Biomedical subjects
Publications and source records attributed to C Davies.
The increasing refinement of artificial anti-incontinence devices has provided new hope for incontinent patients. The aim of this paper is to show the design and function, and to indicate the use of radiology in evaluation of function, of the latest prostheses. The complications peculiar to these devices are illustrated and the use of radiology in identifying these complications is indicated.
Magnetic monodisperse polymer particles were developed and the necessary conditions established to use them for both quantification and fractionation of human peripheral blood mononuclear cell populations. The particles consist of a styrene divinylbenzene core into which magnetite has been deposited by an in situ oxidation process. Thereafter the core has been coated with a hydrophilic polymer containing epoxy and hydroxyl groups. The particles have strong nonspecific binding capacity for protein and can be coated with the appropriate antibodies by physical adsorption only. However, the hydroxyl groups on the outer polymer also make covalent coupling possible. After appropriate blocking they can be used in a rosette assay for quantification of mononuclear leukocytes previously sensitized with monoclonal antibodies. Furthermore, a suitable magnet makes it possible to deplete the cell suspension efficiently of the rosette-forming cells. We have thoroughly investigated the functional properties of human mononuclear cells depleted of T lymphocytes by this technique. Our results show that T cells are virtually completely eliminated, as demonstrated by flow cytometry and various functional assay systems.
The effect of gamma interferon (IFN-gamma) on proliferation and antigenic characteristics of cell lines belonging to the B-cell progenitor compartment was studied. We observed a selective effect of recombinant IFN-gamma but not IFN-alpha on proliferation of the B-precursor cell lines Reh and KM3. On day 4, after addition of 400 mu/ml IFN-gamma the [3H]thymidine uptake in these cells was reduced to 60% and 45% respectively, while no effect of IFN-gamma was evident on the proliferation of the more mature B-cell lines Raji, Ramos, B85, and Daudi. On the other hand, both Reh and Ramos showed induction of major histocompatibility complex (MHC) class I antigen expression in response to 400 mu/ml IFN-gamma. In contrast to 12-O-tetradecanoyl-phorbol-13-acetate (TPA), IFN-gamma did not induce increased MHC class II antigen expression on Reh cells. Taken together, our results indicate that IFN-gamma fulfils distinct functions at different levels in the development of B cells.
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The stability of expression of a membrane antigen on human FME melanoma cells was investigated by means of flow cytometric cell sorting and analysis. The melanoma-associated 250 kd antigen was strongly expressed on all cells, as recognized by binding of the monoclonal antibody 9.2.27. By flow cytometric cell sorting, cells of high and low antigen expression were isolated, and the difference in antigen expression between the two populations was examined as a function of time in culture. Immediately after sorting, the median fluorescence intensities of the two populations differed by a factor of 2.7. After the first few days in culture, much of the range in antigen expression of the parent population was regenerated. However, a lasting difference in antigen expression was established, corresponding to 50% higher density of antigen on the cells sorted for high fluorescence intensity, compared to those sorted for low intensity. After trypsin treatment, which removed the antigen from the cell surface, normal antigen expression was regained after 2-3 days in culture, with the same difference between the two populations as before the trypsin treatment. The stability of the established difference in antigen expression between the two sorted subpopulations indicates that expression of this antigen is a precisely controlled, heritable characteristic of the FME melanoma cells.
Glutathione transferases are believed to play an important protective role in the various tissues of animals and man by catalysing the glutathione conjugation of electrophilic drugs and electrophilic drug metabolites. Many of these compounds have the potential to react with vital cellular macromolecules in the absence of this enzyme system. We have investigated the interaction of a number of high ceiling diuretics with the glutathione transferases contained in the cytosolic fraction of the rat liver. Of bumetanide, ethacrynic acid, furosemide, indacrynic acid and tienilic acid, only ethacrynic acid was conjugated with glutathione. Further experiments revealed that ethacrynic, indacrynic and tienilic acids are all potent inhibitors of glutathione S- aryltransferase . Glutathione S- alkyltransferase and glutathione S-epoxide transferase were also inhibited by the diuretics, but to a lesser extent than glutathione S- aryltransferase . The diuretics giving the greatest inhibition of these reactions were chemically related to ethacrynic acid. The concept where inhibition of glutathione-S-transferase by a drug may enhance its own toxicity is considered. This mechanism has also the potential of enhancing the toxicity of other concurrently administered drugs which normally require glutathione S-transferase for detoxication.
Centrally acting drugs often act 'biphasically', especially on animal locomotor activities: the same drug stimulates and depresses, depending either on dose or on time since administration. We propose a third, hitherto neglected, type of biphasic effect, well illustrated by chlordiazepoxide, which depends, instead, on the length of time an animal is exposed to a test environment: in an unfamiliar Y-maze, rats' spontaneous locomotion (number of entries into the arms of the Y) was stimulated to begin with, but switched to depression in a few minutes. The stimulant phase appeared to be independent of dose, while the depressant phase showed log linear dose dependence.
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The expression of a melanoma-associated antigen, recognized by the monoclonal antibody 9.2.27, has been studied in the human FME melanoma cell line, grown as a monolayer under various conditions in vitro and as tumours in athymic mice. Two-parameter flow cytometric measurements of DNA and immunofluorescence showed that the antigen expression was uniform throughout the cell cycle. Highest expression of the melanoma-associated antigen was found in cultures in which the medium was frequently renewed (4 times in 6 days) and no contact inhibition was present. In comparison, the antigen expression of cells subjected to medium starvation (6 days without medium renewal) was reduced to 44%, and the cell size, as measured by forward angle light scatter, to 82% of the values found for optimally growing cells. Intermediate conditions, such as scanty medium supply or contact inhibition of growth, gave smaller effects. Two-parameter measurements of cell size and immunofluorescence demonstrated a positive correlation between cell size and antigen expression. The reduction in cell size, therefore, could explain part, but not all, of the reduction in antigen expression on medium-starved and contact-inhibited cells. The antigen expression on FME cells grown as xenografts in athymic mice varied between individual tumours and was lower than on cells from optimal in vitro growth. Due to smaller cell size, the antigen density was, however, comparable to that on cells from optimal in vitro growth.
In order to study blood pressure variability we have measured blood pressure, heart rate, plasma noradrenaline and adrenaline concentration and plasma renin activity during sleep and during the waking process in 20 subjects with borderline hypertension. The responses to a number of standardized tests were also measured. These were reading, mental arithmetic, change in posture, physical exercise and the response to intravenously injected phenylephrine and noradrenaline. The sensitivity of the baroreflex for heart rate control was also determined from the relationship between heart period (R-R interval) and change in systolic pressure after the injection of phenylephrine. Blood pressure was also recorded continuously for 24 hours. From the lowest levels achieved during sleep, blood pressure rose as the subjects regained consciousness but was not restored to its baseline value until mental activity was also restored by reading. Blood pressure rose further with mental arithmetic. These changes were accompanied by a greater proportional rise in plasma adrenaline than in plasma noradrenaline concentrations. Plasma renin activity changed little. The pressor responses to phenylephrine and noradrenaline were inversely related to baroreceptor sensitivity. The fall in blood pressure with sleep and the rise with mental arithmetic was also inversely related to the sensitivity of the reflex. Systolic pressure recorded throughout the day was inversely related to the R-R interval in each subject. The slope of this relationship and range of R-R interval was greatest in the subjects with the most sensitive baroreflexes.
The effect of beta-adrenoceptor antagonists with varying lipophilicity on microsomal phase I and II reactions was investigated using rat hepatic microsomes. The degree of inhibition of ethoxyresorufin deethylase paralleled octanol/water partition coefficients: propranolol greater than alprenolol greater than timolol greater than metoprolol greater than atenolol. Propranolol (highly lipophilic) and atenolol (hydrophilic) also had widely different effects on 7-ethoxycoumarin deethylase inhibition and on disopyramide N-dealkylation. However the inhibition of harmol conjugation was not related in the same way to octanol/water partition coefficient as was the phase I reactions.
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Leukemic cells from a patient with Sézary syndrome were studied with a panel of monoclonal antibodies. Despite their typical morphology, the cells expressed an unusual surface phenotype. They simultaneously expressed OKT4 and OKT8 reactivity, indicating a more immature origin of the neoplastic cells than what has previously been observed in Sézary syndrome, but they were OKT6 negative. In response to 12-O-tetradecanoyl phorbol-13-acetate (TPA) the cells underwent phenotypic alterations, as the OKT4 reactivity was significantly reduced and the OKT8 expression was retained. Thus, following TPA, the cells expressed a surface phenotype consistent with the cytotoxic/suppressor T-cell subset in normal peripheral blood. The findings are discussed in relation to normal T-cell maturation and differentiation processes.
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Excretion of plasminogen activator from colonies of Syrian hamster embryo cells has been studied after sequential exposure of the cells to benzo[a]pyrene (3 days), and 12-O-tetradecanoyl-phorbol-13-acetate (3 days). The excretion of plasminogen activator was assayed using the fibrin/agarose overlay technique. The frequency of plasminogen activator-positive colonies was about two times higher for morphologically transformed colonies than for colonies with normal morphology growing on the same dish. Thus, 9% of the transformed colonies, compared to 4% of the colonies with normal morphology, gave clear zones of lysis in the fibrin/agarose overlay after 2 h of incubation. The frequency of plasminogen activator-positive colonies on untreated dishes was 2%. The addition of protease inhibitors strongly reduced the formation of clear zones of lysis, while they did not affect the frequency of morphologically transformed colonies. The data show that the expression of plasminogen activator is not an obligatory event in the process of morphological transformation.
Patients may receive information about their medicine from the prescriber, the pharmacist and the manufacturer (in a package insert). If it is to be used effectively, all this information must be integrated: the different sources should complement, and not seem to contradict one another. Prescribers and pharmacists should therefore have at hand the text of any package inserts that patients will receive with prescribed medicines. In addition, doctors might be helped by an aide-mémoire, reminding them about the information which a patient needs to have about a medicine. Methods for improving patients' use of such information are also summarized.
Newly excysted juvenile Fasciola hepatica were injected intraperitoneally into previously sensitized rats. They were recovered at various intervals post-injection and examined by light and electron microscopy. The challenge flukes were rapidly coated with peritoneal cells which, in the early stages, were mainly eosinophils. The eosinophils adhered closely to the flukes and degranulated on to their surface releasing cytochemically detectable peroxidase. Vacuoles formed in the tegument of the flukes beneath the adherent eosinophils and these increased in size until they spanned the width of the tegument, thus destroying its continuity. From 4 h post-injection some of the flukes had lost their teguments and were surrounded by phagocytic cells, particularly neutrophils; at this stage they were judged to be dead. During the first five minutes post-injection degranulating mast cells were associated with the challenge flukes. Their role in eosinophil chemotaxis is discussed as are the possible mechanisms of eosinophil adherence and degranulation. Using an anti-C3 fluorescein conjugate, it was demonstrated that C3 was not bound to the surface of challenge flukes either in vivo or in vitro in immune serum.
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