Search PubMed⌕ Search

Biomedical subjects

R D Milner

Publications and source records attributed to R D Milner.

At least 19 recordsLinked to original sources
PubMed1992

Genetic linkage studies of X-linked hypophosphataemic rickets in a Saudi Arabian family.

UNLABELLED: OBJECTIVE, PATIENTS AND DESIGN: X-linked hypophosphataemic rickets (HYP) is the most common inherited form of rickets and the gene causing this disorder has been localized to Xp22.3-p21.3 by linkage studies of affected families of Northern European origin. In addition, the locus order Xpter-(DXS207-DXS43,DXS197)-HYP-DXS41-X cen has been established and the flanking markers are useful for the presymptomatic diagnosis of HYP. However, a recent study indicates locus heterogeneity and this may hinder the use of the flanking markers for presymptomatic diagnosis in additional families and in particular those from different populations. We have therefore investigated one Saudi-Arabian family (13 affected and six unaffected members) with hypophosphataemic rickets for linkage to these and other X-linked markers. A total of 17 cloned human X chromosome sequences identifying restriction fragment length polymorphisms were used to localize the mutant gene causing this disorder in the Saudi Arabian family. RESULTS: Nine (four from Xp and five from Xq) of the 17 X-linked DNA probes proved informative and linkage was established between HYP and the DSX41 locus, peak LOD score = 4.22 (recombination fraction, theta = 0.00). A positive peak LOD score of 2.32 (theta = 0.05) was also obtained between HYP and the DXS207 locus. Thus, the HYP gene in this Saudi Arabian family is linked to two of the four flanking markers which demonstrated linkage in families of Northern European origin. CONCLUSION: We conclude that the X-linked hypophosphataemic rickets gene in a Saudi Arabian family is located in the Xp22.3-p21.3, a region where this gene has previously been mapped by linkage studies of families of Northern European origin. Our studies have not demonstrated locus heterogeneity, so the flanking markers for HYP previously established in the families of Northern-European origin will be useful in the genetic counselling and presymptomatic diagnosis of this disorder in the Saudi Arabian family.

Adolescent↗
PubMed1991

Mortality, neoplasia, and Creutzfeldt-Jakob disease in patients treated with human pituitary growth hormone in the United Kingdom.

OBJECTIVE: To determine the cause of death and incidence of neoplasia in patients treated with human pituitary growth hormone. DESIGN: A long term cohort study established to receive details of death certification and tumour registrations through the Office of Population Censuses and Surveys and NHS central register. PATIENTS: All patients (1246 male, 662 female) treated for short stature with pituitary growth hormone under the Medical Research Council working party and health services human growth hormone committee. MAIN OUTCOME MEASURES: Death or development of neoplasia. RESULTS: 110 patients died (68 male, 42 female; aged 0.9-57 years) from 1972 to 1990. Fifty three death were from neoplasia responsible for growth hormone deficiency (27 craniopharyngioma, 24 other intracranial tumour, two leukaemia); two from histiocytosis X; and 13 from pituitary insufficiency. Six patients died of Creutzfeldt-Jakob disease, six of other neurological disorders, and eight of acute infection. Other deaths were apparently unrelated to growth hormone deficiency or its treatment. Seventeen tumours (in 16 patients) were identified during or after growth hormone treatment. Four were in patients with previous intracranial neoplasia and two were after cranial irradiation. Thirteen were intracranial, the others being Hodgkin's lymphoma, osteosarcoma, carcinoma of colon, and basal cell carcinoma. CONCLUSIONS: Recurrence or progression of intracranial tumours and potentially avoidable metabolic consequences of hypopituitarism were the main causes of death. Growth hormone treatment probably did not contribute to new tumour development. Creutzfeldt-Jakob disease after pituitary growth hormone treatment continues to occur in the United Kingdom. This cohort must remain under long term review.

Adolescent↗
PubMed1991

A new syndrome of congenital hypoparathyroidism, severe growth failure, and dysmorphic features.

Twelve infants (six boys, six girls) with severe hypocalcaemic tetany or convulsions were seen over a three year period. Nine patients were symptomatic in the newborn period. Their hypocalcaemia was associated with hyperphosphataemia and very low concentrations of immunoreactive parathyroid hormone. None of the babies suffered from congenital cardiac disease. Cell mediated immunity, measured in five patients, was normal. There were no chromosomal abnormalities but all patients shared several dysmorphic features including deep set eyes, microcephaly, thin lips, beaked nose tip, external ear anomalies, micrognathia, and depressed nasal bridge. Mental retardation of varying degree was found in all patients. All had severe intrauterine and postnatal growth retardation. Four patients have died. The remaining eight patients are on treatments with vitamin D and calcium supplements with no change in their growth pattern. We believe that this association of congenital hypoparathyroidism with severe growth failure and dysmorphism represents a new syndrome.

Abnormalities, Multiple↗
PubMed1991

Tissue and serum insulin-like growth factor I (IGF I) concentrations in rats subjected to temporary protein-energy malnutrition early in life.

Rats subjected to temporary protein-energy malnutrition and subsequent nutritional rehabilitation remain smaller than adequately fed animals, have a subnormal insulin secretion and persisting cellular hypoplasia in several tissues. This investigation studies whether impaired production of insulin-like growth factor I (IGF I) is another persisting consequence of malnutrition. Rats were subjected to severe protein-energy malnutrition between 3 and 6 weeks of age and subsequently fed adequate diet up to 12 weeks of age. Serum and tissue samples for analysis of IGF I were obtained at 12 weeks of age. IGF I concentrations were similar in serum, heart, liver and lung of previously malnourished and control rats. In the kidneys of previously-malnourished rats the IGF I concentration was twice that of control rats. Results suggest that during protein-energy malnutrition and subsequent nutritional rehabilitation IGF I tissue concentrations are primarily regulated by the prevailing plane of nutrition. It is speculated that the temporary protein-energy malnutrition blunts the cellular capacity for IGF I production and, except in the kidney, prevents increased IGF I tissue concentrations and associated compensatory growth.

Aging↗
PubMed1991

Long-term effects on glucose tolerance and insulin secretory response to glucose following a limited period of severe protein or energy malnutrition in young rats.

The long-term effects on growth, glucose tolerance and insulin secretory response to glucose of temporary malnutrition early in life have been investigated. Rats were weaned onto either normal diet (18% protein), a protein-restricted diet (5% protein) or a diet adequate in protein but restricted in amount to equal the energy intake of protein-restricted rats ("energy restriction"). From 6 weeks of age and onwards all rats were fed normal diet. Body weight gain was inhibited by both protein and energy restriction but growth was resumed when rats were transferred to normal diet. Protein restriction impaired glucose tolerance and blunted insulin secretory response to glucose. Following refeeding glucose tolerance was normalized but insulin secretory response remained impaired at 12 weeks of age. Energy restriction did not initially affect glucose tolerance and insulin secretion. However, after refeeding male energy restricted rats developed a delayed and exaggerated insulin secretory response to glucose without concomitant deterioration of glucose tolerance. It is suggested that temporary protein restriction at a young age impairs pancreatic B-cell function and decreases peripheral sensitivity to insulin. By contrast, temporary energy restriction does not directly affect B-cell function but confers insulin resistance and compensatory increases of the insulin secretory response to glucose later in life. These models of malnutrition offer possibilities to further study long-term effects of early nutritional insults.

Animals↗
PubMed1990

Growth failure secondary to moyamoya syndrome.

We describe a boy who presented at the age of 7 years with short stature due to hypopituitarism. Six months after starting appropriate hormone replacement treatment at the age of 8 he suffered his first generalised convulsion. Further neuroradiological investigation led to the diagnosis of moyamoya syndrome.

Arterial Occlusive Diseases↗
PubMed1990

Protein-energy malnutrition induces changes in insulin sensitivity.

Early protein deprivation impairs glucose tolerance and insulin secretion, but the former generally recovers first. We have therefore investigated insulin sensitivity in vivo and in isolated muscle and cultured hepatocytes during protein-energy malnutrition and long-term follow-up in rats. Rats were weaned at 3 weeks onto normal rat chow (N rats) or onto 5% protein diet (LP rats). At 6 w of age LP rats were transferred to N chow. Insulin sensitivity was studied in the three systems at 3, 6, 12 and 24 w. At 6 w LP rats showed a greater and more prolonged fall in serum glucose in response to injected insulin than age--or weight--matched N, but by 12 w the difference was not significant. Similarly, soleus muscle from 6 w LP showed a higher basal rate of glucose transport and responded to a lower insulin dose than N, but there was no difference in sensitivity at 12 w. Hepatocytes from 6 w LP showed higher basal incorporation of glucose into glycogen than N, but insulin sensitivity was not different. Thymidine incorporation into hepatocyte DNA responded to lower insulin doses in 6 w LP than N. There was a decrease in insulin sensitivity with age in all experimental systems. Increased insulin sensitivity during malnutrition was seen in all tissues studied but differences between the two groups were not significant at 12 w and probably do not account for the normal glucose tolerance in the presence of low serum insulin levels previously reported.

Animals↗
PubMed1989

Long-term follow-up after early protein-calorie malnutrition in young rats: sex difference in glucose tolerance and serum insulin levels.

Acute protein-calorie malnutrition impairs both glucose tolerance and insulin secretion, and long-term pancreatic damage leading to malnutrition diabetes has been postulated. The present study has investigated this association in rats weaned onto 5% protein (LP) or 18% protein (normal, N) diet from age 3 weeks to 6 weeks. From 6 weeks both LP and N rats were fed N diet for the remainder of the experiment. LP rats did not grow while on the LP diet and remained significantly lighter for several weeks. Nose to tail tip length was identical for the two groups in both sexes at both 24 and 48 weeks, and mean body weight was not significantly less in LP than N after 18 weeks in either sex. Protein/DNA ratios in LP (an index of cell size) remained lower than N in heart, skeletal muscle, and lung at 24 and 48 weeks, but not in gut, liver, or kidney tissues. Thus, skeletal growth was apparently not impaired by the early malnutrition, but muscle tissue did not catch up. The similarity in final body weight implies greater adipose stores in older LP rats. At 12 weeks there was no difference in glucose tolerance tests (GTT) either between males and females within a dietary group or between N and LP, despite impaired insulin secretion in LP. Both fasting glucose levels and GTT deteriorated markedly between 12 and 48 weeks in all rats, but especially in LP males. Serum insulin levels following glucose injection were lower at 48 weeks than 12 weeks.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1989

Changes in leg length and height during treatment with somatotropin.

Knemometry has been used in a short term double blind placebo controlled trial in 13 patients with normal variant short stature receiving treatment with somatropin to assess the power of the change in lower leg velocity at one month to predict the increase in height velocity at six months. Used in this way the method has a positive predictive value and sensitivity of 90% and a negative predictive value and specificity of 50%. Although not a perfect discriminatory test, knemometry is a more reliable and less invasive way of analysing the likely value of a growth promoting treatment than metabolic assays in individual patients. Given the possible future rapid expansion of the use of somatropin in short stature of various aetiologies there is a need for a relatively simple and inexpensive means of evaluating response to treatment.

Adolescent↗
PubMed1989

Fetal growth signals.

Explore the source record for details and available documents.

Embryonic and Fetal Development↗
PubMed1989

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↗
PubMed1989

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↗
PubMed1986

Which children should have growth hormone therapy?

Existing criteria for the diagnosis of growth hormone (GH) deficiency do not identify all children who can be made to grow faster with GH. There is a spectrum of GH secretion in short slowly growing normal children and in some cases the secretion may be inadequate to promote optimum growth in height. A diagnostic/therapeutic trial of GH therapy, with auxological monitoring, may be the only means of identifying some patients who will benefit. Assessment of the place for GH therapy in the treatment of short stature requires special knowledge of childhood diseases, growth, and endocrinology.

Anthropometry↗
PubMed1985

Insulin as a growth factor.

Insulin is a potent mitogen for many cell types in vitro. During tissue culture, supraphysiological concentrations of insulin are necessary to promote cell replication in connective or musculoskeletal tissues. Insulin promotes the growth of these cells by binding, with low affinity, to the type I insulin-like growth factor (IGF) receptor, not through the high affinity insulin receptor. In other cell types, such as hepatocytes, embryonal carcinoma cells, or mammary tumor cells, the type I IGF receptor is virtually absent, and insulin stimulates the growth of these cells at physiological concentrations by binding to the high affinity insulin receptor. Both receptor systems activate phosphorylation reactions within the cell which extend to ribosomal proteins. Insulin acts synergistically with other factors, such as platelet-derived growth factor and epidermal growth factor, to stimulate the progression of cells through the cycle of proliferation. Abnormal insulin secretion or action, before or after birth, often is associated with disordered growth suggesting that insulin may function as a growth factor in vivo. Poor growth follows impaired insulin secretion in diabetes mellitus. This is associated with reduced circulating levels of IGF's which may be partly responsible for the growth failure. Insulin has a direct action on release of IGF's from the liver in vitro, but during experimental diabetes there is a reduced number of hepatic somatotropic receptors which could limit the ability of growth hormone to regulate IGF release. Diabetic children, treated conventionally, have normal circulating IGF levels, but both growth rate and serum IGF concentration may increase dramatically when diabetic control is optimized.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1979

Experience with human growth hormone in Great Britain: the report of the MRC Working Party.

The Working Party on human growth hormone (hGH) has during the past decade developed a system for the evaluation and treatment of patients suffering from hGH lack. Today there are nineteen measurement centres in the United Kingdom at which patients are assessed and where the effects of therapy are monitored. The current supply of hGH, which is prepared from pituitary glands collected by pathologists in the National Health Service, is just enough to meet demand, but research conducted on behalf of the Working Party suggests that hGH deficiency is more common than has been thought and that the prevalence may be as high as one in 10 000. If, as is hoped, patients are diagnosed younger and more patients with partial deficiency are recognized, demand may soon outstrip supply. Work is in progress to define better methods of hGH production and optimal dose regimens, both of which will help to minimize the problem of supply and demand. A few children have anti-hGH antibodies, which block growth as a result of treatment. Improved hGH production techniques may result in a less antigenic product and the resolution of this problem. Many of the Working Party's activities began as research and have evolved into service. Because of this shift in emphasis, and although much research is still to be done, responsibility for provision of treatment with hGH transferred from the Medical Research Council to the Department of Health and Social Security in July 1977.

Adolescent↗