Biomedical subjects
Publications and source records attributed to G Harris.
Approaches developed by the DHSS's central analytical team as a basis for comparing national priorities are explained by Gordon Harris, an economic adviser to the department, and Colin Parker, who recently completed a period of secondment to the department as an operational research consultant.
The germ-free nude mouse represents a most useful animal for investigating the effects of a congenital deficiency of T-lymphocytes on various physiological processes, including haemopoiesis. Nude mice (nu/nu) of the CBA strain, nonmutant inbred CBA mice, and inbred C3H mice were reared in germ-free isolators and used to compare (1) the haematological parameters of nu/nu mice and CBA mice at different ages and (2) the labelling pattern of circulating leucocytes at various times after a single intraperitoneal injection of 3H-thymidine into 3-month-old nu/nu and C3H mice. The data suggest that the deficiency of T-lymphocytes in nu/nu mice may lead to a disturbance of haemopoiesis in 2 to 6-month animals which is characterised by a mild macrocytosis and a very marked reduction in the proportion of labelled leucocytes which can be seen in the blood after an injection of 3H-thymidine. Despite these perturbations, unstressed nu/nu mice were able to maintain adequate numbers of blood cells (other than lymphocytes) in their circulation. Nine-month-old nu/nu mice did not show a macrocytosis and the disappearance of the marcrocytosis at this age was associated with an increase both in the blood lymphocyte count and in the mass of lymphoid tissue in the spleen and mesenteric lymph nodes.
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The exchange of radioactivity between lymphocytes, labelled with (3H) thymidine after stimulation with Concanavalin A, and recipient V79 fibroblasts in culture was studied. The radioactive material involved in this exchange was macromolecular deoxyribonucleic acid as well as its breakdown products. This deoxyribonucleic acid from lymphocytes localised in the nuclei of the host cells soon after contact between donor and recipients. This occurred even when the V79 fibroblasts were confluent at high cell density, and thus in a steady, non-growing state with respect to cell numbers. The fate of the radioactive donor lymphocyte deoxyribonucleic acid, substituted with bromodeoxyuridine, was followed in the recipient cells by analysing its buoyant density in caesium chloride gradients. This deoxyribonucleic acid was found to become associated with the nuclear deoxyribonucleic acid of the host cells, involving both retention of relatively intact donor deoxyribonucleic acid as well as its breakdown and re-utilisation for host cell deoxyribonucleic acid synthesis. Non-growing recipient cells were found to retain the donor deoxyribonucleic acid in relatively intact form for much longer periods than when the same cells were in logarithmic growth phase.
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Choroidal osteomas caused visual symptoms in four healthy young women. A positive 32P test led to enucleation and histopathologic confirmation of the diagnosis in one patient. The characteristic ophthalmoscopic findings in these patients included the following: (1) slightly and irregularly elevated, yellow-white, juxtapapillary, choroidal tumor and well-defined geographic borders; (2) diffuse and mottled depigmentation of the overlying pigment epithelium; and (3) multiple small vascular networks on the tumor surface. A diffuse mottled pattern of hyperfluorescence in the area of the tumor occurred during the early and later stages of angiography. The tumors were ultrasonically dense, and the orbital tissue behind them was rendered silent. The tumors were visible on routine orbital x-ray films and computerized tomograms. The latter study demonstrated the tumors as having the consistency of normal bone.
Self-reported psychoneurotic characteristics and aspects of affective status have been examined within the adult population of a market town and the surrounding rural community using a standardized instrument. Features of anxiety in particular are more common amongst females than males, peaking in the third, fourth (phobic avoidance behaviour being also especially evident at this time) and fifth decades of life. Many of the characteristics are also importantly related to age in both sexes and to social class. Some are widespread within the population and probably reflect more enduring personality traits. Others are less common, more age specific (e.g. early adult life, middle age, the menopause in females; the involutional period in males) and are probably more often construed by the individuals concerned and by others as 'illness'. The similarity of the relevant segment of the present profiles to those previously obtained from a suburban population aged 40-65 years is noteworthy. The most likely interpretation is that the measuring instrument is reliable and that the reporting behaviour of psychoneurotic and effective characteristics and morbidity is identical in both populations.
The appearance of labelled lymphocytes in the blood of adult thymectomized mice was followed for 21 days after a single injection of [3H] thymidine. The results showed that the expected changes in their life-span resulting from thymic deprivation were not reflected in the kinetics of labelling of these cells with this radioactively-labelled precursor for DNA synthesis. Turnover of DNA and exchange of label between cells must be considered in relation to the results, as had been previously concluded from similar studies of intact mice (Harris, 1975a).
The fate of mouse spleen cells, stimulated with Concanavalin (Con A) and labelled with [3H] thymidine in culture, has been followed after transfer into recipients, syngeneic to the cell donors. The labelled cells, localizing in the spleen, were found mainly in the white pulp in both germinal centre and periarteriolar sheath areas. The number of cells with labelled nuclei found in the spleens of recipients was much greater than could be accounted for simply on the basis of the radioactivity present. Using donor cells, whose DNA had been substituted with bromodeoxyuridine (BUdr) in sufficient amounts to increase its buoyant density, it was concluded that redistribution of label rather than cell division was responsible for this increase of labelled nuclei. In addition to these findings, the spleens of recipient mice showed evidence of a vigorous immunological response to the donor cells, very similar to that following injection of an antigen such as sheep red cells. These results show that caution must be exercised in interpreting the results of transfer of lymphocytes into recipients, even when a highly stable molecule such as DNA contains the radioactively-labelled material such as [3H] thymidine.
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Psychoneurotic scores in a sample of all patients between the ages of 17 and 70 in a group practice have been studied, and the relationship with psychoactive drug prescribing examined. In addition some social factors have been studied, namely, the use of alcohol and tobacco, and self-medication.The psychoneurotic scores of those prescribed psychoactive drugs are significantly higher than those for the general population, but do not fall after treatment.
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The DNA-synthesizing ability of mouse spleen cells in vitro and in vivo is paralleled by their levels of cytoplasmic thymidine kinase. However, a very high level of nuclear-associated enzyme activity developed in cultures of both non-stimulated and mitogen-transformed lymphocytes. This activity did not appear in the spleens of mice during the primary immune response to sheep erythrocytes (SRC) or following administration of Convanavalin A (Con A). Feedback inhibition studies with TTP demonstrated that the nuclear enzymes were more sensitive than the cytoplasmic activities. The thermal stabilities of the nuclear enzymes were also found to be greater than the corresponding cytoplasmic ones. Furthermore, analysis of the rate of thermal inactivation indicated that both the cytoplasmic and nuclear enzymes present in transformed lymphocytes in vitro were far more heat-stable than those activities normally found in the mouse spleen, even after antigenic challenge with SRC in vivo or incubation in vitro in the absence of mitogenic stimulation.
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Using long exposures of stripping film autoradiographs before processing, mixtures of weakly and strongly labelled nuclei were seen in different areas of the mouse spleen. Previous results (Harris et al., 1973) led to the conclusion that many cells, not in division cycle, were labelling with (3H) thymidine and that this process was important for the development of specific antibody-producing cells following stimulation with an antigen such as sheep red cells (SRC). The present data are an analysis of the (3H) thymidine labelling kinetics in the spleens of mice reared in conventional or germ-free conditions. The labelling seen in the 24 h following an injection of (3H) thymidine could best be interpreted on the basis of synthesis of unstable DNA. The changes in the pattern, and distribution of labelled nuclei as well as the intensity of their labelling was not compatible with cell division only, but was also the result of movement of labelled material between the lymphoid cells of the organ. Germ-free mice were followed for 24 days following a single injection of (3H) thymidine. The rate of uptake of label into the spleen was much slower than has been found previously in mice reared in conventional conditions. When SRC were injected 2 h after giving (3H) thymidine the labelling of lymphoid cells in the spleen and blood was quite different to controls given (3H) thymidine alone. Detailed analysis indicated that turnover of labelled material, presumably DNA, as well as cells was involved. This turnover of DNA could be considered to be metabolic in the sense that renewal, increase in amount, loss, and transfer to other cells were involved. These, and other studies, in vivo (Harris & Olsen, 1973) and in vitro (Harris et al. 1975) indicate that such processes, involving DNA, are highly relevant to the development of antibody-producing capacity by cells responding to antigenic challenge.
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The responses of lymphocytes cultured with various stimulants were analysed with respect to DNA synthesis and cell division. Autoradiographic labelling with [3H]thymidine indicated that similar proportions of cells had incorporated this labelled precursor for DNA synthesis during both short and long periods of exposure to this specific precursor for DNA synthesis. Changes in labelling index (LI) after pulsing these cells with [3H]thymidine showed that exchange of labelled material, which could not be chased out with unlabelled thymidine, was responsible for the increases of LI seen. Failure to prevent this increase with excess unlabelled thymidine indicated that direct incorporation of [3H]thymidine did not account for this exchange. Using hydroxyurea and colcemid arrest to analyse cell cycle events in these cultures, it was shown that approximately 70 per cent of the responding cells in cultures of stimulated lymphocytes, while actively synthesizing DNA, were not in cell cycle for division. It was concluded that DNA turnover, involving synthesis and exchange of newly synthesized material, possibly DNA, was occurring in these cells.