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N. H. HUNT
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A. D. PERRIS
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SUMMARY

Circadian changes in mitotic activity in rat bone marrow and thymus have been demonstrated to closely parallel variations in total and ionized calcium concentrations in plasma. These fluctuations in plasma calcium concentration and tissue mitosis were abolished by parathyroidectomy. Significant changes in plasma phosphate and magnesium concentrations were also observed over the 24 h period. The evidence suggests that hour-to-hour variations in the systems controlling calcium homeostasis determine the levels of mitosis in rat bone marrow and thymus.

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N. H. HUNT
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A. D. PERRIS
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SUMMARY

Subcutaneous injections of ovine erythropoietin preparations caused parallel increases in bone marrow mitotic activity and plasma calcium concentrations. These activities appeared to be a specific property of the erythropoietin molecule and were not due to an impurity. The increased mitosis and hypercalcaemia which followed erythropoitein injection in normal rats did not occur in the aparathyroid animal. Although a functional parathyroid gland was essential for the erythropoietin-induced changes, the mode of interaction between erythropoietin and the parathyroid gland remains to be established.

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A. D. Perris
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D. J. Edwards
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M. J. Atkinson
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ABSTRACT

Xenografts of mouse tail skin to the rib cages of normal and sham-parathyroidectomized rats caused an increase in plasma calcium concentration and concomitant increase in bone marrow mitosis. Neither was elicited in aparathyroid rats and graft survival was prolonged in these animals.

No hypercalcaemic episode was associated with the delayed hypersensitivity response induced by painting rat ears with oxazolone. Compared with the response in sham-parathyroidectomized rats, that in parathyroidectomized rats was enhanced although both responses were less than that in normal rats.

Parathyroidectomy of parental donors did not affect the ability of their splenic lymphocytes to mount a graft-versus-host response in F1 hybrid recipients. When sham-operated and aparathyroid parents were sensitized with F1 hybrid lymphocytes no differences were observed in a subsequent graft-versus-host response in F1 recipients. However, when aparathyroid F1 recipients were employed a marked reduction in the graft-versus-host reaction was observed.

Thus the clonal expansion of cells with specific reactivity to certain antigens in secondary lymphoid tissue, which is driven by those same specific antigens, is not affected or only moderately affected by the parathyroid status of the animal. However, the more general increase in lymphocyte numbers promoted by non-specific mitogenic lymphokines is markedly impaired in the hypocalcaemic parathyroidectomized rat. Furthermore, the parathyroid gland is essential for the development of a hypercalcaemic episode which follows antigenic challenge and causes cell proliferation in primary lymphoid tissues. This surge of mitosis could serve to replenish the depleted pools of virgin T and B lymphocytes in the secondary lymphoid tissue which occur as a result of their response to antigens.

J. Endocr. (1984) 102, 257–263

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N. H. HUNT
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A. D. PERRIS
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P. A. SANDFORD
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SUMMARY

Two days after a severe haemorrhage plasma calcium concentrations and bone marrow mitotic activity in rats were significantly increased and so remained for a further 5–6 days until the haematocrit had returned to normal. The first 48 h after bleeding were characterized by hypocalcaemia. During this phase two significant peaks in mitotic activity were observed at 4 and 18 h after haemorrhage. The mitotic surge 4 h after bleeding was still present in adrenalectomized and parathyroidectomized animals but in rats which were either hypophysectomized or had congenital diabetes insipidus this mitotic response was absent. Vasopressin was shown to stimulate bone marrow mitotic activity both in vivo and in vitro whereas angiotensin, aldosterone and erythropoietin had no rapid, direct mitogenic action on these cells. This novel hypophysial–bone marrow system suggests that vasopressin may assist in post-haemorrhagic recovery in blood cell numbers in the circulation.

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J. I. MORGAN
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A. K. HALL
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A. D. PERRIS
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Department of Biological Sciences, University of Aston in Birmingham, Gosta Green, Birmingham, B4 7ET

(Received 17 April 1975)

Within a population of rat thymic lymphocytes there exists a group of cells which may be induced to enter prematurely the DNA synthetic phase and subsequently to enter mitosis (Whitfield, Rixon, MacManus & Balk, 1972). This response can be elicited in vivo by injections of calcium or magnesium chloride (Smith, Gurson, Riddell & Perris, 1975). Similarly, in isolated suspension cultures of thymic lymphocytes an increase in the calcium or magnesium concentration also evokes this response (Morgan & Perris, 1974).

The mitogenic action of calcium is not evident in female rats, which can be attributed to the presence of oestrogen (Smith et al. 1975). This can be simulated in the culture system by addition of 0·1 μg oestradiol/ml to the cell suspension (Morgan & Perris, 1974). Under these conditions the ability of raised

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D. J. EDWARDS
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J. J. RIMMER
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M. J. ATKINSON
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A. D. PERRIS
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When rats or mice were immunized with sheep red blood cells, bacterial lipopolysaccharides or bovine serum albumin, a proliferative response could be detected in the bone marrow and spleen. This response was associated with a hypercalcaemic phase. Parathyroidectomy, which resulted in a protracted hypocalcaemia, prevented the development of an increase in levels of plasma calcium. This operation also prevented the rise in bone marrow proliferation following antigenic challenge, but did not ablate the normal proliferative response to antigen by cells in the spleen. Antibody production and numbers of antibody-forming cells were not significantly reduced by parathyroidectomy. These results suggest that there is a pool of antigen-insensitive cells in the bone marrow which are stimulated after antigenic challenge. It is postulated that these events are mediated by the development of a parathyroid-dependent hypercalcaemia which stimulates the cells non-specifically. These events may form part of a cellular homeostasis, replacing cells in peripheral lymphoid tissues.

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G. R. SMITH
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MOLLY L. GURSON
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A. J. RIDDELL
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A. D. PERRIS
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SUMMARY

In the male rat injections of CaCl2 and MgCl2 stimulated mitosis in bone marrow and thymus tissue. The magnesium salt was also mitogenic in the normal female, but calcium only exerted its mitogenic effect after ovariectomy. Oestradiol, but not progesterone replacement therapy abolished calcium-induced mitosis in the ovariectomized rat. The inability of calcium to stimulate cell division was also apparent in the thyroparathyroidectomized female rat, suggesting the oestradiol blockade did not operate via some indirect action on the calcium homeostatic hormones calcitonin or parathyroid hormone.

When thymic lymphocytes derived from male or female rats were isolated and maintained in suspension, increased calcium or magnesium concentrations in the culture medium stimulated the entry of cells into mitosis. Addition of oestradiol to the culture medium abolished the mitogenic effect of increased calcium levels, but had no effect on magnesium-induced proliferation. These experiments suggested that oestradiol might act at the cell surface to prevent the influx of calcium but not magnesium ions into the interior of the cell and thus to block the sequence of biochemical events which lead to the initiation of DNA synthesis and culminate in mitosis.

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