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1. Adrenal glands of guinea-pigs with avitaminosis-C and hypovitaminosis-C were examined and compared with those of normal controls fed on diets containing ascorbic acid as well as with pair-fed controls kept on restricted food intakes. Guinea-pigs with avitaminosis-C were also injected with either adrenocorticotrophic hormone (ACTH) or cortisone and compared with normal controls or pair-fed controls similarly injected.

2. Adrenals of animals with avitaminosis-C increased in absolute (20%) and relative weight (120%). The number of mitoses increased fourfold in the middle stage and tenfold in the terminal stage of the deficiency. The zona fasciculata contained many lipid-free, hyperplastic and dividing cells. Cortisone prevented the increase in weight and in mitoses and also the histological changes. Administration of ACTH to guinea-pigs with early avitaminosis increased the mitoses fourfold, but when given to normal guinea-pigs mitoses increased sevenfold. Histological changes were similar to those seen in advanced avitaminosis.

3. In the adrenals of animals with hypovitaminosis-C, neither the absolute weight nor the number of mitoses were greater than normal but the relative weight of the glands was doubled.

4. It is concluded that the increase in adrenal weight which occurred in avitaminosis-C was the result of a hyperplastic response to high levels of endogenous ACTH known to be present in the blood of deficient animals.

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JC Osgerby, DC Wathes, D Howard, and TS Gadd

The placenta is a highly efficient multifunctional organ, mediating the exchange of nutrients, gases and waste products between the dam and fetus. This study investigated the effects of chronic maternal undernutrition (70% of estimated requirement) on the placental growth trajectory in the ewe on days 45, 90 and 135 of gestation. The insulin-like growth factor (IGF) system was investigated using in situ hybridisation analysis to determine if nutritionally mediated alterations in placental growth were regulated through modifications in placental IGF expression. Placental weight increased between days 45 and 90 (P<0.01), accompanied by a reduction in maternal placentome IGF binding protein (IGFBP)-3, -5 and -6 expression (P<0.05), although IGF-II mRNA levels in maternal villi remained unchanged. Placentome number was unaffected by diet or gestational age. Placental weight remained constant between days 90 and 135 in ewes on 100% maintenance rations but decreased over this period (P<0.05) in ewes on the 70% rations. Gross morphology also altered, so the underfed ewes had more type C and type D placentomes and fewer type B placentomes than their well-fed counterparts on day 135 (P<0.05). These changes were accompanied by higher IGFBP-6 mRNA expression in the maternal placental villi in undernourished ewes (P<0.05). The change in shape from a type A to a type C placentome was accompanied by flattening of the placentome and a reduction in the ratio of the area of unattached fetal allantochorion to interdigitated maternal and fetal villi. Within the intercotyledonary endometrium, expression of IGFBPs-3 and -5 mRNA in the glandular epithelium increased between days 45 and 90, showing an opposite trend with time to that found in the adjacent placentomes. This indicates tissue-specific control of IGFBP expression. In conclusion, this study has shown clear time-related changes in the uterine IGFBP system during pregnancy, which accompany changes in placental growth. Altered IGFBP expression may play a role in determining placental size in relation to nutritional status, but is unlikely to be the only mediator.

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JC Osgerby, DC Wathes, D Howard, and TS Gadd

Modifications in maternal nutrition during pregnancy can significantly disrupt fetal growth and subsequent post-natal health and survival. This study investigated the effects of undernutrition on fetal growth and the potential mechanisms involved. Tissue from pregnant ewes (n=27) was investigated on days 45, 90 and 135 of gestation (term = approximately 150 days). The thoracic girth (P<0.05) was greater in fetuses from nutrient restricted ewes on day 45 and there was also a trend towards an increased gut weight (P<0.08). By day 90, the fetal brain and thymus weight were lighter in underfed than in well-fed animals whilst the weight of the fetal ovaries was heavier (P<0.05). On day 135 the fetal heart, pancreas, thymus, gut and kidney weights were lighter in undernourished ewes (P<0.05). When expressed as a percentage of fetal body weight, significance was retained in the heart, pancreas and thymus (P<0.05). Bone growth was also affected. At day 90 the fetal femur and metatarsal were longer in underfed mothers (P<0.05). In contrast, the fetal humerus and scapula were shorter in underfed than in well-fed animals on day 135 (P<0.05) when the weight of the semitendinosus muscle (P<0.05) was also reduced. The fall in fetal glucose (P<0.1), insulin (P<0.01) and IGF-I (P<0.01) levels in underfed ewes on day 135 may have compromised fetal growth. Fetal plasma IGF binding protein-2 also increased between days 90 and 135 in underfed ewes (P<0.03), whilst levels were unaltered in well-fed animals. Although maternal and fetal plasma IGF-I levels increased with gestation (P<0.01) and the placentome morphology altered in all ewes (P<0.05), the fall in placental mass (P<0.05), amniotic and allantoic glucose concentrations (P<0.05) and maternal plasma glucose and insulin levels (P<0.05) in underfed ewes in late gestation may have compromised fetal substrate delivery. These perturbations in fetal development may have significant implications on adult health and carcass conformation, raising important health and economic issues in medical and agricultural sectors.

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We have reported that the mouse ventro-lateral hypothalamus releases a humoral factor in vitro which stimulates insulin secretion by isolated islets (Idahl & Martin, 1971). We report here similar studies extended to rats, and attempts to isolate this hypothalamic factor and to demonstrate its presence in blood.

Ventro-lateral (VLH) and ventro-medial hypothalami (VMH) of 16 rats were separated and extracted with 3 ml Gey & Gey (1936) buffer at 37 °C for 30 min. Aliquots (0·4 ml) of the extract were tested for stimulatory capacity by incubation (20 min at 37 °C) with five islets of Langerhans. The incubation medium contained glucose (3·3 mmol/l and albumin (1 mg/ml), in a final volume of 0·5 ml Gey & Gey buffer. The amount of insulin released into the medium was compared with the amount released by the same islets during a preliminary 20-min incubation in a medium without the extract (baseline). Insulin

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Helen E MacLean, Alison J Moore, Stephen A Sastra, Howard A Morris, Ali Ghasem-Zadeh, Kesha Rana, Anna-Maree Axell, Amanda J Notini, David J Handelsman, Ego Seeman, Jeffrey D Zajac, and Rachel A Davey

We used our genomic androgen receptor (AR) knockout (ARKO) mouse model, in which the AR is unable to bind DNA to: 1) document gender differences between males and females; 2) identify the genomic (DNA-binding-dependent) AR-mediated actions in males; 3) determine the contribution of genomic AR-mediated actions to these gender differences; and 4) identify physiological genomic AR-mediated actions in females. At 9 weeks of age, control males had higher body, heart and kidney mass, lower spleen mass, and longer and larger bones compared to control females. Compared to control males, ARKO males had lower body and kidney mass, higher splenic mass, and reductions in cortical and trabecular bone. Deletion of the AR in ARKO males abolished the gender differences in heart and cortical bone. Compared with control females, ARKO females had normal body weight, but 14% lower heart mass and heart weight/body weight ratio. Relative kidney mass was also reduced, and relative spleen mass was increased. ARKO females had a significant reduction in cortical bone growth and changes in trabecular architecture, although with no net change in trabecular bone volume. In conclusion, we have shown that androgens acting via the genomic AR signaling pathway mediate, at least in part, the gender differences in body mass, heart, kidney, spleen, and bone, and play a physiological role in the regulation of cardiac, kidney and splenic size, cortical bone growth, and trabecular bone architecture in females.