Search

Mathematics is a language -- a way of describing, recording in mathematical sentences, and interpreting the symbols used to denote relationships. It is also an activity involving a way of thinking and a means of using relationships to solve problems. Opportunities must be provided for these activities in mathematics teaching. (Author/JN)

Abstract Background The enzyme 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) converts inactive cortisone into active cortisol in insulin target tissues. In people with type 2 diabetes, skeletal muscle (SkM) 11βHSD1 is upregulated by the potent glucocorticoid dexamethasone. The HSD11B1 gene has two promoters designated P1 and P2. CCAAT/enhancer-binding protein beta (C/EBPβ) is known to regulate expression of 11βHSD1 via the P2 promoter. In this study, we investigated the potential role of altered DNA methylation of the P1 and P2 promoters in the observed dexamethasone-induced upregulation of SkM 11βHSD1 oxoreductase activity in human diabetic subjects. SkM biopsies from 15 people with type 2 diabetes were collected before and after treatment with oral dexamethasone 4 mg/day for 4 days and SkM 11βHSD1, C/EBPβ and P1 and P2 promoter region mRNA levels were measured by quantitative RT-PCR. 11βHSD1 oxoreductase activity was quantified by measuring the conversion of radiolabeled 3H-cortisone to cortisol by thin layer chromatography. Analysis of HSD11B1 promoter methylation (P1 and P2) was performed using Sequenom MassARRAY EpiTYPER analysis. Results Dexamethasone treatment resulted in a significant increase in 11βHSD1 mRNA levels (P = 0.003), oxoreductase activity (P = 0.017) and C/EBPβ mRNA (P = 0.015), and increased expression of both the P1 (P = 0.008) and P2 (P = 0.016) promoter regions . The distal P1 promoter region showed a significant reduction in methylation following dexamethasone (P = 0.026). There was a significant negative correlation between the change in methylation at this site and the increment in 11βHSD1 oxoreductase activity (r = −0.62, P = 0.014). Conclusions Our findings of reduced methylation in the HSD11B1 P1 promoter in association with increased 11βHSD1 oxoreductase activity implicate complex multi-promoter epigenetic mechanisms in the regulation of 11βHSD1 levels in SkM.

Objective: To determine if testosterone treatment effect on glycaemia is mediated through changes in total fat mass, abdominal fat mass, skeletal muscle mass, non-dominant hand-grip, oestradiol (E2), and sex hormone-binding globulin (SHBG)., Design: Mediation analysis of a randomised placebo-controlled trial of testosterone., Methods: Six Australian tertiary care centres recruited 1007 males, aged 50-74 years, with waist circumference ≥95 cm, serum total testosterone ≤14 nmol/L (immunoassay), and either impaired glucose tolerance or newly diagnosed type 2 diabetes on an oral glucose tolerance test (OGTT). Participants were enrolled in a lifestyle programme and randomised 1:1 to 3 monthly injections of 1000 mg testosterone undecanoate or placebo for 2 years. Complete data were available for 709 participants (70%). Mediation analyses for the primary outcomes of type 2 diabetes at 2 years (OGTT ≥ 11.1 mmol/L and change in 2-h glucose from baseline), incorporating potential mediators: changes in fat mass, % abdominal fat, skeletal muscle mass, non-dominant hand-grip strength, E2, and SHBG, were performed., Results: For type 2 diabetes at 2 years, the unadjusted OR for treatment was 0.53 (95% CI:.35-.79), which became 0.48 (95% CI:.30-.76) after adjustment for covariates. Including potential mediators attenuated the treatment effect (OR 0.77; 95% CI:.44-1.35; direct effect) with 65% mediated. Only fat mass remained prognostic in the full model (OR: 1.23; 95% CI: 1.09-1.39; P < .001)., Conclusion: At least part of the testosterone treatment effect was found to be mediated by changes in fat mass, abdominal fat, skeletal muscle mass, grip strength, SHBG, and E2, but predominantly by changes in fat mass., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Endocrinology.)

Objective: Measurement of hypertonic saline-stimulated copeptin has recently been described for the differentiation of polyuria-polydipsia syndrome. This study aims to determine the copeptin response to intravenous 3% hypertonic saline, including evaluation of adverse effects, in a local cohort of healthy adults >18 years in Australia., Design: Prospective clinical study., Methods: Twenty healthy volunteers (10 males and 10 females) were recruited. Participants underwent infusion of 3% hypertonic saline via a previously described standardized protocol, until the plasma sodium was ≥150 mmol/L, with measurement of plasma copeptin., Results: Mean peak sodium was 152 mmol/L ± SD 1.4 with osmolality 315 mmol/kg ± SD 3.9. Median volume of hypertonic saline infused to reach target sodium ≥ 150 mmol/L was 1536 mL (IQR 1362, 1992). Mean rate of plasma sodium rise was 5.9 mmol/L/hour ± SD 1.5. Hypertonic saline-stimulated copeptin had non-parametrical distribution with median of 33.8 pmol/L (IQR 27.6, 63.6). Overall median symptom burden was 6/10 (range 3/10-9/10). Copeptin was significantly higher for those who experienced nausea and/or vomiting (n = 13) (median 39.0 pmol/L; IQR 32.5, 90), compared to those participants who did not experience either (median 20.0 pmol/L; IQR 13.0, 31.0) (P = 0.003). There were no serious adverse events., Conclusion: Hypertonic saline-stimulated copeptin measurements were similar in our population compared with previously reported reference intervals in healthy volunteers. There is a wide range of stimulated copeptin measurements in the healthy population. Nausea and vomiting are common adverse effects which enhance the copeptin response., (© 2021 John Wiley & Sons Ltd.)

Background: Men who are overweight or obese frequently have low serum testosterone concentrations, which are associated with increased risk of type 2 diabetes. We aimed to determine whether testosterone treatment prevents progression to or reverses early type 2 diabetes, beyond the effects of a community-based lifestyle programme., Methods: T4DM was a randomised, double-blind, placebo-controlled, 2-year, phase 3b trial done at six Australian tertiary care centres. Men aged 50-74 years, with a waist circumference of 95 cm or higher, a serum testosterone concentration of 14·0 nmol/L or lower but without pathological hypogonadism, and impaired glucose tolerance (oral glucose tolerance test [OGTT] 2-h glucose 7·8-11·0 mmol/L) or newly diagnosed type 2 diabetes (provided OGTT 2-h glucose ≤15·0 mmol/L) were enrolled in a lifestyle programme and randomly assigned (1:1) to receive an intramuscular injection of testosterone undecanoate (1000 mg) or placebo at baseline, 6 weeks, and then every 3 months for 2 years. Randomisation was done centrally, including stratification by centre, age group, waist circumference, 2-h OGTT glucose, smoking, and first-degree family history of type 2 diabetes. The primary outcomes at 2 years were type 2 diabetes (2-h OGTT glucose ≥11·1 mmol/L) and mean change from baseline in 2-h OGTT glucose, assessed by intention to treat. For safety assessment, we did a masked monitoring of haematocrit and prostate-specific antigen, and analysed prespecified serious adverse events. This study is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12612000287831., Findings: Between Feb 5, 2013, and Feb 27, 2017, of 19 022 men who were pre-screened, 1007 (5%) were randomly assigned to the placebo (n=503) and testosterone (n=504) groups. At 2 years, 2-h glucose of 11·1 mmol/L or higher on OGTT was reported in 87 (21%) of 413 participants with available data in the placebo group and 55 (12%) of 443 participants in the testosterone group (relative risk 0·59, 95% CI 0·43 to 0·80; p=0·0007). The mean change from baseline 2-h glucose was -0·95 mmol/L (SD 2·78) in the placebo group and -1·70 mmol/L (SD 2·47) in the testosterone group (mean difference -0·75 mmol/L, -1·10 to -0·40; p<0·0001). The treatment effect was independent of baseline serum testosterone. A safety trigger for haematocrit greater than 54% occurred in six (1%) of 484 participants in the placebo group and 106 (22%) of 491 participants in the testosterone group, and a trigger for an increase of 0·75 μg/mL or more in prostate-specific antigen occurred in 87 (19%) of 468 participants in the placebo group and 109 (23%) of 480 participants in the testosterone group. Prespecified serious adverse events occurred in 37 (7·4%, 95% CI 5·4 to 10·0) of 503 patients in the placebo group and 55 (10·9%, 8·5 to 13·9) of 504 patients in the testosterone group. There were two deaths in each group., Interpretation: Testosterone treatment for 2 years reduced the proportion of participants with type 2 diabetes beyond the effects of a lifestyle programme. Increases in haematocrit might be treatment limiting. Longer-term durability, safety, and cardiovascular effects of the intervention remain to be further investigated., Funding: Australian National Health and Medical Research Council, Bayer, Eli Lilly, University of Adelaide, and WW (formerly Weight Watchers)., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: The aim of the study was to compare the response rates and costs of phone call vs. short message service (SMS) screening reminders to prospective randomized controlled trial (RCT) participants., Study Design and Setting: This study was a randomized evaluation within a large Australian diabetes prevention RCT. Participants were men aged 50-74 years, overweight or obese, without a previous type 2 diabetes diagnosis. Those eligible on a prescreening questionnaire who did not attend a further screening assessment within 4 weeks were randomized to receive an SMS or phone call reminder (N = 709). The primary outcome was attendance for further screening assessment within 8 weeks of prescreening., Results: Attendance was 18% (62/354) in the SMS reminder group, and 23% (80/355) in the phone reminder group, with no statistically significant difference in response according to reminder type (relative risk = 1.29, 95% confidence interval [CI]: 0.96-1.73, P = 0.09). The lower confidence limits for response to SMS (95% CI: 14-22%) and phone reminders (95% CI: 18-27%) did not include the 8-week attendance rate before this evaluation, 12%. Phone reminders cost substantially more than SMS reminders (AU$6.21 vs. AU$0.53 per reminder)., Conclusion: SMS reminders were as adequate a method as phone reminders to boost RCT screening uptake and were considerably more affordable., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Effective interventions are required to prevent the current rapid increase in the prevalence of Type 2 diabetes. Clinical trials of large-scale interventions to prevent Type 2 diabetes are essential but recruitment is challenging and expensive, and there are limited data regarding the most cost-effective and efficient approaches to recruitment. This paper aims to evaluate the cost and effectiveness of a range of promotional strategies used to recruit men to a large Type 2 diabetes prevention trial., Methods: An observational study was conducted nested within the Testosterone for the Prevention of Type 2 Diabetes (T4DM) study, a large, multi-centre randomised controlled trial (RCT) of testosterone treatment for the prevention of Type 2 diabetes in men aged 50-74 years at high risk of developing diabetes. Study participation was promoted via mainstream media-television, newspaper and radio; direct marketing using mass mail-outs, publicly displayed posters and attendance at local events; digital platforms, including Facebook and Google; and online promotions by community organisations and businesses. For each strategy, the resulting number of participants and the direct cost involved were recorded. The staff effort required for each strategy was estimated based on feedback from staff., Results: Of 19,022 men screened for the study, 1007 (5%) were enrolled. The most effective recruitment strategies were targeted radio advertising (accounting for 42% of participants), television news coverage (20%) and mass mail-outs (17%). Other strategies, including radio news, publicly displayed posters, attendance at local events, newspaper advertising, online promotions and Google and Facebook advertising, each accounted for no more than 4% of enrolled participants. Recruitment promotions cost an average of AU$594 per randomised participant. The most cost-effective paid strategy was mass mail-outs by a government health agency (AU$745 per participant). Other paid strategies were more expensive: mail-out by general practitioners (GPs) (AU$1104 per participant), radio advertising (AU$1081) and newspaper advertising (AU$1941)., Conclusion: Radio advertising, television news coverage and mass mail-outs by a government health agency were the most effective recruitment strategies. Close monitoring of recruitment outcomes and ongoing enhancement of recruitment activities played a central role in recruitment to this RCT., Trial Registration: ANZCTR, ID: ACTRN12612000287831 . Registered on 12 March 2012.

Carriers of succinate dehydrogenase (SDHx) mutations are at risk of developing phaeochromocytomas, catecholamine secreting extra-adrenal paragangliomas and non-secretory head and neck paragangliomas and require lifelong surveillance. There is no current consensus on the optimal surveillance strategy. This study describes the outcomes of a cohort of 50 SDHx mutation carriers followed at a tertiary Australian hospital using a surveillance protocol involving annual clinical review with plasma/urine metanephrines and biennial magnetic resonance imaging from skull base to pelvis., (© 2019 Royal Australasian College of Physicians.)

Background: Low circulating testosterone is associated with an increased risk of developing type 2 diabetes (T2DM) in overweight men with impaired glucose tolerance (IGT)., Aims: To determine in a multi-centre, double-blinded placebo-controlled randomized trial whether testosterone treatment combined with lifestyle intervention (Weight Watchers) relative to lifestyle intervention alone reduces T2DM incidence and improves glucose tolerance at 2 years., Study Population: Overweight or obese men aged 50-74 years with a serum testosterone of ≤14 nmol/L and IGT or newly diagnosed T2DM established by an oral glucose tolerance test (OGTT)., Setting, Drug and Protocol: Six Australian capital city-based tertiary care centres. Participants were randomized 1:1 and injected with testosterone undecanoate (1000 mg/4 mL) or vehicle (4 mL castor oil), at baseline, 6 weeks and 3-monthly thereafter. PRIMARY ENDPOINTS: (a) Proportion of participants with 2-hour OGTT ≥11.1 mmol/L at 2 years, and (b) a difference at 2 years ≥0.6 mmol/L in the mean 2-hour OGTT glucose between treatments., Secondary Endpoints: Fasting insulin, HbA1c, body composition, maximal handgrip strength; sexual function and lower urinary tract symptoms; serum sex steroids and sex hormone binding globulin; mood and psychosocial function; adherence to lifestyle intervention; and healthcare utilization and costs., Safety: Overseen by an Independent Data Safety Monitoring Committee. Haematocrit, lipids and prostate-specific antigen (PSA) are assessed 6-monthly and information relating to haematological, urological and cardiovascular adverse events from each clinic visit. SUB-STUDIES: (a) Changes in bone density and micro-architecture, (b) motivation and behaviour, (c) telomere length, (d) extended treatment up to 4 years, and (e) hypothalamo-pituitary testicular axis recovery at treatment end., (© 2018 John Wiley & Sons Ltd.)

A plethora of physiological processes show stable and synchronized daily oscillations that are either driven or modulated by biological clocks. A circadian pacemaker located in the suprachiasmatic nucleus of the ventral hypothalamus coordinates 24-hour oscillations of central and peripheral physiology with the environment. The circadian clockwork involved in driving rhythmic physiology is composed of various clock genes that are interlocked via a complex feedback loop to generate precise yet plastic oscillations of ∼24 hours. This review focuses on the specific role of the core clockwork gene Period1 and its paralogs on intra-oscillator and extra-oscillator functions, including, but not limited to, hippocampus-dependent processes, cardiovascular function, appetite control, as well as glucose and lipid homeostasis. Alterations in Period gene function have been implicated in a wide range of physical and mental disorders. At the same time, a variety of conditions including metabolic disorders also impact clock gene expression, resulting in circadian disruptions, which in turn often exacerbates the disease state.

Pituitary tumour apoplexy (PA) is a rare clinical syndrome that occurs as a result of acute haemorrhage and/or infarction within a frequently undiagnosed pituitary tumour. The sudden enlargement of the pituitary mass undergoing PA is responsible for a wide range of acute symptoms/signs (severe headache, visual loss, diplopia, hypopituitarism, impaired consciousness) which, together with the radiological evidence of a pituitary lesion, establish the diagnosis. The optimal care of PA requires involvement of a multidisciplinary team including endocrinologist, neurosurgeon, neuroophthalmologist and the management strategy that depends on the clinical manifestations, as well as the presence of co-morbidities. Prompt surgical decompression is initially indicated in cases with severe or progressive impairment of the visual acuity or the visual fields or with altered mental state and leads to visual and neurological recovery in most of the patients. The patients with mild, stable clinical picture (including those with isolated ocular palsies) can be managed conservatively (support of fluid and electrolyte balance and stress doses of steroids in most cases) with favourable visual and neurological outcome. Frequent reassessment is mandatory because the clinical course can be unpredictable; if progression of symptoms occurs, later elective surgery is indicated and is beneficial, especially in terms of visual outcome. The endocrinological outcome is less favourable, irrespective of the treatment option, with many patients remaining on long-term replacement therapy. Despite the above guidelines, clear proof of optimal outcomes in the form of randomised controlled trials is lacking. Regrowth of the pituitary tumour years after a PA episode is possible and patients require long-term surveillance., (© 2015 European Society of Endocrinology.)

Objective: Glucagon secretion is stimulated by fasting and inhibited postprandially, a pattern that mimics the secretory profiles of both ghrelin and GH. We thus hypothesized that glucagon may be a determinant of the changes in circulating ghrelin and GH that occur in relation to meals. The objective of the study was to explore this hypothesis by determining the ghrelin and GH response to a bolus of glucagon or saline in healthy subjects., Subjects and Measurements: Nine healthy volunteers, mean age 47 years (range 33-58) and body mass index (BMI) 24 kg/m2 (range 20.9-27.6) were recruited and received either 1 mg glucagon (n = 9) or 1 ml saline (n = 6) subcutaneously on separate days between 0800 and 0830 h after an overnight fast. Venous blood was then sampled at 15-min intervals during the first hour, followed by 30-min intervals up to 4 h for glucose, insulin, GH, cortisol, somatostatin and ghrelin., Results: Mean +/- SE basal ghrelin was 213.1 +/- 34.3 pmol/l and decreased significantly by 15 min after glucagon administration to 179.3 +/- 28 pmol/l (P = 0.01), then remaining suppressed relative to the basal value until 240 min after glucagon. Plasma insulin increased from a basal value of 46.7 +/- 7.7 pmol/l to a peak of 327.1 +/- 54.9 pmol/l (P < 0.0001). There was an inverse statistical relationship between the increase in insulin over the first 120 min and the decrease in ghrelin (P = 0.005), while somatostatin, GH and glucose were not significant contributors to the decrease in ghrelin (P > 0.05). Mean +/- SE basal GH was 7.3 +/- 2.9 microg/l and increased by 150 min after glucagon to a peak of 20.5 +/- 6.8 microg/l (P = 0.006). Changes in neither ghrelin nor glucose were related to the increase in GH (P = 0.7). Saline administration did not produce any significant change in ghrelin, insulin or somatostatin although the expected diurnal reduction in cortisol (P < 0.05) was observed., Conclusions: Our study found no evidence that glucagon stimulates ghrelin secretion in humans and supports the hypothesis that insulin is a negative regulator of ghrelin secretion in the postprandial state. We did not find a negative relationship between endogenous somatostatin and ghrelin despite earlier reports that exogenously administered somatostatin analogues suppress plasma ghrelin. Finally, glucagon-induced GH secretion is not mediated by an increase in plasma ghrelin.

It has been suggested that CRH is a placental clock that controls the duration of pregnancy and that the timing of the rise in CRH may permit prediction of the onset of labor. We have performed a prospective longitudinal study, in 297 women, to examine the utility of a single second-trimester plasma CRH measurement to predict preterm delivery. Venous blood samples were taken at 4-weekly intervals, beginning at 16-20 wk gestation, until delivery for CRH and its binding protein. A time point at which a single plasma CRH test might give optimal data to predict preterm delivery was determined. Thirty-one subjects delivered prematurely (10.4%). Sampling for plasma CRH at 26 wk gestation seemed the optimal time point to maximize sensitivity and specificity of the test. The mean (+/- SD) plasma CRH in women at this gestation who eventually delivered after spontaneous labor within 1 wk of their due date (39-41 wk, n = 127) was 34.7 +/- 27.0 pM. A plasma CRH of more than 90 pM at 26 wk gestation had a sensitivity of 45% and a specificity of 94% for prediction of preterm delivery. The positive predictive value was 46.7%. Calculation of free CRH did not improve these figures. In conclusion, a single measurement of plasma CRH, toward the end of the second trimester, may identify a group at risk for preterm delivery, but over 50% of such deliveries will be unpredicted. These data do not support the routine clinical use of plasma CRH as a predictor of preterm labor.