No description available.

No description available.

Since the acceptance of the Citric Acid Cycle as the major route of oxidation in almost all tissues, considerable interest has been focussed on the control of this most fundamental metabolic pathway. This thesis describes studies carried out to investigate the control of the Citric Acid Cycle in heart muscle, using a computer simulation model of the pathway. The simulation technique used was that known as CHEK. This is a program designed for digital computer simulation which is not only rapid and easy to handle, but also allows the simulation of a large number of chemical reactions such as those describing a complex metabolic pathway. The simulation model of the Citric Acid Cycle was constructed by formulating models of each of tne component enzymes of the Cycle from information available in the literature and joining these together. Published values for the concentrations of enzymes, coenzymes and intermediates, and ratios of the various forms of the coenzymes were also used. To assess the control features of the Cyclic enzymes in the simulation studies, the concepts of Sensitivity (control strength) and Elasticity (effector strength) were employed.

No description available.

Three attempts at developing a radioimmunoassay for prostaglandin E were made. Two of these attempts resulted in the production of anti-sera directed mainly to prostaglandin B. The third attempt was designed to produce anti-sera specfic to prostaglandin F, a prostaglandin readily formed from prostaglandin E by reduction with sodium borohydride. The influence of age, sex and hormonal state have been studied with reference to the reduction of prostaglandin E to prostaglandin F by the enzyme systems present in sheep blood and liver samples from chicken, rabbit and guinea-pig. Ovarian steroid hormones have been found to influence the enzyme activity and preliminary evidence would suggest a link between these hormones and prostaglandin metabolism.

No description available.

Since the early 1900's, many investigators have studied the effects of pituitary ablation and the mode of action of the hypophyseal hormones. Initially, work was mainly directed towards the purification and bioassay of the various hormones, although the effects of hormone administration were also studied. Recently, attempts have been made to synthesise some of the hormones. The aim of this thesis is to describe a series of studies undertaken in an attempt to develop new assay methods for growth hormone and the gonadotropins and the application of these procedures. (89) An investigation of the bioassay for growth hormone depending on the increase in tibial epiphyseal cartilage width in immature hypophysectomised rats has shown that the method is not specific and is of low sensitivity. The procedure has been used to compare the potency of pituitary extracts from different species and to provide a measure of the effect on body growth and on cartilage width of two synthetic compounds and of nerve section. A dithiocarbamoylhydrazine derivative, Compound 33» 828 (I.C.I.) was found to have a markedly inhibitory effect on general body growth and cartilage width, possibly due to the toxicity of the compound. A synthetic polypeptide, Ciba 50920-Ba which is claimed to have an adrenocorticotrophic hormone-like action on the adrenal, had no marked effect on cartilage growth. It has also been shown that the artificial induction of muscular atrophy in young rats by section of the sciatic nerve did not interfere with cartilage growth and that the administration of pituitary hormones to animals treated in this way was without effect. (166) A haemagglutination-inhibition method has been developed for the assay of growth hormone and has proved to be sensitive and highly specific. When estimates of the growth hormone potency of standard pituitary preparations were made by both the bioassay described above and the immunological method, similar results were obtained. The immunological procedure was, however, found not to be sufficiently sensitive for clinical application. A latex particle agglutination-inhibition method for the quantitative determination of human chorionic gonadotrophin has also been developed. This again proved to be unsuitable for clinical application. (88) The pyruvic acid oontent of the immature rat ovary, both prior to and following gonadotrophic stimulation, was estimated by two different methods. A marked rise in pyruvic acid was noted following initial stimulation with pregnant mare serum gonadotrophin, but this rapidly fell to a low level which could not be altered by further gonadotrophic stimulation. The relationship between pyruvic acid and gonadotrophic stimulation is discussed. (65) The studies reported in this thesis have shown that the methods available for the quantitative determination of growth hormone and gonadotrophins axe not entirely satisfactory because of poor sensitivity or lack of specificity. However, despite these limitations, useful information can be obtained by these procedures although it is clear that they are not suitable for clinical application. The development of more sensitive and specific methods for the estimation of these hormones is therefore necessary and it is suggested that future work in this field should be directed towards this end.

Distribution of the antiplasmins is human plasma fractions has been re-investigated, and in addition to the α1 and α2 globulin antiplasmins, a high inhibitory activity was demonstrated in the β-lipoprotein fraction, Cohn Fraction III-O. Ejeperiaents with Fraction 111-0 and norsal seroa established that this antiplasoin was associated with the main β -lipoprotein component. In certain clinieal conditions where the lipoprotein and antiplasmin levels are raised it has been shown that the increase is due to the β -lipoprotein antiplasmin and not to the α antiplasmins. This observation has been correlated with the current theories concerning the aetiology of atherosclerosis.

No description available.

Gallstones are a common clinical problem associated with significant morbidity and mortality whether managed conservatively or by surgery. Since a sizeable proportion of the resources of the community is spent dealing with the clinical sequelae of these stones, much interest has been focused on their pathogenesis. This has been stimulated over the last ten years by improvements in methodology and, perhaps more importantly, by new concepts from physical chemistry. Gallstones, in the western hemisphere, consist of crystalline cholesterol or salts of calcium including the carbonate, phosphate, bilirubinate and palmitate, or a combination of these. A significant minority (20 - 40%) contain micro-organisms. The species involved have, however, changed over the years and, within the recent past, actinomycetes have been isolated. Early theories of gallstone pathogenesis are discussed in relation to the currently accepted ideas on the importance of the cholesterol-solubilising system in bile. The cascade of data on this aspect of stone formation is contrasted with the lack of information on either the solubilising system for, or solubility properties of, the calcium salts in bile. The work described here aims to fill part of this hiatus. The calcium-binding system in bile was analysed from two viewpoints. Initial studies showed that a substantial proportion (60 - 80%) of the calcium in hepatic and gallbladder bile would not pass through an ultrafiltration membrane with a molecular weight cut-off = 1,000. It seemed, therefore, that much of the calcium in bile was chemically bound to species retained by the filter. Subsequent studies dealt systematically with the potential contribution to the calcium-binding system of each major class of molecule in bile, namely, lipids, proteins, polysaccharides, and molecules with molecular weights less than 1,000. In hepatic bile, micelles of bile salt and lecithin could account for 78% of the calcium bound. This contrasted with gallbladder bile in which micelles accounted for only 50% of the detectable calcium binding. However, proteins and acidic polysaccharides were capable of binding substantial quantities of calcium in gallbladder bile. The low molecular weight fraction (less than 1,000 M.W.) accounted for significant quantities of bound calcium in both hepatic and gallbladder bile (12 - 18% of the total). These molecular species all have a role to play in calcium binding in bile under physiological or pathological conditions because it was demonstrated firstly, that calcium binding in bile was reversible and secondly that the affinity of each of these species for calcium was roughly similar. This was performed by quantitative binding studies which also showed that there was a large reserve of calcium-binding sites. Interestingly, several of the species which bound calcium in soluble form, under certain circumstances also formed insoluble deposits. The methods and results are discussed in relation to data in the field. The various weaknesses of the analytical techniques are highlighted in order to emphasise the difficulties which still exist in working with bile despite the recent advances in methodology. The manner in which the choice of techniques used to study calcium binding was dictated by the affinity of binding is described. The broader implications of calcium binding in bile in terms of movement of bile from hepatic duct to gall¬ bladder, of diurnal variations in the composition of bile, and of changes in the serum calcium concentration, are outlined. It is shown that those inorganic salts of calcium commonly found in gallstones, in all probability, exist in supersaturated conditions in bile. The calciumbinding system therefore seems to behave in this respect not unlike the cholesterol-solubilising system in bile. Finally, an hypothesis is offered to account for the distribution of calcium between the various binding species involved and the ionised form. The potential for precipitation of many of these components is indicated and the possible relevance of precipitation of calcium complexes to gallstone nucleation is discussed.