Observations in man and animals on the distribution and excretion of sodium and potassium

The work described in the papers submitted was begun in 1950 when radioactive isotopes of sodium and potassium first became available for biological research. The initial investigations were made with ²⁴Na and methods were developed leading to the measurement of the amount of sodium in the human body that was free to exchange with the isotope. This afforded a means of ascertaining the amount of metabolically active sodium in the body and is commonly referred to as "exchangeable sodium" or Naₑ. During the course of this work it was found that there was a large amount of sodium in bone but that about 75 per cent was not available for exchange. This was confirmed by the use of the long half-life isotope ²²Na. The significance of the large amount of sodium in bone could not be investigated in man but studies in rats under various experimental conditions showed that in states of acute depletion sodium was withdrawn from the bones especially in young animals . This work demonstrated that ²²Na is not safe for use in man as a small amount may be retained in bone for a long period.The amount of exchangeable potassium in the body can likewise be measured with the isotope ⁴²K. Practically all the potassium in animals was available for exchange. When exchangeable sodium and potassium are measured simultaneously, as is often required, special techniques must be developed because the half lives of the isotopes ²⁴Na and ⁴²K (15.0 and 12.3 hours) are close. The introduction of tetraphenyl boron proved extremely satisfactory for the separation of potassium from sodium in biological fluids. Rubidium was thought to have a similar distribution to potassium in the body but investigations with the isotope ⁸⁶Rb showed that it was not a reliable alternative to ⁴²K.Previous to the use of sodium and potassium radioisotopes the only way to study the metabolism of these electrolytes in the human body was by cumulative metabolic balance methods. In long term investigations this is extremely laborious. However, measurements of Naₑ, and Kₑ at intervals can demonstrate cumulative changes, are simpler and less time consuming, and gave results in good agreement with the balance method. Furthermore, the isotope techniques yielded a measure of the amounts of sodium and potassium in the body . The potassium content of the body was related to the lean tissue mass; in comparison with healthy males the amount of potassium was reduced in females and in those with wasting diseases. In chronic disease there was an increase in the proportion of sodium in the body and this was seen to the greatest extent in oederenatous states.Characteristic changes in sodium and potassium metabolism take place after the infliction of an injury or a surgical operation (12, 13). These consisted in a retention of sodium and an enhanced excretion of potassium lasting over a few days. These changes are probably related to the levels of adrenocortical hormones in the blood as trauma increases adrenal secretion, but this response was detected in patients undergoing bilateral adrenalectomy and in patients with Addison's disease (adrenal insufficiency) given a constant exogenous supply of adrenal steroids during an operation. It is now known that the blood levels are elevated by surgical operation even in these circumstances as the metabolism and excretion of the steroids are delayed.Electrolyte metabolism may be deranged in thyroid disorders and accordingly measurements were made of exchangeable sodium and potassium in hypothyroidism and hyperthyroidism before and after treatment. Treatment of hypothyroidism with thyroxine led to a decrease in both Naₑ and Kₑ due probably to a loss of myxoedematous tissue. Successful therapy of hyperthyroidism was associated with an increase in Kₑ due to restoration of lost muscular tissue. Changes in Naₑ were variable and not readily interpreted. In some patients there was little change but in many there was a moderate decrease in Naₑ on return to health. Decalcification of the skeleton may occasionally occur in hyperthyroidism and it was considered possible that some of the difficulties in interpretation of Naₑ changes might be due to alteration in bone sodium content. However, experimental studies in rats given large doses of thyroxine did not demonstrate any effects on bone sodium metabolism. A mild degree of cardiac failure occurs in many thyrotoxic patients and the decrease in Naₑ is probably related to a loss of a small amount of latent oedema. This has been confirmed in subsequent unpublished observations.A similar pattern of changes in body electrolyte composition, namely an excess of sodium and a loss of potassium, has already been noted in cardiac patients . It was particularly evident in patients with severe mitral stenosis and after successful surgical treatment serial measurements showed a gradual restoration of the body composition towards normal. A delay in the excretion of ingested sodium is a recognised early feature of congestive cardiac failure and it was thought that this might be related to the increased sodium content of the body. This was investigated in dogs with experimental valvular lesions of the heart. Considerable changes in the ability to excrete sodium developed without any gross alterations in the amount of exchangeable sodium in the body. The reduction in sodium excretion rate could not be attributed to the dilution of infused sodium in an expanded body sodium pool. The abnormality was apparently due to a direct effect of the cardiac lesions on renal function.The introduction of chlorothiazide, an effective oral diuretic, constituted a considerable advance in aiding the excretion of the excess of sodium present in cardiac failure. However, chlorothiazide often caused a considerable excretion of potassium as well as sodium which is particularly disadvantageous in the depleted cardiac patient. This potassium loss was attributed to the carbonic anhydrase inhibitor activity of chlorothiazide. However, a later derivative, hydroflumethiazide, which was a negligible carbonic anhydrase inhibitor, nevertheless under certain circumstances caused a marked loss of potassium. The liability to lose potassium was thought not to be related so much to the choice of the thiazide diuretic as to the circumstances under which it was given. This hypothesis was tested experimentally in normal men and it was demonstrated that the extent of potassium loss following the administration of a thiazide diuretic was related to adrenal mineralocorticoid activity. Excessive potassium loss may be prevented by giving an aldosterone antagonist. Triamterene, a recently introduced oral diuretic enhances sodium excretion but depresses potassium excretion; this was probably due to a direct action on the distal renal tubule. It may be used in conjunction with a thiazide and together they may promote a large sodium diuresis without excessive potassium loss. This recent work on the action of diuretics in relation to the excretion of sodium and potassium has been reviewed in the Bradshaw lecture

Immunohistological Observations on Foetal Pancreas and Isolated Pancreatic Islet Transplantation in Rats

Although it is now rare for a patient to succumb to the acute metabolic derangements of diabetes mellitus, diabetic patients still have a reduced life expectancy and many develop disabling complications. The balance of the available evidence suggests that near-physiological control of glucose metabolism at an early stage in the disease would prevent many of the microangiopathic and neuropathic changes otherwise seen. At present, whole organ or segmental pancreatic transplantation offers the most physiological system of insulin administration available, but the hope for the future is that isolated islet or foetal pancreas transplantation will become a clinical reality. As well as requiring only a relatively minor procedure for effective transplantation, an advantage that isolated islets and foetal pancreas have over whole organ or segmental pancreas grafts is the ability to survive in vitro allowing storage and a potential opportunity for immunomodulation. Immunomodulation prior to transplantation aims to reduce immunogenicity by altering the antigen content of a graft. Following the realisation of the particular importance of MHC class II positive cells in antigen presentation, much attention has been focussed on methods of removing these cells. Although foetal tissues generally express much lower levels of MHC antigens than adult organs, rat foetal pancreas allografts are rapidly rejected and immunomodulation of this tissue has been particularly difficult to achieve. Experiments described in this thesis confirm the low levels of MHC antigen expression in the freshly isolated rat foetal pancreas. However, removal from the foetal environment resulted in an increased antigen expression in foetal pancreas maintained in tissue culture and stimulation with interferon-gamma (IFN-gamma) demonstrated the ability of the foetal pancreas to synthesise and express MHC antigens. DA foetal pancreas, which is rapidly rejected when transplanted to the renal subcapsular site of PVG recipients, responded to allografting by demonstrating a marked increase in MHC class I antigen expression on all cell types. This increased class I expression included exocrine cells which had been shown to remain negative in isografts. In allografts, MHC class II antigens were expressed de novo on duct epithelium and exocrine cells whilst endocrine cells remained resistant to the induction of class II expression. Isograft class II expression was unchanged. Class II expression on exocrine cells and duct epithelium (which are absent in purified islet preparations) would be of importance if these cells were then able to function as antigen presenting cells and this could provide one possible explanation for the comparative resistance of foetal pancreas to immunomodulation. The function of foetal pancreas transplants can be affected by factors other than graft rejection and serial immunohistological examination offers an alternative method of graft assessment. Using this technique, Cyclosporin A treatment was found to prolong the survival of DA allografts in PVG and Lewis recipients, although subsequent discontinuation of Cyclosporin A was followed by rapid rejection. Cyclosporin A was also found to have a profound effect on the antigen expression of foetal pancreas allografts with the pattern of expression coming to resemble that of the isograft. In addition, both the magnitude and phenotype of the cellular infiltrate was also affected. Induction of antigen expression on the cells of rejecting allografts is probably a consequence of the local release of lymphokines and may precede any evidence of cellular damage by several days. Supportive evidence for a local release of lymphokine was provided by the observed increase in antigen expression on the allograft recipient's renal tubular cells adjacent to the transplanted foetal pancreas. This induced expression on renal tubular cells occurred only when rejection was present and although some evidence of a very limited graft-versus-host reaction was seen in parent strain to F1 transplant experiments, renal tubular-antigen induction appeared to be a consequence of the local release of lymphokine rather than as a result of graft-versus-host-mediated damage to the recipient's renal tubules. Evidence that IFN-gamma represented a possible candidate as a lymphokine of particular importance in the induction of antigen expression was provided by observing a pattern of changes in the pancreas glands of adult rats given systemic IFN-gamma which was similar to that seen in allografted foetal pancreas. (Abstract shortened by ProQuest.)

The Saskatchewan Environmental Code: A Provincial Approach for Managing GHGs Emissions

AbstractThis paper provides a broad description of the Saskatchewan Environmental Code (SEC), its purposes, and potential implications for the provincial energy and environmental sectors.We start with an introduction to the framework of the Saskatchewan Environmental Code, followed by a discussion of the Results-Based Regulations (RBR) and the differences between RBR and the more traditional Prescriptive-Based Regulations (PBR). Next, we summarize the 19 chapters grouped in the five divisions of the SEC and finish with a brief description of the public review and future tasks for the full development of the SEC.The new Saskatchewan Environmental Code is key component of the Ministry's move to a Results- Based Regulatory model which will enhance environmental protection while encouraging innovation. The new model represents a significant shift away from prescriptive legislation and regulations to a focus on holding proponents accountable for achieving desirable environmental outcomes