Corticosteroid-Binding Globulin – a Targeted Delivery System for Cortisol. Physiology and Responses to Acute and Chronic Inflammation

Corticosteroid-binding globulin (CBG) is the large glycoprotein principally responsible for transporting the life-sustaining hormone cortisol. Levels of biologically active free cortisol are regulated by the concentration and the cortisol-binding affinity of CBG. A member of the serine protease inhibitor superfamily, CBG has a single high-affinity cortisol-binding site per molecule and an exposed reactive centre loop that acts as a protease bait domain for neutrophil elastase, inducing permanent conformational change upon enzymatic cleavage. Allosteric modulation of the inherently plastic binding site reduces the cortisol-binding affinity of CBG by ten-fold (high cortisol-binding affinity CBG [haCBG] -> low cortisolbinding affinity CBG [laCBG]), favouring cortisol release in vitro. The targeted deposition of free cortisol at sites of inflammation facilitates down-stream genomic and non-genomic immunomodulatory, anti-inflammatory effects, neurocognitive and metabolic effects. Novel measurement of haCBG and total CBG by enzyme-linked immunosorbent assay is at the forefront of research into CBG cleavage in vivo. The present thesis utilises this recent development in seven clinical studies to translate existing evidence of the cleavage phenomenon to the clinical setting for the first time, with the aim of determining whether haCBG levels were associated with illness severity and clinical outcomes in inflammatory states. We hypothesised that depletion of anti-inflammatory CBG-cortisol is a key mechanism in the pathogenesis of uncontrolled inflammation in systemic inflammatory disorders. Studies of haCBG and laCBG levels in acute inflammatory conditions showed that increasing illness severity in sepsis and septic shock was associated with markedly reduced circulating haCBG concentrations in vivo, with illness severity correlating better with haCBG levels than either free or total cortisol levels. CBG cleavage also occurred in patients with severe infection, including Pseudomonal infection. Administration of the pro-inflammatory cytokine tumour necrosis factor-α did not induce CBG cleavage or the acute phase response immediately (< 6 hours) post-infusion. These studies suggest that in acute inflammation, depletion of haCBG may limit the availability of cortisol to inflammatory sites, perpetuating inflammation, however greater than six hours is required for CBG cleavage to become effectual. Additionally, the pathogen inciting a systemic inflammatory response may influence the propensity for CBG cleavage. We also present evidence of CBG as a thermocouple early in inflammation to enhance free cortisol levels. In contrast, chronic inflammatory states displayed reduced CBG cleavage, including the metabolic syndrome and rheumatoid arthritis, in association with worsening disease activity. Thus compromised cleavage may hinder CBG-mediated delivery of anti-inflammatory cortisol. Studies in patients with α1 antitrypsin deficiency showed that paradoxically, proteolytic cleavage of CBG was reduced despite increased neutrophil elastase activity. Our data suggest cleavage is mediated by alternate proteases in some circumstances. In pregnancy, CBG increases three-fold, and we show that this increase is due to haCBG alone which may provide an increased reservoir of CBG-bound cortisol for immunomodulatory purposes in puerperal infection. In comparison, the rise in CBG in women receiving exogenous oestrogens is due to elevated haCBG as well as laCBG, while neither haCBG nor laCBG levels change following menopause, challenging the mechanisms governing oestrogen-mediated CBG production. In summary, this pioneering research reveals perturbations in haCBG and laCBG levels in health and disease which had hitherto been unrecognised. The absolute pool of haCBGcortisol, and the accessibility of that pool to cleavage bears significant influence over inflammatory outcomes. Post-translational modification including glycosylation or genetic CBG variation may contribute to haCBG dysregulation. The role and relevance of CBG as a releasing agent and an anti-inflammatory molecule is more complex and adapted than currently appreciated, and holds great opportunity for diagnostic and therapeutic application.Thesis (Ph.D.) -- University of Adelaide, Adelaide Medical School, 201

Sheep Updates 2008 - part 1

This session covers five papers from different authors: KEYNOTE 1. Global trends in consumer and community expectations and their affect on the market, Dr David Hughes, Imperial College, London. (Powerpoint) PLENARY 2. Animal welfare - trends and opportunities, Tony Higgs, Di Evans, Department of Agriculture and Food WA 3. Australia\u27s live sheep exports to Saudi Arabia, Scott Hansen, Meat & Livestock Australia 4. Livestock Welfare Challenges in Road Transport, Dr Mike Paton, Department of Agriculture and Food, Western Australia 5. My 2020 Summit Experience, Mary Nenke, Producer Kukerin W

A nationwide assessment of hepatocellular adenoma resection:Indications and pathological discordance

Hepatocellular adenomas (HCAs) are benign liver tumors associated with bleeding or malignant transformation. Data on the indication for surgery are scarce. We analyzed indications and outcome of patients operated for HCAs 50 mm (52%), suspicion of (pre)malignancy (28%), and (previous) bleeding (5.1%). No difference was observed in HCA-subtype distribution between small and large tumors. Ninety-six (43%) patients had a postoperative change in diagnosis. Independent risk factors for change in diagnosis were tumor size <50 mm (adjusted odds ratio [aOR], 3.4; p < 0.01), male sex (aOR, 3.7; p = 0.03), and lack of hepatobiliary contrast-enhanced magnetic resonance imaging (CE-MRI) (aOR, 1.8; p = 0.04). Resection for small (suspected) HCAs was mainly indicated by suspicion of (pre)malignancy, whereas for large (suspected) HCAs, tumor size was the most prevalent indication. Male sex, tumor size <50 mm, and lack of hepatobiliary CE-MRI were independent risk factors for postoperative change in tumor diagnosis

Emerging Role of Corticosteroid-Binding Globulin in Glucocorticoid-Driven Metabolic Disorders

Glucocorticoid hormones (GCs) are critical for survival since they ensure the energy supply necessary to the body in an ever challenging environment. GCs are known to act on appetite, glucose metabolism, fatty acid metabolism, and storage. However, to be beneficial to the body, GC levels should be maintained in an optimal window of concentrations. Not surprisingly, conditions of GC excess or deficiency, e.g., Cushing's syndrome or Addison's disease, are associated with severe alterations of energy metabolism. Corticosteroid-binding globulin (CBG), through its high specific affinity for GCs, plays a critical role in regulating plasma GC levels and their access to target cells. Genetic studies in various species including humans have revealed that CBG is the major factor influencing interindividual genetic variability of plasma GC levels, both in basal and stress conditions. Some, but not all, of these genetic studies have also provided data linking CBG levels to body composition and insulin levels. The examination of CBG-deficient mice submitted to hyperlipidic diets unveiled specific roles for CBG in lipid storage and metabolism. An influence of CBG on appetite has not been reported but remains to be more finely analyzed. Finally, only male mice have been examined under high-fat diet, while obesity is affecting women even more than men. Overall, a role of CBG in GC-driven metabolic disorders is emerging in recent studies. Although subtle, the influence of CBG in these diseases could open the way to new therapeutic interventions since CBG is easily accessible in the blood

Geochemistry and mineragraphy of the Nairne Pyrite deposit, Brukunga, South Australia

This item is only available electronically.A mineragraphic study of the mineralogy of tension gash veins at the Nairne Pyrite Deposit, has revealed the existence of boulangerite, stannite ullmannite, freibergite, pyrargyrite and cubanite. Larger amounts of pyrite, pyrrhotite, galena, arsenopyrite, sphalerite and chalcopyrite were also observed. Sulphur, iron and trace element geochemistry of the deposit has been studied in relation to the ore beds, waste beds and enclosing meta-shales. A statistical interpretation of the geochemical data was made using correlation coefficients and cluster analyses. Elemental ratios (Co/Ni, Cu/Zn, S/Se) were calculated. The results of carbon analyses add weight to the proposed theory of a sedimentary origin for the Nairne Pyrite Deposit.Thesis (B.Sc.(Hons)) -- University of Adelaide, School of Earth and Environmental Sciences, 197

Corticosteroid-binding globulin cleavage is paradoxically reduced in alpha-1 antitrypsin deficiency: implications for cortisol homeostasis

Abstract not availableMarni A. Nenke, Mark Holmes, Wayne Rankin, John G. Lewis, David J. Torp

Corticosteroid-binding globulin cleavage may be pathogen-dependent in bloodstream infection

Abstract not availableMarni A. Nenke, John G. Lewis, Wayne Rankin, David Shaw, David J. Torp