The physiology and pathophysiology of hepcidin

Hepcidin, the critical iron regulatory factor, is a small peptide produced by the hepatocytes in response to increased body iron and inflammation. Circulating hepcidin controls both intestinal iron absorption and the release of iron from macrophages into plasma via a negative iron feedback system. I developed a novel competitive immunoassay for hepcidin using a polyclonal antibody produced against synthetic hepcidin. I validated the immunoassay and determined it was able to discriminate between healthy controls and selected disease groups. I compared the immunoassay against another established method of measuring hepcidin. I established that plasma hepcidin has a diurnal rhythm and that plasma hepcidin increases in response to intravenous iron in anaemic patients. Elevated levels of hepcidin in renal failure may have a role in the erythropoietin resistance observed in renal anaemia. In haemodialysis patients, hepcidin levels were significantly elevated, but there was no correlation with inflammatory markers. Elevated hepcidin was associated with anemia, but erythropoietin dose was negatively correlated with hepcidin, suggesting that erythropoietin suppresses hepcidin levels. This was confirmed in patients when hepcidin levels significantly decreased after erythropoietin treatment. The association between plasma hepcidin and other iron parameters were also examined in healthy controls after erythropoietin administration and venesection. Profound hepcidin suppression was observed after an erythropoietin dose, with peak levels reduced by 73.2%, and then gradually recovering over the following two weeks. A similar but more gradual change in hepcidin was observed after reducing hematocrit by removal of 250 mL blood. The studies suggested that the marrow–hepcidin axis is regulated by factors other than those specifically investigated. In summary, I have developed and validated a novel immunoassay for hepcidin which will allow further investigation of the vital role of this peptide in iron homeostasis and human physiology

The changing role of local government in Australia : National survey findings

[Extract] The aim of this report is to analyse public perceptions on the changing role of local government in Australia. Exploring how the Australian public views and understands the expansion of local government activity, from the Three Rs to a more expansive if still limited tier of government, offers crucial insights about the sector’s current state and future direction. This report presents the findings from a new national survey of 1,350 respondents who were asked what they saw the role local government to be, what services the sector should deliver, and whether acting on controversial issues to do with national identity, refugee support, and climate change, for example, should be within local government’s remit

The Three Rs and Beyond : Public Perceptions on the Role of Australian Local Government Today

Despite the growing consensus among local government scholars and practitioners that the sector has now moved beyond the ‘Three Rs’, there remains a trenchant perception in public debate that when local councils do more than provide the narrow range of local services to property they are overreaching. But to what extent are these views actually reflective of Australian public opinion? This article reports on the findings of a new national survey and analyses public perceptions on the changing role of local government in Australia. It reaches three key findings. The first is that Australians have now largely outgrown the three longstanding ideological underpinnings of Australian urban politics. The second is that Australians increasingly have an appetite for local government to address contentious cultural and political issues. Finally, the third is that local council category had little effect in determining how residents conceived of the role of local government

Enhancing perceptions of employability amongst first-year arts students and implications for student belonging

Despite being a degree that leads to diverse employment in a wide range of industries, the Bachelor of Arts (BA) has long had a bad reputation when it comes to employment outcomes for graduates. The challenge of overcoming this disjuncture has significant implications for current and prospective BA students, especially with respect to attrition and student satisfaction. In this article, we examine whether interventions that highlight the professional outcomes of the BA have the potential to enhance students’ perceived job prospects and sense of belonging in their study. Specifically, we sought to explore whether careers-focused events that introduce Arts students to professionals with a BA qualification can enhance their perceptions of employability and whether these enhanced perceptions of employability help improve their sense of belonging. The findings confirmed that students enrolled in generalist degrees like the BA do have lower perceived future career prospects, but that careers-focused interventions can enhance perceived career prospects as well as produce a higher sense of student belonging

Circulating pancreatic polypeptide concentrations predict visceral and liver fat content

CONTEXT AND OBJECTIVE: No current biomarker can reliably predict visceral and liver fat content, both of which are risk factors for cardiovascular disease. Vagal tone has been suggested to influence regional fat deposition. Pancreatic polypeptide (PP) is secreted from the endocrine pancreas under vagal control. We investigated the utility of PP in predicting visceral and liver fat. PATIENTS AND METHODS: Fasting plasma PP concentrations were measured in 104 overweight and obese subjects (46 men and 58 women). In the same subjects, total and regional adipose tissue, including total visceral adipose tissue (VAT) and total subcutaneous adipose tissue (TSAT), were measured using whole-body magnetic resonance imaging. Intrahepatocellular lipid content (IHCL) was quantified by proton magnetic resonance spectroscopy. RESULTS: Fasting plasma PP concentrations positively and significantly correlated with both VAT (r = 0.57, P < .001) and IHCL (r = 0.51, P < .001), but not with TSAT (r = 0.02, P = .88). Fasting PP concentrations independently predicted VAT after controlling for age and sex. Fasting PP concentrations independently predicted IHCL after controlling for age, sex, body mass index (BMI), waist-to-hip ratio, homeostatic model assessment 2-insulin resistance, (HOMA2-IR) and serum concentrations of triglyceride (TG), total cholesterol (TC), and alanine aminotransferase (ALT). Fasting PP concentrations were associated with serum ALT, TG, TC, low- and high-density lipoprotein cholesterol, and blood pressure (P < .05). These associations were mediated by IHCL and/or VAT. Fasting PP and HOMA2-IR were independently significantly associated with hepatic steatosis (P < .01). CONCLUSIONS: Pancreatic polypeptide is a novel predictor of visceral and liver fat content, and thus a potential biomarker for cardiovascular risk stratification and targeted treatment of patients with ectopic fat deposition

Hemorrhage-Adjusted Iron Requirements, Hematinics and Hepcidin Define Hereditary Hemorrhagic Telangiectasia as a Model of Hemorrhagic Iron Deficiency

BACKGROUND: Iron deficiency anemia remains a major global health problem. Higher iron demands provide the potential for a targeted preventative approach before anemia develops. The primary study objective was to develop and validate a metric that stratifies recommended dietary iron intake to compensate for patient-specific non-menstrual hemorrhagic losses. The secondary objective was to examine whether iron deficiency can be attributed to under-replacement of epistaxis (nosebleed) hemorrhagic iron losses in hereditary hemorrhagic telangiectasia (HHT). METHODOLOGY/PRINCIPAL FINDINGS: The hemorrhage adjusted iron requirement (HAIR) sums the recommended dietary allowance, and iron required to replace additional quantified hemorrhagic losses, based on the pre-menopausal increment to compensate for menstrual losses (formula provided). In a study population of 50 HHT patients completing concurrent dietary and nosebleed questionnaires, 43/50 (86%) met their recommended dietary allowance, but only 10/50 (20%) met their HAIR. Higher HAIR was a powerful predictor of lower hemoglobin (p = 0.009), lower mean corpuscular hemoglobin content (p<0.001), lower log-transformed serum iron (p = 0.009), and higher log-transformed red cell distribution width (p<0.001). There was no evidence of generalised abnormalities in iron handling Ferritin and ferritin(2) explained 60% of the hepcidin variance (p<0.001), and the mean hepcidinferritin ratio was similar to reported controls. Iron supplement use increased the proportion of individuals meeting their HAIR, and blunted associations between HAIR and hematinic indices. Once adjusted for supplement use however, reciprocal relationships between HAIR and hemoglobin/serum iron persisted. Of 568 individuals using iron tablets, most reported problems completing the course. For patients with hereditary hemorrhagic telangiectasia, persistent anemia was reported three-times more frequently if iron tablets caused diarrhea or needed to be stopped. CONCLUSIONS/SIGNIFICANCE: HAIR values, providing an indication of individuals' iron requirements, may be a useful tool in prevention, assessment and management of iron deficiency. Iron deficiency in HHT can be explained by under-replacement of nosebleed hemorrhagic iron losses

Prohepcidin Levels in Refractory Anaemia Caused by Lead Poisoning

Recent research evidence suggests a central role for hepcidin in iron homeostasis. Hepcidin is a hormone synthesized in the liver. Hepcidin is also thought to play a vital role in the pathogenic mechanism of anaemia in patients with inflammation or chronic disease. A 38-year-old female who presented with recurrent abdominal pain was found to have raised urinary porphyrins and a blood lead level of 779 μg/l. Her haemoglobin level was 8.3 g/dl. Her MCV was normal. Serum ferritin, B12 and folate were normal. Her serum prohepcidin level was 2,489 ng/ml (normal <450 ng/ml). To our knowledge, this is the first report of raised prohepcidin levels in a patient with anaemia of chronic disease resulting from lead poisoning

How Local Governments Govern Culture War Conflicts

While local governments have traditionally been thought relatively powerless and unpolitical, this has been rapidly changing. Recent years have seen local governments jump headfirst into a range of so-called culture war conflicts like those concerning LGBTI rights, refugee protection, and climate change. Using the Australia Day and Columbus Day controversies as case studies, this Element rejuvenates research on how local governments respond to culture war conflicts, documenting new fronts in the culture wars as well as the changing face of local government. In doing this, this Element extends foundational research by advancing four new categories of responsiveness that scholars and practitioners can employ to better understand the varied roles local governments play in contentious culture war conflicts.</jats:p

Hepcidin-25 in diabetic chronic kidney disease is predictive for mortality and progression to end stage renal disease

Background Anemia is common and is associated with impaired clinical outcomes in diabetic chronic kidney disease (CKD). It may be explained by reduced erythropoietin (EPO) synthesis, but recent data suggest that EPO-resistance and diminished iron availability due to inflammation contribute significantly. In this cohort study, we evaluated the impact of hepcidin-25—the key hormone of iron-metabolism—on clinical outcomes in diabetic patients with CKD along with endogenous EPO levels. Methods 249 diabetic patients with CKD of any stage, excluding end-stage renal disease (ESRD), were enrolled (2003–2005), if they were not on EPO-stimulating agent and iron therapy. Hepcidin-25 levels were measured by radioimmunoassay. The association of hepcidin-25 at baseline with clinical variables was investigated using linear regression models. All-cause mortality and a composite endpoint of CKD progression (ESRD or doubling of serum creatinine) were analyzed by Cox proportional hazards models. Results Patients (age 67 yrs, 53% male, GFR 51 ml/min, hemoglobin 131 g/L, EPO 13.5 U/L, hepcidin-25 62.0 ng/ml) were followed for a median time of 4.2 yrs. Forty-nine patients died (19.7%) and forty (16.1%) patients reached the composite endpoint. Elevated hepcidin levels were independently associated with higher ferritin-levels, lower EPO-levels and impaired kidney function (all p<0.05). Hepcidin was related to mortality, along with its interaction with EPO, older age, greater proteinuria and elevated CRP (all p<0.05). Hepcidin was also predictive for progression of CKD, aside from baseline GFR, proteinuria, low albumin- and hemoglobin-levels and a history of CVD (all p<0.05). Conclusions We found hepcidin-25 to be associated with EPO and impaired kidney function in diabetic CKD. Elevated hepcidin-25 and EPO-levels were independent predictors of mortality, while hepcidin-25 was also predictive for progression of CKD. Both hepcidin-25 and EPO may represent important prognostic factors of clinical outcome and have the potential to further define “high risk” populations in CKD