143 research outputs found
MEN1 Surveillance Guidelines:Time to (re)Think?
Clinical practice guidelines for patients with multiple endocrine neoplasia type 1 (MEN1) recommend a variety of surveillance options. Given progress over the past decade in this area, it is timely to evaluate their ongoing utility. MEN1 is characterized by the development of synchronous or asynchronous tumors affecting a multitude of endocrine and nonendocrine tissues, resulting in premature morbidity and mortality, such that the rationale for undertaking surveillance screening in at-risk individuals appears robust. Current guidelines recommend an intensive regimen of clinical, biochemical, and radiological surveillance commencing in early childhood for those with a clinical or genetic diagnosis of MEN1, with the aim of early tumor detection and treatment. Although it is tempting to assume that such screening results in patient benefits and improved outcomes, the lack of a strong evidence base for several aspects of MEN1 care, and the potential for iatrogenic harms related to screening tests or interventions of unproven benefit, make such assumptions potentially unsound. Furthermore, the psychological as well as economic burdens of intensive screening remain largely unstudied. Although screening undoubtedly constitutes an important component of MEN1 patient care, this perspective aims to highlight some of the current uncertainties and challenges related to existing MEN1 guidelines with a particular focus on the role of screening for presymptomatic tumors. Looking forward, a screening approach that acknowledges these limitations and uncertainties and places the patient at the heart of the decision-making process is advocated
Mifepristone reduces insulin resistance in patient volunteers with adrenal incidentalomas that secrete low levels of cortisol : a pilot study
Background: Incidental adrenal masses are commonly detected during imaging for other pathologies. 10% of the elderly
population has an ‘adrenal incidentaloma’, up to 20% of these show low-grade autonomous cortisol secretion and 60% of
patients with autonomous cortisol secretion have insulin resistance. Cortisol excess is known to cause insulin resistance, an
independent cardiovascular risk marker, however in patients with adrenal incidentalomas it is unknown whether their
insulin resistance is secondary to the excess cortisol and therefore potentially reversible. In a proof of concept study we
examined the short-term effects of glucocorticoid receptor (GR) antagonism in patients with an adrenal incidentaloma to
determine whether their insulin resistance was reversible.
Methodology/Principal Findings: In a prospective open-label pilot study, six individuals with adrenal incidentalomas and
autonomous cortisol secretion were treated with mifepristone (a GR antagonist) 200 mg twice daily and studied for 4 weeks
on a Clinical Research Facility. Insulin resistance at four weeks was assessed by insulin resistance indices, lnHOMA-IR and
lnMatsuda, and AUC insulin during a 2-hour glucose tolerance test. Biochemical evidence of GR blockade was shown in all
individuals and across the group there was a significant reduction in insulin resistance: lnHOMA-IR (1.0vs0.6; p = 0.03),
lnHOMA-%beta (4.8vs4.3; p = 0.03) and lnMatsuda (1.2vs1.6; p = 0.03). Five out of six individuals showed a reduction in
insulin AUC .7237 pmol/l.min, and in two patients this showed a clinically significant cardiovascular benefit (as defined by
the Helsinki heart study).
Conclusions: Short-term GR antagonism is sufficient to reduce insulin resistance in some individuals with adrenal
incidentalomas and mild cortisol excess. Further assessment is required to assess if the responses may be used to stratify
therapy as adrenal incidentalomas may be a common remediable cause of increased cardiovascular risk
Complications of Cushing's syndrome: state of the art
Cushing's syndrome is a serious endocrine disease caused by chronic, autonomous, and excessive secretion of cortisol. The syndrome is associated with increased mortality and impaired quality of life because of the occurrence of comorbidities. These clinical complications include metabolic syndrome, consisting of systemic arterial hypertension, visceral obesity, impairment of glucose metabolism, and dyslipidaemia; musculoskeletal disorders, such as myopathy, osteoporosis, and skeletal fractures; neuropsychiatric disorders, such as impairment of cognitive function, depression, or mania; impairment of reproductive and sexual function; and dermatological manifestations, mainly represented by acne, hirsutism, and alopecia. Hypertension in patients with Cushing's syndrome has a multifactorial pathogenesis and contributes to the increased risk for myocardial infarction, cardiac failure, or stroke, which are the most common causes of death; risks of these outcomes are exacerbated by a prothrombotic diathesis and hypokalaemia. Neuropsychiatric disorders can be responsible for suicide. Immune disorders are common; immunosuppression during active disease causes susceptibility to infections, possibly complicated by sepsis, an important cause of death, whereas immune rebound after disease remission can exacerbate underlying autoimmune diseases. Prompt treatment of cortisol excess and specific treatments of comorbidities are crucial to prevent serious clinical complications and reduce the mortality associated with Cushing's syndrome
Qualitative impact assessment of land management interventions on ecosystem services (“QEIA”). Report-3 theme-3: soils
This project assessed the impacts of 741 potential land management actions, suitable for agricultural land in England, on the Farming & Countryside Programme’s Environmental Objectives (and therefore Environment Act targets and climate commitments) through 53 relevant environmental and cultural service indicators.
The project used a combination of expert opinion and rapid evidence reviews, which included 1000+ pages of evidence in 10 separate reports with reference to over 2400 published studies, and an Integrated Assessment comprising expert-derived qualitative impact scores.
The project has ensured that ELM schemes are evidence-based, offer good value for money, and contribute to SoS priorities for farming
What is the appropriate management of non-functioning pancreatic neuroendocrine tumours disclosed on screening in adult patients with multiple endocrine neoplasia type 1?
Adrenocortical incidentalomas and bone: from molecular insights to clinical perspectives.
The original version of this article unfortunately contained a mistake in Figure 1. There is a typo in the word "osteoclastogenesis" and the word "activity" is missing in the same entity. It should be "osteoclastogenesis" instead of "osteoclestogenesis"
Qualitative impact assessment of land management interventions on ecosystem services (“QEIA”). Report-3 theme-4: water
This project assessed the impacts of 741 potential land management actions, suitable for agricultural land in England, on the Farming & Countryside Programme’s Environmental Objectives (and therefore Environment Act targets and climate commitments) through 53 relevant environmental and cultural service indicators.
The project used a combination of expert opinion and rapid evidence reviews, which included 1000+ pages of evidence in 10 separate reports with reference to over 2400 published studies, and an Integrated Assessment comprising expert-derived qualitative impact scores.
The project has ensured that ELM schemes are evidence-based, offer good value for money, and contribute to SoS priorities for farming
The effectiveness of policies promoting sustainable permanent grasslands across five European countries (representing five biogeographic regions): mapping, understanding, and key stakeholder perceptions
The purpose of this report is to identify, map, and evaluate the most relevant European policies seen to influence permanent grassland (PG) management. To accomplish this, an interdisciplinary, crossnational team from the UK, Switzerland, Spain, Czech Republic, and Sweden reviewed over 50 in-depth policy frameworks. With direction from expert stakeholders and a review of the policy landscape, we identified the most relevant policy instruments influencing PGs across five different biogeographic regions in Europe (Alpine, Atlantic, Boreal, Continental, and Mediterranean).
The mapping of each country’s policy mix was guided inter-alia by a ‘cascade framework’ to illustrate the entry points, intermediary actors, mechanisms and pathways through which policies deliver their intended effects on PGs. This entailed an in-depth analysis of publicly available government sources documenting the aims, objectives, targets, monitoring systems, outputs and outcomes of each policy instrument. In total, 24 policies were mapped using 50 different criteria, with 15 of the policies unique to the case study countries. This resulted in an extensive excel database of over 3400 unique cells containing rich qualitative data.
The excel data were coded in a consistent manner across the country teams so that they could be compared, synthesized, and used to identify patterns in the policy mix and logic of intervention. We show, for instance, that across Europe, the dominant policy logic uses regulations and incentives to influence farmer adoption of desired landscape compositions. This directly influences, but does not guarantee, the range of ecosystem services (ES) that are possible from the landscape. At the same time, we discovered a lack of policies targeting consumer demand for PG ecosystem services and only a few designed to drive sustainable PG management by directly promoting the value of PGs with beneficiaries.
To complement the policy mapping, stakeholders’ assessed the perceived effectiveness of the policy mix in each country. This evaluation included over 50 interviews with key stakeholders across Europe representing government, academia, farmers, and special interests, and covered perceptions of democracy, legitimacy, relevance, efficiency and impact in relation to the effectiveness of policies relevant to the management of PG. Our findings reveal generally positive perceptions of grassland policy effectiveness across Europe, with special interest groups being the least positive and governments the most. The in-depth country case studies reveal striking similarities, as well as differences between countries and stakeholder groups, which are illustrative of the problems, challenges, and barriers confronting policy effectiveness.
We conclude this report by offering insights and policy implications. In particular, we suggest that the following four points are taken into consideration to improve the PG policy landscape: 1) Reduce complexity and administrative burden to make policies more understandable and accessible. 2) Require stakeholder involvement when developing strategic plans and assessing policy. 3) Encourage consideration of trade-offs between PG management and ES delivery, by designing policies to explicitly target the interaction between landscape structures and ES (or target them in parallel). 4) Encourage a balance of policy logic, by moving away from targeting farmers with regulation or subsidies to manage the landscape towards targeting consumer demand for ES (through information) and the value of ES (such as direct payments for regulating and cultural services)
Modified-release hydrocortisone to provide circadian cortisol profiles
Context: Cortisol has a distinct circadian rhythm regulated by the brain's central pacemaker. Loss of this rhythm is associated with metabolic abnormalities, fatigue, and poor quality of life. Conventional glucocorticoid replacement cannot replicate this rhythm.
Objectives: Our objectives were to define key variables of physiological cortisol rhythm, and by pharmacokinetic modeling test whether modified-release hydrocortisone (MR-HC) can provide circadian cortisol profiles.
Setting: The study was performed at a Clinical Research Facility.
Design and Methods: Using data from a cross-sectional study in healthy reference subjects (n = 33), we defined parameters for the cortisol rhythm. We then tested MR-HC against immediate-release hydrocortisone in healthy volunteers (n = 28) in an open-label, randomized, single-dose, cross-over study. We compared profiles with physiological cortisol levels, and modeled an optimal treatment regimen.
Results: The key variables in the physiological cortisol profile included: peak 15.5 mu g/dl (95% reference range 11.7-20.6), acrophase 0832 h(95% confidence interval 0759-0905), nadir less than 2 mu g/dl (95% reference range 1.5-2.5), time of nadir 0018 h (95% confidence interval 2339-0058), and quiescent phase (below the mesor) 1943-0531 h. MR-HC 15 mg demonstrated delayed and sustained release with a mean (SEM) maximum observed concentration of 16.6 (1.4) mu g/dl at 7.41 (0.57) h after drug. Bioavailability of MR-HC 5, 10, and 15 mg was 100, 79, and 86% that of immediate-release hydrocortisone. Modeling suggested that MR-HC 15-20 mg at 2300 h and 10 mg at 0700 h could reproduce physiological cortisol levels.
Conclusion: By defining circadian rhythms and using modern formulation technology, it is possible to allow a more physiological circadian replacement of cortisol. (J Clin Endocrinol Metab 94: 1548-1554, 2009
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