optn on bone metabolism. Bone Histomorphometrical analysis of OptnD477N/D477N mice showed higher bone resorption parameters (Oc.N/BS and Oc.S/BS) compared to wild type (WT). Osteoid analysis showed evidence of increased bone formation parameters (OS/BS and OV/BV) in mutant mice compared to WT. Calcein labelling showed a significant difference in mineral apposition rate (MAR) from mutant mice compared to WT. Analysis of serum biomarkers of bone turnover showed evidence of enhanced bone turnover in mutant mice compared to WT. Micro computed tomography (μCT) analysis of 4 and 14 months old mice showed no significant differences in bone morphology between WT and OptnD477N/D477N mice of both sexes. In conclusion, this study has shown for the first time that OPTN plays a role in regulating bone turnover by acting as a negative regulator of osteoclast differentiation. The data obtained from this study strongly suggest the crucial role of OPTN in RANK signalling. The effect of OPTN on osteoblast activity may be direct or indirect compensation for increased osteoclast activity. Further detailed studies will be required to explore the underlying mechanism of OPTN including downstream RANK signalling and a complete knockout model to corroborate these findings.
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Ogilvie, D. J. "The genetics of collagen in brittle bone disease". Thesis, University of Oxford, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.235046.
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Billah, Ahmed Mohammed El-Motaz. "Markers of bone turnover in health and disease". Thesis, University of Nottingham, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295769.
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Numan, Mohamed. "Gene-environment interaction in Paget's disease of bone". Master's thesis, Université Laval, 2017. http://hdl.handle.net/20.500.11794/27518.
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La maladie osseuse de Paget (MP) est une maladie métabolique de l’os. Bien que les facteurs génétiques jouent un rôle important dans la pathogénie de la MP, les facteurs environnementaux tels que la résidence rurale et l’exposition au chauffage au bois ont été associés avec la MP. Afin d’étudier le rôle des polluants de l'air extérieur et intérieur sur la MP, nous avons administré un questionnaire chez 140 patients canadiens-français avec la MP et 113 témoins sains. Ce questionnaire portait sur la pollution de l'air extérieur, comme la résidence près d'une autoroute, d’une station de bus, de train ou d’un aéroport, d’une station d'essence, et sur les polluants de l'air intérieur en mettant l'accent sur les combustibles de chauffage (charbon, bois, huile) et l'exposition au tabac. Dans un sous-groupe de patients, la concentration urinaire de 17 métaux lourds et de 11 hydrocarbures aromatiques polycycliques a été mesurée par spectrométrie de masse. À la lumière de ce que nous savions dès le questionnaire et les dosages urinaires, nous avons identifié certains toxiques pouvant être des facteurs de risque pour la MP. Pour explorer les effets in vitro de ces toxiques sur les ostéoclastes dans la MP, nous avons réalisé une différentiation in vitro de monocytes du sang périphérique provenant de plus de 40 participants, patients, porteurs sains de mutation dans le gène SQSTM1, et des témoins sains, en ostéoclastes traités avec ou sans les toxiques identifiés. La morphologie des ostéoclastes, le pourcentage de résorption osseuse, les niveaux d'expression génique, et les niveaux de stress oxydatif cellulaire ont été analysés. Les résultats ont montré un effet inhibiteur du condensé de la fumée de cigarette et des métaux lourds sur la morphologie et la fonction des ostéoclastes. De plus, des taux élevés de stress oxydatif chez les ostéoclastes des patients ont été observés, et un profil hétérogène des effets de métaux lourds sur l'expression des gènes a été identifié.Paget's disease of bone (PDB) is a metabolic bone disease. Although genetic factors play an important role in the pathogenesis of PDB, environmental factors such as rural residence and the exposure to wood heating was associated with PDB. In order to study the role of outdoor and indoor air pollutants on PDB, we performed a survey in 140 French-Canadian patients with PDB and 113 healthy controls. The survey covered the outdoor air pollution such as the residence near a highway, a bus station, a train or an airport or a gas station, and indoor air pollutants by focusing on heating fuels (carbon, wood, oil) and exposure to tobacco smoke. In a subgroup of patients, urinary concentration of 17 heavy metals and 11 polycyclic aromatic hydrocarbons was measured by mass spectrometry. In light of what we knew from the survey and urinary assays, we identified certain toxics that could be risk factors for PDB. To explore the in vitro effects of these toxics on osteoclasts in PDB, we conducted in vitro monocytes differentiation from peripheral blood of more than 40 participants, patients, healthy carriers of p.Pro392Leu mutation, and healthy controls, which osteoclasts were treated with or without the identified toxic. The morphology of osteoclasts, the percentage of bone resorption, gene expression level, and cellular oxidative stress levels were assayed. The results showed an inhibitory effect of cigarette smoke condensate and heavy metals on morphology and function of patients’ osteoclasts. Further, high levels of oxidative stress in patients’ osteoclasts were observed, and a heterogenic profile of heavy metals effect on gene expression was identified.
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Gowers, Kate Hayley Christine. "Characterisation of bone marrow progenitor cells in disease". Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/11068.
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The bone marrow serves as a reservoir for leukocytes and stem cells, from where cells can be mobilised into the circulation and can be recruited to sites of inflammation. Mobilisation of cells out of the bone marrow is dependent on their migration across the bone marrow sinusoidal endothelium, which is thought to be structurally and functionally different to endothelial cells from other vascular beds. In order to characterise the bone marrow endothelium and to study the molecular mechanisms involved in the mobilisation of cells, a protocol to isolate bone marrow endothelial cells and to grow them in vitro was developed. The bone marrow contains a number of distinct progenitor cell populations, including endothelial progenitor cells (EPCs) and mesenchymal stem cells (MSCs). Whether these populations of stem cells are recruited from the bone marrow to the lungs was investigated in two contrasting models of lung disease: the house dust mite (HDM) model of allergic airways disease and the bleomycin model of pulmonary fibrosis. In the HDM model increased recruitment of EPCs to the inflamed lungs was associated with increased peribronchial angiogenesis, and reduced EPC numbers in the bone marrow. Blocking VEGF inhibited EPC recruitment to the inflamed lungs and reduced the associated peribronchial angiogenesis. In this model, no recruitment of MSCs to the inflamed lungs was observed. However, in the bleomycin model, a significant elevation in MSC numbers was observed in the circulation, lung tissue and BAL fluid. Experiments to block the recruitment of MSCs to the lungs in response to bleomycin injury were performed, along with investigations into the recruitment of exogenously administered MSCs to the injured lungs. A population of MSCs residing in the naïve lungs was identified, which are phenotypically similar to bone marrow MSCs, but can be distinguished by their size and expression of specific cell surface antigens.
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Ormarsdóttir, Sif. "Osteoporosis in chronic liver disease /". Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-5021-0/.
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Huang, C. C. "Pathophysiology of post-transplantation bone disease : mechanisms of bone loss after orthotopic liver transplantation". Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604707.
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To enhance our understanding of the pathophysiology of bone disease associated with liver transplantation and of the mechanisms underlying bone loss in the three month period following transplantation, this prospective study was undertaken as follows: (1) bone pathophysiology was evaluated pre- and three months post-transplantation in transiliac biopsies using tetracycline-assisted histomorphometry; (2) cellular activities of bone formation and resorption pre- and post- transplantation were studied using quantitative enzyme cytochemistry in combination with histomorphometric methods; (3) cellular activities for markers of bone energy metabolism and biosynthesis and/or cell proliferation were investigated using quantitative enzyme cytochemistry; (4) plasma markers for bone metabolism were investigated at regular intervals in collaboration with other laboratories. It was concluded from this study that rapid bone loss early after transplantation is due both to increased bone turnover and a negative remodelling balance at the individual bone remodelling site. These changes were at least partially mediated by increased PTH levels secondary to a negative balance in plasma calcium. Cyclosporin A is known to increase intracellular calcium levels and inhibit calcium release from mitochondria. It also reduces glomerular filtration rate which could be sufficient to depress extracellular calcium levels and thereby cause the observed rise in PTH levels. The consequences of this for post transplant bone remodelling is a markedly enhanced risk of osteoporosis in these patients. Ensuring replete calcium and vitamin D levels pre-transplantation and supplementation of cyclosporin A treatment with vitamin D metabolites and calcium post-transplantation followed by careful monitoring of plasma calcium concentrations might offer a better overall outcome for preventing transplantation-associated osteoporosis at this early stage post transplantation.
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MacPherson, Heather. "Role of the nitric oxide synthase pathway in bone cell function and bone disease". Thesis, University of Aberdeen, 1999. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU112398.
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Nitric oxide acts as a signalling molecule in several tissues and organ systems and recent work has shown that it is also produced in bone. The aim of this thesis was to investigate the role of the nitric oxide synthase pathway in bone cell function and bone disease. Studies with primary human osteoblasts indicated that they had the ability to produce nitric oxide under conditions of cytokine stimulation using the iNOS pathway and in response to fluid flow using the ecNOS pathway. Cytokine induced nitric oxide had a differentiation-inducing effect as reflected by a decrease in cell proliferation and an increase in the expression of alkaline phosphatase. Further investigations showed that p27Kjpl was induced in response to cytokine stimulation in primary human osteoblasts suggesting that this may have been responsible for cytokine induced inhibition of cell growth. An investigation of the expression of the different isoforms of nitric oxide synthase in human metabolic bone diseases revealed that ecNOS was the predominantly expressed isoform in bone. The primary human osteoblasts also showed widespread expression of ecNOS protein. In view of this, a genetic association study was carried out to investigate the relationship between a polymorphism in the ecNOS gene, bone mineral density and fracture incidence. A significant relationship was found between bone mineral density and presence of the ecNOS polymorphism, but the polymorphism was not found to be associated with osteoporotic fracture. In summary, nitric oxide produced via the inducible nitric oxide synthase pathway in human osteoblast-like cells inhibits cell proliferation and increases cell differentiation. This inhibition of cell proliferation was associated with increased expression of the cell cycle inhibitory protein p27Kipl. ecNOS was shown to be the predominant isoform of nitric oxide synthase expressed under basal conditions and in response in fluid flow. A polymorphism in this gene was shown to be associated with decreased bone mass.
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Choi, Chung-yue. "Free radicals and bone marrow diseases a potential role of nitric oxide in graft-versus-host disease after bone marrow transplant /". Hong Kong : University of Hong Kong, 2000. http://sunzi.lib.hku.hk/hkuto/record.jsp?B23273367.
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Taggart, Frances Margaret. "The epidemiology of Paget's disease of bone in Europe". Thesis, University of Southampton, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.328623.
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Rios, Visconti Micaela. "Genetic and environmental determinants of Paget's disease of bone". Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/20421.
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Genetic factors play an important role in the pathogenesis of Paget’s Disease of Bone (PDB). The most important predisposing gene is SQSTM1 which is mutated in about 10% of patients, additionally common variants at seven other loci have also been shown to predispose to PDB as well as environmental factors which are also important in the pathogenesis of PDB. Little research has been conducted on the relationship between the genetic variants that predispose to PDB and disease severity. Similarly, only limited information exists on the role that gene-environment interactions play in the pathogenesis of PDB or its severity. The aim of the present thesis was to explore these issues in participants of the Paget’s Disease Randomised Trial of Intensive versus Symptomatic Management study (PRISM) and other study cohorts. In chapter 3, I investigate the relationship between SQSTM1 mutation status, disease severity and clinical outcome in 737 patients from the PRISM study. Mutations of SQSTM1 were detected in 80/737 (10.9%) patients. Mutation carriers had an earlier age at diagnosis; a greater number of affected bones and more commonly had required orthopaedic surgery and bisphosphonate therapy than those without mutations. Quality of life was significantly reduced in carriers and during the study; fractures were more common although most of these occurred in unaffected bone. This study demonstrates that SQSTM1 mutations are strongly associated with disease severity and complications of PDB. In chapter 4, I study associations between common genetic variants identified by genome wide association (GWAS), clinical severity and extent of PDB, alone and in combination with SQSTM1 mutations. This showed that these common variants were also associated with severity and extent of PDB in PRISM, but with weaker effects than SQSTM1 mutations. The findings were replicated in a multinational study involving 1940 subjects from centres in Italy, Spain and Australia. In all cohorts the GWAS risk alleles acted in an additive manner with SQSTM1 mutations to regulate disease severity and extent. By combining information from SQSTM1 status and the new risk alleles, however, we are able to develop a genetic risk score which delineated three distinct groups with markedly differing effects on disease extent and severity. In chapter 5, I study associations between PDB, severity and extent in relation to circulating levels of IgG antibodies against various viruses including Rubella, respiratory syncytial virus, distemper, varicella zoster virus, measles and mumps. We found little evidence of an interaction between viral antibody titres and SQSTM1 in predicting disease severity with the notable exception of mumps virus where subjects with the highest levels of antibodies that were SQSTM1 positive had in increased age at diagnosis than the other genotype / viral antibody groups. Overall the studies do provide no support for the notion that patients with PDB have an abnormal antibody response to paramyxovirus or have had previous infections with these viruses more frequently than controls. This of course does not exclude the possibility that PDB patients might have a clinically occult slow virus infection which is not accompanied by an abnormality in the immune response. . This raises the possibility that genetic testing may be of value in identifying individuals at risk of developing severe disease and those at risk of complications. I also demonstrate that PBD patients have abnormalities in circulating antibodies to various viruses suggesting that the disease may be associated with disturbance in the response of the immune system to infectious agents but further investigation is required. This, perhaps, could explain the changes in the severity and prevalence of PDB that have been observed over recent years in several countries.
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PAOLETTI, Nicola. "Formal Computational Modelling of Bone Physiology and Disease Processes". Doctoral thesis, Università degli Studi di Camerino, 2014. http://hdl.handle.net/11581/401835.
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This thesis addresses the definition and the application of formal techniques in the field of Computational Systems Biology, with particular focus on bone remodelling (BR), the cellular process of bone renewal, and on the analysis and control of disease processes. Firstly, we study the multiscale and spatial mechanisms that connects disruptions at the molecular signalling level, to osteoporosis and other diseases characterized by low bone mass and structural weakening at the tissue level. We define a modelling framework based on a formal specification language which extends the Shape Calculus, a process algebra with spatial and geometrical primitives. The executable side is obtained by encoding the specification into an agent-based model, where agents are enriched with stochastic actions and perception. This framework is used to define a novel spatial and individual-based model of bone remodelling, parametrized in order to reproduce both healthy and osteoporotic conditions, and to analyse how the disposition of bone cells affects bone microstructure at the tissue level. Secondly, we propose a methodological study aiming at evaluating and comparing different models of bone remodelling and different techniques for the analysis of bone diseases and of stabilization and homeostasis-related properties. We consider a non-linear ODE model, over which we perform simulation and sensitivity analysis; a stochastic model on which we employ probabilistic model checking; and a hybrid piecewise-multiaffine approximation of the ODEs, supporting model checking and LTL-based parameter synthesis. We extend the model in order to describe osteoporosis and osteomyelitis (a bone infection) and we show how quantitative verification methods could provide clinically meaningful diagnostic estimators. Thirdly, we investigate the use of formal languages and hybrid techniques in the modelling of disease processes and in the synthesis of treatment strategies. In particular, hybrid models allow us to describe the disease dynamics in a continuous fashion, while the scheduling of multiple drugs discretely. We define a process-algebraic language for specifying general disease processes and treatments, called D-CGF (an extension to the CGF process algebra), from which multiple semantics can be derived: stochastic hybrid automata and hybrid dynamical systems. Then, hybrid non-linear control is employed to compute the optimal scheduling of multiple therapies. The approach is applied to an epidemic model of the H1N1 influenza, where we derive the optimal combination of vaccination and antiviral treatments.
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Burdon, Peter Charles Edward. "Regulation of neutrophil mobilisation from the bone marrow". Thesis, Imperial College London, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289739.
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Kawai, Shunsuke. "In vitro bone-like nodules generated from patient-derived iPSCs recapitulate pathological bone phenotypes". Doctoral thesis, Kyoto University, 2020. http://hdl.handle.net/2433/245828.
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京都大学0048
新制・課程博士
博士(医学)
甲第22143号
医博第4534号
新制||医||1039(附属図書館)
京都大学大学院医学研究科医学専攻
(主査)教授 妻木 範行, 教授 森本 尚樹, 教授 別所 和久
学位規則第4条第1項該当
Doctor of Medical Science
Kyoto University
DFAM
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Uno, Jennifer Kikue. "Bone Mineralization in a Murine Model of Inflammatory Bowel Disease". Diss., Tucson, Arizona : University of Arizona, 2006. http://etd.library.arizona.edu/etd/GetFileServlet?file=file:///data1/pdf/etd/azu%5Fetd%5F1650%5F1%5Fm.pdf&type=application/pdf.
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Daroszewska, A. "Role of osteoprotegerin and p62 in Paget's disease of bone". Thesis, University of Aberdeen, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.590957.
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Paget’s Disease of Bone (PDB) is a common condition characterised by focally increased bone turnover, which is believed to be caused by an aberrant osteoclast. Genetic factors are important in the pathogenesis of PDB and mutations in the TNFRSF11B encoding osteoprotegerin (OPG) and Sequestosome 1 (SQSTM1 ) encoding SQSTM1 or p62 cause juvenile and classic PDB of late onset respectively. OPG and p62 play an important role in the RANK-NFκB signalling pathway, key for normal osteoclastogenesis. I have shown that the TNFRSF11B G1181C polymorphism causing a lysine to asparagine change in the 3rd codon of the OPG signal peptide (SP-OPG) predisposes to PDB. Heterozygous cases for G1181C are prone to severe disease as opposed to homozygous cases (a positive heterosis effect). There is a difference in cellular localisation of respective SP-OPG variants and a degree of cellular accumulation of the SP-OPG variant containing lysine in the 3rd codon, suggesting that the latter may be inefficiently secreted at times of high demand at a local level, which could lead to increased bone resorption. Studies of p62 revealed a novel interaction between p62 and P-IκB-α and between p62 and VCP. PDB-causing mutations of the p62 UBA domain interfered with the interaction between p62 and P-IκB-α, but not between p62 and VCP, shedding a new light on the mechanism underlying the pathogenesis of PDB. Accumulation of IκB-α in the presence of the PDB-causing mutations of p62 was present, suggesting that p62 may regulate IκB-α degradation. Implications of these findings are discussed. This work provides novel insights into the molecular mechanisms underlying PDB and the findings are expected to become the groundwork for further studies trying to unravel the complexity of the pathogenesis of Paget’s disease of bone.
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Nicholas, Richard Martin. "A laboratory and clinical study of Paget's disease of bone". Thesis, Queen's University Belfast, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.317547.
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Greenland, William Edward Peverell. "Radionuclide conjugates of calcitonin for imaging bone disease and cancer". Thesis, University of Kent, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252555.
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Van, den Broek Dirk Hendrik Nicolaas. "Mineral and bone disorder in cats with chronic kidney disease". Thesis, Royal Veterinary College (University of London), 2018. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.766340.
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Middleton, Anna. "Whole body vibration training in chronic disease: muscle, bone, function". Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/20714.
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Muscle pull from regular physical activity is crucial for optimal development of the skeleton during growth and maintenance of bone mineral density (BMD) throughout life. Mitochondrial Respiratory Chain Disorders (MRCD) and Cystic Fibrosis (CF) are two chronic diseases that exhibit reduced lean tissue mass and impaired exercise capacity, which negatively impacts bone health in these populations. Whole body vibration training (WBVT) is an emerging therapeutic modality that has been successful in improving BMD and muscle mass and function in heath and disease. Aim: To evaluate whether 6 months of home-based WBVT improves BMD, muscle function, exercise capacity and quality of life (QoL) in people with MRCD or CF. Methods: Participants were enrolled for 15-18 months: 3-6 months observation; 6 months home-based WBVT (3 x 3mins daily at 20Hz on a Galileo® Home vibration platform); 6 months follow-up. Participants attended four study visits and completed: dual energy x-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT) to assess BMD; muscle function testing on the Leonardo Jumping Platform (LJP); 6-minute walk test (6MWT) and/or formal exercise testing to assess exercise capacity; and disease specific QoL questionnaires. Linear mixed models analysis was used to assess changes between visits. Results: The MRCD cohort had 23 participants (13 male) mean (SD) age 31.0 (19.8) years and the CF cohort, 16 participants (8 male) mean (SD) age 12.8 (3.5) years. Statistically significant improvements in BMD of the legs were seen in the MRCD and CF cohorts for both DXA and pQCT. Muscle force during hopping and co-ordination during the chair rise test on the LJP improved significantly post WBVT in the CF. Exercise capacity did not change in the MRCD or CF cohorts after WBVT. QoL showed improvements in both cohorts. Conclusions: WBVT was well tolerated. WBVT improved BMD, aspects of muscle function, and QoL in people with MRCD or CF and may be a useful adjunct to physiotherapy exercise programs.
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Patterson, Catherine Elizabeth. "Histomorphometry-based modeling and simulation of multiple myeloma bone disease". Diss., University of Iowa, 2016. https://ir.uiowa.edu/etd/3161.
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Multiple myeloma is a plasma cell cancer that affects the bones, immune system, and kidneys. In this thesis, we focus on the impact on the bone, specifically routine bone remodeling. The bone remodeling process is governed by chemical signaling between several cell populations. In multiple myeloma patients, this process is out of balance. Bone destruction outpaces bone replacement, leaving patients with bone lesions. We describe the cell-signaling network that regulates bone remodeling and explain how it is impacted by multiple myeloma. We then present a series of mathematical models describing the bone remodeling process. We lay a thorough mathematical foundation, starting with the derivation of Savageau's power law approximations. Next, we introduce a novel one-dimensional moving-boundary partial differential equation model of this biological system. Our model improves upon models from the literature by including new cell populations, specifically osteoclast precursors, stromal cells, and tumor cells. We also discuss the model's computational results and their significance. We then discuss image processing techniques that can be used on bone marrow biopsies to gather data on the growth of a multiple myeloma tumor. By analyzing these medical images, we can extract tumor cell counts. In particular, we give the results of such an analysis for one patient using color unmixing. Image processing techniques, such as the ones presented here, could be used for validation of the models we present. The long-term goal of this project is the creation of a diagnostic tool that will aid oncologists in selecting the best treatment plan for their patients with multiple myeloma.
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Frith, Julie C. "Studies into the mechanism of action of clodronate". Thesis, University of Sheffield, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.299577.
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Vinholes, Jeferson Jose Fonseca. "Effects of bone metastases on bone metabolism : implications for assessment of response to bisphosphonates and systemic anti-cancer therapy". Thesis, University of Sheffield, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264749.
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Pan, Beiqing. "Mechanisms of skeletal disease mediated by haematological malignancies /". Title page, table of contents and abstract only, 2004. http://web4.library.adelaide.edu.au/theses/09PH/09php1871.pdf.
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Thesis (Ph.D.)--University of Adelaide, Dept. of Medicine and The Hanson Centre, Institute of Medical and Veterinary Science, 2004."August 2004" Errata inside front cover. Bibliography: leaves 126-159.
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Phan, Tuan (Tony). "Functional characterisation of an osteoclast-derived osteoblastic factor (ODOF)". University of Western Australia. School of Surgery and Pathology, 2004. http://theses.library.uwa.edu.au/adt-WU2005.0028.
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[Truncated abstract] Bone is a living tissue and is maintained by the coordinate action of osteoblasts and osteoclasts. The intercellular communication between these two cells is the quintessential mechanism in bone remodelling. Unfortunately, the importance of this interaction is often neglected and its significance is only realised when disruption of this “cross-talk” results in debilitating bone diseases. Additionally, the number of known proteins that are involved in this “cross-talk”, especially those that are osteoclast-derived, and act specifically on osteoblasts, is limited. This discrepancy leads to the question: Can osteoclasts directly control the growth and function of osteoblastic cells by expressing specific proteins that bind directly to osteoblasts? If so, is it possible to use these proteins to control and, possibly, treat bone disease? The objective of this thesis is to identify and characterise osteoclast-derived factors that can modulate bone homeostasis, as well as contribute to the intercellular communication between osteoblasts and osteoclasts ... Collectively, the data in this thesis culminates in one important conclusion: the identification of a novel paracrine secretory factor that has the potential to directly induce the formation of bone. These findings represent the first ever characterisation of a protein that allows the osteoclasts to directly control the growth and function of osteoblasts. Due to the potential function of ODOF to induce bone formation, this protein may be used therapeutically to treat bone disease.
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Mkukuma, Lovemore D. "Characterisation of the material properties of bone in health and disease". Thesis, University of Aberdeen, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252126.
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This thesis describes a study characterising some of the material properties of cancellous bone from patients suffering from either osteoporosis or osteoarthritis whose femoral heads were surgically removed during hip replacement operations. For comparison, a variety of animal bones, having a range of mineral contents, and synthetic hydroxyapatite were also studied. These material properties were studied using the following techniques: thermogravimetric analysis linked to mass spectrometer (TGA-MS), powder x-ray diffraction (PXRD), mercury intrusion porosimeter (MIP) and high-temperature x-ray diffraction (HTXRD). The animal bones used were deer antler, whale periotic fin, whale ear bone, whale tympanic bulla, cod clythrum and porpoise ear. The TGA-MS determined the organic and the mineral proportions in bone and within the mineral the amount of the different types of carbonate was identified and quantified. The PXRD was used to measure the lattice dimensions and the crystallite sizes of human bone in order to find out if these parameters are altered in diseased bone. In synthetic hydroxyaptite (SHA), the PXRD was employed to determine the optimum sintering temperature as well as for monitoring the phase change that occurred when SHA was heated to high temperature. Phase monitoring was further carried in two of the animal species using HTXRD. This was used in preference to post-sinter-quenching of samples in order to obtain true, in-situ measurements of the composition at each temperature.
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Hjorth-Hansen, Henrik. "Novel cytokines in growth control and bone disease of multiple myeloma". Doctoral thesis, Norwegian University of Science and Technology, Faculty of Medicine, 2001. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-315.
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Myelomatose (benmargskreft) er en blodsyk dom som rammer ca 200 nordmenn årlig. Sykdommen kan ikke kureres og karakteriseres av symptomer som benmargssvikt og infeksjonstendenns, men kanskje først og fremst av sykelig nedbrytning av skjelettet. Pasientene rammes i høy utstrekning av benbrudd, hvirvelsammenfall og skjelettsmerter. Mekanismene for bennedbrytning og vekstkontroll står sentralt i avhandlingsarbeidet som består av fem artikler om cytokiners rolle i myelomatose. Cytokiner er signalsubstanser som benyttes i celle-celle-kommunikasjon. Det er sannsynligvis ubalanse av cytokiner som forårsaker den sykelige nedbrytningen av bensubstansen.
Det første delarbeidet omhandler funnet av hepatocyttvekstfaktor (HGF) som er uttrykt hos nesten alle pasienter med myelomatose Dette påvises med forskjellige teknikker og det benyttes bl a en separasjonsmetode for myelomceller basert på Ugelstadkuler som ble utviklet ved IKM i 1993. Videre påvises forhøyede nivåer av HGF i serum fra pasienter. Et interessant funn er at HGF reseptor også er uttrykt i pasientprøver, hvilket kan tale for at myelomceller kan ha en selvstimulerende (autokrin) funksjon.
I det andre delarbeidet vises en dyremodell for myelomatose i immundefekte mus. Et hovedpoeng er at det lar seg gjøre å få vekst av myelomceller i musebenmarg med påvisbare tegn til patologisk bennedbrytning på røntgen og ved histologisk undersøkelse. Musene har forhøyede nivåer av HGF i serum. Benlesjonene ble karakterisert ved hjelp av histomorfometri. Denne undersøkelse viste 99% reduksjon av de bendannende cellene (osteoblaster) og 33% reduksjon av bennedbrytende celler (osteklaster).
I tredje delarbeidet viser man at HGF induserer interleukin (IL)-11-produksjon i osteoblaster. IL-11 er en kjent påskynder av benresorpsjon og osteoklastaktivator. Et interessant fenomen er at HGF ser ut til å være bundet til heparansulfat på cellemembranen og at slikt membranbundet HGF virker bedre enn løselig HGF. Effekten av HGF potensieres av cytokinene TGF-beta og IL-1. En styrke ved arbeidet er at såvel ferskisolerte pasientceller som cellelinjer viser identiske mønstre. Arbeidet angir en mulig måte som HGF kan befremme bennedbrytning.
I fjerde delarbeid vises at cytokinet IL-15 forhindrer programmert celledød (apoptose) i myelomcellelinjen OH-2. Det var fra før kjent at myelomceller relativt hyppig lar seg stimulere av cytokinet IL-6, som fortsatt er den mest anerkjente myelomvekstfaktoren. IL-15 var tilnærmet like potent antiapoptotisk som IL-6, og befremmet også kortvarig proliferasjon. IL-15s effekt kunne potensieres av TNF-alfa
I femte delarbeid påvises at cytokinet benmorfogent protein (BMP)-4 hemmer vekst av myelomceller. BMP-4 befremmer bendannelse. Effekten av BMP-4 kom fram i IL-6-stimulerte cellelinjer og pasientprøver. Effekten skyldtes såvel induksjon av apoptose som stopp i cellesyklus G1-fase. Dette er et mulig viktig funn siden man kan tenke seg at pasienter med myelomatose kunne behandles med BMP-4 eller lignende substanser. På slik måte ville såvel skjelettnedbrytningen som myelomcellevekst kunne påvirkes gunstig.
Arbeidet bidrar til forståelse av molekylære mekanismer for bendestruksjon og myelomcellevekst og ble veiledet av profesor dr. med. Anders Waage. Henrik Hjorth-Hansen har vært stipendiat i Den norske kreftforening, og undersøkelsen ble dessuten støttet av Kreftfondet ved RiT og Blix’ legat.
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Ivanauskaitė, Deimantė. "Alveolar bone loss in radiographic modalities for diagnosis of periodontal disease". Doctoral thesis, Lithuanian Academic Libraries Network (LABT), 2011. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2011~D_20110621_164329-13939.
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Radiographic modalities are used in addition to clinical methods to gain information about the patients. In the examination of the periodontium, which is comprised of the gingiva, alveolar bone, periodontal ligament, and cementum, the radiographic examination plays an integral role for diagnosis of periodontal disease. The diagnosis periodontitis is based on a finding of alveolar bone loss. Changes of the alveolar bone can be assessed by different radiographic modalities, such as intraoral radiography (bitewing and periapical radiography) and panoramic radiography. Analysis of alveolar bone loss (alveolar bone level, detection of vertical bone defect and furcation involvement) in radiographic modalities and a systematic review could be helpful to suggest the more applicable radiographic methods for diagnosis of periodontal disease. The purpose of the present study was to examine diagnostic properties of panoramic radiography for the assessment of alveolar bone loss for the diagnosis of periodontal diseases as compare to posterior bitewing radiography. For 96 patients panoramic and posterior bitewing radiographs were performed and results of analysis of visibility of radiographic images and assessment of alveolar bone loss were compared. Also, the systematic review on diagnostic properties of panoramic radiography in the assessment of alveolar bone loss was performed. Based on the results of this study, recommendations for clinical practice and for research were proposed.Rentgeniniai tyrimo metodai taikomi, kad būtų papildyti klinikinio tyrimo duomenys. Tiriant periodontą, kurį sudaro dantenos, dantinė atauga, periodonto raiščiai ir cementas, rentgeninis tyrimas svarbus diagnozuojant periodonto ligas, nes jo metu nustatomi dantinės ataugos pokyčiai. Dantinės ataugos pokyčiams vertinti daromos rentgeno nuotraukos taikant vidinių burnos rentgeno nuotraukų darymo metodus, t. y. kandimo ar dantų šaknų rentgeno nuotraukų darymo metodus, ir išorinės burnos rentgeno nuotraukos darymo metodą, t. y. panoraminės rentgeno nuotraukos darymo metodą. Atlikus dantinės ataugos pokyčių (kaulo lygio arba rezorbcijos, kaulo defekto ir tarpšaknio kaulo pažeidimų) analizę, taikant rentgeninius metodus, ir padarius sisteminę literatūros apžvalgą, galima būtų pasiūlyti tinkamiausią rentgeno metodą periodonto ligoms diagnozuoti. Šio darbo tikslas – ištirti ir palyginti panoraminės rentgeno nuotraukos ir kaplių bei krūminių dantų rentgeno nuotraukų darymo metodų diagnostikos ypatybes vertinant dantinės ataugos pokyčius periodonto ligoms diagnozuoti. Kiekvienam, iš 96 pacientų įtrauktų į tyrimą, buvo padaryta panoraminė rentgeno nuotrauka ir kaplių bei krūminių dantų kandimo rentgeno nuotraukos. Atlikta dantinės ataugos rentgeno atvaizdo vizualioji kokybė analizė ir vertinimai skirtingose rentgeno nuotraukose bei palyginti rezultatai. Padaryta sisteminė literatūros apžvalga apie panoraminės rentgeno nuotraukos vertę diagnozuojant periodonto ligas. Pagal šio tyrimo... [toliau žr. visą tekstą]
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Lin, Feng. "Minimal residual disease after bone marrow transplantation for chronic myeloid leukaemia". Thesis, Imperial College London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285196.
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Messiou, Christina. "Investigation of quantitative biomarkers of treatment response in malignant bone disease". Thesis, Institute of Cancer Research (University Of London), 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.538326.
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Parker, Cornelle R. "Evaluation of renal bone disease in transplant recipients and related conditions". Thesis, University of Nottingham, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.342044.
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Appleman, Stephanie S. M. D. "Bone Disease in TPN-dependent Infants and Children with Intestinal Failure". University of Cincinnati / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1320326652.
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Hadi, Tamer. "THE ROLE OF p62 IN OSTEOCLASTOGENESIS AND PAGET’S DISEASE OF BONE". VCU Scholars Compass, 2012. http://scholarscompass.vcu.edu/etd/3312.
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Paget’s disease (PDB) is the second most common metabolic bone disease after osteoporosis, affecting up to 3% of adults over age 55. It is characterized by focal lesions of bone resorbed by hyperactive osteoclasts coupled with rapid formation of highly disorganized, low quality bone formed by osteoblasts. Such lesions cause skeletal deformity, fractures, and other symptoms that significantly decrease quality of life. In 2001, mutations in the SQSTM1/p62 gene were found in a subset of Paget’s patients. The work summarized in this dissertation sought to answer two broad questions: what is the function of p62 in normal bone homeostasis and how do PDB-associated mutations alter it? These studies took advantage of two mouse models: p62 knock-out (KO) mice, and p62P394L “knock-in” (KI) mice carrying the most common PDB-associated mutation. KO, KI, and wildtype (WT) controls were aged to one year for skeletal-histological characterization. No differences were observed in a variety of bone parameters between WT and KO bones, while bones from age-matched KI mice exhibited a 33% decrease in bone volume and a 25% increase in osteoclast formation. In vivo, TNF-α caused a potent induction of osteoclastogenesis in calvariae of WT and KI, but not KO, mice. In vitro, RANKL induced osteoclast formation in a dose-dependent manner in WT and KI, but not KO, cultures. Gene expression profiling of RANKL-treated osteoclast progenitors from WT, KO, and KI mice was then performed to identify the changes in signaling pathways responsible for these effects. Surprisingly, gene expression patterns from all three groups were consistent with robust activation of NFκB signaling in RANKL-treated samples, indicating that p62 is dispensable for RANKL activation of NFκB. Interestingly, gene expression patterns in KO cells suggested impaired proliferation and response to reactive oxygen species (ROS), a finding which was confirmed in cell culture experiments. In contrast, KI cells displayed enrichment for genes associated with the unfolded protein response, consistent with p62’s role in ubiquitin-mediated protein degradation via proteolysis and autophagy. These studies have therefore generated several novel hypotheses concerning the role of p62 in both normal bone homeostasis and Paget’s disease of bone.
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Laslett, Laura Louise. "Screening for low bone mineral density in patients with respiratory disease". Title page, table of contents and abstract only, 2003. http://web4.library.adelaide.edu.au/theses/09MSB/09msbl3456.pdf.
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"October, 2003" Bibliography: leaves 204-223. Patients with respiratory disease have decreased mean bone mineral density (BMD) and thereby increased risk of fractures compared to people without respiratory disease. A clinical screening tool was developed to identify patients unlikely to have low BMD who do not require bone densitometry, and estimated number needed to screen (NNS) and number needed to treat to prevent one hip fracture in this patient group. The screening tool was found to have a high negative predictive value, and therefore may assist clinicians to identify those who would benefit most from densitometry. Using this screening tool together with NNS may enable the development of a cost-effective screening programme for low BMD in respiratory patients.
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Irani, Dilshad Minocher. "Role of the surface associated material of Eikenella corrodens in bone resorption associated with periodontal disease : a research thesis submitted in fulfilment of the requirements for the degree of Master of Science in Dentistry". Title page, contents and summary only, 1998. http://web4.library.adelaide.edu.au/theses/09DSM/09dsmi65.pdf.
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Martinelli, Mark J. "Morphometric analyses of bone and cartilage of the equine metacarpophalangeal joint". Thesis, University of Glasgow, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.284973.
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