Acute effects of kisspeptin administration on bone metabolism in healthy men

CONTEXT: Osteoporosis results from disturbances in bone formation and resorption. Recent non-human data suggests that the reproductive hormone, kisspeptin, directly stimulates osteoblast differentiation in vitro and thus could have clinical therapeutic potential. However, the effects of kisspeptin on human bone metabolism are currently unknown. OBJECTIVE: To assess the effects of kisspeptin on human bone metabolism in vitro and in vivo. DESIGN: In vitro study: Mono- and co-cultures of human osteoblasts and osteoclasts treated with kisspeptin. Clinical study: Randomized, placebo-controlled, double-blind, two-way crossover clinical study in twenty-six men investigating the effects of acute kisspeptin administration (90 minutes) on human bone metabolism, with blood sampling every 30 minutes to +90 minutes. PARTICIPANTS: In vitro study: Twelve male blood donors and eight patients undergoing hip replacement surgery. Clinical Study: Twenty-six healthy eugonadal men (age 26.8±5.8 years). INTERVENTION: Kisspeptin (versus placebo). MAIN OUTCOME MEASURES: Changes in bone parameters and turnover markers. RESULTS: Incubation with kisspeptin in vitro increased alkaline phosphatase levels in human bone marrow mesenchymal stem cells by 41.1% (P=0.0022), and robustly inhibited osteoclastic resorptive activity by up to 53.4% (P<0.0001), in a dose-dependent manner. Kisspeptin administration to healthy men increased osteoblast activity, as evidenced by a 20.3% maximal increase in total osteocalcin (P=0.021) and 24.3% maximal increase in carboxylated osteocalcin levels (P=0.014). CONCLUSIONS: Collectively, these data provide the first human evidence that kisspeptin promotes osteogenic differentiation of osteoblast progenitors and inhibits bone resorption in vitro. Furthermore, kisspeptin acutely increases the bone formation marker osteocalcin but not resorption markers in healthy men, independent of downstream sex-steroid levels. Kisspeptin could therefore have clinical therapeutic application in the treatment of osteoporosis

A unified approach to Darboux transformations

We analyze a certain class of integral equations related to Marchenko equations and Gel'fand-Levitan equations associated with various systems of ordinary differential operators. When the integral operator is perturbed by a finite-rank perturbation, we explicitly evaluate the change in the solution. We show how this result provides a unified approach to Darboux transformations associated with various systems of ordinary differential operators. We illustrate our theory by deriving the Darboux transformation for the Zakharov-Shabat system and show how the potential and wave function change when a discrete eigenvalue is added to the spectrum.Comment: final version that will appear in Inverse Problem

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

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

Using theory to improve low back pain care in Australian Aboriginal primary care: a mixed method single cohort pilot study

Background: Low back pain (LBP) care is frequently discordant with research evidence. This pilot study evaluated changes in LBP care following a systematic, theory informed intervention in a rural Australian Aboriginal Health Service. We aimed to improve three aspects of care; reduce inappropriate LBP radiological imaging referrals, increase psychosocial oriented patient assessment and, increase the provision of LBP self-management information to patients. Methods: Three interventions to improve care were developed using a four-step systematic implementation approach. A mixed methods pre/post cohort design evaluated changes in the three behaviours using a clinical audit of LBP care in a six month period prior to the intervention and then following implementation. In-depth interviews elicited the perspectives of involved General Practitioners (GPs). Qualitative analysis was guided by the theoretical domains framework. Results: The proportion of patients who received guideline inconsistent imaging referrals (GICI) improved from 4.1 GICI per 10 patients to 0.4 (95 % CI for decrease in rate: 1.6 to 5.6) amongst GPs involved in the intervention. Amongst non-participating GPs (locum/part-time GPs who commenced post-interventions) the rate of GICI increased from 1.5 to 4.4 GICI per 10 patients (95 % CI for increase in rate: .5 to 5.3). There was a modest increase in the number of patients who received LBP self-management information from participating GPs and no substantial changes to psychosocial oriented patient assessments by any participants; however GPs qualitatively reported that their behaviours had changed. Knowledge and beliefs about consequences were important behavioural domains related to changes. Environmental and resource factors including protocols for locum staff and clinical tools embedded in patient management software were future strategies identified. Conclusions: A systematic intervention model resulted in partial improvements in LBP care. Determinants of practice change amongst GPs were increased knowledge of clinical guidelines, education delivered by someone considered a trusted source of information, and awareness of the negative consequences of inappropriate practices, especially radiological imaging on patient outcomes. Inconsistent and non-evidence based practices amongst locum GPs was an issue that emerged and will be a significant future challenge. The systematic approach utilised is applicable to other services interested in improving LBP care

An analysis of the sedimentary hosts to mineralisation at the Cattlegrid Orebody, Mt. Gunson.

This item is only available electronically.The Cattlegrid Orebody is located at the disconformable contact between the Willouran Pandurra Formation and the overlying Marinoan Whyalla Sandstone. Mineralisation is located on a palaeo high of Pandurra quartzite known as the Pernatty Culmination. The Pandurra Formation at the Cattlegrid Mine is a moderately to moderately well-sorted, cross-bedded quartz arenite. Grainsize analysis and cross-bedding data indicates it to be of fluviatile origin, while packing and compaction of the grains suggests a considerable thickness of quartzite has been removed by erosion. The bimodal Whyalla Sandstone is a texturally­inverted subfelsarenite, with well-rounded and spherical quartz grains in a poorly- to moderately-sorted fabric. Ripple marks, truncation of sandy and clay laminations, and a grain-size analysis suggests the Whyalla Sandstone to be a beach deposit. Syndepositional faulting, thickness of the beach deposit and the textural inversion suggest the sandstone to have been reworked by successlve transgressions and regressions. It is in the fractured and brecciated upper Pandurra Formation that the bulk of the mineralisation (chalcocite, bornite, chalcopyrite) is found in fractures and vughs. Basal Whyalla Sandstone is also richly mineralised. Throughout the Cattlegrid Mine, one, occasionally two, predominant lenticular clay bands show evidence of acting as a glide plane. Squeezing of the clay into fractures of the overlying quartzite, striations, and sharp transitions from the Upper Cattlegrid Breccia to the underlying mosaic breccia and displacement of sand wedges, all suggest sliding. The topmost Cattlegrid Breccia is thought to be a bajada breccia underlain by the mosaic breccia, considered to be due to a normal weathering cycle and mild tectonic activity. Gelifluction or periglacial mass movement processes are considered to be the mechanism responsible for the formation of tepee-like anticlines and sand wedges. Cryostatic pressures resulting from the melting of the active and talik layers and lateral movement over the permanently-frozen ground and/or clay band is considered to result in the water-escape anticlinal structures. Tensional fractures resulting from this movement initiated ice wedges. Fluid inclusion data suggest a calcium-rich, highly saline, dense brine precipitated copper-sulphide mineralisation. Waters of a surface origin e.g., connate, meteoric, are therefore ruled out due to the high Ca content and paucity of Na and K salts. YPMA has suggested that these dense brines created instability in the brecciated quartzite due to excessive pore pressures. This instability has caused slumping along a decollement surface and formation of the anticlinal structures and sand wedges. Similar structures are observed in Upper Mississippi Valley Pb-Zn districts. The mixing of this dense copper­-bearing brine with less saline connate waters of the Whyalla Sandstone has caused precipitation of copper sulphides at the disconformable contact.Thesis (B.Sc.(Hons)) -- University of Adelaide, School of Physical Sciences, 198