Fetal growth signals.
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Embryonic and Fetal Development↗
Biomedical subjects
R D Milner
Publications and source records attributed to R D Milner.
Newborn splenic volumes vary under different malaria endemic conditions.
Ultrasound was used to measure newborn splenic dimensions and calculate the volumes in a malarious and a non-malarious region of Papua New Guinea. The median splenic volume of infants born in Madang, where malaria transmission is high throughout the year, was 5.2 cm3/kg, while that of infants born in Goroka, where malaria is not endemic, was 2.6 cm3/kg. The cause of this difference is unknown, but possible explanations include fetal exposure to malaria antigens in utero and the high incidence of inherited red cell disorders in the malarious regions of Papua New Guinea.
Animals↗
Immunological distribution of one form of insulin-like growth factor (IGF)-binding protein and IGF peptides in human fetal tissues.
Insulin-like growth factors (IGFs) are expressed by, and are biologically active on, human fetal cells. The mitogenic actions of IGF-I are modulated by the 21-41 kDa class of IGF-binding proteins (IGF-BPs). Using a rabbit anti-human IGF-BP antibody raised against a highly pure 26 kDa IGF-BP derived from amniotic fluid, we have compared the cellular location of IGF-BP and IGF peptides in tissue sections from prostaglandin-induced human abortuses of 14-16 weeks of gestation. The monoclonal and polyclonal antibodies used were raised against human IGF-I, but did not distinguish between IGF-I and IGF-II. Positive staining for IGF-BP was seen in every tissue except brain, spleen and thyroid. With the exception of skin, the cellular distribution of IGF-BP was similar to that of IGF peptides. Strong immunostaining was found in hepatocytes, hepatic erythropoietic cells, pulmonary epithelium, the tubular epithelium of kidney, intestinal epithelia, the fetal adrenal cortex and cardiac and skeletal muscle fibres. In skin, IGF-BP was located throughout the dermis and in the germinal layer of the epidermis. IGF peptide in skin was restricted to the deeper dermal layers. In the tibial epiphyseal growth plate both IGF-BP and IGF peptide were located in chondrocytes throughout the proliferation and hypertrophic zones. The similarity in distribution of IGF-BP and IGF peptides in fetal tissues suggests that the latter may exist predominantly complexed to IGF-BP in or on the surfaces of cells in vivo. The distribution of IGF-BP may define the sites of biological action of IGF peptides.
Adrenal Cortex↗
Free running asthma screening test.
The free running asthma screening test (FRAST) was evaluated in 503 Sheffield schoolchildren aged 6 to 12 years and compared with responses to an asthma questionnaire. The FRAST measured peak expiratory flow rate (PEFR) before and at 1, 5, and 10 minutes after maximum voluntary running for at least 5 minutes in a standardised environment. A fall in PEFR of greater than 15% in at least two postexercise readings was defined as abnormal. Six (1%) children did not do the test and 69 (14%) failed to complete it. Of these, 14 were known asthmatics, 18 were not testable, and 37 were normal when retested. There were 14 abnormal FRAST results among 412 'normal' children who completed the test and 10 of these were subsequently diagnosed asthmatic. None of 14 children with an abnormal FRAST result had been identified as wheezy, chesty, or asthmatic in the questionnaire. In this sample there was, on average, one child in every school class with unrecognised exercise induced bronchospasm. The FRAST is an acceptable, feasible, and cost effective way of identifying such potential asthmatics at school.
Asthma↗
Effect of maternal hyperalimentation on intrauterine growth retardation.
The effect of maternal hyperalimentation on intrauterine growth retardation was studied by performing unilateral uterine vessel ligation on day 17 in Wistar rats. Test animals were given food supplements by gavage for three days postoperatively whereas control animals received saline. The caloric intake and weight gain of the test dams was significantly greater than that of the controls from days 17 to 20 but not over the longer period, day 14 to 23. The survival and growth of fetuses in the unoperated horn were similar in test and control rats. Fetal survival in the ligated horn was doubled by maternal food supplementation but the growth and development of the survivors were not improved.
Animals↗
Variation in lower leg growth with alternate day steroid treatment.
Daily growth of the lower leg in a child receiving alternate day oral steroids for Crohn's disease was measured by knemometry. Growth occurred on days free of treatment. This may represent a direct observation of the growth sparing effect of alternate day steroid medication.
Anthropometry↗
Placental lactogen and growth hormone receptors in human fetal tissues: relationship to fetal plasma human placental lactogen concentrations and fetal growth.
The specific binding of human placental lactogen (hPL) and human GH (hGH) to particulate cell membranes from human fetal liver and skeletal muscle at 12-19 weeks gestation was examined. Fetal liver and muscle specifically bound [125I]hPL. This binding was inhibited by increasing concentrations of unlabeled hPL (half-maximal concentrations, 2.2 and 3.4 nmol/L, respectively). Scatchard analysis of the hepatic membrane binding revealed curvilinear plots with higher (Kd, 2.2 nmol/L) and lower (Kd, 24 nmol/L) affinity sites, while binding to muscle involved a single receptor class of Kd 5.6 nmol/L. The binding capacities for the two hepatic sites correlated positively with fetal body weight. [125I]hGH specifically bound to liver, but not muscle, with higher (Kd, 1.6 nmol/L) and lower (Kd, 8.6 nmol/L) affinity sites. [125I]PRL bound to hepatic membranes, but was preferentially displaced by hPL or hGH. Between 4 and 500 micrograms/L (mean, 82 micrograms/L, 3.8 nmol/L) hPL were present in fetal plasma. The findings identify distinct hPL receptors in human fetal liver and skeletal muscle and a hepatic hGH receptor in midgestation.
Embryonic and Fetal Development↗
Transforming growth factor beta inhibits DNA synthesis in hepatocytes isolated from normal and regenerating rat liver.
The inhibitory action of transforming growth factor beta (TGF beta) on DNA synthesis in hepatocytes isolated from the liver of normal rats or from the liver remnant of rats 18 h following partial hepatectomy was compared. Continuous exposure to TGF beta inhibited DNA synthesis of cultured hepatocytes to a similar degree in both groups when labelled with 3H thymidine from 24-48 h or 48-72 h. At 20 pM TGF beta, 3H-thymidine incorporation was reduced by 64-78% in hepatocytes from normal liver and by 60-73% in cells from 18 h regenerating liver. The nuclear labelling index was reduced by 70-80% in all cells. Exposure to TGF beta at concentrations up to 500 pM from 0-24 h had no effect on 3H-thymidine incorporation, but exposure at 20 pM for 24 h periods thereafter was uniformally effective. These results indicate that there is no change in sensitivity of hepatocytes from 18 h regenerating liver to TGF beta, compared with normal cells, and that TGF beta may act at some point in the G1 phase of the cell cycle to inhibit hepatocyte growth.
Animals↗
Regulation of DNA synthesis in human fetal hepatocytes by placental lactogen, growth hormone, and insulin-like growth factor I/somatomedin-C.
Hepatocytes were isolated by gentle collagenase digestion of liver fragments from human fetuses of 8-16 weeks gestation obtained following prostaglandin-induced pregnancy terminations. They were maintained on collagen-coated tissue culture dishes in selective arginine-free medium for up to 72 hr, and the action of hormones and growth factors on DNA synthesis was studied by autoradiography following incubation with 3H-thymidine. The labeling index of hepatocytes was consistently enhanced by 25-250 ng/ml human placental lactogen (HPL), 25-250 ng/ml human growth hormone (HGH), 10-50 ng/ml insulin-like growth factor I/somatomedin-C (IGF I/Sm-C), and 10% dialyzed fetal calf serum, reaching a maximum of three- to four-fold greater than in basal medium alone. Under basal conditions, 30% of hepatocytes stained positively for the presence of IGF peptides using a monoclonal antibody raised against purified human IGF I/Sm-C. Although this proportion did not change following treatment with HGH and HPL, IGF I/Sm-C released by cells into culture medium was considerably increased in the presence of both hormones. Incubation with the SmC 1.2 monoclonal antibody abolished the increase in labeling index in response to IGF I/Sm-C and partially blocked the response to both HPL and HGH. These results indicate that both HPL and HGH stimulate DNA synthesis in human fetal hepatocytes and suggest that this effect is at least partly indirect through the release and paracrine action of IGF I/Sm-C.
DNA Replication↗
Interaction between endocrine and paracrine peptides in prenatal growth control.
The evidence reviewed here shows that the endocrinology of fetal growth is very different from that operating postnatally. Pituitary hormones play little part in stimulating growth of the lean body mass or skeleton although growth hormone (GH) may be involved, in some as yet ill defined way in the ontogeny of the fetal pancreatic islet and insulin secretion. Insulin is important because it stimulates fetal cellular anabolism but acts in a permissive manner: with too little insulin growth is inhibited, with too much growth proceeds at a genetically predetermined rate. Placental lactogen (PL), or other peptides within the GH/PL family, may act as a true growth-promoting hormone in the fetus; it stimulates both cellular metabolism and mitosis. The part played by endocrine control mechanisms in the fetus is set in context by an appreciation of the importance of locally acting tissue growth factors, and in particular the somatomedins. Their part in fetal growth control is intimately bound up with the plane of nutrition experienced by the fetus. It is concluded that the simplest analysis that makes biological sense involves a consideration of hormones, tissue growth factors and nutrition, not hierarchically but as mutually interacting variables.
Animals↗
Sitting heights in Sheffield, 1985: have standards changed?
A community study was performed on 354 schoolchildren aged 4 to 13 years to assess whether the published UK standards for sitting height and leg length applied to the local population. The schoolchildren showed no significant difference from UK standards in standing height, but had significantly shorter sitting heights and significantly longer legs. When compared to children measured in several European studies, the Sheffield children had normal sitting: standing height ratios, whereas ratios from the published UK standards were significantly greater than those from the rest of Europe.
Adolescent↗
Current views on the treatment of Turner's syndrome.
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Anabolic Agents↗
Knemometry as a predictor of response to somatrem in Turner's syndrome.
The response of 13 children with Turner's syndrome to somatrem, 2 IU/day, has been determined for a 4-week period of treatment using knemometric measurements, and compared to 6 months of treatment assessed by conventional auxology. In this small series, knemometry was able to predict those children in whom hGH therapy was not beneficial.
Adolescent↗
Knemometry in assessment of linear growth.
A rigorously designed auxological study was carried out to assess the operational characteristics of the knemometer and the value of short term lower leg and height measurements in estimating and predicting rates of linear growth. Measurements were made on 18 normal children monthly for six months and on six normal children weekly for six weeks. Six other children measured weekly underwent tonsillectomy after three weeks to determine the effect of stress on growth. The measurement protocol permitted estimations of both inter- and intraobserver variation. Knemometry is a sensitive, precise, and robust technique that enables accurate measurements to be made of the lower leg by interchangeable observers. The lower leg does not grow smoothly and variations in growth rate seen in both healthy children and children with transient intercurrent stress limit the practical clinical value of knemometry to the measurement of linear growth in the short term.
Anthropometry↗
Prediction and management of nocturnal hypoglycaemia in diabetes.
Blood glucose measurements were made at 2200, 0200, and 0800 h in 102 children with diabetes during a 24 hour planned admission to hospital. Nocturnal hypoglycaemia (less than 3.0 mmol/l) occurred in 24 of 71 (34%) children on twice daily insulin and in three of 31 (10%) children on once daily insulin. Predictive value modelling showed that a blood glucose concentration of less than 7 mmol/l at 2200 h was the best predictor of nocturnal hypoglycaemia, with a sensitivity of 63%, specificity of 94%, and positive and negative predictive values of 83%. Blood glucose measurement at 0800 h had no predictive value for nocturnal hypoglycaemia. The mean (SD) glycosylated haemoglobin concentration of children on twice daily insulin who had nocturnal hypoglycaemia was 55 (8) mmol HMF/mol Hb, which was significantly less than that of children on twice daily insulin who did not have hypoglycaemia (64 (11) mmol HMF/mol Hb) or those on once daily insulin (62 (11) mmol HMF/mol Hb). A controlled trial was then performed in which 29 children with diabetes who had a blood glucose concentration at 2200 h of less than 7 mmol/l measured by Reflocheck were randomised into two groups, one of which received 10 g carbohydrate supplement and the other of which did not. Thirteen of the 14 children in the control group had hypoglycaemia at 0200 h, whereas the snack prevented hypoglycaemia in 12 of 15 in the test group. Blood glucose values in the two groups at 0800 h were similar. We conclude that bedtime glucose measurement in children on twice daily insulin is a useful predictor for nocturnal hypoglycaemia, which can be prevented by a small carbohydrate snack in those at risk.
Adolescent↗
United Kingdom multicentre clinical trial of somatrem.
In a multicentre clinical trial 54 children aged 4.0 to 17.3 years, who had growth hormone deficiency that had not previously been treated, were given biosynthetic methionyl growth hormone (somatrem) 4 units three times a week by subcutaneous or intramuscular injection for one year. Height was measured every three months for at least one year before and during treatment. Forty two patients responded to treatment with an increase in growth of greater than 1.5 cm/year. The remaining 12 who grew more slowly were less obviously short and had a higher pretreatment growth than those who responded. The three who responded and the one who did not had undergone therapeutic spinal irradiation before starting the drug. If a whole year's pretreatment growth rate of less than 5 cm/year had been used as a diagnostic criterion the prediction of those who responded would have slightly improved. About two thirds of the patients developed antibodies against growth hormone and Escherichia coli protein; these were, however, of low and fluctuating titre and binding capacity, and did not influence the response to treatment. No adverse side effects were encountered. We conclude that somatrem is a safe and effective alternative to pituitary growth hormone.
Adolescent↗
Growth hormone in short, slowly growing children and those with Turner's syndrome.
Results of an aborted placebo controlled trial of treatment with human pituitary growth hormone in children with Turner's syndrome and short, slowly growing children are reported. One child in each group had a considerable reduction in growth rate standard deviation score while taking growth hormone. The remaining eight patients with Turner's syndrome and 10 short, slowly growing patients who received growth hormone showed mean rises in growth rate of greater than two standard deviation scores. Neither placebo group showed a mean increase in growth rate standard deviation score. These differences were significant.
Adolescent↗
Effects of human placental lactogen and growth hormone on the production of insulin and somatomedin C/insulin-like growth factor I by human fetal pancreas in tissue culture.
We have investigated the ability of glucose, human GH and human placental lactogen (hPL) to alter the content and release of somatomedin C/insulin-like growth factor I (SM-C/IGF-I), and the biosynthesis, content and release of insulin from cultured human fetal pancreas. Fetal pancreatic explants obtained from glands following prostaglandin-induced abortion between 12 and 21 weeks of gestation were maintained in free-floating culture for 3-5 days before the experiments. The explants were then cultured for 3 days in medium containing either 2.7 or 16.7 mmol glucose/l with or without GH (4.5 or 45.5 nmol/l) or hPL (4.6 or 46.5 nmol/l). Serum-free medium from the final 24 h of culture was collected and SM-C/IGF-I and insulin were measured radioimmunologically in both conditioned medium and tissue explants extracted with acid ethanol. Insulin biosynthesis, determined by immunoprecipitation of [3H]leucine incorporated into insulin, was not significantly altered by any experimental variable. Incubation in the presence of 16.7 mmol glucose/l caused an increase of insulin release from explants, but had no consistent action on insulin content, compared with medium containing 2.7 mmol glucose/l. The pancreatic content and release of SM-C/IGF-I were independent of these glucose concentrations. Neither GH nor hPL altered insulin or SM-C/IGF-I content or release in the presence of the lower glucose concentration. At the higher glucose concentration, 45.5 nmol GH/l did not alter insulin release but caused a significant increase in SM-C/IGF-I content.(ABSTRACT TRUNCATED AT 250 WORDS)
Culture Techniques↗