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D Burt

Publications and source records attributed to D Burt.

At least 37 records · Page 2Linked to original sources
PubMed1996

Conservation of synteny between the genome of the pufferfish (Fugu rubripes) and the region on human chromosome 14 (14q24.3) associated with familial Alzheimer disease (AD3 locus)

The genome of the pufferfish (Fugu rubripes) (400 Mb) is approximately 7.5 times smaller than the human genome, but it has a similar gene repertoire to that of man. If regions of the two genomes exhibited conservation of gene order (i.e., were syntenic), it should be possible to reduce dramatically the effort required for identification of candidate genes in human disease loci by sequencing syntenic regions of the compact Fugu genome. We have demonstrated that three genes (dihydrolipoamide succinyltransferase, S31iii125, and S20i15), which are linked to FOS in the familial Alzheimer disease focus (AD3) on human chromosome 14, have homologues in the Fugu genome adjacent to Fugu cFOS. The relative gene order of cFOS, S31iii125, and S20i15 was the same in both genomes, but in Fugu these three genes lay within a 12.4-kb region, compared to >600 kb in the human AD3 locus. These results demonstrate the conservation of synteny between the genomes of Fugu and man and highlight the utility of this approach for sequence-based identification of genes in human disease loci.

Acyltransferases↗
PubMed1996

Expression and regulation of Cek-8, a cell to cell signalling receptor in developing chick limb buds.

The Eph-related receptor tyrosine kinase gene, Cek-8, is expressed in mesenchyme at the tip of chick limb buds, with high levels of transcripts posteriorly and apically but fading out anteriorly. Expression of Cek-8 in distal mesenchyme is regulated by apical ridge- and FGF-polarising signals and retinoic acid, and is uniform across the anteroposterior axis in talpid3 mutants. These data indicate that Cek-8 expression responds to regulatory signals during limb patterning and suggest that this receptor tyrosine kinase may have a role in coordinating responses to signals in the progress zone of early buds. Later on in limb development, Cek-8 expression is associated with cell condensations that form tendons and their attachments to cartilage rudiments and then in developing feather buds.

Animals↗
PubMed1995

Etomidate potentiation of GABAA receptor gated current depends on the subunit composition.

The role of the gamma 2 subunit in etomidate potentiation of GABAA receptor-gated chloride current was studied by whole cell patch clamp experiments on H293 cells expressing GABAA receptors. The GABAA receptor subunits alpha 1 beta 1 with or without the gamma 2 subunit expressed well, with an overall peak current of 157 +/- 42 pA/pF. At a clinically relevant concentration, etomidate potentiates the peak current induced by GABA equally well in receptors with or without the gamma 2 subunit. In contrast, the time course of current decay was prolonged only in receptors with the gamma 2 subunit. This gamma 2 subunit-dependent prolongation of the current time course was not blocked by the benzodiazepine receptor antagonist flumazenil. These results show that etomidate, an imidazole general anesthetic, interacts with the GABAA receptor in a gamma 2 subunit-dependent manner.

Action Potentials↗
PubMed1995

Serum sialic acid concentration and coronary heart disease in NIDDM.

OBJECTIVE--To examine the association between serum sialic acid concentrations and coronary heart disease (CHD) in a cross-sectional study of non-insulin-dependent diabetes mellitus (NIDDM). RESEARCH DESIGN AND METHODS--NIDDM patients (n = 145) attending a diabetic clinic were studied. CHD status was assessed by questionnaire and electrocardiogram coding, and potential risk factor assessment included measurement of fasting serum lipid and lipoprotein concentrations, blood pressure, and urinary albumin excretion rate (AER). RESULTS--Male NIDDM patients with CHD had a higher serum sialic acid level than those without CHD: 2.56 (2.24, 2.72) mmol/l vs. 2.24 (2.18, 2.30) mmol/l, P = 0.01, mean (95% confidence interval). They were also older, had a longer duration of diabetes, had a higher AER, had higher total triglyceride, very-low-density lipoprotein triglyceride and cholesterol, and lipoprotein(a) concentrations, and had a lower apolipoprotein A1 concentration. In an age adjusted multiple lipoprotein(a), hypercholesterolemia, and hypertension were associated with CHD. In women, only hypertension treatment was associated with CHD. CONCLUSIONS--There is a strong univariate association between elevated serum sialic acid and CHD in men (but not women) with NIDDM.

Adult↗
PubMed1993

11-beta-hydroxysteroid dehydrogenase activity and gene expression in the hypertensive Bianchi-Milan rat.

OBJECTIVE: 11 beta-Hydroxysteroid dehydrogenase (11 beta-HSD), by converting the active steroids cortisol and corticosterone to their inactive metabolites, regulates steroid exposure to the mineralocorticoid and glucocorticoid receptors. We explored the hypothesis that a defect in 11 beta-HSD could result in overstimulation of either the mineralocorticoid or glucocorticoid receptors with subsequent hypertension in an established animal model of hypertension, the Bianchi-Milan hypertensive (BMH) rat. DESIGN AND METHODS: Groups of BMH rats with established hypertension (42-46 days old) and prehypertensive rats (22 days old) were compared with age-matched normotensive control rats. Kidney and liver 11 beta-HSD and glucocorticoid receptor messenger RNA (mRNA) levels were assessed by Northern and dot-blot analyses, and 11 beta-HSD activity as percentage conversion of [3H]-corticosterone to [3H]11-dehydrocorticosterone by tissue homogenate. RESULTS: Hepatic 11 beta-HSD activity and gene expression were significantly reduced in the hypertensive BMH rat compared with its normotensive genetic control. 11 beta-HSD activity was also reduced in the prehypertensive BMH rat (aged 25 days) from hypertensive parents, excluding hypertension per se as the cause of the abnormality. Plasma corticosterone was higher in the hypertensive rats. There was no difference in renal 11 beta-HSD activity or gene expression between hypertensive and normotensive BMH rats, or in glucocorticoid receptor gene expression in the liver or kidney. CONCLUSIONS: Normal levels of renal 11 beta-HSD mRNA and activity are found in the BMH rat. However, the hypertensive BMH rat does demonstrate impaired hepatic 11 beta-HSD activity which occurs at a pretranslational level, although it is not clear how this relates to the pathogenesis of hypertension in this model.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1991

Liquorice.

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11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1991

Cellular immune recognition of HLA-G-expressing choriocarcinoma cell line Jeg-3.

Jeg-3 choriocarcinoma cells express class-I MHC HLA-G and low levels of a novel HLA-C product. The functional significance of such novel MHC class-I expression in regard of the cellular immune response has been investigated. Jeg-3 cells are NK-insensitive, but susceptible to LAK cytotoxicity, some of which is mediated by T cells. No Jeg-3-specific CTL or proliferative responses could be generated in allogeneic responder PBMC from several different donors. There was no detectable xenogeneic recognition of Jeg-3 cells even when preceded by in vivo priming. Jeg-3 cells are able to suppress proliferative responses in humans and others species. This is not reproduced by conditioned medium from the Jeg-3 cells, but can be overridden by IL-2. The ability of the Jeg-3 choriocarcinoma (trophoblast) cells to suppress in the MLR may reflect the processes which are shared to enable the survival of the foetus in a semi-allogeneic mother or a tumour in its host. It is not clear whether there is any relationship between the unusual class-I-MHC expression by trophoblast and the putative regulatory properties of the latter.

Animals↗
PubMed1990

Potentiation of hydrocortisone activity in skin by glycyrrhetinic acid.

The enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD), which catalyses the conversion of cortisol to the inactive steroid cortisone in man (and corticosterone to 11-dehydrocorticosterone in rodents), was demonstrated by immunohistochemistry in skin biopsy samples from healthy volunteers and from patients with psoriasis and eczema. In-vitro studies confirmed the presence of the enzyme in skin from nude mice and showed that it is inhibited by glycyrrhetinic acid, the major active component of liquorice. By means of the skin vasoconstrictor assay, glycyrrhetinic acid was shown to potentiate the action of hydrocortisone. This work suggests a novel means of targeting glucocorticoid therapy.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1989

The specificity of the human mineralocorticoid receptor: clinical clues to a biological conundrum.

Data from in vitro studies show that the mineralocorticoid receptor has an equal affinity for cortisol and aldosterone. This contrasts with the well known selectivity of aldosterone for binding to tissues such as the kidney despite the much higher circulating levels of glucocorticoids. This paper puts forward the hypothesis that the enzyme 11 beta-hydroxysteroid dehydrogenase (11 beta-OHSD) is responsible for determining this selectivity. Congenital or acquired deficiency of this enzyme results in a failure of the normal protective mechanism by which cortisol is converted to cortisone or corticosterone to 11-dehydrocorticosterone. As a result the receptor is exposed to cortisol or corticosterone in high concentration which results in sodium retention and potassium loss. In contrast the hippocampal type 1 receptor is associated with much lower 11 beta-OHSD activity and is thus not aldosterone-selective.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1989

The kidney is the major site of cortisone production in man.

The major site of cortisol metabolism in man has been thought to be the liver. Studies in patients with either congenital or acquired deficiency of 11 beta-hydroxysteroid dehydrogenase (an enzyme responsible for the interconversion of cortisol to cortisone) suggested that the kidney was an important site of cortisone production. In 88 patients with proven renal disease but normal liver function, arbitrarily divided into four groups on the basis of plasma creatinine, 0900 h plasma cortisone was significantly reduced in all groups when compared with 47 controls (e.g. 21 +/- 3 nmol/l (mean +/- SEM) in patients with plasma creatinine greater than 0.45 mmol/l vs 62 +/- 3 nmol/l in controls, P less than 0.001). 0900 h plasma cortisol was not significantly different. There was an inverse correlation between plasma creatinine and plasma cortisone (r = -0.55, p less than 0.01). Four anephric patients had a 0900 h plasma cortisone level of 6 +/- 1 nmol/l. We conclude that the kidney is a major site for the conversion of cortisol to cortisone and hence cortisone production in man. The relevance of this to the pathophysiology of salt and water metabolism in renal disease remains to be elucidated.

Adult↗
PubMed1989

A lack of genetic linkage of renin gene restriction fragment length polymorphisms with human hypertension.

Because renin is an important enzyme in blood pressure regulation, we studied the possibility that an alteration in the structure of the human renin gene is genetically linked to human essential hypertension or associated with levels of plasma renin activity or blood pressure. By using specific DNA probes, we have identified four polymorphisms in the human renin gene with the restriction enzymes Taq I, HindIII, Bgl I, and Bgl II. The gene location of all of these polymorphisms except for the Bgl II polymorphism has been determined, and their frequencies were initially estimated in a population of 50 random subjects. To test the clinical significance of these polymorphisms, we studied 68 persons from a large Utah pedigree with a high incidence of hypertension. Among nine relatives with hypertension, genetic linkage without recombination was ruled out by observing several obligate recombinants. We also found no significant association of the restriction fragment length polymorphisms with quantitative measurements of sitting or standing, systolic or diastolic blood pressures, or plasma renin activity in 59 untreated members of this pedigree. Although we found no genetic linkage in this set of study subjects, the characterization of the restriction fragment length polymorphisms for the renin gene may be useful in future studies of other selected pedigrees for the presence of one or more of these to be a genetic marker in hypertension.

Gene Frequency↗
PubMed1989

Licorice inhibits corticosteroid 11 beta-dehydrogenase of rat kidney and liver: in vivo and in vitro studies.

In humans, glycyrrhetinic acid (GE), the active pharmacological ingredient of licorice, produces symptoms resembling those caused by excess mineralocorticoid secretion. We are proposing that 11 beta-dehydrogenase inhibition, and not intrinsic mineralocorticoid activity, is the primary mechanism of licorice induced pseudoaldosteronism. Glycyrrhizic acid (glycyrrhetinic acid glucuronide), when given orally to rats, partially inhibited renal 11 beta-dehydrogenase. In rats treated with dexamethasone before glycyrrhizic acid administration there was similar enzyme inhibition, suggesting that antimineralocorticoid effects of dexamethasone in licorice excess states are not mediated through a direct effect on 11 beta-dehydrogenase activity. Dispersed renal proximal tubular preparations, kidney homogenates, and microsomes readily converted corticosterone to 11-dehydrocorticosterone. GE and its synthetic analog carbenoxolone inhibited the conversion in these systems in a dose-dependent manner. Corticosteroid 11-oxoreductase, which was present in kidney homogenates at a level 10-20% that of 11 beta-dehydrogenase was not inhibited by any of the agents. With homogenate and microsomes, the Ki of GE was about 10(-9)-10(-8) M; with intact tubules, the Ki of GE was about 10(-5)-10(-6) M. It is suggested that a permeability barrier slows the entry of GE into the tubule cells. We conclude that the effects of licorice on corticosteroid metabolism in the kidney are based on its inhibition of 11 beta-dehydrogenase. Our data, supplemented by published evidence, is inconsistent with the conclusion that interaction with mineralocorticoid receptors accounts for the pharmacological effects of GE.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1988

Localisation of 11 beta-hydroxysteroid dehydrogenase--tissue specific protector of the mineralocorticoid receptor.

In vitro the mineralocorticoid receptor is non-specific and does not distinguish between aldosterone and cortisol. In vivo certain tissues with this receptor are aldosterone selective (eg, kidney and parotid) whereas others with the same receptor are not (eg, hippocampus and heart). Experiments in rats showed that 11 beta-hydroxysteroid dehydrogenase (which converts cortisol to cortisone in man and corticosterone to 11-dehydrocorticosterone in the rat) was much more highly concentrated in aldosterone-selective tissues than in non-selective tissues. The localisation in the selective tissues was such that the enzyme could act as a paracrine or possibly an autocrine mechanism protecting the receptor from exposure to corticosterone. Autoradiographic studies showed that protection is lost when the enzyme is inhibited; 3H-corticosterone and 3H-aldosterone were bound to similar sites. These findings seem to explain why sodium retention, hypokalaemia, and hypertension develop in subjects with congenital deficiency of 11 beta-OHSD and those in whom the enzyme has been inhibited by liquorice.

11-beta-Hydroxysteroid Dehydrogenases↗