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The University of Oxford and St Hilda's College are delighted to announce the creation of a new Chair of Clinical Therapeutics thanks to initial, generous, philanthropic support from Professor John Climax. The donation was confirmed at a signing ceremony on Friday 15th December 2017.
Skeletal blood flow measured with 18F in patients with osteomalacia and hyperparathyroidism.
Blood flow to bone was measured using the 18F clearance method described by Wootton et al. (1976) in osteomalacia (nine cases) and primary hyperparathyroidism (eight cases). Bone blood flow was elevated above normal in the osteomalacia group and was normal in the hyperparathyroid group (range 3.6%-6.8% blood volume/min). It is suggested that bone blood flow is linked with the osteoblastic response of bone, and remains normal in cases of hyperparathyroidism when no clinical signs of bone involvement are present.
Changes in plasma calcium and in radiocalcium kinetics after termination of 5-week infusions of synthetic parathyroid peptide in dogs.
Nine dogs were infused at constant rates with the synthetic parathyroid peptide hPTH 1-34 (initially sc) to produce consistent hypercalcaemia. Over the final week, the infusions were iv. Radioisotopic tracers were injected iv 30 days (5 dogs) and 2 days (9 dogs) before the infusions were suddenly terminated. In 5 dogs, complete urine collections were obtained via a bladder catheter over 8 h beginning 2 h before stopping the infusions. Cessation of treatment caused small rises in the urinary Ca: creatinine ratio. Plasma calcium levels fell by a mean of 0.44 mmol/l, of which total urine calcium excretion only accounted for 55%. Immediately after the PTH infusions were stopped, consistent but transient increases were seen in the ratio of 'new' 47Ca to 'old' 45Ca label, suggesting inflow of 40Ca of high 47Ca specific activity from a fairly rapidly exchangeable bone pool. These data confirm and extend previous evidence that the immediate response of the calcium equilibrium between bone and bloodstream to rapid changes in plasma PTH concentrations in the supra-physiological range is paradoxical relative to the classical later response.
Peripheral and axial measurements of trabecular bone density in patients suspected of idiopathic vertebral osteoporosis.
In 18 patients with idiopathic crush fracture syndrome, iliac trabecular bone volume measured in 8 mm trephine biopsies correlated well with trabecular bone density as estimated in low thoracic or high lumbar vertebrae by computed tomography (CT). The CT of trabecular bone in the radius correlated poorly with the other two measurements, but it discriminated fairly well between patients and age-matched controls. These results suggest that abnormally low trabecular bone density values in the radius may be useful in predicting some patients at risk for crush fractures, but ranking patients in order of severity of axial bone loss after they have acquired a fracture requires measurements on the spine or iliac crest.
Effects of two treatment regimes with synthetic human parathyroid hormone fragment on bone formation and the tissue balance of trabecular bone in greyhounds.
The adult greyhound was found to be similar to adult man with respect to kinetic and histomorphometric indices of calcium metabolism. The relationship between trabecular bone tissue balance and the pattern of human PTH fragment 1-34 (hPTH 1-34) administration by daily injections or continuous sc infusions was investigated in this model and the results compared to those from a clinical trial of hPTH 1-34 in involutional osteoporosis (peptide administration by single daily injections). In the dogs, the daily injection regime elevated plasma levels of immunoreactive hPTH 1-34 for no more than 4 h/day. The greyhounds so treated showed significantly increased indices of bone formation (surface osteoid, plasma alkaline phosphatase activity, and skeletal accretion rate of calcium) and resorption (number of osteoclasts, resorption surfaces). Iliac trabecular bone volume increased significantly, as it did in the patients. The infusions did not significantly increase the trabecular bone volume or the 47Ca accretion rate, two parameters which increased in parallel in dogs and patients treated successfully by daily injections. The osteoclastic surfaces, however, were clearly increased by continuous infusions, while the increases in the osteoblastic surfaces were less statistically significant. Since hPTH 1-34 may inhibit osteogenesis in Friedenstein chambers, it is possible that the increased osteoblastic activity induced by the daily injection regime in trabecular bone is dependent on the noncontinuous nature of the PTH stimulus.
Regional bone density measurements compared to total body calcium in osteoporosis.
In 21 women with crush fracture osteoporosis quantities related to trabecular bone density in lumbar vertebrae and in the distal radius were significantly correlated (r = 0.50, P less than 0.05). When the group was enlarged to include data from other patients without osteoporosis, a higher coefficient of correlation was obtained (r = 0.69, P less than 0.001). Total body calcium, measured by in vivo neutron activation analysis, was significantly correlated to quantities related to cortical bone mass in the radius and femur. Thus, these quantities could be used to make estimates of total body calcium in osteoporotic patients. There was no significant correlation between total body calcium and quantities related to trabecular bone density, measured by computed tomography, in vertebrae or in the distal radius.
Rates of new bone formation in patients with crush fracture osteoporosis.
1. Calcium balances and formation rates of new bone measured with an improved tracer technique using 85Sr have been determined simultaneously in 21 patients with idiopathic osteoporosis and vertebral crush fractures. 2. A weak positive association was found between calcium balance and the kinetically measured calcium accretion rate, which is the sum of the true rate of bone formation and various long-term exchange processes. 3. The more negative balances were associated with significantly greater early loss of tracer taken up into bone by 'accretion', so that long-term (greater than 200 day) uptake was reduced. 4. This indicates that patients actively losing bone mineral have lower true rates of bone formation and higher rates of long-term exchange than their fellow patients who are more nearly in calcium equilibrium. 5. No statistically significant association was found between measured rates of bone resorption and calcium balance.
Interpretation of tracer studies on plasma protein turnover: comparison of methods and optimization of techniques.
1. A comparison of several published methods for analysing plasma protein turnover data has been undertaken, with particular reference to rapidly metabolized proteins such as members of the complement series. 2. With the exception of the equilibrium time method, most methods proved adequate for the determination of overall fractional catabolic rates. A further exception is that the renal clearance method becomes invalid when the fractional catabolic rate approaches the renal iodide clearance, but this may be the method of choice for slowly metabolized proteins if accurate urine collections can be ensured. 3. For the measurement of the ratio of extra to intra-vascular protein pool size a clear preference emerged for the method of C. M. E. Matthews (1957, Physics in Medicine and Biology, 2, 36-53). For rapidly metabolized proteins the calculations must be preceded by a correction for the non-protein bound iodide retained in the intra- and extra-vascular spaces. 4. The accurate calculation of fractional catabolic rate in the extravascular pool generally requires more experimental data than are commonly collected as well as an accurate correction for non-protein bound label that remains unexcreted. Only two techniques hold promise of accurate results: Nosslin's rate equations method and a development of Vitek's deconvolution method described herein. Nosslin's integrated rate equations method is particularly affected by systematic errors in renal iodide clearance estimates and should probably not be further used for this purpose.
Steady state relations between control proteins regulating the formation of the alternative pathway C3 convertase.
A steady state algebraic Mass Action analysis of the factors controlling the concentration of the alternative pathway C3 convertase is presented. The positive feedback loop does not make this portion of the complement system insensitive to variation in control protein concentrations; on the contrary, a hyperbolic relationship is revealed between C3 convertase and a complex product of the control protein concentrations which contains some mathematical non-linearities. The consequences of this relationship are explored. It is found that variations in the concentration of any one control protein will have an effect which can only be predicted if its initial concentration and those of the other control proteins are known. The system is capable of responding with a considerable range of amplitudes to a given signal which raises the question as to whether the feedback loop confers biological advantage, not only by augmenting the activation of C3 to C3b, but through its potential for flexibility in responding to an activating stimulus. The analysis may also prove useful in the design and evaluation of experiments to determine the reaction rate constants governing the interactions between the control proteins in the fluid phase in vitro.