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1
Cheng, Tak Sum. "Molecular identification and characterization of novel osteoclast V-ATPase subunits." University of Western Australia. School of Surgery and Pathology, 2008. http://theses.library.uwa.edu.au/adt-WU2008.0068.
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[Truncated abstract] Osteoclasts are multinucleated giant cells responsible for the resorption of the mineralized bone matrix during the process of bone remodelling. During activation towards bone resorption, polarization of the osteoclast results in the formation of a unique plasma membrane, the ruffled border, the actual resorptive organelle of the osteoclast. Through this domain protons are actively pumped into the resorption lacuna creating an acidic microenvironment that favours the dissolution of the mineralized bone matrix. The polarised secretion of protons is carried out by the action of the vacuolar-type (H+)-ATPase (V-ATPase), composed of functionally and structurally distinct subunits of the V1 and V0 domains. The general structure of the V-ATPase complex is highly conserved from yeast to mammals, however, multiple isoforms for specific V-ATPase subunits do exist exhibiting differential subcellular, cellular and tissue-specific localizations. This study focuses on the molecular identification and characterization of V-ATPase accessory subunit Ac45 and the d2 isoform of the V0 domain d subunit in osteoclasts. Using the techniques of cDNA Subtractive Hybridization and DNA Micro-Array analyses respectively, the accessory subunit Ac45 and the d2 isoform of the V0 domain d subunit were identified in RAW264.7-cells derived OcLs. ... Using web-based computational predictions, two possible transmembrane domains, an N-terminus 'signal anchor' sequence and a C-terminus dilysine- like endoplasmic reticulum (ER) retention signal were identified. By confocal microscopy, EYFP-tagged e was found to localize to the perinuclear region of transfected COS-7 cells in compartments representing the ER and Golgi apparatus with some localization in late endosomal/lysosomal-like vesicles. ER truncation of e did not alter its subcellular localization but exhibited significantly weaker association with Ac45 compared to the wild-type as depicted by BRET analyses. Association with the other V0 subunits remain unaffected. This may hint at a possibility that Ac45 may play a role in the masking of the ER signal of e following it's incorporation into the V0 domain. Although no solid evidence for a role in the assembly of the mammalian VATPase have been established, subunit e still represents a potential candidate whose role in the V-ATPase complex requires further investigation. Collectively, the data presented in this thesis has provided further insight into the composition of the osteoclast V-ATPase proton pump by: 1) identifying an accessory subunit, Ac45 which shows promise as a potential candidate for the regulation and/or targeting of the V-ATPase complex in osteoclasts and truncation of its targeting signal impairs osteoclastic bone resorption; 2) identification and preliminary characterization of the d2 isoform of the V0 domain d subunit whose exact role in the V-ATPase complex and in osteoclasts remains to be determined, although its has been implicated to be essential for osteoclastic function; and 3) Preliminary characterization of subunit-e, a potential assembly factor candidate for the mammalian V-ATPase V0 domain.
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Van, Greunen Francois. "Microcomputer-assisted diagnosis of inherited disorders of the skeleton." Master's thesis, University of Cape Town, 1988. http://hdl.handle.net/11427/25754.
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Several hundred inherited disorders of the skeleton have been delineated. Individually these conditions are rare, but as a group they cause much crippling and hardship. Several factors, including the rarity and complexity of the manifestations of these conditions, as well as semantic overlap, impede the accurate diagnosis which is essential for effective treatment. In this regard, the adoption of microcomputers warrants evaluation as a high technology aid. Microcomputers have developed tremendous capabilities during recent years. The state of the art has become such that a diagnostic aid facility on such a device has been demonstrated in various disciplines of medicine and may also be feasible in the area of inherited skeletal disorders. The study which forms the basis of this thesis, concerns the investigation of this feasibility and has led to the development of an effective working model which sets the basis for microcomputer-aided diagnosis. The design features followed in this project are similar to those conventionally employed for "Expert systems" on mainframe computers. A comprehensive knowledge base consisting of over 200 skeletal disorders and 700 radiographic and clinical manifestations, has resulted. Furthermore, the application is capable of "learning", although inference as employed by the inference engines of real expert systems, is not employed. In this context learning implies that the knowledge base, with the passage of time, improves considerably when used by experts. Serendipitous findings in this regard are: • 1) Considerable improvement of existing profile descriptions can occur without any increased demands on computer memory and storage space; • 2) Growth of the knowledge base in the form of additional disease profiles can be effected with very modest inroads on memory and storage resources. The computerized diagnostic aid which resulted from this thesis, has been demonstrated to be successful in both the Department of Human Genetics of the University of Cape Town and the Department of Paediatrics of the Johannes Gutenberg University in Mainz. Evaluated both in terms of efficiency and utility, the system provides an enhancement to the specialist genetic diagnostician. These achievements have been effected by means of a unique newly developed application of compressed bit-mapping, attained by writing the applicable programs in Turbo Pascal and 8086- assembler languages. Calculations indicate that much larger data bases may possibly be implemented on present-day microcomputers by means of the methods developed in this project.
3
Foster, Bruce Kristian. "Epiphyseal plate repair using fat interposition to reverse physeal deformity : an experimental study." Title page, contents and summary only, 1989. http://web4.library.adelaide.edu.au/theses/09MD/09mdf754.pdf.
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Bibliography: leaves 169-197. Hypothesises that the physis has an internal mechanism of repair to restore physeal function. Aims to establish a defined degree of deformity by partial growth plate excision, then to examine different methods of reversal of such deformity to observe the process of growth plate repair. A secondary aim was to define the percentage of physis that could be resected yet still enable reversal of deformity.
4
Albogami, Mohammed Mater. "Bone loss in osteoporosis and rheumatoid arthritis diseases : the effects of disease mechanisms, age, gender and ethnic origin on responsiveness to treatment." Thesis, Queen Mary, University of London, 2014. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8901.
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Bone makes up a framework that provides protection for internal body organs. The homeostasis of bone is maintained by a balanced process involving old bone degradation and new bone formation. However, this balance can be altered in pathophysiological conditions such as in postmenopausal osteoporosis and in patients with rheumatoid arthritis (RA). In recent years, new therapies have been developed to reduce bone resorption. However, there is disparity in patients’ response to these therapies. The reasons are unclear although age, gender, ethnic background and lifestyle have all been suggested to play a part. For patients with chronic inflammatory conditions, treatment was revolutionised by the discovery and application of biologic therapies that target pro-inflammatory proteins and/or pathways. However, whilst the anti-inflammatory effect of these biologic agents is well-established, their effect on bone loss is just emerging. In RA, it is not clear whether the beneficial anti-inflammatory effects of biologic anti-tumour necrosis factor alpha (TNFα) agents are accompanied by parallel improvements in bone erosion/density, whether there are differences between patient groups and what factors influence the response. In order to address these issues, a database on the factors that influence responsiveness of patients with osteoporosis to bisphosphonates, a treatment that suppresses bone resorption, was established. Based on the outcome of this study, the influence of the key factor(s) that affect bone response to treatment in combination with excess pro-inflammatory cytokine production on bone response in RA patients was determined. Significant improvement in bone mineral density (BMD) and plasma levels of bone biomarkers has been shown in this study with biologic anti-TNFα agents. The improvement in BMD was not always consistent with improvement the clinical response to treatment as assessed by changes in disease activity score 28(DAS28). The study also provides a mechanistic explanation for how blockade of TNFα in patients can reverse the balance of bone loss in patients with RA. Thus, the data show that treatment of patients with biologic anti-TNFα agents reduces the number of osteoclast precursors (OCs) in the blood.
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Whitton, Robert Christopher. "Carpal disease in racing horses." Thesis, The University of Sydney, 1997. https://hdl.handle.net/2123/26702.
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Thirteen Standardbred horses were trained on a treadmill for 31 weeks as part of a larger study into the effects of overtraining. Synovial fluid was collected from the midcarpal joint at the start, and at seven, 15, 21, 26 and 30 weeks of training. Low grade signs of midcarpal joint disease developed in all horses during the last 16 weeks of the program. Synovial fluid leukocyte counts remained unchanged throughout the study, whereas total protein concentration and lactate dehydrogenase activity increased significantly with training. Sulfated glycosaminoglycan (GAGs) levels increased initially, but then decreased. Correlations between the clinical signs of joint disease and sulfated GAG levels were weak.
Synovial fluid sulfated GAGs were compared with other diagnostic variables for predicting the degree of articular cartilage damage in horses with midcarpal joint disease. Interpretation of radiographs was found to be the most accurate for the prediction of articular damage. Synovial fluid analysis was found to be of little value. There was no correlation between sulfated GAG concentration and articular cartilage damage, and no significant difference between sulfated GAG concentrations from horses with clinical evidence of joint disease and horses with no signs of joint disease trained on a treadmill.
Anatomical dissections of the midcarpal joint were performed on ten cadavers. The medial palmar intercarpal ligament (MPICL) was found to consist of four fibre bundles. The predominant orientation of these was proximodorsal to distopalmar. The lateral palmar intercarpal (LPICL) and dorsomedial intercarpal (DMICL) ligaments had a similar orientation but were simpler in structure. The alignment of these ligaments suggested that they resisted transverse forces across the midcarpal joint. Using a dorsal transverse displacement of 1.5 mm of the proximal row of carpal bones relative to the distal row of carpal bones, it was demonstrated that the palmar intercarpal ligaments provided 22.7% of the restraining force while only contributing 9% of the ligamentous cross sectional area.
A study of 32 racing horses presented with midcarpal joint disease confirmed the high frequency of MPICL tearing (51%). Enlargement of the DMICL was also common (33%). There was no correlation between the severity of signs of midcarpal joint disease and the severity of MPICL tearing. An inverse relationship was demonstrated between subchondral bone damage within the midcarpal joint, and MPICL tearing (R=-0.55). There was no association between DMICL enlargement and osteochondral damage. A postmortem study of 142 joints of horses with no history of midcarpal joint disease demonstrated that the frequency of MPICL tearing in racing horses was 91%. Severity of tearing of the MPICL increased significantly with age. Histopathological evidence of degeneration (loss of organisation of collagen fibres) was consistently observed in MPICLs of adult horses. These changes were not observed in unborn term foals, but were present from one month of age. Enlarged DMICLs had regular collagen arrangement, but discrete areas of fibrovascular infiltration were consistently observed.
The race records of 42 horses undergoing midcarpal joint carpal arthroscopy were examined. Using multiple regression the extent of subchondral bone damage was the best predictor of postoperative performance. The addition of the grade of MPICL tearing significantly improved the prediction of postoperative performance, whereas the inclusion of the extent of articular cartilage damage had no effect.
6
Karunaratne, Malintha P. Angelo. "Analysis of alterations in matrix quality at nanoscale in metabolic bone diseases using synchrotron X-ray diffraction." Thesis, Queen Mary, University of London, 2013. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8490.
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Bone diseases such as osteoporosis and rickets cause significant reduction in bone quantity and quality, leading to mechanical abnormalities. While the reduction of bone quantity can be assessed using clinical tools like DXA and pQCT, there is little quantitative knowledge of how altered bone quality in diseased bone increases fracture risk. There is a clear need to develop high-resolution diagnostic techniques to close the gap between onset of fracture relevant changes and diagnosis. Here, a functional imaging technique (in situ synchrotron X-ray imaging with micromechanics) was developed to measure alterations in fibrillar deformation mechanisms in rickets, glucocorticoid-induced osteoporosis (GIOP), and premature ageing. During applied loading, percentage shifts in Bragg peak positions arising from the meridional collagen stagger, measured from the small angle X-ray scattering (SAXS) patterns, give fibrillar level strain as a function of applied stress in real time. To link nanostructural changes to altered fracture risk and deformability, well defined animal (mouse) models created via N-ethylnitrosurea mutagenesis were used. The fibril modulus, maximum fibril strain and fibril-to-tissue strain ratio were determined, complemented by quantitative backscattered scanning electron microscopy and microcomputed tomography to measure microscale mineralisation. A significant reduction of fibril modulus and enhancement of maximum fibril strain was found in rickets and GIOP mice. A significantly larger fibril strain/tissue strain ratio was found in GIOP mice compared to wild-type mice, indicative of a lowered mechanical competence at the bone matrix level. The effects of altered in vivo muscular force distributions on the skeletal system in rickets were measured using position resolved scanning SAXS. Increase of mineral nanoplatelet alignment is observed in wild-type mice near zones of large in-vivo muscle force but not in rachitic mice. These results demonstrate the ability of synchrotron-based in situ X-ray nanomechanical imaging to identify functional alterations in nanoscale bone quality in metabolic bone diseases.
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Almasabi, Abeer. "Determination of Hydroxyproline in Bone Collagen: Potential Application as a Biomarker for Bone Diseases." Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/38420.
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Hydroxyproline (Hyp), a non-proteinogenic amino acid is a component of the organic material in bone. It has been used for 14C-dating of bone and the measurement of Hyp could be used as a biomarker in bone metabolism. Hydroxyproline is a component of collagen, the main structural protein in bone. The analyses of 14C in collagen and Hyp in human bones may provide timing information about bone processes and diseases, such as osteoarthritis and osteoporosis. The analysis of Hyp in bones (e.g., the determination of Hyp content) primarily relies on a spectrometric technique, liquid chromatography-mass spectrometry (LC-MS), and the determination of 14C content requires accelerator mass spectrometry (AMS). Moreover, to obtain these materials from bone requires the successful extraction of collagen and thr separation of Hyp from the collagen.
This study aims at comparing methods for extracting collagen from bone, which do not destroy the Hyp. These methods include the use of either NaOH, KOH or HCl in one stage of the extraction process and separating sufficient Hyp for 14C analysis. This will provide information to determine whether Hyp can be used as a biomarker for bone diseases like osteoarthritis and osteoporosis.
A preliminary 14C AMS analysis on collagen extracted by the NaOH method was carried out on human bones previously analyzed for forensic purposes. This demonstrated the ability of this technique to provide recent (post 1950) timing information.
The collagen extractions by three different methods were first conducted on modern chicken bone, and the results showed that KOH method is the best bone collagen extraction method, yielding a largest quantity of Hyp. The KOH method was then employed to extract collagen from cow bone as a test of a more human-like (mammalian) material. As this was successful, collagen was extracted from diseased human bone fragments, obtained from the Ottawa Hospital. The data revealed that Hyp was successfully obtained from these bones.
The study demonstrates that the extraction as well as the separation methods (preparative HPLC) can provide sufficient Hyp from bones for 14C AMS analysis. This will lead to future studies of Hyp in bone turnover, which may lead to its use as a novel biomarker for bone diseases such as osteoarthritis and osteoporosis.
8
Liang, Chao. "Aptamer-functionalized lipid nanoparticles targeting osteoblasts as a novel RNA Interference-based bone anabolic strategy." HKBU Institutional Repository, 2016. https://repository.hkbu.edu.hk/etd_oa/325.
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Osteoporosis remain major clinical challenges. RNA interference (RNAi) provides a promising approach for promoting osteoblastic bone formation to settle the challenges. However, the major bottleneck for translating RNAi with efficacy and safety to clinical bone anabolic strategy is lack of osteoblast-specific delivery systems for osteogenic siRNAs. Previously, we developed a targeting system involving DOTAP-based cationic liposomes attached to oligopeptides (AspSerSer)6, (also known as (DSS)6), which had good affinity for bone formation surface. Using this system, osteogenic Pleckstrin Homology Domain Containing, Family O Member 1 (Plekho1) siRNA could be specifically delivered to bone formation surface at tissue level and promoted bone formation in osteopenic rodents. However, concerns still exist regarding indirect osteoblast-specific delivery, detrimental retention in hepatocytes, mononuclear phagocyte system (MPS)-induced dose reduction and inefficient nanoparticle extravasation. Aptamers, selected by cell-based Systematic evolution of ligands by exponential enrichment (cell-SELEX), are single-stranded DNA (ssDNA) or RNA which binds to target cells specifically by distinct tertiary structures. By performing positive selection with osteoblasts and negative selection with hepatocytes and peripheral blood mononuclear cells (PBMCs), we aimed to screen an aptamer that could achieve direct osteoblast-specific delivery and minimal hepatocyte and PBMCs accumulation of Plekho1 siRNAs. In addition, lipid nanoparticles (LNPs) have been widely used as nanomaterials encapsulating siRNA due to their small particle size below 90 nm. Polyethylene glycol¡(PEG) as the mostly used hydrophilic polymer, could efficiently prevent LNPs from MPS uptake. So, LNPs with PEG shielding could serve as siRNA carriers to realize efficient extravasation from fenestrated capillaries to osteoblasts and help reduce MPS uptake of the siRNAs. Recently, we screened an aptamer (CH6) by cell-SELEX specifically targeting both rat and human osteoblasts and developed the aptamer-functionalized LNPs encapsulating osteogenic Plekho1 siRNA, i.e., CH6-LNPs-siRNA. Our results demonstrated that CH6-LNPs-siRNA had an average particle size below 90 nm and no significant cytotoxicity in vitro. CH6 aptamer facilitated osteoblast-selective uptake of Plekho1 siRNA and gene silencing in vitro. In this study, we further found that CH6 aptamer facilitated the bone-specific distribution of siRNA by biophotonic imaging and quantitative analysis. Immunohistochemistry results showed that CH6 achieved in vivo osteoblast-specific delivery of Plekho1 siRNA. Dose-response experiment indicated that CH6-LNPs-siRNA achieved almost 80% gene knockdown at the siRNA dose of 1.0 mg/kg and maintained 12 days for over 50% gene silencing. microCT, bone histomorphometry and mechanical testing confirmed that CH6 facilitated bone formation, leading to improved bone micro-architecture, increased bone mass and enhanced mechanical properties in osteoporotic rodents. Furthermore, CH6-LNPs-siRNA achieved better bone anabolic action when compared to the previously developed (AspSerSer)6-liposome-siRNA. There was no obvious toxicity in rats injected with CH6-LNPs-siRNA. All these results indicated that osteoblast-specific aptamer-functionalized LNPs could act as a novel RNAi-based bone anabolic strategy and advance selectivity of targeted delivery for osteogenic siRNAs from tissue level toward cellular level. In addition, the generation of ssDNA from double-stranded PCR products is an essential step in selection of aptamers in SELEX. We found that the size separation derived from unequal primers with chemical modification could be a satisfactory alternative to the classic magnetic separation.
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Vasseleu, Cathryn. "Cleidocranial dysplastic mutant in the mouse : dental findings." Thesis, The University of Sydney, 1986. https://hdl.handle.net/2123/26032.
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Cleidocranial dysplasia is a genetic disorder which affects not only processes of osteogenesis, but also processes of tooth eruption, tooth induction, and craniofacial growth. These last three complications make the condition one which may interest those working in the fields of oral and craniofacial biology. The condition is neither life-threatening nor incapacitating. However, elucidation of the pathological process which it embodies may provide valuable insights into the normal mechanisms of tooth eruption, tooth induction and craniofacial growth, each of which remains a largely unsolved puzzle. The discovery of a mouse mutant which appears to have a genetic disorder homologous to the condition found in humans may provide scientists with an opportunity to study aspects of the disorder in a detailed manner which might otherwise be impossible. The extent to which the condition affects craniofacial growth and the dentition of the Ccd mutant has not been investigated, but if such processes are similarly affected in both mice and humans, then elucidation of these in the House may assist scientists not only in achieving an understanding of human Cleidocranial dysplasia, but may also help with the unravelling of normal mechanisms of craniofacial and dental development.
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Björnsdóttir, Sigrídur. "Bone spavin in Icelandic horses : aspects of predisposition, pathogenesis and prognosis /." Uppsala : Dept. of Clinical Radiology, Swedish Univ. of Agricultural Sciences ([Institutionen för klinisk radiologi], Sveriges lantbruksuniv, 2002. http://epsilon.slu.se/avh/2002/91-576-6382-3.pdf.
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Wang, Cathy Ting-Peng. "Molecular dissection of RANKL signaling pathways in osteoclasts." University of Western Australia. School of Surgery and Pathology, 2007. http://theses.library.uwa.edu.au/adt-WU2008.0037.
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[Truncated abstract] Bone remodeling is intricately regulated by osteoclast-mediated bone resorption and osteoblast-mediated bone formation. The elevation in osteoclast number and/or activity is a major hallmark of several common pathological bone disorders including post-menopausal osteoporosis, osteoarthritis, Paget's disease, and tumour-mediated osteolysis. Receptor activator of nuclear factor kappa B ligand (RANKL) is a key cytokine for osteoclast differentiation and activation. The association of RANKL to its cognate receptor, RANK, which is expressed on osteoclast precursors and mature osteoclasts, is essential for osteoclast formation and activation. The intimate interaction between RANKL and RANK triggers the activation of a cascade of signal transduction pathways including NF-κB, NFAT, MAPK and PI3 kinase. Although osteoclast signaling pathways have been intensively studied, the precise molecules and signaling events which underlie osteoclast differentiation and function remain unclear. In order to dissect the molecular mechanism(s) regulating osteoclast differentiation and activity, this thesis herein explores the key RANKL/RANK-mediated signaling pathways. Four truncation mutants within the TNF-like domain of RANKL [(aa160-302), (aa160-268), (aa239-318) and (aa246-318)] were generated to investigate their potential binding to RANK and the activation to RANK-signal transduction pathways. All were found to differentially impair osteoclastogenesis and bone resorption as compared to the wild-type RANKL. The impaired function of the truncation mutants of RANKL on osteoclast formation and function correlates with their reduced ability to activate crucial RANK signaling including NF-κB, IκBα, ERK and JNK. Further analysis revealed that the truncation mutants of RANKL exhibited differentially affinity to RANK as observed by in vitro pull-down assays. ... It is possible that Bryostatin 1 acts via upregulation of a fusion mechanism as the RANKL-induced OCLs are morphologically enlarged, exhibiting increased nuclei number expressing high level of DC-Stamp. Furthermore, Rottlerin was shown to inhibit NF-κB activity, whereas Bryostatin 1 showed the opposing effects. Both inhibitor and activator were also found to modulate other key osteoclastic signaling pathways including NFAT and total c-SRC. These findings implicate, for the first time, Protein Kinase C delta signaling pathways in the modulation of RANKL-induced osteoclast differentiation and activity. Taken together, the studies presented in this thesis provide compelling molecular, biochemical and morphological evidence to suggest that: (1) RANKL mutants might potentially serve as peptide mimic to inhibit RANKL-induced signaling, osteoclastogenesis and bone resorption. (2) A cross talk mechanism between extracellular Ca2+ and RANKL exist to regulate on osteoclast survival. (3) TPA suppressed RANKL-induced osteoclastogenesis predominantly during the early stage of osteoclast differentiation via modulation of NF-κB. (4) Selective inhibition of Protein Kinase C signaling pathways involved in osteoclastogenesis might be a potential treatment method for osteoclast-related bone diseases. (5) Protein Kinase C delta signaling pathways play a key role in regulating osteoclast formation and function.
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Payne, Scott Andrew. "An Electron Energy-Loss Spectroscopic Investigation of Molecular Interactions at Hydroxyapatite-Collagen Interfaces in Healthy and Diseased (Osteogenesis Imperfecta) Human Bone and Biomineralized Tissue-Engineered Bone." Diss., North Dakota State University, 2018. https://hdl.handle.net/10365/27928.
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At its primary level (nm scale) bone is a nanocomposite consisting of a mineral (hydroxyapatite) phase which gives bone its strength and an organic (type I collagen) phase giving bone its fracture toughness. Hydroxyapatite, (HAP) Ca10(PO4)6(OH)2, is the most abundant mineral in the human body. Bone tissue has a complex hierarchical structure spanning multiple length scales (cm to nm). Characterization of mineral composition in biomineralized tissues such as bone at their primary level, is very challenging and requires instrumentation with nanometer-scale spatial resolution. Transmission electron microscopy (TEM) combines high spatial resolution with visual correlation of diffraction and elemental-composition data. Electron energy-loss spectroscopy (EELS) is a sensitive technique used to probe electronic structure at the molecular level. TEM-based EELS is the only available technique that can provide information about the chemical and coordination environment of minerals with nm scale spatial resolution. Prior studies in our group has developed a method to create biomimetic HAP using biomineralization routes inside the clay galleries of montmorillonite clay modified with amino acids (in-situ HAPclay). Incorporation of in-situ HAPclay into polymer scaffolds and seeding with human mesenchymal stem cells has enabled the cells towards differentiation into osteoblastic lineages without differentiating media. Because of the importance of these materials for bioengineering applications, TEM-EELS was used to evaluate differences and similarities among HAP, biomimetic in-situ HAPclay, modified MMT clay, and ?-tricalcium phosphate. Osteogenesis imperfecta (OI), also known as brittle bone disease, is an inheritable disease characterized by increased bone fragility, low bone mass, and bone deformity caused primarily by mutation in collagen type I genes and is expressed as changes in structure and mechanics at the macrostructural level of bone. Therefore the mineralization of HAP in OI bone and the molecular basis of OI bone disease makes this an interesting system for molecular-level investigations. Small changes in the valence band and outer electronic structures of the diseased bone have been revealed through EELS. These small changes observed in the electron energy-loss spectra of the OI bone appear to play important biological roles towards development of the disease.National Science Foundation under Grant Nos. 0619098, 0821655, 0923354, and 1229417
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Dang, Lei. "Osteoblastic PLEKHO1 contributes to joint inflammation in rheumatoid arthritis." HKBU Institutional Repository, 2019. https://repository.hkbu.edu.hk/etd_oa/687.
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Background: Osteoblasts participating in the inflammation regulation gradually obtain concerns. However, its role in joint inflammation of rheumatoid arthritis (RA) is largely unknown. Here, we investigated the role of osteoblastic pleckstrin homology domain-containing family O member 1 (PLEKHO1), a negative regulator of osteogenic lineage activity, in regulating joint inflammation in RA. Methods: The level of osteoblastic PLEKHO1 in RA patients and collagen-induced arthritis (CIA) mice was examined. The role of osteoblastic PLEKHO1 in joint inflammation was evaluated by a CIA mice model which was induced in osteoblast-specific Plekho1 conditional knockout mice and mice expressing high Plekho1 exclusively in osteoblasts, respectively. The effect of osteoblastic PLEKHO1 inhibition was explored in a CIA mice model. The mechanism of osteoblastic PLEKHO1 in regulating joint inflammation was performed by a series of in vitro studies. Results: PLEKHO1 was highly expressed in osteoblasts from RA patients and CIA mice. Osteoblastic Plekho1 deletion ameliorated joint inflammation, whereas overexpressing Plekho1 only within osteoblasts exacerbated local inflammation in CIA mice. PLEKHO1 was required for TNF receptor-associated factor 2 (TRAF2)-mediated the ubiquitination of receptor-interacting serine/threonine-protein kinase 1 (RIP1) to activate nuclear factor kappa-light-chain-enhancer of activated B (NF-kB) pathway for inducing inflammatory cytokines production in osteoblasts. Moreover, osteoblastic PLEKHO1 inhibition improved joint inflammation and attenuated bone formation reduction in CIA mice. Conclusions: These data strongly suggest that highly expressed PLEKHO1 in osteoblasts mediates joint inflammation in RA. Targeting osteoblastic PLEKHO1 may exert dual therapeutic action of alleviating joint inflammation and promoting bone repair in RA.
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Fernandes, Fernanda [UNESP]. "Análise do colo femoral de ratas adultas e senis após tratamento com ocitocina." Universidade Estadual Paulista (UNESP), 2016. http://hdl.handle.net/11449/143823.
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Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)
Este estudo teve como objetivo analisar e comparar a ação da ocitocina (OT) no metabolismo ósseo de ratas Wistar cíclicas (12 meses) e acíclicas (18 meses/período de periestropausa). Os animais foram distribuídos em quatro grupos: (1) animais com 12 meses que receberam injeção com veículo NaCl (Veh/12); (2) animais com 12 meses que receberam injeção de OT (Ot / 12); (3) animais com 18 meses que receberam injeção com veículo NaCl (Veh/18); (4) animais com 18 meses que receberam injeção de OT (Ot / 18). Cada grupo foi composto por 8 animais. Os animais receberam duas injeções intraperitoneais de NaCl (0,15 M – grupo controle) ou OT (134 ug / kg – grupo tratado) com 12 horas de intervalo. Força, microarquitetura e biomarcadores ósseos [fosfatase alcalina (FAL) e fosfatase ácida resistente ao tartarato (TRAP)] foram analisados. Imunoistoquímica foi realizada para fator de transcrição relacionado com o Runt 2 (RUNX2), osterix (OSX), osteocalcina (OCN), osteopontina (OPN), proteína óssea morfogenética 2 e 4 (BMP-2/4), periostina (PER), esclerostina (ESC) e TRAP. Os animais que receberam OT demonstraram melhora significante na dosagem plasmática: aumento na FAL dos animais de 12 meses (p < 0,0001) e 18 meses (p = 0,0138); diminuição na TRAP dos animais de Ot / 12 (p = 0,0465) e Ot / 18 (p = 0,0045). Houve melhora nos parâmetros biomecânicos: força máxima (N) do grupo Ot / 18 (p = 0,0003); rigidez óssea (x103N/mm) do grupo Ot / 12 (p = 0,0223) e Ot / 18 (p = 0,0145); microarquitetura óssea cortical do grupo Ot / 18 para Ct.Ar (mm2 ) (p = 0,0416) e Ct.Po (%) (p = 0,0102); microarquitetura óssea trabecular para Tb.N (1/mm) (p = 0,0016) e Tb.Sp (p = 0,00010); todos os grupos foram comparados ao seus respectivos controles (Veh/12; Veh/18). Em resumo, os resultados demonstraram que a administração de OT foi eficaz para prevenir a perda de massa óssea em ratas Wistar velhas com hipoestrogenismo, reforçando este agente anabólico como forte alternativa terapêutica para prevenção e tratamento da osteoporose (OP), reduzindo os índices da doença e fraturas osteoporóticas.
This study aimed to analyze and compare the acting of oxytocin (OT) on bone metabolism of cyclic (12 months) and acyclic Wistar rats (18 months/peri-estropause period). Animals were allocated to four groups: (1) animals with 12 months that received vehicle injection NaCl (Veh/12); (2) animals with 12 months that received OT injection (Ot / 12); (3) animals with 18 months that received vehicle (Veh/18) and (4) animals with 18 months that received OT injection (Ot / 18). Eight animals composed each group. The animals received two intraperitoneal injections of NaCl (0.15 M - control group) or OT (134 ug / kg - treated groups) with 12 hours apart. Bone strength, microarchitecture, and biomarkers [alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP)] were assessed. Immunohistochemistry was performed for runt-related transcription factor 2 (RUNX2), osterix (OSX), osteocalcin (OCN), osteopontin (OPN), bone morphogenetic protein 2 and 4 (BMP- 2/4), periostin (PER), sclerostin (ESC) and TRAP. Animals that received OT showed significant improvements at plasma assay: increase in the ALP from the animals with 12 months (p < 0.0001) and 18 months (p = 0.0138); decrease in the TRAP from the Ot / 12 (p = 0.0465) and Ot / 18 (p = 0.0045). There was improvements at biomechanical parameters: maximum load (N) from the Ot / 18 (p = 0.0003); bone stiffness (x103N/mm) from the Ot / 12 (p = 0.0223) and Ot / 18 (p = 0.0145); cortical bone microarchitecture from the Ot / 18 to Ct.Ar (mm2 ) (p = 0.0416) and Ct.Po (%) (p = 0.0102); trabecular bone microarchitecture to Tb.N (1/mm) (p = 0.0016) and Tb.Sp. (p = 0.00010); all groups compared to its respective controls (Veh/12; Veh/18). In summary, the results showed the OT administration was effective to prevent the bone loss in old Wistar rats with hypoestrogenism, reforcing this anabolic agent as powerful therapeutic alternative to prevention and treatment for osteoporosis (OP), to reduce the rates of disease and osteoporotic fractures.
CNPq: 133834/2014-0
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Cha, Ming Chuan 1955. "The effect of zinc deficiency on the growth promoting actions of growth hormone and insulin-like growth factor-I /." Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=55484.
Full textAbstract:
The effect of zinc deficiency on the growth promoting effect of circulating IGF-I and the direct growth effect of GH on long bone growth were investigated. Food intake was decreased by lack of zinc in the diet. Tissue zinc content and plasma alkaline phosphatase activity were reduced by zinc deficiency. Systemic administration of human IGF-I increased the body weight, tail length and tibia epiphyseal cartilage width of control animals. This somatogenic action was impaired by zinc deficiency, as evidenced by continued weight loss, no increase in tail length and decreased tibial epiphyseal cartilage width of zinc deficient animals. Unilateral arterial infusion of GH increased the tibial epiphyseal width of the treated limb but not of the non-treated limb in control rats. However, no difference was found between the infused and the non-infused limb of zinc deficient animals, suggesting the occurrence of GH resistance on long bone growth in zinc deficiency. We conclude that zinc deficiency inhibits the growth promoting action of circulating IGF-I and the direct growth effect of GH on long bone growth.
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Alfonso, Durruty Marta Pilar. "Biosignificance of Harris lines as stress markers in relation to moderate undernutrition and bone growth velocity a New Zealand white rabbit model for the study of bone growth /." Diss., Online access via UMI:, 2008.
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Chan, Cheuk-wing Wilson, and 陳卓榮. "ER stress in the pathogenesis of osteochondrodysplasia." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43085192.
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Patel, Mamta Jashvantlal. "Suppression of osteoblast activity by disuse is prevented by low magnitude mechanical loading through a bone morphogenic protein-dependent Mechanism." Diss., Georgia Institute of Technology, 2008. http://hdl.handle.net/1853/22663.
Full textAbstract:
Musculoskeletal pathologies associated with decreased bone mass, including osteoporosis and disuse-induced bone loss, affect millions of Americans annually. Many pharmaceutical treatments have slowed osteoporosis, but there is still no countermeasure for bone loss observed in astronauts. Additionally, high magnitude and low frequency impact has been recognized to increase bone and muscle mass under normal but not microgravity conditions. However, a low magnitude and high frequency (LMHF) mechanical load experienced in activities such as postural control has also been shown to be anabolic to bone. While several clinical trials have demonstrated that the LMHF mechanical loading normalizes bone loss in vivo, the target tissues and cells of the mechanical load and underlying mechanisms mediating the responses are unknown. As such, the objectives of this project are to analyze cellular and molecular changes induced in osteoblasts by LMHF loading and to investigate the utility of a LMHF mechanical load in mitigating microgravity-induced bone loss. The central hypothesis of the project is that simulated microgravity or disuse conditions induce bone loss by inhibiting expression of genes critical in regulating bone formation, osteoblast differentiation, and subsequent mineralization while a LMHF mechanical load prevents these effects. To test this hypothesis, we developed an in vitro disuse system using the Random Positioning Machine (RPM). For the first time, we reported systemic gene expression studies in 2T3 preosteoblasts using the RPM disuse system showing that 140 genes were altered by RPM exposure with over two-fold statistically significant changes. Moreover, we also utilized an independent simulator called the Rotating Wall Vessel (RWV) to partially validate the in vitro disuse systems and to confine the list of genes to those most critical in regulating bone formation. After comparative studies, we constricted the list to 15 commonly changed genes, three of which were not only decreased with disuse but also increased with mechanical loading in vivo. Furthermore, we employed the RPM disuse system to evaluate the mechanism by which a LMHF load mitigates bone loss. Exposure of osteoblasts to the RPM decreased both ALP activity and mineralization even in the presence of bone morphogenic protein 4 (BMP4), and the LMHF mechanical loading prevented the RPM-induced decrease in both markers. Mineralization induced by LMHF mechanical loading was enhanced by treatment with BMP4 and blocked by the BMP antagonist noggin, suggesting a role for BMPs in this response. In addition, LMHF mechanical loading rescued the RPM-induced decrease in gene expression of ALP, runx2, osteomodulin, parathyroid hormone receptor 1, and osteoglycin. These findings show that osteoblasts directly respond to LMHF mechanical loading, potentially leading to normalization or prevention of bone loss caused by disuse or microgravity conditions. The mechanosensitive genes identified here provide potential targets for pharmaceutical treatments that may be used in combination with LMHF mechanical loading to better treat osteoporosis, disuse-induced bone loss, or microgravity-induced bone loss.
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Biason, Talita Poli [UNESP]. "Densidade mineral óssea em adolescentes usuárias de anticoncepcional oral combinado." Universidade Estadual Paulista (UNESP), 2013. http://hdl.handle.net/11449/99233.
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000748628.pdf: 1456061 bytes, checksum: b5ef0d0192e00742b4d0ca806b84a009 (MD5)Avaliar a densidade mineral óssea (DMO) e o conteúdo mineral ósseo (CMO) de adolescentes do sexo feminino, usuárias de anticoncepcional oral combinado (AOC) de baixa dosagem padronizado (EE 20 μg/ Desogestrel 150 μg), por período de um ano de seu uso e comparar os dados obtidos aos de adolescentes saudáveis da mesma faixa etária, não usuárias. Trata-se de um estudo controlado paralelo não randomizado. Sessenta e sete adolescentes, de 12 a 20 anos de idade, foram divididas em grupo de usuárias de AOC (n=41) e grupo controle (n=26). As adolescentes pertencentes aos dois grupos foram submetidas a exame físico geral e especial para obtenção de peso, estatura, índice de massa corpórea (IMC), avaliação dos caracteres sexuais secundários (critérios de Tanner), obtenção de idade óssea (IO) pelo método de Greulich & Pyle, ingestão de cálcio obtida pelo recordatório de 3 dias e obtenção da idade do evento menarca. As usuárias de AOC foram submetidas ao exame de Densitometria Óssea por atenuação de raio x de dupla energia (DXA), no momento de inclusão no trabalho; 6 e 12 meses depois, para obtenção de CMO (g) e DMO (g/cm2) em região lombar (L1-L4), fêmur proximal total, corpo total e corpo subtotal. O grupo controle foi avaliado através da DXA, no momento inicial; 12 meses depois, para obtenção de DMO e CMO, nos mesmos locais. A comparação entre as variáveis dos grupos de não usuárias e usuárias de AOC, no momento zero, foi realizada através do teste de Mann-Whitney, fixado o nível de significância de 5% ou utilizado o p-valor correspondente, enquanto para a comparação evolutiva dos grupos utilizou-se a variação das porcentagens das medianas das variáveis relativas à massa óssea, nos momentos inicial e final. Não houve diferenças estatísticas nas comparações entre as idades cronológicas (IC) e IO, entre as variáveis antropométricas e as resultantes do...
To evaluate bone mineral density (BMD) and bone mineral content (BMC) in female adolescents taking a standard low dose (EE 20μg/ Desogestrel 150μg) combination oral contraceptive (COC) over a one year period and comparing them to healthy adolescents from the same age group not taking COC’s. A non-randomized parallel control study with 67 adolescents from 12 to 20 years of age divided into user (COC; n=41) and control (n=26) groups. Both groups were submitted to a general physical and specific examination for weight, height, body mass index (BMI), secondary sexual characteristics evaluation (Tanner criteria), bone age (BA) by the Greulich & Pyle method, calcium intake by 3 days diet recording, and obtaining age at menarche. COC users underwent bone density exam by dual-energy X-ray absorptiometry (DXA) at time of inclusion in the study and at 6 and 12 months, to obtain BMC (g) and BMD (g/cm2) in the lumbar (L1-L4) and total proximal femur regions, for whole body and subtotal whole body. The Control group underwent DXA at inclusion and 12 months to obtain BMD and BMC in the same locations. Comparisons between groups at moment zero was through the Mann-Whitney test with significance level fixed at 5% or corresponding p value; evolutive group comparisons used variations in median percentages for bone mass variables at start and final moments. There were no statistical differences in chronological (CA) and BA, anthropometric variables, and bone densitometry results at the initial moment between COC and control groups. However after 12 months follow-up, COC users presented low bone mass acquisition in the lumbar spine BMD and BMC median variation percentages between initial and final moments (+2.07% and +1.57% respectively) while the control group presented expressive variations (+12.16% and +16.84% respectively). Total body BMD and BMC presented similar behaviour; variation in the COC group was +0.84% and +1.22%, considerably lower ...
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Valverde, Franco Gladys 1972. "The role of fibroblast growth factor receptor 3 in post-natal cartilage and bone metabolism /." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=115917.
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FGFR 3 is one of a family of four high affinity receptors for FGF ligands. Activating mutations in FGFR 3 result in skeletal dysplasias that vary in severity from undetectable to neonatal lethal. Mice with congenital deficiency of FGFR3 develop severe kyphosis and skeletal overgrowth. FGFR3 is also expressed in calvarial pre-osteoblasts, osteoblast and articular chondrocytes, although it biological role in these cells remains undefined. By changing the genetic background of the Fgfr3-/- mice we were able to extend their lifespan and examine its impact on post-natal skeletal growth. To investigate the implication of FGFR 3 in post-natal cartilage and bone metabolism we used a combination of imaging, classic histology, molecular biology and biomechanical testing. The results demonstrated that the synovial joints of young adult Fgfr3-/- mice revealed a progressive deterioration, loss of the joint space width and changes in the subchondral bone. These alterations were accompanied by an increase of cartilage matrix degradation. Increased aggrecan and collagen type II degradation products, generated by MMPs were detected with DIAPEN and COL2-3/4C antibodies. Increased collagen type X, cellular hypertrophy and loss of proteoglycan at the articular surface were also demonstrated. A novel micro-mechanical indentation protocol revealed that the humeral heads of Fgfr3-/- mice were less stiff than those of wild type littermates. On the other hand, young adult Fgfr3-/- mice are osteopenic due to reduced cortical bone thickness and defective trabecular bone mineralization. The reduction in mineralized bone and lack of trabecular connectivity observed by micro-computed tomography were confirmed by histological and histomorphometric analyses, which revealed a significant decrease in calcein labeling of mineralizing surfaces and a significant increase in osteoid in the long bones of 4-month-old Fgfr3-/- mice. Primary cultures of adherent bone marrow-derived cells from Fgfr3-/- mice expressed markers of differentiated osteoblasts but developed fewer mineralized nodules than Fgfr3+/+ cultures of the same age. These data point to a major role for FGFR3 signaling in development and homeostatic maintenance of cartilage and bone post-natally and identify FGFR3 as a potential target for intervention in degenerative disorders of cartilage, osteopenia and those associated with defective bone mineralization.
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Pedroni, Marcus Vinícius Costa 1985. "Análise molecular e funcional dos genes formadores e reguladores do colágeno tipo I em pacientes com osteogênese imperfeita = Molecular and functional analysis of regulatory and structure-related genes of type I collagen in patients with osteogenesis imperfecta." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310406.
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Orientadores: Lília Freire Rodrigues de Souza Li, Carlos Eduardo SteinerDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências
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Resumo: A Osteogênese Imperfeita (OI) é um distúrbio genético caracterizado por baixa massa e fragilidade óssea, e outras manifestações do tecido conjuntivo, decorrente de defeitos qualitativos ou quantitativos do colágeno tipo I. Está associada a mutações nos genes COL1A1 e COL1A2 que codificam respectivamente as cadeias pro'alfa'1-(I) e pro'alfa'-2(I) formadoras da molécula do colágeno tipo I, e mais raramente mutações nos genes reguladores. A OI manifesta-se através de diferentes fenótipos (I-IV), segundo a classificação de Sillence et al. O objetivo deste trabalho foi a análise molecular dos genes COL1A1 e COL1A2 em famílias brasileiras portadoras de OI, em suas diferentes formas clínicas. Fizemos biópsia da pele de 12 famílias com OI para cultura primária dos fibroblastos. Desta cultura extraímos RNA total, que foi usado como molde para transcrição reversa e reação em cadeia de polimerase (PCR) dos genes e sequenciamento automático direto de cDNA. A expressão gênica foi determinada por Real Time PCR e o padrão e grau de expressão das proteínas do colágeno foram analisados por Imunocitoquímica e Western blot. Identificamos nove mutações missense em heterozigose em nove famílias, e duas mutações com alteração na matriz de leitura em famílias com fenótipos dos tipos I, III ou IV de OI. No gene COL1A1 encontramos quatro mutações já descritas: c.613G>A (p.P205A); c.769G> A (p.G257R); c.859G>A (p.G287S); c.1678G>A (p.G560R). No gene COL1A2 encontramos uma mutação já descrita: c.2314G> A (p.G772S) e quatro novas mutações: c.214G>A (p.G72S); c.775G>A (p.G259S); c.793G> C (p.G265R) e c.3467G>A (p.R1156K). Encontramos hiperexpressão dos transcritos de COL1A1 e COL1A2, porém expressão normal das cadeias 'alfa'1 e 'alfa'2 da proteína do colágeno em todos os pacientes. As cadeias mutada apresentaram padrão desorganizado nas células. Pacientes com OI apresentaram hiperexpressão dos genes de colágeno tipo I sugerindo que estes genes são regulados e que as meia vidas destas proteínas estão reduzidas
Abstract: Osteogenesis Imperfecta (OI) is a genetic disorder characterized by low bone mass and bone fragility, and other manifestations of connective tissue, due to qualitative or quantitative defects of type I collagen. It is associated with mutations in COL1A1 and COL1A2 genes, that encode respectively the pro'alpha'-1(I) and pro'alpha'-2(I) chains, forming the molecule of type I collagen, and more rarely mutations in regulatory genes. The OI is manifested by various phenotypes (I-IV), according to the classification of Sillence et al. The objective of this study was the molecular analysis of COL1A1 and COL1A2 genes in Brazilian families with OI, in its different clinical forms. We performed skin biopsy from 12 families with OI for primary culture of fibroblasts. From this culture, we made total RNA extract, which was used as template for reverse transcription and polymerase chain reaction (PCR), and automated sequencing directly from cDNA. Gene expression was determined by Real Time qPCR and the level of expression of collagen proteins were analyzed by immunocytochemistry and Western Blot. We identified heterozygous mutations in 11 families that have phenotypes of types I, III or IV of OI. In the COL1A1 gene found four previously described mutations: c.613G> A (p.P205A), c.769G> A (p.G257R), c.859G> A (p.G287S), c.1678G> A (p. G560R). In the COL1A2 gene we found one previously described mutation: c.2314G> A (p.G772S) and four new mutations: c.214G> A (p.G72S), c.775G> A (p.G259S), c.793G> C (p.G265R) and c.3467G> A (p.R1156K). We found upregulation of the transcripts of COL1A1 and COL1A2 genes, but a normal expression of 'alpha'1 and 'alpha'2 protein chains in all patients. The mutant chain showed disorganized on the immunocytochemestry. Patients with OI showed upregulation of type I collagen genes, suggesting regulation and decreasing half lives of the proteins
Mestrado
Saude da Criança e do Adolescente
Mestre em Ciências
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Neves, Camila de Castro [UNESP]. "Estudo radiográfico retrospectivo de lesões ósseas mandibulares em cães." Universidade Estadual Paulista (UNESP), 2006. http://hdl.handle.net/11449/89086.
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neves_cc_me_jabo.pdf: 1932738 bytes, checksum: 2cc1bbf1472ac069094d5b9277cdf091 (MD5)Universidade Estadual Paulista (UNESP)
Com o presente estudo relata-se a freqüência, localização e tipo de alterações encontradas em 77 cães com suspeita de lesão óssea na mandíbula, em imagens radiográficas, do arquivo do Setor de Radiologia do Hospital Veterinário Governador Laudo Natel (HV), da Faculdade de Ciências Agrárias e Veterinárias, da Universidade Estadual Paulista (FCAV/UNESP), Câmpus de Jaboticabal, SP, no período de janeiro de 2001 a janeiro de 2006, correlacionando sexo, idade e raça dos animais. A pesquisa revelou 37 (48,05%) cães com lesões mandibulares. Dentre os cães acometidos 44,16% eram de raça indefinida e 14,29% da raça Poodle. Do total 33,77% eram machos e a idade mais afetada estava entre seis e nove anos (23,38%). A fratura (38,96%) foi à alteração mais encontrada e o local de maior ocorrência foi à região de premolares (24,38%) e molares (10,39%) do corpo da mandíbula.
The present study reported the frequency, placement and kind of changes in 77 dogs supposed to have lesions at jawbone in radiographic images from the Radiological Sector archive, at the Veterinary Hospital Governador Laudo Natel (HV), of the Veterinary Faculty from São Paulo State University (FCAV/UNESP), Jaboticabal, SP, between January 2001 to January 2006, correlating sex, age and the breed of the animals. The study revealed 37 (48, 5%) of dogs with jawbone lesions. Among the dogs that were taken ill, 44,16% had no defined breed and 14,29% were Poodle. They were 33,7% male and the most affected age range was between six and nine (23,38%). The fracture (38,96%) was the most common change and it occurred most frequently in the premolar region (10,39%) and molar region (10,39%) of the mandible body.
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Costin, Graham A. "Skeletal health education : effects of an educational intervention on health behaviour and health behaviour indicators of adolescent girls." Thesis, Queensland University of Technology, 1998.
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Education provides the critical link between the acquisition of knowledge about the determinants of skeletal health and the availability of that knowledge for application by the wider population. Hence it is one strategy with the capacity to reduce the increasing worldwide incidence of skeletal health problems, in particular osteoporosis. An expanding aged population
requiring increasing care and support for osteoporosis-induced problems and suffering indicates the need for a concerted response incorporating education.
Although osteoporosis is typically associated with old age, the nature of precipitating factors causing bone resorption to exceed that of accretion, and how these factors might be influenced to alter such outcomes are incompletely understood. However, there is increasing evidence, largely from cross-sectional studies, showing that environmental factors such as physical activity and nutrition play a significant role in optimising the genetic potential for the development of peak bone mass.
There is also growing speculation that interventions which promote these factors during childhood and adolescence may increase peak bone mass, thus delaying the development of porotic bone. Al though the optimal dose levels for maximising the effects of these factors have yet to be established, there is sufficient evidence to support the manipulation of these factors to enhance bone accumulation.
Therefore, the general aim of this thesis was to examine the effects of a skeletal health educational intervention
on bone-enhancing lifestyle practices of adolescent girls.
A definite association between skeletal health education and the adoption of lifestyle practices regarded as beneficial to bone growth and development had not been established in the literature. Therefore, the project needed to develop an original educational intervention program focused on these practices, prior to implementation and evaluation. Based on Social Cognitive Theory and current health education practice, this program emphasised the adoption of specific health behaviours and the outcomes, therefore, in addition to the intervention outcomes, the implementation process was assessed.
Responses to this process were obtained from the adolescent girl participants and the teacher-observers using questionnaires and focus group discussions. The respondents found the program and its application very effective and beneficial. The effect of educational interventions on related interaction between mother /daughter couples who participate in the interventions together has not been established in the literature. Therefore, a small group of mothers and their adolescent daughters participated in a separate implementation of the program.
Over the subsequent four weeks, they recorded the nature and frequency of interactions which related to the skeletal health program. This study revealed that joint participation in the program resulted in several forms of cooperative interaction. Although this involved moderate levels of active interaction in physical activity and food organization sessions, the dominant areas were verbal communication and shared eating experiences at meal times.
In summary, health behaviours were maintained at or above
recommended levels during the intervention and over the
subsequent six months. Knowledge and body image satisfaction were the only health behaviour indicators which increased significantly during the intervention and this increase was largely retained six months later. From a curriculum evaluation perspective, the positive results for both the process and outcome measures of the intervention supported its utility.
The substantial amount of mother/daughter interaction resulting from their joint participation in the intervention indicates the potential of this such initiatives to enhance educational outcomes,development of the knowledge, attitude, belief and skill indicators of these behaviours.
The program was implemented in seven weekly sessions of 45 minutes to 13 year old adolescent girls in two similar girls catholic colleges. The intervention group of 97 girls from three year 8 classes at one college represented the total cohort of that age group. The comparison group comprised one year 8 class of 32 girls from the second
college. Data on the health behaviour and health behaviour
indicators were collected from this convenience sample of 129 adolescent girls using a pre-test/post-test/follow-up design.
An examination of results from qualitative and quantitative data revealed differential intervention impacts. No significant intervention effects (P < 0.05) were found for the important bone influencing behaviours of calcium intake, physical activity participation, alcohol consumption, cigarette use and caffeine intake. However, the girls commenced the study with calcium intake and physical activity participation at or above recommended levels, and extremely low drug usage. This pattern of behaviour was maintained throughout the study. The health behaviour indicator results revealed that the intervention girls acquired significantly more skeletal health knowledge than their comparison group (P < 0.001) and that this
knowledge was largely retained over the following six months.
This finding suggests that the intervention was very effective in establishing knowledge needed as a foundation for any further skeletal health initiatives. Body image satisfaction also increased significantly (P < 0.05) and much of this increase was retained six months later. However, when an importance dimension was added to this measure of satisfaction, the significant, between-group difference was not sustained. Self-efficacy for physical activity and for sensible eating did not show significant between-group differences. Similarly changes in the
expected outcomes and perceived barriers for these behaviours did not vary significantly between the two groups of girls.
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Tag, Naima. "The added value of SPECT/CT in complicated osteomyelitis." Thesis, Stellenbosch : Stellenbosch University, 2013. http://hdl.handle.net/10019.1/85553.
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ENGLISH ABSTRACT: Background: The detection of bone infection can be very difficult especially in bone with altered
structure due to prior trauma or surgical procedures. Complicated osteomyelitis (COM) is becoming a
public health problem especially with the difficult choice between, high cost surgery and prolonged
courses of intravenous or oral antibiotic therapy, as well as the social and psychological effect of longterm
disease and disability of the patient. The correct localisation of especially bone infection is still a
challenge for the clinician. The single photon emission computed tomography/low dose computed
tomography (SPECT/CT), by fusing the functional information with the anatomical parts, is a wellestablished
tool used in many nuclear medicine studies. This improves the overall quality of the study
with more clear answers. The aim of the study was to determine the added value of SPECT/CT in the
management of complicated osteomyelitis (COM) in patients with endo-prosthesis, post traumatic
osteomyelitis with and without metal implants and diabetic foot.
Methods: This was a prospective study, between February 2010 and February 2012. Patients with
suspected COM who fulfilled the selection and inclusion criteria were included. All had abnormal three
phase bone scan followed by infection imaging with 99mTc labelled white blood cells and 99mTc -colloid if
the99mTc labelled white blood cell study was abnormal. 67Ga citrate was used in vertebral involvement.
Planar and SPECT/CT images were reviewed for presence of abnormal uptake and for its localization in
bone and soft tissue. Scan results were defined as positive or negative. Both planar and SPECT/CT
images were compared regarding diagnosis and precise localization of infection. The final diagnosis was
obtained from surgical specimen or microbiological culture as well as clinical follow-up of all patients.
Results: There were 72 patients, 29 male and 43 female with mean age of 57 yrs [range 27-88].There
were 24 patients with prosthesis, 16 with hip prosthesis (PH=16), and 8 with knee prosthesis (PK=8).
There were 44 patients with post traumatic osteomyelitis, 26 with metal implants (TOM=26) and 18
without metal implants (TOWM= 18). Four patients had diabetic foot (DF= 4). Infection was diagnosed
in 19/72 patients on planar images and in 21/72 on SPECT/CT. Infection was diagnosed in 4 patients
with prosthesis, 16 patients with post traumatic injury and one diabetic foot patient. The four patients
with prosthesis, SPECT /CT added diagnostic value by excluding osteomyelitis in 3 patients and by
defining the exact extent and localizing soft tissue and bone infection (STI/OM) in one patient. In 16
patients with post traumatic OM on planar images, SPECT /CT added diagnostic value, by excluding OM in 4 patients and confirming only STI, better localisation of the uptake in bone
and soft tissue in 5 patients, of them 2 patient was negative on planar, and in 7 patients, confirmed and
defined the exact extent of
both OM and STI. One diabetic foot was positive for STI on the planar, the SPECT/CT added diagnostic
value by defining the extent of the infection.
In summary the added value of SPECT/CT was:
a. Overall infection:
1. Exclusion of osteomyelitis by confirming only soft tissue involvement: 7 patients (10%)
2. Better localization in bone and soft tissue: 6 patients (8%)
3. Better delineation of extent of infection: 9 patients (12%)
4. None: 50 patients (70%)
b. In positive cases only:
1. Exclusion of osteomyelitis by confirming only soft tissue involvement: 7 patients (33%)
2. Better localization in bone and soft tissue: 5 patients (24%)
3. Better delineation of extent of infection: 9 patients (43%)
4. None: 0 patients
The overall sensitivity, specificity, positive predictive value, negative predictive value and accuracy for
infection, on planar was 90%, 100%, 100%, 97%, 97%, respectively and for SPECT/CT 100%, 100%,
100%, 100%, 100%. For OM on planar, the sensitivity, specificity , positive predictive value, negative
predictive value and accuracy was 100%, 89%, 53%, 100%, 90%, respectively and for SPECT/CT 100%,
100%, 100%, 100%, 100%.
Conclusion:
In complicated osteomyelitis, SPECT/CT is useful in localizing, defining the exact extent of infection
where the planar images are abnormal, with no added value if the planar images are negative. We
recommend in clinical practice the routine use of hybrid SPECT/CT imaging in complicated osteomyelitis
when planar images are abnormal.AFRIKAANSE OPSOMMING: Agtergrond: Die opspoor van beeninfeksie is veral moeilik in been wat as gevolg van vorige trauma of chirurgiese prosedures misvorm is. Gekompliseerde osteomiëlitis word ‘n gesondheidsprobleem veral as gevolg van die moeilike keuse tussen hoë koste chirurgie en langdurige kursusse binneaarse of orale antibiotika, asook die sosiale en sielkundige gevolge van langstaande siekte en die gestremdheid van die pasiënt. Die korrekte lokalisering van veral beeninfeksie is steeds ‘n uitdaging vir die geneesheer. Enkel foton emissie rekenaartomografie / lae dosis rekenaartomografie (SPECT/CT), die kombinasie van funksionele en anatomiese inligting, is ‘n goed gevestigde metode in baie kerngeneeskunde ondersoeke. Dit verbeter die algemene kwaliteit van die studie met ‘n meer spesifieke antwoord. Die doel van hierdie studie was om die bykomende waarde van SPECT/CT in die hantering van gekompliseerde osteomiëlitis in pasiënte met endo-protese, post traumatise osteomiëlitis met en sonder metaal prosteses asook diabetiese voet te bepaal. Metode: ‘n Prospektiewe studie is tussen Februarie 2010 en Februarie 2012 gedoen. Pasiënte met vermoedelik gekompliseerde osteomiëlitis wat aan die keuse en insluitingskriteria voldoen het, is ingesluit. Almal het abnormale drie-fase beenflikkergramme gehad, gevolg deur infeksiebeelding met 99mTc gemerkte witselle en 99mTc kolloïed indien die 99mTc gemerkte witselstudie abnormaal was. 67Ga sitraat is gebruik wanneer daar werwelaantasting teenwoordig was. Die planare en SPECT/CT beelde is vergelyk ten opsigte van diagnose en presiese lokalisering van die infeksie. Die finale diagnose is met behulp van chirurgiese monsters en mikrobiologiese kweking asook die kliniese opvolg van alle pasiënte bepaal. Resultate: Die studie het 72 pasiënte, 29 mans en 43 vroue, met gemiddelde ouderdom van 57 jaar [27 – 88 ingesluit]. Daar was 24 pasiënte met prosteses, waarvan 16 met heupprosteses (PH= 16) en 8 met knieprosteses (PK= 8). Van die 44 pasiënte met post traumatiese osteomiëlitis, het 26 metaal prosteses (TOM= 26) en 18 geen metaalprosteses gehad nie (TOWM= 18). Vier pasiënte het diabetiese voet gehad (DF= 4). By 19/72 van die pasiënte is infeksie op die planare beelde gediagnoseer en in 21/72 op die SPECT/CT beelde. Die bykomende twee gevalle was 1 met TOM en 1 met TOWM. Infeksie is by 4 pasiënte met prosteses, 16 pasiënte met post traumatiese besering en 1 met diabetiese voet gediagnoseer. In die vier pasiënte met prosteses, het SPECT/CT ‘n diagnostiese bydrae gelewer om osteomiëlitis by 3 van die pasiënte uit te skakel en die presiese omvang en lokalisering van sagte weefsel en beeninfeksie (STI/OM) in een pasiënt te bepaal. In 16 pasiënte met post traumatise osteomiëlitis op die planare beelde, was SPECT/CT van diagnostiese waarde, waar osteomiëlitis in 4 pasiënte uitgesluit is, en slegs STI bevestig is. Beter lokalisering van die opname in been en sagte weefsel was in 5 pasiënte moontlik, van wie 2 op die planare beelde negatief was, en in 7 pasiënte bevestig en die presiese omvang met beide OM en STI gedefinieer is. Een diabetiese voet was positief vir STI op die planare beelde, maar die SPECT/CT het diagnostiese waarde verbeter deur die omvang van die infeksie beter te toon. Ter opsomming, was die waarde van die SPECT/CT: 1. Uitsluiting van osteomiëlitis deur slegs van sagte weefsel aantasting te bevestig: 7 pasiënte 10% 2. Beter lokalisering in been en sagte weefsel: 5 pasiënte 7% 3. Beter definisie van omvang van infeksie: 9 pasiënte 12% 4. Geen bykomende waarde: 51 pasiënte 71% Die algehele sensitiwiteit, spesifisiteit, positiewe voorspellingswaarde, negatiewe voorspellingswaarde en akkuraatheid vir die opspoor van infeksie vir die planare beelde was 90%, 100%, 100%, 97%, 97%, onderskeidelik en vir die SPECT/CT 100%, 100%, 100%, 100% en 100%. Vir osteomiëlitis was sensitiwiteit, spesifisiteit, positiewe voorspellingswaarde, negatiewe voorspellingswaarde en akkuraatheid van planare beelde 100%, 89%, 53%, 100%, 90%, onderskeidelik en die van SPECT/CT 100%, 100%, 100%, 100% , 100%. Gevolgtrekking: SPECT/CT is nuttig in die lokalisering en definiëring van die presiese omvang van die infeksie in gekompliseerde osteomiëlitis in gevalle waar die planare beelde abnormaal is, met geen bykomende waarde wanneer planare beelde negatief is nie. Ons beveel SPECT/CT beelding as roetine in kliniese praktyk aan wanneer planare beelde in gekompliseerde osteomiëlitis abnormaal is.
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周志豪. "跟痛症內服中藥治療規律的文獻研究." HKBU Institutional Repository, 2009. http://repository.hkbu.edu.hk/etd_ra/1042.
Full text
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譚健斌. "股骨頭缺血性懷死的中醫藥治療文獻研究." HKBU Institutional Repository, 2006. http://repository.hkbu.edu.hk/etd_ra/755.
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Guañabens, Gay Nuria. "Osteodistrofia de la cirrosis biliar primaria." Doctoral thesis, Universitat de Barcelona, 1987. http://hdl.handle.net/10803/22838.
Full textAbstract:
La cirrosis biliar primaria es una enfermedad hepática que se manifiesta por un patrón clínico, bioquímico e histológico de colestasis crónica. Su curso puede complicarse con el desarrollo de una patología metabólica ósea cuyo tipo, frecuencia y mecanismos patogenéticos no están bien establecidos.
Esta tesis se ha realizado con el fin de analizar la prevalencia y tipo de enfermedad metabólica ósea que se asocia a la cirrosis biliar primaria (CBP) e investigar los factores que influyen en su desarrollo.
1) PACIENTES Y MÉTODOS
Se han estudiado 20 pacientes con CBP (18M, 2 V) con una edad media de 48.6 +/- 10.6 años. A todos ellos se ha practicado: estudio del grado de colestasis biológica y de la función hepatocelular, además de determinaciones bioquímicas y hormonales (25-hidroxivitamina D; 1,25 dihidroxivitamina D y parathormona N-terminal) del metabolismo mineral.
En 16 pacientes se determinó la capacidad de absorción intestinal de calcio. A todos los pacientes se practicaron radiografías de la columna vertebral y biopsia ósea, por vía transilíaca, tras doble "marcaje" con tetraciclinas, para análisis histomorfométrico en especimen óseo no decalcificado. El estudio histomorfométrico se realizó mediante el método semiautomático y se analizaron parámetros estáticos y dinámicos.
2) RESULTADOS
Siete pacientes tenían una osteoporosis al presentar una reducción del volumen trabecular. Tres de ellos tenían asociado un trastorno moderado de la mineralización ósea que no cumplía criterios de osteomalacia.
Quince pacientes (5 con osteoporosis) tenían una disminución del grado de formación ósea y en 19 casos la reabsorción ósea era normal o estaba disminuida.
Los pacientes con osteoporosis tenían una duración de la CBP más prolongada (5.4 +/- 2.8) que los pacientes sin osteoporosis (2.0 +/- 2.1 a p= 0.07). Además, la osteoporosis fue significativamente más frecuente en las mujeres postmenopáusicas, ya que 6 de los 7 pacientes con osteoporosis (86%) pero sólo 3 de los 11 sin osteoporosis (27%) eran mujeres postmenopaúsicas (p= 0.02). Por otro lado, los pacientes con osteoporosis tenían con mayor frecuencia una malabsorción intestinal de calcio (80%) que los pacientes sin osteoporosis (18%) (p= 0.03). Aunque la severidad de la colestasis no se relacionó con la presencia de osteoporosis, sí se halló una relación lineal inversa entre la absorción intestinal de calcio y la concentración plasmática de sales biliares (r= -0.55, p < 0.05) y el nivel sérico de la fosfatasa alcalina (r= -0.5, p < 0.05).
Cuatro pacientes, dos de ellos con trastornos de la mineralización ósea, tenían niveles séricos bajos de 25-hidroxivitamina D. Sin embargo, los niveles séricos del metabolitos 1,25-dihidroxivitamina D fueron normales en todos los casos.
3) CONCLUSIONES
Los resultados de este estudio indican que:
1.- La osteoporosis es la enfermedad metabólica ósea que comúnmente se asocia a la cirrosis biliar primaria. Su prevalencia fue del 35% en nuestra serie analizada.
2.- Los pacientes con cirrosis biliar primaria de nuestro medio no desarrollan una osteomalacia, aunque no es infrecuente que presenten un trastorno moderado de la mineralización ósea. Un 15% de los pacientes desarrollaron este trastorno.
3.- La osteoporosis asociada a la cirrosis biliar primaria es de bajo "turnover" óseo y su base fisiopatológica es un déficit de la formación ósea. El 71% de los pacientes con osteoporosis tenían un déficit de la formación ósea, alteración que también presentaba el 83% de los pacientes sin osteoporosis. Ello permite sugerir que un elevado porcentaje de pacientes con cirrosis biliar primaria y masa ósea normal están en alto riesgo de desarrollar una osteoporosis.
4,- Los factores de riesgo implicados en el desarrollo de osteoporosis en la cirrosis biliar primaria son: duración de la hepatopatía, estado postmenopáusico y malabsorción intestinal de calcio.
5,- El desarrollo de un trastorno moderado de la mineralización ósea es más frecuente en los pacientes con déficit de 2S-hidroxivitamina D. Sin embargo, el "status" deficitario de vitamina D no es exclusivo de los pacientes con trastorno de la mineralización ósea.
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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.
Full textAbstract:
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.
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Neves, Camila de Castro. "Estudo radiográfico retrospectivo de lesões ósseas mandibulares em cães /." Jaboticabal : [s.n.], 2006. http://hdl.handle.net/11449/89086.
Full textAbstract:
Orientador: Cíntia Lúcia ManiscalcoBanca: Júlio Carlos Canola
Banca: Jorge Luiz Oliveira Costa
Resumo: Com o presente estudo relata-se a freqüência, localização e tipo de alterações encontradas em 77 cães com suspeita de lesão óssea na mandíbula, em imagens radiográficas, do arquivo do Setor de Radiologia do Hospital Veterinário "Governador Laudo Natel" (HV), da Faculdade de Ciências Agrárias e Veterinárias, da Universidade Estadual Paulista (FCAV/UNESP), Câmpus de Jaboticabal, SP, no período de janeiro de 2001 a janeiro de 2006, correlacionando sexo, idade e raça dos animais. A pesquisa revelou 37 (48,05%) cães com lesões mandibulares. Dentre os cães acometidos 44,16% eram de raça indefinida e 14,29% da raça Poodle. Do total 33,77% eram machos e a idade mais afetada estava entre seis e nove anos (23,38%). A fratura (38,96%) foi à alteração mais encontrada e o local de maior ocorrência foi à região de premolares (24,38%) e molares (10,39%) do corpo da mandíbula.
Abstract: The present study reported the frequency, placement and kind of changes in 77 dogs supposed to have lesions at jawbone in radiographic images from the Radiological Sector archive, at the Veterinary Hospital Governador Laudo Natel (HV), of the Veterinary Faculty from São Paulo State University (FCAV/UNESP), Jaboticabal, SP, between January 2001 to January 2006, correlating sex, age and the breed of the animals. The study revealed 37 (48, 5%) of dogs with jawbone lesions. Among the dogs that were taken ill, 44,16% had no defined breed and 14,29% were Poodle. They were 33,7% male and the most affected age range was between six and nine (23,38%). The fracture (38,96%) was the most common change and it occurred most frequently in the premolar region (10,39%) and molar region (10,39%) of the mandible body.
Mestre
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Mkhize, Felicity Nomfuzo. "Investigating the high incidence of bone disorders in a broiler farm : a case study." Thesis, Stellenbosch : University of Stellenbosch, 2006. http://hdl.handle.net/10019.1/3346.
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Thesis (MPhil (Animal Sciences))--University of Stellenbosch, 2006.Rickets is described as a disease that affects young growing poultry. Poorly mineralized bones with thickened and irregular growth plates characterize it. The onset of rickets is characterized by a failure of mineralization of cartilage and bone. Other symptoms of rickets include reluctance to movement in affected birds. These birds will sit on their hocks and if startled they use their wings for balance. On necropsy, bones are soft and fragile and they have thickened growth plates. In this study 30% of the chicks aged between 7 and 8 days from a broiler flock, started showing splay leg problems. Affected chicks were unable to support their weight on their legs, some showing paralysis. The bones were soft and rubbery. To try and identify the possible cause, bones from the affected chicks were analyzed for calcium (Ca) and phosphorus (P) to determine the Ca:P ratio. Blood serum was also analyzed for the mineral content. Ca and P were the main focus of the tests as the problem was suspected to be rickets. The feed was analyzed for protein, Ca and P. The bone analysis showed a Ca:P ratio of less than 2:1, while results of the blood serum showed an inverse Ca: P ratio. The analysis results of the feed as well as the bones showed an imbalance in the Ca:P ratio which according to literature and research done is a possible cause for rickets. These findings combined with the symptoms displayed by the affected birds, lead to the suggestion that the problem in this study was rickets.
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Brock, Ryane Schmidt [UNESP]. "Retalho ósseo de gálea e periósteo preenchido com pó de osso: estido em coelhos." Universidade Estadual Paulista (UNESP), 2012. http://hdl.handle.net/11449/87352.
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Defeitos ósseos decorrentes de traumas, ressecções de tumores ou mesmo malformações congênitas, são encontrados com freqüência na prática médica. O tratamento destas deformidades é feito mediante reconstruções cirúrgicas, principalmente na cirurgia plástica, proporcionando aos pacientes melhor qualidade de vida. Os defeitos ósseos são corrigidos preferencialmente com enxertos ósseos autológos por não causarem rejeição, mas estes apresentam como desvantagens a morbidade das áreas doadoras e a grande porcentagem de absorção dos enxertos, com diminuição ou perda do resultado final. Outros métodos de reconstrução, como o uso de materiais aloplásticos, são utilizados mas, muitas vezes, evoluem com rejeição e extrusão ou infecção, e necessitam ser retirados. Retalhos livres, compostos de osso com músculo ou derme e subcutâneo, em casos graves, representam a melhor opção. Entretanto, este método requer preparo específico da equipe cirúrgica, maior tempo de cirurgia e, muitas vezes, apresenta trombose vascular e perda do retalho. Avaliar a viabilidade e a formação óssea em retalho gáleoperiostal preenchido com pó de osso em calota craniana de coelhos. Foram estudados 40 coelhos divididos em dois grupos, o primeiro com retalho gáleo-periostal e o segundo com o mesmo retalho, porém preenchido com pó de osso. Os resultados demonstraram neoformação óssea em ambos, mas com diferenças na estrutura e conformação óssea. O retalho gáleo-periosteal preenchido com pó de osso em calota craniana de coelhos é viável. A formação óssea ocorreu em ambos os grupos, preenchido ou não com pó de osso. A maturidade do tecido ósseo foi maior nos retalhos preenchidos com pó de osso
Osseus defects from traumas, tumor ressections or congenital malformations are usual in medical practice. The treatment of these deformities has been made with reconstructive surgeries, specially in plastic surgery, to give the patients better quality of life. The osseus defects are usually corrected with autologous bone grafts. These grafts are used because they do not cause rejection. However, they have disadvantages like the donnor site morbidity, the high number of absorption of these grafts and the final result partial or total lost. Other reconstruction methods like alloplastic materials are used, but they have high percentage of rejection and extrusion or even infection of these materials, which need to be taken off. Flaps of bone and muscle or dermis and subcutaneous are considered the best choice in difficult cases. However, this method needs specific training of the medical group, longer surgeries and, sometimes, presents the flap necrosis after vascular thrombosis. To study the viability and bone neoformation in a vascularized galea and periosteum flap filled with bone fragments. Fourty rabbits were studied, and divided into two groups. One had a simple galea and periosteum flap done and the other had the same flap done but filled with bone fragments of the calvaria. The results demonstrated bone formation in both groups, but with differences in the bone form and structure. The galea-periosteum flap filled with bone dust at rabbit’s calvaria is viable. The bone formation happened in both groups, with or without bone dust. Bone maturity was higher in the flaps filled with bone dust
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Aguiar, Simone dos Santos. "Pesquisa da amplificação e/ou deleção genica atraves da tecnica de hibridização genomica comparativa (CGH) e da leção dos genes P53 e RB1 atraves da tecnica de hibridação in situ fluorescente (FISH) no tecido do tumor de crianças e adolescentes com ost." [s.n.], 2006. http://repositorio.unicamp.br/jspui/handle/REPOSIP/312071.
Full textAbstract:
Orientador: Silvia Regina BrandaliseTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: Introdução Os osteossarcomas (OS) são tumores agressivos, primários de osso, com prognóstico reservado. As deleções dos genes supressores de tumor, RBl e P53, localizados nos cromossomos 13 e 17 respectivamente, são freqüentemente encontradas neste tipo de tumor. As alterações citogenéticas encontradas nos OS são de alta complexidade, porém nenhuma delas é recorrente, não podendo caracterizá-lo. A técnica da Hibridização Genômica Comparativa (CGH) é uma ferramenta muito precisa para o estudo das deleções e amplificações gênicas ocorridas neste tumor. Materiais e Métodos. Tecido tumoral de 41 crianças com OS foi analisado pela técnica de CGH para pesquisar possíveis ganhos e/ou perdas gênicas . A técnica da Hibridização In Situ Fluorescente (FISH) foi realizada para estudar as deleções dos genes P53 e RBl. Vinte e quatro pacientes eram do sexo feminino e 17 do sexo masculino, com mediana de 12 anos e 4 meses. Resultados. As anormalidades cromossômicas observadas com a técnica de CGH foram diversas e variadas, especialmente ganhos nos cromossomos lp, 2p, 3q, 5q,5p e 6p e, perdas nos cromossomos 14q (50% no - 14q 11.2), 15q e 16p. Alto índice de perdas foi observado no cromossomo 21 (26 de 41 casos; p=0,008), sendo a região mais freqüentemente afetada a 21ql 1.2. Com relação ao estudo dos supressores tumorais, a deleção do P53 ocorreu em 68,3% dos casos (p=0,02) e do RBl em 87,5% dos casos (p=0,000001). Conclusão. Apesar de ambos supressores (PS3 e RBl) estarem deletados na maioria dos pacientes, este evento parece não estar associado ao prognóstico. Anormalidades ainda não reportadas presentes no cromossomo 21 nos OS pediátricos, sugerem que a seqüência mapeada nesta região cromossômica possa estar envolvida na patogênese deste tumor
Abstract: Background. Osteosarcomas (OS) are aggressive bone tumors and often have a poor prognosis. It is already known that abnormalities in chromosomes 13 and 17 are frequently observed in OS patients, being also expected a deletion of RBI and P53 genes. The tumors exhibit karyotypes with a high degree of complexity, that has made it difficult to determine if any recurrent chromosomal aberrations could characterize OS. To address inherent difficulties associated with classical cytogenetic analysis, comparative genomic hybridization (CGH) has been applied to OS tissue. Patients and Methods. Forty one pediatric OS specimens were analyzed by CGH techniques, and the expression of RBI and P53 were analyzed by FISH . Twenty four patients were girls and 17 boys. Median age was 12 years and 4 months.Results. Chromosomal abnormalities were highly diverse and variable specially gains in chromosome lp, 2p, 3q, 5q , 5p and 6p and losses in chromosome 14q (50% in - 14q 11.2), 15q and 16p. High level of losses in chromosome 21 were present (26 of 41 cases; p-0,008), being 21 q 11.2 region the most frequent one. Concerning about genes expression, P53 is deleted in 68,3% of the cases (p=0,02) and RBI in 87,5% (p=0,000001) .Conclusion. Although both oncogenes (P53 and RBI) are deleted in OS population, it remains impossible to determine if this abnormality is a prognostic factor. These new and unreported findings in chromosome 21 of pediatric OS tumors, suggest that specific sequences mapping these chromosomal regions, would likely to play a role in the development of OS
Doutorado
Pediatria
Mestre em Saude da Criança e do Adolescente
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Buck, Cecília Oliveira Barbosa 1975. "Estudo clínico-epidemiológico das osteocondrodisplasias de manifestação perinatal na América do Sul." [s.n.], 2011. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308793.
Full textAbstract:
Orientador: Denise Pontes CavalcantiTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Osteocondrodisplasias (OCD) ou displasias esqueléticas são um grupo heterogêneo de doenças genéticas que afetam o crescimento. e o desenvolvimento do esqueleto e possuem alta morbimortalidade associada. Apesar dos avanços recentes no diagnóstico pré-natal e no conhecimento das bases moleculares das OCD, o seu diagnóstico ainda se baseia em anamnese, exame físico e radiografias de esqueleto. A prevalência habitualmente referida de 2,0/10.000, baseada em poucos estudos com populações pequenas, é subestimada. O objetivo deste estudo foi avaliar a epidemiologia das OCD na América do Sul (AS) utilizando uma grande população de mais de 1,5 milhões de nascimentos. Os casos de OCD foram selecionados dos arquivos do ECLAMC (um programa colaborativo de base hospitalar, caso-controle, para vigilância de defeitos congênitos) por dois códigos específicos (75640-OCD e 75650-Osteogenesis Imperfecta). Todos os casos nascidos entre 2000-2007 foram revisados e os diagnósticos finais foram escalonados em quatro níveis de evidência diagnóstica (NED), sendo o NED1 (padrão-ouro) casos com boas radiografias ou estudo molecular confirmando o diagnóstico. No período do estudo, 132 hospitais em 9 paises sul-americanos observaram 1.544.496 nascimentos. Todos os 51.827 controles nascidos no mesmo período foram utilizados para comparação. Excluídos 44 casos, a prevalência geral foi de 3,2/10.000 (IC95% 2,9-3,5) (492 casos em 1.544.496 nascimentos) e 33,6 (25,3-42,3) nos natimortos. Casos letais foram 50% (natimortos e óbito neonatal precoce). O diagnóstico foi referido como pré-natal na maioria dos casos (359-73%). Os grupos de OCD mais frequentes, segundo a classificação internacional, foram: G-1 (FGFR3) - 31%; G-25 (OI) - 23,5%; G-9 (CCP) - 4,5%; G-2 (Colágeno 2) - 4%; G-18 (Bent bones) - 4%. As prevalências das OCD mais comuns foram: OI - 0,74 (0,61-0,89); D. Tanatofórica - 0,47 (0,36-0,59); Acondroplasia - 0,44 (0,33-0,56); D. Campomélica - 0,10 (0,05-0,16). A taxa de mutação/gameta/geração para Acondroplasia foi 1,74 (1,25-2,25) x 10-5. Idade paterna, paridade e consanguinidade foram maiores nos casos que nos controles (31,2 anos X 28,9 anos; 2,6 X 2,3; 5,4% X 1,0%; P < 0,001). Idade materna elevada nos casos em relação aos controles (26,4 anos X 25,4 anos, P < 0,001) não foi confirmada por regressão logística considerando idades paterna e materna e paridade como fatores de risco para OCD (OR=1,63 para idade paterna > 39 anos; 0,79 para idade materna > 34 anos e 1,3 para paridade > 1). Peso e idade gestacional foram menores nos casos que nos controles (2498,1 g X 3198,6 g, P < 0,001), permanecendo a diferença para o peso após estratificação apenas para gestações de 31-35, 36-40 e 41-44 semanas (P<0,001, P<0,001 e P<0,05, respectivamente). A prevalência geral de 3,2/10.000 encontrada parece mais verossímil, sustentada por uma população numerosa e heterogênea, com grande diversidade étnica em sua composição, onde interrupções da gestação não são permitidas. Este estudo também observou uma alta taxa de diagnóstico pré-natal das OCD na AS e confirmou: a elevada morbi-mortalidade associada às OCD, a idade paterna elevada (especialmente nos casos de herança dominante) e altas taxas de consangüinidade nos casos de OCD (especialmente os de herança recessiva) e na população controle da AS
Abstract: Osteochondrodysplasias (OCD) are a heterogeneous group of genetic diseases that affect skeletal growth and development with a high infant morbid-mortality. Despite the great advances in prenatal diagnosis and knowledge of OCD molecular bases in the last twenty years, OCD diagnosis still relies upon anamnesis, clinical examination and skeletal X-rays. The currently accepted birth prevalence rate of OCD (2.0/10,000), based on few studies with small populations, is underestimated. This study aimed to assess OCD epidemiology in South America (SA) based on a large population of more than 1.5 million births. The OCD cases were ascertained from ECLAMC (a case-control, collaborative hospital-based program for birth defects surveillance) database through two specific codes (75640 for "generic" OCD and 75650 for Osteogenesis Imperfecta). All cases born from 2000 to 2007 were revised and final diagnoses ranked in four diagnostic evidence levels (DEL), being the DEL1 (gold-standard) those cases with good X-rays or DNA test supporting a certain diagnosis. During the 8-year period, 132 hospitals from nine South-American countries examined 1,544,496 births. For comparative analysis, all 51,827 controls born in the same period were used. After excluding 44 cases, overall OCD birth prevalence was 3.2 per 10,000 (95% CI 2.9-3.5) (492 cases per 1,544,496 births) and 33.6 (25.3-42.3) among stillbirths. Lethal cases (stillbirths plus early neonatal death) were 50%. Prenatal ultrasound diagnosis was referred in most cases (359 - 73%). The most frequent OCD groups, according to the international classification, were: G-1 (FGFR3) - 31%; G-25 (OI) - 23,5%; G-9 (SRP) - 4,5%; G-2 (Collagen 2) - 4% and G-18 (Bent bones) - 4%. The prevalence of the main OCD types were: OI - 0.74 (0.61-0.89); Thanatophoric D. - 0.47 (0.36-0.59); Achondroplasia - 0.44 (0.33-0.56); Campomelic D. - 0.10 (0.05-0.16). The mutation rate/gamete/generation for Achondroplasia was 1.74 (1.25-2.25) x 10-5. Paternal age, parity and consanguinity rate were significantly increased in cases compared to controls (31.2 years X 28.9 years; 2.6 X 2.3; 5.4% X 1.0%; P < 0.001). Increased maternal age in cases against controls' (26.4 years X 25.4 years, P < 0.001) was not confirmed by logistic regression including paternal age (OR=1.63 for paternal age > 39 years), parity (OR=1.3 for parity > 1) and maternal age (OR=0.79 for maternal age > 34 years) as risk factors for OCD. Birth weight and gestational age were lower in cases than in controls (2498.1 g X 3198.6 g, P < 0.001), and the difference for birth weight remained significant for gestational ages 31-35, 36-40 and 41-44 weeks after stratification (P < 0.001, P < 0.001 and P < 0.05, respectively). The OCD overall birth prevalence rate of 3.2 per 10,000 found seems more verisimilar, supported by a large and heterogeneous population with great ethnic diversity and without pregnancy terminations. This study also indicates a high rate of prenatal OCD diagnosis in SA and confirms: the high OCD-associated infant morbid-mortality, the increased paternal age (especially for cases with autosomal dominant inheritance) and the high parental consanguinity rates in both OCD cases (especially those with autosomal recessive inheritance) and in SA control population
Doutorado
Genetica Medica
Doutor em Ciências Médicas
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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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Wedin, Rikard. "Metastatic bone disease /." Stockholm, 2000. http://diss.kib.ki.se/2000/91-628-3829-6/.
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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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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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Poulet, Blandine. "Characterising a model for non-invasive loading of the murine joint : initial studies into the interplay between mechanical and genetic factors in osteoarthritis." Thesis, Royal Veterinary College (University of London), 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.558982.
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Sarrión, Pérez-Caballero Patricia. "Estudio genético de dos fenotipos óseos: osteocondromatosis múltiple y alta masa ósea." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/127188.
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Mi trabajo de tesis está compuesto por dos estudios diferenciados. Por un lado, el análisis molecular de la Osteocondromatosis Múltiple (MO) en pacientes españoles y latinoamericanos. El uso combinado de dos métodos complementarios en la búsqueda de mutaciones (detección de la dosis génica y análisis de la secuencia de ADN) ha permitido descubrir la causa de MO en el 95% de los pacientes españoles y en el 83% de los pacientes latinoamericanos analizados. Se han genotipado los exones y las regiones intrónicas flanqueantes de los genes causantes de la MO, EXT1 y EXT2, en 39 pacientes españoles y 27 latinoamericanos. Se ha identificado la mutación causal en 37 de los pacientes españoles, 29 en EXT1 y 8 en EXT2, 18 de las cuales no habían sido descritas previamente. Tras el análisis mutacional en los pacientes latinoamericanos se ha identificado la mutación causal en 18 de ellos. El análisis mediante MLPA ha permitido descubrir mutaciones de tipo mosaico y se ha confirmado que este tipo de mutaciones también pueden dar lugar a MO. También se ha realizado un estudio de la correlación genotipo-fenotipo en estos pacientes. Este estudio ha permitido determinar que los pacientes españoles con mutaciones missense tienen menor número de osteocondromas que los pacientes con otro tipo de mutaciones. En los pacientes latinoamericanos no se ha podido establecer ninguna correlación entre el grado de severidad de la MO y el gen mutado.
Por otra parte, mi tesis aborda el estudio genético molecular del fenotipo alta masa ósea (HBM) en probandos españolas. Se encontraron 13 casos con este fenotipo en los que se analizaron los exones relevantes del gen LRP5, descrito como causante de la HBM y de su inhibidor DKK1. No se encontraron mutaciones en las regiones analizadas del gen LRP5. En una probando con HBM se ha identificado un cambio missense en DKK1 (p.Y74F), no descrito previamente, que podría ser la causa del fenotipo. Se realizó un estudio de 55 loci autosómicos asociados con la densidad mineral ósea (DMO) para comprobar si las probandos tienen un mayor número de alelos protectores frente a la pérdida de masa ósea. En la mayoría de los casos de HBM estudiados, los niveles de DMO se distribuyen inversamente al número de alelos de riesgo de osteoporosis. El único caso en el que esto no se cumple es el que presenta el mayor valor de Z-score y su alta masa ósea podría explicarse por una variante genética rara y penetrante. Por otro lado, se pudo disponer de osteoblastos primarios de dos probandos con HBM y de 5 muestras control y se realizó un análisis transcriptómico de estas células para analizar la expresión diferencial de genes relevantes en el metabolismo óseo en este tipo celular. En el estudio de expresión en osteoblastos primarios se ha observado una correlación negativa entre el valor de Z-score y la expresión de IL6R, DLX3, TWIST1 y PPARG. Este estudio transcriptómico apunta a que tanto un aumento en los niveles de RUNX2 como una disminución en la cantidad de SOX6 podrían tener un papel en algunos casos de HBM. Teniendo en cuenta los resultados obtenidos, se propone un modelo de heterogeneidad genética para la HBM, en la que hay casos debidos a efectos pequeños y aditivos de diversos genes y otros causados principalmente por mutaciones en un único gen.There are two different studies that compose my thesis. The first one is a molecular analysis of multiple osteochondromas (MO) in Spanish and Latin American patients. MO is a genetically heterogeneous disease caused by mutations in two genes: EXT1 and EXT2. On sequencing all exons and flanking regions of those two genes in the samples of 39 unrelated patients, 37 pathogenic mutations were identified. Twenty-nine different mutations were found in the EXT1 gene, while 8 were found in EXT2. Eighteen out of the 37 mutations were novel. After the mutational analysis in Latin American patients the causative mutation in 18 of them has been identified. MLPA analysis has revealed mosaic mutations and it has been confirmed that such mutations can also lead to MO. Also a study of genotype-phenotype correlation in these patients was made. On the second one, my thesis addresses the molecular genetic study of high bone mass phenotype (HBM). Thirteen cases were found with this phenotype and the relevant exons of LRP5, described as HBM causative gene, and DKK1, that is LRP5 inhibitor, were sequenced. No mutations in the relevant exons of LRP5 were found. A rare missense change in DKK1 was found in one woman (p.Y74F). Fifty-five BMD SNPs were genotyped in the HBM cases to obtain risk scores for each individual. Z-scores were negatively correlated with these risk scores, with a single exception, which may be explained by a rare penetrant genetic variant. An expression analysis in primary osteoblasts from two HBM cases and five controls was carried out. It showed that IL6R, DLX3, TWIST1 and PPARG were negatively related to Z-score. One HBM case presented with high levels of RUNX2, while the other displayed very low SOX6. In conclusion, we provide evidence of heterogeneity and the additive effects of several genes for the HBM phenotype.
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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.
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Hauser, Barbara. "Mechanism of bone loss in rheumatic diseases." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/22823.
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Osteoporosis and fragility fractures are recognized complications of inflammatory rheumatic diseases. This is thought to result from the effects of chronic inflammation, relative immobility and corticosteroid use. A rare syndrome of osteoporosis in a patient with coeliac disease has been described which results from production of neutralizing antibodies to the bone protective protein osteoprotegerin (OPG). The aim of my thesis is to evaluate prevalence and clinical predictors of osteoporosis in a contemporary cohort of patients with rheumatoid arthritis (RA) and to investigate the role of OPG autoantibodies in the pathogenesis of osteoporosis in rheumatic diseases. In a retrospective cohort study, I found that the overall prevalence of osteoporosis in patients with RA was 29.9% which is in keeping with older reports that recorded a prevalence rate between 17% and 36%. In our contemporary cohort osteoporosis was significantly more common than in a gender and age matched control cohort (17.4%). Further analysis showed that only age and BMI were independent predictors of osteoporosis in RA. A predictive tool based on age and BMI was developed which had 91.4% sensitivity for the detection of osteoporosis in an independent RA population. I went on to screen for the presence of autoantibodies to OPG in patients with various rheumatic diseases. In a study of 75 patients with rheumatoid arthritis and 199 healthy controls OPG autoantibodies were detected in two controls (1%) compared with seven patients with RA (9.3%). The RA patients with detectable OPG antibodies had a longer disease duration, higher DAS28 scores and higher levels of the bone resorption marker CTX than RA patients who did not have autoantibodies. Purified IgG from patients with high levels of OPG antibodies blocked the ability of recombinant OPG to inhibit RANKL induced NFκB activation in a HEK293 cell based assay indicating that they were functional. In a further study of 134 patients with ankylosing spondylitis (AS), 16 patients (11.9%) had detectable OPG antibodies. The presence of OPG-Ab was independently associated with reduced hip bone mineral density and an increased risk of fractures in this population. In patients with a longer disease duration we have also observed that there was a higher discrepancy between spinal and hip BMD in OPG-Ab positive patients compared with OPG ab negative patients (p=0.003). In order to investigate if OPG antibodies affected measurement of serum RANKL concentrations as detected by ELISA using OPG as the capture reagent, I measured OPG ab and free RANKL concentrations in 55 rheumatic disease patients. Surprisingly there was a significant positive correlation between free RANKL and OPG Ab concentrations (r=0.430, p=0.001) which was the opposite to what I had expected. These findings reject the hypothesis that OPG ab block binding of synthetic OPG to RANKL in the ELISA. In conclusion, I have shown that osteoporosis is a common complication in RA and I have developed a new risk prediction tool for the use in clinical practice. I have also found that OPG antibodies are produced more commonly in patients with RA and AS than in healthy controls and that antibody levels correlate with bone resorption markers in RA and bone mineral density in AS patients. In vitro studies have shown that some OPG antibodies have functional effects on RANKL signalling. These findings raise the possibility that OPG antibodies may contribute to the pathogenesis of local and systemic bone loss in rheumatic diseases and signal the need to study the relationship between these antibodies and bone disease in large-scale longitudinal studies.
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蔡聰筎 and Chung-yue Choi. "Free radicals and bone marrow diseases: a potential role of nitric oxide in graft-versus-host disease after bonemarrow transplant." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2000. http://hub.hku.hk/bib/B31224222.
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Garazdiuk, O. I. "The role of bone disorders in chronic kidney disease and systemic connective tissue diseases progression, evaluation and therapeutic approaches." Thesis, БДМУ, 2021. http://dspace.bsmu.edu.ua:8080/xmlui/handle/123456789/18586.
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Ding, Hongliu. "Bone Health and Coronary Heart Disease in Postmenopausal Women with Breast Cancer Treated with Tamoxifen: A Dissertation." eScholarship@UMMS, 2008. https://escholarship.umassmed.edu/gsbs_diss/404.
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Breast cancer, osteoporosis, and coronary heart disease (CHD) are three major threats to women’s health. Postmenopausal women with breast cancer are also at high risk for osteoporosis and CHD. Adjuvant tamoxifen therapy is not only an effective treatment for breast cancer, but has been shown to have a beneficial effect on bone and the cardiovascular system. Although tamoxifen has been convincingly demonstrated to be able to preserve bone mineral density (BMD), an unexpected increase of risk of fractures in patients treated with tamoxifen has been reported. The findings of the association of tamoxifen and CHD from previous studies were either borderline or inconsistent. To clarify the discrepancy between BMD and fractures and test the potential beneficial effect of tamoxifen on CHD, I conducted a series of retrospective studies in postmenopausal women with breast cancer who participated in the Cancer Surveillance in HMO Administrative Data (IMPACT study) or the Study of Osteoporotic Fractures (SOF).
In patients who participated in the IMPACT study, I demonstrated that the association of tamoxifen and fracture incidence varied at different skeletal sites. Although the association of tamoxifen and fractures in the spine (HR=0.40, 95% CI: 0.09-1.85), wrist (HR=2.49, 95% CI: 0.88-7.06), and total body (HR=0.87, 95% CI: 0.49-1.55) was inconclusive, tamoxifen was associated with an apparent reduction of the risk of hip fracture (HR=0.41, 95% CI: 0.17-1.03, p=0.0565). Importantly, the pattern of observed association of tamoxifen with the risks of fractures among postmenopausal women with breast cancer is consistent with its widely reported preserving effect on bone mineral density.
Using SOF data, I found that the association between BMD and fractures in women with breast cancer varied at different skeletal sites, and type of BMD measured. Non-specific BMD was not associated with hip fracture (HR=1.12; 95% CI: 0.78, 1.59). Site-specific BMD was more likely linked with hip fracture (HR=1.43, 95% CI: 0.99, 2.08) while change in BMD did not predict hip fracture (HR=1.05; 95% CI: 0.63, 1.72). The association of spine morphometric fracture with either non-specific or spine-specific BMD was similar (OR=1.40; 95% CI: 1.04, 1.90; OR=1.35, 95% CI: 0.99, 1.85, respectively). Overall, the association of BMD and fracture in elderly women with breast cancer is weak. Only site-specific BMD appears to have a consistently modest association with fractures in the corresponding skeletal sites.
In the IMPACT study population, compared to patients without tamoxifen, the overall incidence of CHD in tamoxifen-treated patients was lower (adjusted HR=0.60, 95% CI: 0.40-0.88). For each year of tamoxifen use, there was a statistically significant decrease in the risk of CHD (HR=0.90, 95% CI: 0.82-0.98). Further analyses categorized by length of tamoxifen use showed that an apparent association with a decreased CHD risk was found in patients who received tamoxifen for two to five years (HR=0.54, 95% CI: 0.33-0.86). No association was detected after the discontinuation of tamoxifen therapy.
In summary, I detected a possible benefit associated with tamoxifen on fractures in the hip, the most common fracture site. I also found that BMD did not predict osteoporotic fractures well in postmenopausal women with breast cancer. In addition, I demonstrated that tamoxifen was associated with a reduced risk of CHD in postmenopausal women with breast cancer in a dose-dependent manner. An apparent benefit was found in those patients who received tamoxifen therapy for at least two years.
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Langford-Smith, Kia Jane. "Non-myeloablative bone marrow transplantation for Mucopolysaccharide diseases." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/nonmyeloablative-bone-marrow-transplantation-for-mucopolysaccharide-diseases(5d3fd9c5-01f2-42aa-81ed-a2ce6ef140fe).html.
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The Mucopolysaccharide (MPS) diseases are a group of lysosomal storage disorders, caused by a lack of the enzymes required for catabolism of glycosaminoglycans (GAGs), leading to severe neurological decline, skeletal deformities, organomegaly, cardiac and respiratory compromise, and premature death. The severe form of MPS I, Hurler syndrome, can be successfully treated using haematopoietic stem cell transplantation (HSCT), but the risks associated with myeloablation and immune suppression limit the broader application of HSCT to attenuated diseases. Successful engraftment in MPS I has been difficult to achieve, and requires fully myeloablative conditioning, whilst reduced intensity conditioning is a risk factor for graft rejection. Non-myeloablative conditioning generating reliable graft acceptance and high donor chimerism could increase safety and applicability of HSCT in genetic disease, therefore the aim of this research was to identify such a regimen in a clinically relevant mouse model of HSCT.Conditioning regimens developed in existing mouse models of HSCT have had limited clinical success, and often require clinically unachievable high cell doses or less stringent strain combinations to overcome allogeneic transplant rejection. To improve clinical relevance we used CBA donors and C57BL/6 recipients, which require full myeloablation with busulfan and immune suppression using non-depleting anti-CD4 and anti-CD8 monoclonal antibodies for engraftment of low cell doses across a major histocompatibility complex barrier. In syngeneic transplant donor chimerism was improved by generating a greater ratio of donor:recipient haematopoietic cells in the bone marrow initially, therefore we tested granulocyte colony stimulating factor (G-CSF), high cell dose and stem cell niche disruption and compared this to anti-CD40L costimulatory blockade in allogeneic transplant performed with a reduced dose of busulfan that was insufficient for graft acceptance. Despite improvements in initial engraftment with some of these treatments, only combined signal 1 and 2 T cell blockade were effective in reducing the dose of busulfan required for long-term graft acceptance. Early detection of MPS is important in treatment success; good disease biomarkers are vital, and biomarkers suitable for monitoring treatment outcome in MPS are lacking. We evaluated serum heparin cofactor II-thrombin (HCII-T) complex for MPS. We determined optimal sample collection and storage conditions, assay limitations and developed measurement in dried blood spots. Dermatan sulphate has a greater effect on in vivo HCII-T complex formation than heparan sulphate, thus in the MPS mouse models HCII-T is a reliable biomarker for MPS I, but not MPS IIIA or IIIB. HCII-T is greatly elevated in MPS I, II and VI patients, who all store dermatan sulphate, but it is also elevated by a small but significant amount in MPS III patients, who store heparan sulphate. HCII-T was also measured longitudinally in MPS I, II and VI patients, compared to an existing clinical biomarker, and validated against clinical outcomes to show that it is a good biomarker of short-term treatment outcomes and responds rapidly to perturbations in treatment. Finally, we determined whether an engraftment defect was observed in the MPS I mouse model, and show that this is present following both syngeneic and allogeneic HSCT. The effect of enzyme replacement therapy (ERT) and anti-inflammatory treatment prior to allogeneic HSCT was investigated, and initial results suggest that ERT, but not ibuprofen, may improve HSCT outcome. Overall, a clinically relevant mouse model of allogeneic HSCT has been developed and used to determine a non-myeloablative conditioning regimen that generates high levels of donor chimerism with a minimal dose of busulfan and blockade of both signal 1 and 2 of T cell activation. The conditions required to observe an engraftment defect in MPS I mice have also been defined, and preliminary studies have suggested that ERT, but not anti-inflammatory treatment, may overcome the engraftment defect in MPS I. Alongside this work, the HCII-T biomarker has been evaluated in MPS mouse models and patients, determining that it correlates well with short-term treatment outcomes. The techniques and models developed here will provide an excellent basis for further work in developing non-myeloablative conditioning for bone marrow transplant in MPS I.
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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.
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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.
Full textAbstract:
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.
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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.
Full textAbstract:
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.
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Laketic-Ljubojevic, Ira. "Glutamate signalling in bone cells." Thesis, University of York, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.311080.
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Reid, Carol Anne. "Texture analysis of bone mineralisation surfaces." Thesis, University of Glasgow, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.287800.
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