Failure of a primary hip arthroplasty is often caused by osteolysis which compromises the patient’s periprosthetic bone stock. Impaction allografting involves the use of morselized allograft bone and cement to stabilize the implant and restore this periprosthetic bone stock. Although clinical results of impaction allografting are favourable, regions of necrotic bone graft have been shown to exist for many years post-operatively and may ultimately lead to implant failure. Previous laboratory research has identified a correlation between mechanical stimuli and bone growth; therefore, the purpose of this study was to develop an in vivo device that would enable the investigation of the effect of mechanical load on bone graft incorporation in impacted allograft hip prostheses. An actuator was developed with a finite volume to enable its subcutaneous implantation along the tibia (20mm x 10mm x 10mm) and spine (35mm x 25mm x 15mm) in a rat bone chamber model. The actuator was designed to deliver a dynamic, (1Hz), compressive, (-6N), load that was controlled telemetrically throughout a 6-week long in vivo study. Independent validations of the mechanical actuator and the electrical control system were performed prior to an electromechanical validation of the integrated system. The responsiveness, quantity and magnitude of the load were investigated. The mechanical actuator was motor-driven and the electrical control system was based on radio frequency signal transmission. The electromechanical actuator conformed to the volumetric restrictions of the rat bone chamber model (tibia: 13mm x 17mm x 10mm; spine: 35mm x 30mm x 11mm). A wide range of operating frequencies (0.5 to 3.0 ± 0.05Hz) was achieved and a telemetrically controlled load was produced for 20 seconds per day throughout a simulated 6 week in vivo study. Due to inefficiencies of the mechanical actuator and voltage limitations of the control system, the magnitude of the compressive load produced by the actuator (-1.67 ± 0.10N) was less than specified by the design criteria. Future work to optimize the actuator design and fabrication is warranted in order to increase the maximum load magnitude; however, the current design provides a novel means to begin the investigation of the role of mechanical load on bone graft incorporation in impaction allografting.

The objective of this study was to examine the link between radiographic measures of bone quality and total knee implant migration as measured by radiostereometric analysis (RSA). Two uncemented total knee arthroplasty studies (n=65) with RSA and bone mineral density (BMD) exams up to two years post surgery, and one study with cemented total knees with one year RSA data (n=18) were examined. Radiograph image texture analysis was used to characterize the bone microarchitecture, and a feasibility study was conducted to determine if a given x-ray machine could be used to obtain bone mineral density at the same time as the RSA exams. Random ForestTM ensemble classification tree statistical models classified patients into groups based on implant migration with a range of cut-points. Models based on bone texture parameters measured from the two year radiographs had a sensitivity of 87.5% and specificity of 80% when classifying patients who had more than 0.3mm maximum total point motion (MTPM) at two years using the one year exam as reference. Other cut-points were examined, with models generally having a lower specificity if the acceptable migration was smaller, and lower sensitivity if higher migrations were tolerable. In a predictive model, post-operative bone texture could be used to create a model with a sensitivity of 75% and a specificity of 80% when predicting those subjects with cemented implants who went on to more than 0.4mm total migration by one year. Bone mineral density of the proximal tibia, as determined by clinical scanners, was not found to increase the accuracy of implant migration group classification. An empirical fit to central regions of a purposed-built cross-wedge calibration phantom returned residuals of less than ±1.5% for the bone-equivalent thicknesses. The coefficient of variation of the region greyscale values in three images spread over three days is under 4%, showing the stability of the system to hold a calibration between phantom exams and patient scans. Scatter and dynamic range issues will need to be considered for an accurate calibration across the full range of areal bone mineral densities in the distal femur and proximal tibia.

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In this study 12 acute myeloid leukaemia (AML) patients (3 in 1<SUP>st</SUP> complete remission (CR), 3 in 2<SUP>nd</SUP> CR, 3 in early relapse or partial remission and 3 in frank relapse) were treated with continuous infusion of recombinant Interleukin-2 (rIL-2). Adverse reactions among these patients were common. In all patients, there were evidence of lymphocyte activation with subsequent upregulation of the cellular cytotoxic functions following the infusion of rIL-2. Despite this, clinical response among patients treated with active disease remains disappointing, with only 1 patient achieving a 3<SUP>rd</SUP> complete remission after being treated in early 2<SUP>nd</SUP> relapse (marrow blast counts of 10%). The other patients had brief periods of stable disease but died eventually of disease progression. No conclusion however can be drawn from patients treated in complete remission due to the small number of patients entered into the study. In vitro studies were performed in a different cohort of AML patients, at presentation and during complete remission. In all the patients, both the Natural Killer (NK) and Lectin-Dependent Cellular Cytotoxicity (LDCC) activities were significantly reduced when compared to normal healthy controls. Patients in complete remission however had higher values than those studied during active diseases. These findings would suggest a strong rationale for the use of immunotherapy capable of upregulating the NK and LDCC activities, e.g. rIL-2. Further rationale for the use of immunotherapy has been drawn from the findings that leukaemia blast cells of AML are immunogenic, as evidenced by data of T cell activation in these patients and the presence of complement-fixing antibodies for autologous myeloblasts. More importantly no stimulation of the myeloblast proliferation by IL-2 was observed in any of the myeloblasts studied. All these findings would point to a good and safe rationale for the use of rIL-2 in AML patients.

No description available.

Osteocalcin, which is produced by the osteoblast, and the urinary pyridinium compounds (pyridinoline and deoxypyridinoline), which are derived from collagen, are widely used as markers of bone turnover. Osteocalcin was extracted from bone in 20% formic acid and separated using a linear 4-60% acetonitrile gradient containing 0.1% TFA at a flow rate of 1ml/min. The standard curve was linear up to 15 <I>μ</I>g of osteocalcin injected, with inter- and intra-assay coefficients of variation of 6.9 and 8.8% respectively while recovery of osteocalcin added to bone extracts averaged 102.7 ± 6.16 %. Having developed this assay it was then used in a series of experiments designed to study the biological function of osteocalcin in bone. Plasma osteocalcin levels decreased with age and showed large between-animal variations; the variability over 24 h was also large but there was no evidence of consistent circadian rhythm. In bone, changes in osteocalcin levels tended to parallel those for calcium whereas pyridinium crosslink levels tended to increase with age. Neither were sufficiently sensitive to detect differences in bone turnover in lambs of the same age but growing at different rates though osteocalcin levels in blood and in bone were sensitive to P-deficiency in sheep but not in pigs and there was little evidence indicating that osteocalcin plays any direct role in the mineralisation process. In separate studies adult sheep were treated with a bone antiresorptive agent, Ibandronate, and its effects on the metabolism and excretion of the pyridinium crosslinks was examined. At rates which have been shown to be effective in reducing bone resorption in humans this compound had little effect on the overall rate of excretion of these crosslinks in these sheep but did alter the proportions excreted in free or in peptide bound form.

The effects of the rate of distraction and of local infusion of IGF-1 upon bone deposition during mandibular distraction osteogenesis was studied in a rabbit model. Five groups of rabbits were studied. All rabbits, except sham operated controls, underwent distraction to 15 mm. The variables studied were the rate of distraction (0.5 mm twice a day versus 1.5 mm twice a day) and the effects of local IGF-1 infusion via osmotic infusion pumps. Analysis by DEXA scanning and three point bending 28 days after the end of distraction demonstrated no difference in density or strength of bone between the experimental groups. Histological examination demonstrated non-union across the distraction gap to be more common in rapidly distracted rabbits. Histomorphometric analysis demonstrated higher mineral apposition rates and less un-mineralised osteoid with slow as opposed to rapid distraction (p = 0.0001). Infusion of exogenous IGF-1 also resulted in a small increase in mineral apposition rate which was significant at slow but not a rapid distraction. Bone densitometry and three point bending results did not reveal any effect of distraction rate or IGF-1 infusion other than greater stiffness associated with IGF-1 infusion during rapid distraction (p = 0.01). It seems probable that the overwhelming stimulus to new bone formation produced by distraction renders the anabolic effects of IGF-1 less significant making it detectable by only the more sensitive analysis. This may be due to maximal stimulation of IGF-1 production by slow distraction thus rendering the administration of exogenous IGF-1 relatively superfluous. Rapid distraction may produce less stimulus to growth factor synthesis or the level of production maybe insufficient to cope with a higher requirement. The complete union of rapidly distracted rabbits who received exogenous IGF-1 may be as a result of levels being restored to optimal.

The Spl polymorphism of the Collagen I alpha 1 gene has previously been associated with low bone density and increased risk of fracture in a number of clinical studies. In chapter 3 the association with fracture was shown to be driven by the Spl polymorphism rather than other single nucleotide polymorphisms located in and around the collagen I alpha 1 gene. In chapter 4, the relationship between the Spl polymorphism and osteoporotic fracture was determined in a prospective population study of men and women. This study confirmed the association between "s" alleles and fracture and showed that COLIA1 genotyping interacted significantly with bone density measurements to enhance prediction of individuals at risk of osteoporotic fracture. In chapter 5, the "s" allele was found to be associated with body size in a population study of young adults. Although there was no association with BMD, individuals who carried the "s" allele were lighter at birth and this trend continued through adolescence and into young adulthood. This suggests that "s" individuals are at increased risk of osteoporosis from an early age, since body size is, in itself a risk factor for osteoporosis. In chapter 6, the effect of Spl alleles on quantitative ultrasound (QUS) was determined in a young post-menopausal population. It was found that there were no significant genotype related differences in broadband ultrasound attenuation (BUA). In chapter 7, family studies were conducted using the quantitative transmission disequilibrium test (qTDT). This showed evidence of a polygenic effect on BMD at the spine and hip and confirmed evidence of an association between Spl "s" alleles and BMD at the femoral neck. The data suggests that the previous associations of Spl alleles and BMD are genuine and not due to population admixture.