5alpha-reduced glucocorticoids, novel endogenous activators of the glucocorticoid receptor.

Metabolism of glucocorticoids to A-ring-reduced dihydro- and tetrahydro-derivatives by means of hepatic 5alpha- and 5beta-reductases has long been regarded as a pathway of irreversible inactivation. However, 5alpha-reduced metabolites of other steroids, e.g.

11 beta-hydroxysteroid dehydrogenase type 1 in obesity and the metabolic syndrome.

11 beta-Hydroxysteroid dehydrogenase type 1 (11HSD1) catalyses the in vivo conversion of inactive to active glucocorticoids. It is a widespread, highly regulated enzyme which amplifies the ligand available for intracellular glucocorticoid receptors. Excessive glucocorticoid exposure causes central obesity, hypertension, dyslipidaemia and insulin resistance, as seen with elevated plasma cortisol in Cushing's syndrome.

A novel azulene synthesis from the Ramirez ylide involving two different modes of its reaction with activated alkynes.

The Ramirez ylide undergoes electrophilic substitution with acetylenedicarboxylates to form Z and E adducts. The latter can react by cycloaddition with another equivalent of the alkyne to provide a new route to novel tetra-substituted azulenes, which show interesting bond localisation and crystal packing effects.

Influence of short-term dietary weight loss on cortisol secretion and metabolism in obese men.

Objectives: Obesity is associated with increased inactivation of cortisol by hepatic A-ring 5alpha- and 5beta-reductases, impaired hepatic regeneration of cortisol from cortisone by 11beta-hydroxysteroid dehydrogenase type 1 (11HSD1), but increased subcutaneous adipose 11HSD1 activity enhancing local cortisol levels in fat. Cause and effect between obesity and abnormal cortisol metabolism is untested.

Design: Acute weight loss was induced by very low calorie diet (VLCD) or starvation in obese men.

Glucocorticoids and 11beta-hydroxysteroid dehydrogenase in adipose tissue.

The highly prevalent metabolic syndrome (insulin resistance, type 2 diabetes, dyslipidemia, hypertension, along with abdominal obesity) resembles Cushing's syndrome. However, in simple obesity, plasma cortisol levels are not elevated. 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), at least in mature adipocytes and hepatocytes, converts inactive circulating 11-keto steroids into active glucocorticoids, amplifying local glucocorticoid action.

Low birth weight predicts higher blood pressure but not dermal capillary density in two populations.

The association between low birth weight and high blood pressure is well established, but underlying mechanisms remain undefined. Vascular rarefaction, which may elevate peripheral vascular resistance, has been observed in capillaries of young men at risk for hypertension and men who had low birth weight. We looked for evidence that capillary rarefaction explains the association of low birth weight with high blood pressure in two cohorts.

The effects of combined aromatase inhibitor and anti-androgen on male territorial aggression in a tropical population of rufous-collared sparrows, Zonotrichia capensis.

Territorial aggression, exhibited by male vertebrates in a reproductive context, is generally thought to be mediated by elevated levels of the gonadal steroid hormone testosterone. Rufous-collared sparrows from Papallacta, Ecuador are only aggressive during the breeding season when plasma testosterone concentrations are elevated. However, previous experiments have determined that during the breeding season testosterone does not increase in response to territorial challenges and testosterone implants do not make males more aggressive.

Review of the quality monitoring methods used by countries using or implementing universal leukoreduction.

Several countries are implementing or have implemented universal leukoreduction (ULR). Specifications, leukocyte counting, and monitoring methods were essential elements in achieving process confidence and conformance. A review of these protocols is presented.

The divergent 5' ends of DPM2 mRNAs originate from the alternative splicing of two adjacent introns: characterization of the hamster DPM2 gene.

Mammalian dolichol-phosphate-mannose (DPM) synthase has three subunits, DPM1, DPM2, and DPM3. In this report, an analysis of the gene and cDNAs of hamster DPM2 is presented. The CHO DPM2 gene has two special features.

A single point mutation resulting in an adversely reduced expression of DPM2 in the Lec15.1 cells.

Mammalian dolichol-phosphate-mannose (DPM) synthase consists of three subunits, DPM1, DPM2, and DPM3. Lec15.1 Chinese hamster ovary cells are deficient in DPM synthase activity.

11beta-hydroxysteroid dehydrogenase type 1 as a novel therapeutic target in metabolic and neurodegenerative disease.

11beta-hydroxysteroid dehydrogenase Type 1 (11HSD1) catalyses regeneration of active 11-hydroxy glucocorticoids from inactive 11-keto metabolites within target tissues. Inhibition of 11HSD1 has been proposed as a novel strategy to lower intracellular glucocorticoid concentrations, without affecting circulating glucocorticoid levels and their responsiveness to stress. Increased 11HSD1 activity may be pathogenic, for example, in adipose tissue in obesity.

Altered peripheral sensitivity to glucocorticoids in primary open-angle glaucoma.

Purpose: Increased levels of glucocorticoids are associated with raised intraocular pressure (IOP). The activity of glucocorticoids is regulated at a prereceptor level by 11beta-hydroxysteroid dehydrogenases (11beta-HSD). This study was an investigation of the central and peripheral sensitivity to glucocorticoids in patients with POAG or ocular hypertension (OHT) and the differential metabolism of glucocorticoids by 11beta-HSDs.

Coping with uncertainty: a call for a new science-policy forum.

The scientific and policy worlds have different goals, which can lead to different standards for what constitutes "proof" of a change or phenomena, and different approaches for characterizing and conveying uncertainty and risk. These differences can compromise effective communication among scientists, policymakers, and the public, and constrain the types of socially compelling questions scientists are willing to address. In this paper, we review a set of approaches for dealing with uncertainty, and illustrate some of the errors that arise when science and policy fail to coordinate correctly.

Body fat distribution and cortisol metabolism in healthy men: enhanced 5beta-reductase and lower cortisol/cortisone metabolite ratios in men with fatty liver.

In Cushing's syndrome, cortisol causes fat accumulation in specific sites most likely to be associated with insulin resistance, notably in omental adipose and also perhaps in the liver. In idiopathic obesity, cortisol-metabolizing enzymes may play a key role in determining body fat distribution. Increased regeneration of cortisol from cortisone within adipose by 11beta-hydroxysteroid dehydrogenase (HSD) type 1 (11HSD1) has been proposed to cause visceral fat accumulation, whereas decreased hepatic 11HSD1 may protect the liver from glucocorticoid excess.

The proteasome: a novel therapeutic target in haematopoietic malignancy.

The proteasome plays a key role in regulating protein degradation in eukaryotic cells. A range of synthetic inhibitors of proteasome activity have been developed which have helped elucidate its role in the cell. These inhibitors have selectively induced apoptosis in malignant cells in vitro suggesting that the proteasome may be a novel therapeutic target.

11beta-hydroxysteroid dehydrogenase type 2 in mouse aorta: localization and influence on response to glucocorticoids.

Both isozymes of 11beta-hydroxysteroid dehydrogenase, which interconvert active and inactive glucocorticoids, are expressed in the mouse aortic wall. Mice deficient in 11HSD type 2 (which converts active corticosterone into inert 11-dehydrocorticosterone) have hypertension and impaired endothelial nitric oxide activity. It has been suggested that 11HSD2 influences vascular function directly by limiting glucocorticoid-mediated inhibition of endothelium-derived nitric oxide.

Local and systemic impact of transcriptional up-regulation of 11beta-hydroxysteroid dehydrogenase type 1 in adipose tissue in human obesity.

In idiopathic obesity circulating cortisol levels are not elevated, but high intraadipose cortisol concentrations have been implicated. 11beta-Hydroxysteroid dehydrogenase type 1 (11HSD1) catalyzes the conversion of inactive cortisone to active cortisol, thus amplifying glucocorticoid receptor (GR) activation. In cohorts of men and women, we have shown increased ex vivo 11HSD1 activity in sc adipose tissue associated with in vivo obesity and insulin resistance.

The clinical significance of cathepsin S expression in human astrocytomas.

Early local invasion by astrocytoma cells results in tumor recurrence even after apparent total surgical resection, leading to the poor prognosis associated with malignant astrocytomas. Proteolytic enzymes have been implicated in facilitating tumor cell invasion and the current study was designed to characterize the expression of the cysteine proteinase cathepsin S (CatS) in astrocytomas and examine its potential role in invasion. Immunohistochemical analysis of biopsies demonstrated that CatS was expressed in astrocytoma cells but absent from normal astrocytes, oligodendrocytes, neurones and endothelial cells.

Obese Zucker rats have reduced mineralocorticoid receptor and 11beta-hydroxysteroid dehydrogenase type 1 expression in hippocampus-implications for dysregulation of the hypothalamic-pituitary-adrenal axis in obesity.

Obese Zucker rats have elevated basal corticosterone levels and an increased stress response suggestive of an increased activity of the hypothalamic-pituitary-adrenal (HPA) axis. We hypothesized that altered central expression of glucocorticoid receptors (GR), mineralocorticoid receptors (MR), and/or 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1) contribute to these changes. In brains from young adult male rats, in situ hybridization and Western blotting showed that obese rats had normal hippocampal GR mRNA and protein levels.

Subcutaneous adipose 11 beta-hydroxysteroid dehydrogenase type 1 activity and messenger ribonucleic acid levels are associated with adiposity and insulinemia in Pima Indians and Caucasians.

Metabolic effects of cortisol may be critically modulated by glucocorticoid metabolism in tissues. Specifically, active cortisol is regenerated from inactive cortisone by the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11-HSD1) in adipose and liver. We examined activity and mRNA levels of 11-HSD1 and tissue cortisol and cortisone levels in sc adipose tissue biopsies from 12 Caucasian (7 males and 5 females) and 19 Pima Indian (10 males and 9 females) nondiabetic subjects aged 28 +/- 7.

Predicting cardiovascular risk factors from plasma cortisol measured during oral glucose tolerance tests.

Increasing evidence suggests that activation of the hypothalamic-pituitary-adrenal (HPA) axis may contribute to the pathogenesis of the metabolic syndrome and obesity. The mechanisms are unknown but may involve alterations in the metabolic responses to feeding that interact with the HPA axis. As it is known that plasma cortisol falls during an oral glucose tolerance test (OGTT), changes in cortisol measured during an OGTT may be altered in the metabolic syndrome.

Ten years on: Safety of short synacthen tests in assessing adrenocorticotropin deficiency in clinical practice.

Since 1988, when a retrospective study of patients attending this unit was published, we have advocated the use of the short synacthen test (SST) as the primary screening investigation to detect ACTH deficiency. However, others have published comparisons of SST and insulin tolerance tests that suggest a significant false negative rate with SST, leading to concern that some patients who pass the SST are in danger from the clinical consequences of ACTH deficiency. To address this, we audited biochemical results and clinical outcome in 63 patients who did not have ACTH deficiency detected (i.