Activation of Estrogen-Responsive Genes Does Not Require Their Nuclear Co-Localization

The spatial organization of the genome in the nucleus plays a role in the regulation of gene expression. Whether co-regulated genes are subject to coordinated repositioning to a shared nuclear space is a matter of considerable interest and debate. We investigated the nuclear organization of estrogen receptor alpha (ERα) target genes in human breast epithelial and cancer cell lines, before and after transcriptional activation induced with estradiol. We find that, contrary to another report, the ERα target genes TFF1 and GREB1 are distributed in the nucleoplasm with no particular relationship to each other. The nuclear separation between these genes, as well as between the ERα target genes PGR and CTSD, was unchanged by hormone addition and transcriptional activation with no evidence for co-localization between alleles. Similarly, while the volume occupied by the chromosomes increased, the relative nuclear position of the respective chromosome territories was unaffected by hormone addition. Our results demonstrate that estradiol-induced ERα target genes are not required to co-localize in the nucleus

The C-peptide of proinsulin: Its diagnostic use and a possible physiological role.

A radioimmunoassay was developed and validated for human C-peptide in unextracted plasma, using a synthetic 31 amino acid human C-peptide for immunogen, standard and tracer. The sensitivity of the assay (10 pg/tube) enabled the measurement of both fasting and stimulated circulating C-peptide levels. Normal ranges were established in lean healthy volunteers after (a) fasting (b) stimulation of insulin secretion using oral and intravenous stimuli (c) suppression of endogenous insulin secretion using exogenous insulin. Human C-peptide measurements were used to investigate patients presenting with hypoglycaemia due to a number of clinical conditions and were found to be of especial use in the differencial diagnosis of the factitious hypoglycaemia of insulin abuse. A rat C-peptide radioimmunoassay was developed and validated to investigate the possibility that C-peptide, as well as insulin, inhibits fat stimulated GIP release. Both exogenous and endogenous C-peptide were shown to inhibit fat stimulated GIP release in rat fed normal laboratory food. However, neither insulin or C-peptide were effective in inhibiting fat stimulated GIP release in rats maintained on shortterm high fat diets. Studies were, therefore, extended to investigate the feed-back inhibition of exogenous insulin on GIP release in humans maintained on low and high fat dietary regimens. Exogenous insulin was found to be ineffective in inhibiting fat stimulated GIP secretion in subjects maintained on a high fat diet. The control of GIP secretion with its consequent effect on insulin secretion via the enteroinsular axis therefore appears to be affected by dietary fat intake

The C-peptide of proinsulin: Its diagnostic use and a possible physiological role.

A radioimmunoassay was developed and validated for human C-peptide in unextracted plasma, using a synthetic 31 amino acid human C-peptide for immunogen, standard and tracer. The sensitivity of the assay (10 pg/tube) enabled the measurement of both fasting and stimulated circulating C-peptide levels. Normal ranges were established in lean healthy volunteers after (a) fasting (b) stimulation of insulin secretion using oral and intravenous stimuli (c) suppression of endogenous insulin secretion using exogenous insulin. Human C-peptide measurements were used to investigate patients presenting with hypoglycaemia due to a number of clinical conditions and were found to be of especial use in the differencial diagnosis of the factitious hypoglycaemia of insulin abuse. A rat C-peptide radioimmunoassay was developed and validated to investigate the possibility that C-peptide, as well as insulin, inhibits fat stimulated GIP release. Both exogenous and endogenous C-peptide were shown to inhibit fat stimulated GIP release in rat fed normal laboratory food. However, neither insulin or C-peptide were effective in inhibiting fat stimulated GIP release in rats maintained on shortterm high fat diets. Studies were, therefore, extended to investigate the feed-back inhibition of exogenous insulin on GIP release in humans maintained on low and high fat dietary regimens. Exogenous insulin was found to be ineffective in inhibiting fat stimulated GIP secretion in subjects maintained on a high fat diet. The control of GIP secretion with its consequent effect on insulin secretion via the enteroinsular axis therefore appears to be affected by dietary fat intake

Prematurity, Immune Function and Infant Feeding Practices

Recently, there has been much interest in the literature in the role of early nutrition and the health of the individual in adulthood. A majority of infants in the UK are born full term, while pretem infants account for 4-6 % of the total births. Milk feeding practices are divided into three groups: breast, combination (breast-fed with formula as ‘top-up’) and bottle (formula). In studies conducted by our group and other researchers immune function in full-term and preterm infants has been assessed by monitoring total and specific immunoglobulin E and specific immunoglobulin G levels. Dietary modification by the pregnant mother with a history of allergy in the family has been shown to have a positive effect with respect to allergy outcome and prevention of atopic disease in the infant. However, this dietary modification has to occur before week 22 of pregnancy and continue until the end of lactation to achieve a beneficial outcome to the infant. The stress of mothers restricting their diets may be disadvantageous to the fetus, and therefore any gain due to the dietary restriction may be lost. Researchers have shown that the early introduction of complementary foods and the greater diversity of these foods appeared to result in an increase in the incidence of atopic disease in the infant. In conclusion, in order to reduce the risk in their babies, mothers with a family history of atopic disease should breast-feed for more than 15 weeks and introduce solid foods after 4 months, limiting the variety until at least 6 months

Prematurity, Immune Function and Infant Feeding Practices

Recently, there has been much interest in the literature in the role of early nutrition and the health of the individual in adulthood. A majority of infants in the UK are born full term, while pretem infants account for 4-6 % of the total births. Milk feeding practices are divided into three groups: breast, combination (breast-fed with formula as ‘top-up’) and bottle (formula). In studies conducted by our group and other researchers immune function in full-term and preterm infants has been assessed by monitoring total and specific immunoglobulin E and specific immunoglobulin G levels. Dietary modification by the pregnant mother with a history of allergy in the family has been shown to have a positive effect with respect to allergy outcome and prevention of atopic disease in the infant. However, this dietary modification has to occur before week 22 of pregnancy and continue until the end of lactation to achieve a beneficial outcome to the infant. The stress of mothers restricting their diets may be disadvantageous to the fetus, and therefore any gain due to the dietary restriction may be lost. Researchers have shown that the early introduction of complementary foods and the greater diversity of these foods appeared to result in an increase in the incidence of atopic disease in the infant. In conclusion, in order to reduce the risk in their babies, mothers with a family history of atopic disease should breast-feed for more than 15 weeks and introduce solid foods after 4 months, limiting the variety until at least 6 months

Probing the diurnal regulation of glycemic control

Diurnal variation in human glycaemic control was reported by several authors in the 1960s. The classic study carried out by Jarrett and Keen giving oral glucose in the morning and evening established that increased glucose intolerance and insulin resistance occurs later in the day (Jarrett & Keen, 1969), a phenomenon often referred to as "afternoon diabetes". However, despite our long-standing knowledge of this phenomenon, its underlying mechanisms are still not well understood..

Probing the diurnal regulation of glycemic control

Diurnal variation in human glycaemic control was reported by several authors in the 1960s. The classic study carried out by Jarrett and Keen giving oral glucose in the morning and evening established that increased glucose intolerance and insulin resistance occurs later in the day (Jarrett & Keen, 1969), a phenomenon often referred to as "afternoon diabetes". However, despite our long-standing knowledge of this phenomenon, its underlying mechanisms are still not well understood..