‘Striking the Right Balance’ in Targeting PPARγ in the Metabolic Syndrome: Novel Insights from Human Genetic Studies

At a time when the twin epidemics of obesity and type 2 diabetes threaten to engulf even the most well-resourced Western healthcare systems, the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) has emerged as a bona fide therapeutic target for treating human metabolic disease. The novel insulin-sensitizing antidiabetic thiazolidinediones (TZDs, e.g., rosiglitazone, pioglitazone), which are licensed for use in the treatment of type 2 diabetes, are high-affinity PPARγ ligands, whose beneficial effects extend beyond improvement in glycaemic control to include amelioration of dyslipidaemia, lowering of blood pressure, and favourable modulation of macrophage lipid handling and inflammatory responses. However, a major drawback to the clinical use of exisiting TZDs is weight gain, reflecting both enhanced adipogenesis and fluid retention, neither of which is desirable in a population that is already overweight and prone to cardiovascular disease. Accordingly, the “search is on” to identify the next generation of PPARγ modulators that will promote maximal clinical benefit by targeting specific facets of the metabolic syndrome (glucose intolerance/diabetes, dyslipidaemia, and hypertension), while simultaneously avoiding undesirable side effects of PPARγ activation (e.g., weight gain). This paper outlines the important clinical and laboratory observations made in human subjects harboring genetic variations in PPARγ that support such a therapeutic strategy

A journal for the modern era.

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Combining field work and laboratory work in the study of financial risk-taking.

A contribution to a special issue on Hormones and Human Competition. Financial markets are periodically destabilized by bubbles and crashes during which investors display respectively what has been called "irrational exuberance" and "irrational pessimism". How can we best study these pathologies in competitive and risk-taking behaviours? In this article, we argue that a science of risk-taking and of the financial markets needs to draw heavily on physiology and especially endocrinology, due to their central roles in moderating human behaviour. Importantly, this science of competition and risk requires the same spectrum of research protocols as is found in mature biological and medical sciences, a spectrum running from field work conducted within financial institutions themselves to more controlled laboratory studies, which permit cause to be distinguished from effect. Such a spectrum of studies is especially important for translational behavioural science

'Striking the Right Balance' in Targeting PPARgamma in the Metabolic Syndrome: Novel Insights from Human Genetic Studies.

At a time when the twin epidemics of obesity and type 2 diabetes threaten to engulf even the most well-resourced Western healthcare systems, the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) has emerged as a bona fide therapeutic target for treating human metabolic disease. The novel insulin-sensitizing antidiabetic thiazolidinediones (TZDs, e.g., rosiglitazone, pioglitazone), which are licensed for use in the treatment of type 2 diabetes, are high-affinity PPARgamma ligands, whose beneficial effects extend beyond improvement in glycaemic control to include amelioration of dyslipidaemia, lowering of blood pressure, and favourable modulation of macrophage lipid handling and inflammatory responses. However, a major drawback to the clinical use of exisiting TZDs is weight gain, reflecting both enhanced adipogenesis and fluid retention, neither of which is desirable in a population that is already overweight and prone to cardiovascular disease. Accordingly, the "search is on" to identify the next generation of PPARgamma modulators that will promote maximal clinical benefit by targeting specific facets of the metabolic syndrome (glucose intolerance/diabetes, dyslipidaemia, and hypertension), while simultaneously avoiding undesirable side effects of PPARgamma activation (e.g., weight gain). This paper outlines the important clinical and laboratory observations made in human subjects harboring genetic variations in PPARgamma that support such a therapeutic strategy.Peer Reviewe

Nuclear imaging in the diagnosis of primary aldosteronism.

PURPOSE OF REVIEW: Primary aldosteronism is increasingly recognized as a common secondary cause of hypertension. Successful demonstration of a unilateral cause (e.g. a classical 'Conn's adenoma') offers the potential for curative adrenalectomy. Adrenal vein sampling (AVS), in conjunction with cross-sectional imaging, remains the 'gold standard' for distinguishing unilateral and bilateral disease, but is technically demanding and frequently unsuccessful or inconclusive. As such, alternative strategies for lateralization, including nuclear medicine techniques, are being developed and brought into clinical practice. RECENT FINDINGS: Metomidate, a potent ligand of CYP11B1 and CYP11B2, can be C11H3-labelled as a PET tracer and has been shown to offer a rapid noninvasive alternative to AVS for localizing unilateral aldosterone-producing adenomas. SUMMARY: Increasing experience with 11C-metomidate PET-CT supports its use as an adjunct to AVS when this has failed, is ambiguous, or cannot be undertaken.A.S.P. and M.G. are supported by the National Institute for Health Research Cambridge Biomedical Research Centre. M.J.B. is a National Institute of Health Research Senior Investigator.This is the final published version. It first appeared at http://journals.lww.com/co-endocrinology/Fulltext/2015/06000/Nuclear_imaging_in_the_diagnosis_of_primary.3.aspx

Order effects in high stakes undergraduate examinations: an analysis of 5 years of administrative data in one UK medical school.

OBJECTIVE: To investigate the association between student performance in undergraduate objective structured clinical examinations (OSCEs) and the examination schedule to which they were assigned to undertake these examinations. DESIGN: Analysis of routinely collected data. SETTING: One UK medical school. PARTICIPANTS: 2331 OSCEs of 3 different types (obstetrics OSCE, paediatrics OSCE and simulated clinical encounter examination OSCE) between 2009 and 2013. Students were not quarantined between examinations. OUTCOMES: (1) Pass rates by day examination started, (2) pass rates by day station undertaken and (3) mean scores by day examination started. RESULTS: We found no evidence that pass rates differed according to the day on which the examination was started by a candidate in any of the examinations considered (p>0.1 for all). There was evidence (p=0.013) that students were more likely to pass individual stations on the second day of the paediatrics OSCE (OR 1.27, 95% CI 1.05 to 1.54). In the cases of the simulated clinical encounter examination and the obstetrics and gynaecology OSCEs, there was no (p=0.42) or very weak evidence (p=0.099), respectively, of any such variation in the probability of passing individual stations according to the day they were attempted. There was no evidence that mean scores varied by day apart from the paediatric OSCE, where slightly higher scores were achieved on the second day of the examination. CONCLUSIONS: There is little evidence that different examination schedules have a consistent effect on pass rates or mean scores: students starting the examinations later were not consistently more or less likely to pass or score more highly than those starting earlier. The practice of quarantining students to prevent communication with (and subsequent unfair advantage for) subsequent examination cohorts is unlikely to be required.University of Cambridge School of Clinical MedicineThis is the final version of the article. It first appeared from BMJ Group via http://dx.doi.org/10.1136/bmjopen-2016-01254

Clinical Evaluation of 11C-Met-Avid Pituitary Lesions Using a ZTE-Based AC Method

Pituitary tumours account for ~16% of central nervous system tumors and they are the second most frequently reported histology in this group. Due to their small size, pituitary surgery is challenging and precise lesion localization through imaging is therefore a critical factor for a successful outcome. Simultaneous positron emission tomography and magnetic resonance imaging is well suited for lesion identification and localization but it requires accurate attenuation correction (AC) to ensure optimal positron emission imaging (PET) imaging. Atlas-based AC methods are often used for this purpose, as they overcome the difficulty of estimating bone tissue density with conventional MR sequences. However, atlas methods can only partially account for interpatient variability. The goal of this paper was to investigate whether direct bone measurement, by means of a zero echo time MR sequence, can significantly improve the accuracy of pituitary tumor imaging with PET

Acromegaly and Cushing's syndrome caused by a neuroendocrine tumor arising within a sacrococcygeal teratoma.

A 60-year-old man with a pre-existing stable sacrococcygeal teratoma developed acromegaly, ectopic Cushing's syndrome, and 5HIAA secretion. To our knowledge, this represents the first reported case of ACTH and serotonin secretion, and likely GHRH or GH cosecretion, from a sacrococcygeal teratoma in an adult

A remarkable case of thyrotoxicosis initially caused by graves’ disease followed by a probable TSHoma – a case report

Abstract: Background: Graves’ disease is the commonest cause of thyrotoxicosis whilst thyrotropin (TSH)-producing pituitary adenomas (thyrotropinomas, TSHomas) are very rare and account for just 1–2% of all pituitary adenomas. Coexistence of a TSHoma and Graves’ disease has been very rarely reported. Here, we report a case of a patient whose initial presentation with primary thyrotoxicosis due to Graves’ disease, was subsequently followed by a relapse of thyrotoxicosis due to a probable TSHoma. Case: A sixty-eight year old woman was referred to our department with classical features of thyrotoxicosis. Initial biochemistry confirmed hyperthyroxinaemia [free thyroxine (fT4) 20.4 pmol/L (reference range 7.0–16.0)] and a suppressed TSH [< 0.02mIU/L (0.50–4.20)]. A technetium pertechnetate uptake scan was consistent with Graves’ Disease. She was treated with carbimazole for 18 months and remained clinically and biochemically euthyroid. After stopping carbimazole her fT4 started to rise but TSH remained normal. Laboratory assay interference was excluded. A TRH stimulation test demonstrated a flat TSH response and pituitary MRI revealed a microadenoma. Remaining pituitary hormones were in the normal range other than a slightly raised IGF-1. An 11C-methionine PET/CT scan coregistered with volumetric MRI (Met-PET-MRICR) demonstrated high tracer uptake in the left lateral sella region suggestive of a functioning adenoma. The patient declined surgery and was unable to tolerate cabergoline or octreotide. Thereafter, she has elected to pursue a conservative approach with periodic surveillance. Conclusion: This is a very unusual case of thyrotoxicosis caused by two different processes occurring in the same patient. It highlights the importance of considering dual pathology when previously concordant thyroid function tests become discordant. It also highlights a potential role of Met-PET-MRICR in the localisation of functioning pituitary tumours

Interoceptive Ability Predicts Survival on a London Trading Floor.

Interoception is the sensing of physiological signals originating inside the body, such as hunger, pain and heart rate. People with greater sensitivity to interoceptive signals, as measured by, for example, tests of heart beat detection, perform better in laboratory studies of risky decision-making. However, there has been little field work to determine if interoceptive sensitivity contributes to success in real-world, high-stakes risk taking. Here, we report on a study in which we quantified heartbeat detection skills in a group of financial traders working on a London trading floor. We found that traders are better able to perceive their own heartbeats than matched controls from the non-trading population. Moreover, the interoceptive ability of traders predicted their relative profitability, and strikingly, how long they survived in the financial markets. Our results suggest that signals from the body - the gut feelings of financial lore - contribute to success in the markets.UK Economic and Social Research Council (Programme Grant), European Research Council (Grant ID: ERC AdG324150:CCFIB), Dr. Mortimer and Theresa Sackler Foundation, National Institute for Health Research Cambridge Biomedical Research Centre, ARC DECRA Fellowship, Queensland Smart Future FundThis is the final version of the article. It first appeared from Nature Publishing Group via https://doi.org/10.1038/srep3298