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Kahn & Baker (1964) and Kahn, Baker & Zanotti (1965) have shown that norethynodrel induces mammary gland proliferation in rats comparable to that in pregnancy. The major ovarian effect appears to be reduction in weight (Saunders & Drill, 1958; Lakshman & Nelson, 1963), while observations on ovarian histology are less consistent (Holmes & Mandl, 1962; Baker, Kahn & Besemer, 1965). Baker, Kahn, Zanotti & Headings (1966) have recently found adrenocortical hypertrophy as a response to norethynodrel, but other investigators have reported variable effects on adrenal weight (Holmes & Mandl, 1962; Edgren, Hambourger & Calhoun, 1959). Some studies of the effects of this steroid on hypophysial weight and histology showed no alterations (Lakshman & Nelson, 1963; Saunders, 1964), although Holmes & Mandl (1962) observed an increased weight with depletion of basophils and an increase in chromophobes. Since changes in thyroid function can influence other endocrine factors, the effects of norethynodrel in

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C E Evans, C Ward, and I P Braidman


Bone metastases in breast cancer may be osteolytic, osteosclerotic, or a mixture of the two. Although stimulation of bone resorption by breast cancer cells has attracted some interest, the formation of osteosclerotic secondary tumours and the influence of human mammary carcinoma cells on osteoblasts (bone forming cells), both important in understanding breast cancer - bone interactions, have been largely neglected. We therefore examined the effects of conditioned medium (CM) from two cultured human breast cancer cell lines (MCF7 and ZR-75) and from primary cultures of breast carcinomas from two patients, on osteoblasts and recruitment of bone-resorbing cells (osteoclasts) in vitro. Osteoblast-like cells (BDC) were cultured from human trabecular bone explants. Osteoclast maturation was studied in fetal rat calvaria cultured on collagen gels. CM from the MCF-7 line and cells derived from one patient each inhibited BDC DNA synthesis, but stimulated osteoclast recruitment. In contrast, CM from the second patient's cells or ZR-75 enhanced DNA synthesis in BDC, but blocked osteoclast maturation. This suggests that human breast carcinomas secrete soluble factors which influence both osteoclasts and osteoblasts. A further unexpected implication is that mammary carcinoma cells may cause local osteosclerosis by directly stimulating osteoblasts, rather than through raised bone turnover in metastases.

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W. F. WARD, R. K. MEYER, and R. C. WOLF


Rats were exposed to either 300 or 500 röntgen (R) acute whole-body X-irradiation on the 5th day of delayed pregnancy induced by ovariectomy. From 0 to 8 days after irradiation, implantation was induced by the administration of oestrogen. Foetal survival to the 20th day of development was used as an index of radiation effect.

If oestrogen was given immediately after exposure to 300 R, or 12 h later, only 30–35% of the embryos survived, significantly less (P < 0·01) than the non-irradiated control values of 74–79%. When implantation was postponed for 24 h or more, embryonic survival ranged from 57 to 64% and was not significantly different from that of controls.

After exposure to 500 R X-irradiation, embryonic survival increased linearly from 2% to a maximum of 41% as the interval between irradiation and oestrogen administration increased from 0 to 48 h. Embryonic survival never reached control levels after 500 R, regardless of the interval between irradiation and implantation. The irradiation regimens also induced developmental abnormalities, doubled the incidence of dead foetuses (death at a late stage of development), and significantly reduced foetal and placental weights at autopsy.

The results confirm that recovery from potentially lethal X-irradiation damage can occur during delayed implantation, and demonstrate that both the extent and the rate of recovery are functions of the radiation dose.

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Intra-uterine pressure changes were recorded at the end of pregnancy and during parturition in eight ewes by means of endo-radiosondes implanted in one uterine horn some weeks previously. Recordings were made at frequent intervals so that the progress of parturition could be carefully monitored. When the early stages of parturition were established, a single injection of 80 mg. progesterone in oil was made in six ewes. As a result, parturition was delayed and the intra-uterine pressure waves declined or were abolished. Delivery of the lambs occurred up to 7 days later. In two ewes the injection was given somewhat later during parturition and, in these animals, the depressant effect of progesterone was much less. The increased intra-uterine pressure waves which followed digital examination of the cervical canal were abolished for more than 20 hr. in all eight ewes. Determination of threshold doses of oxytocin showed wide variations and revealed no more than a general trend of increasing myometrial sensitivity with approaching parturition, a trend which was temporarily reversed in five ewes by the injection of progesterone. The eight ewes delivered 13 viable lambs and one dead lamb.

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SJ Heasman, KM Giles, C Ward, AG Rossi, C Haslett, and I Dransfield

Glucocorticoids represent one of the most effective clinical treatments for a range of inflammatory conditions, including severe acute inflammation. Although glucocorticoids are known to affect processes involved in the initiation of inflammation, the influence of glucocorticoids on the mechanisms by which acute inflammation normally resolves have received less attention. Apoptosis of granulocytes present at inflamed sites leads to their rapid recognition and internalisation by macrophages, a process which may be important for resolution of inflammation. However, if clearance of either eosinophils or neutrophils is impaired, these cells rapidly undergo secondary necrosis leading to release of pro-inflammatory mediators from the phagocyte, potentially prolonging inflammatory responses. Physiologically relevant concentrations of glucocorticoids accelerate eosinophil apoptosis whilst delaying neutrophil apoptosis during in vitro culture. Here we discuss key pathways regulating the granulocyte apoptotic programme and summarise the effects of glucocorticoids on monocyte differentiation and the consequent changes to apoptotic cell clearance capacity. Definition of the mechanisms underlying resolution of inflammatory responses following glucocorticoid treatment may unveil new targets for modulation of inflammatory disease, allowing co-ordinated augmentation of granulocyte apoptosis together with increased macrophage capacity for clearance of apoptotic cells.

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P. C. Wynn, I. G. Maddocks, G. P. M. Moore, B. A. Panaretto, P. Djura, W. G. Ward, E. Fleck, and R. E. Chapman


Specific receptor sites for murine epidermal growth factor (EGF) have been characterized and their distribution determined in ovine skin. Binding of 125I-labelled EGF to skin membrane particles was temperature- and time-dependent, with equilibrium being reached within 1 h at 23 °C. Analysis of skin biopsies collected from ten castrated Merino sheep demonstrated the presence of a single class of saturable, high-affinity binding sites with a dissociation constant of 64 ± 4 (s.e.m.) pmol/l and a binding capacity of 33·8 ± 4·5 fmol/mg protein. Skin particle binding of 125I-labelled EGF was inhibited equipotently by mouse salivary gland EGF, EGF produced by recombinant DNA procedures and urogastrone. The EGF peptides 1–48, 6–53 and 7–53, derived from the native molecule by enzymatic cleavage, were much less potent. The relative binding potency of these molecules was correlated with their ability to induce precocious eyelid opening in mice and to inhibit wool follicle activity. Synthetic fragments representing the major structural domains of the EGF molecule (EGF(29–44), EGF(33–42) and EGF(3–31)) were inactive in both the receptor and bioassays. Auto-radiography of skin sections incubated with 125I-labelled EGF in vitro or of sections from skin which was perfused with 125I-labelled EGF in vivo demonstrated that EGF receptors were localized in undifferentiated cells of the epidermis and sebaceous glands, the inner and outer root sheath and bulb of wool follicles and in dermal arterioles. Differences in receptor concentration were observed between follicles following in-vivo perfusion of 125I-labelled EGF but not when the in-vitro labelling technique was used. The presence of receptors in these regions is consistent with the morphological changes in sheep skin in reponse to EGF administration which have been reported previously.

Journal of Endocrinology (1989) 121, 81–90

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T H M Da Costa, D H Williamson, A Ward, P Bates, R Fisher, L Richardson, D J Hill, I C A F Robinson, and C F Graham


Transgenic mice were made by introducing extra copies of the mouse insulin-like growth factor-II (IGF-II) gene driven by the bovine keratin 10 promoter (BKVI). The adult plasma IGF-II levels were elevated at least three times in one line. In this line, there was a lower lipid content of both brown and white adipose depots at 2–4 months of age, and 40% less fat in the carcass at 7–9 months. The low lipid phenotype was not detected in the carcass at 2 weeks after birth. The lean characteristic was attributed to circulating IGF-II because the transgene was not expressed in fat. At 2–4 months of age, the transgenes oxidized more oral lipid, and less of this lipid was incorporated into the whole body and the epididymal fat. In contrast, the interscapular brown adipose tissue maintained lipid incorporation and lipoprotein lipase activity despite its reduced size. The altered activity of the brown adipose tissue may account for the gradual onset and persistence of the lean feature of the transgenic mice. There were no substantial changes in lipogenesis which could account for the low fat content. The plasma levels of IGF-I, insulin, glycerol, non-esterified fatty acids, triacylglycerols and glucose were not greatly changed and the pituitary GH content was within the normal range.

Journal of Endocrinology (1994) 143, 433–439