Exploring the Behavioral and Metabolic Phenotype Generated by Re-Introduction of the Ghrelin Receptor in the Ventral Tegmental Area

Ghrelin receptor (Ghr-R) signaling in neurons of the ventral tegmental area (VTA) can modulate dopaminergic function and the reward-related effects of both palatable foods and drugs of abuse. In this study, we re-introduced the Ghr-R in VTA neurons in Ghr-R knockout mice (Ghr-RVTA mice) to specifically study the importance of the constitutively active Ghr-R for VTA neuronal signaling. Our results showed that re-introduction of the Ghr-R in the VTA had no impact on body weight or food intake under basal conditions. However, during novel environment stress Ghr-RVTA mice showed increased food intake and energy expenditure compared to Ghr-R knockout mice, demonstrating the significance of Ghr-R signaling in the response to stress. Ghr-RVTA mice also showed increased cocaine-induced locomotor activity compared to Ghr-R knockout mice, highlighting the importance of ghrelin signaling for the reward-related effects of activation of VTA neurons. Overall, our data suggest that re-introduction of the Ghr-R in the mesolimbic reward system of Ghr-R knockout mice increases the level of activation induced by both cocaine and novelty stress

Structural Basis for Dityrosine-Mediated Inhibition of α-Synuclein Fibrillization

[Image: see text] α-Synuclein (α-Syn) is an intrinsically disordered protein which self-assembles into highly organized β-sheet structures that accumulate in plaques in brains of Parkinson’s disease patients. Oxidative stress influences α-Syn structure and self-assembly; however, the basis for this remains unclear. Here we characterize the chemical and physical effects of mild oxidation on monomeric α-Syn and its aggregation. Using a combination of biophysical methods, small-angle X-ray scattering, and native ion mobility mass spectrometry, we find that oxidation leads to formation of intramolecular dityrosine cross-linkages and a compaction of the α-Syn monomer by a factor of √2. Oxidation-induced compaction is shown to inhibit ordered self-assembly and amyloid formation by steric hindrance, suggesting an important role of mild oxidation in preventing amyloid formation

Cytomorphology review of 100 newly diagnosed lower-risk MDS patients in the European LeukemiaNet MDS (EUMDS) registry reveals a high inter-observer concordance

Objectives To examine contemporary survival patterns in the general population of patients diagnosed with chronic myeloid leukaemia (CML), and to identify patient groups with less than optimal outcomes. Design Prospective population-based cohort. Setting The UK's Haematological Malignancy Research Network (catchment population 3.6 million, with >2000 new haematological malignancies diagnosed annually). Participants All patients newly diagnosed with CML, from September 2004 to August 2011 and followed up to 31 March 2013. Main outcome measure Incidence and survival. Results With a median diagnostic age of 59 years, the CML age standardised (European) incidence was 0.9/100 000 (95% CIs 0.8 to 0.9), 5-year overall survival was 78.9% (72.3 to 84.0) and 5-year relative survival 88.6% (81.0 to 93.3). The efficacy of treatment across all ages was clearly demonstrated; the relative survival curves for those under 60 and over 60 years being closely aligned. Survival findings were similar for men and women, but varied with deprivation; the age and sex adjusted HR being 3.43 (1.89 to 6.22) for deprivation categories 4–5 (less affluent) versus 1–3 (more affluent). None of these differences were attributable to the biological features of the disease. Conclusions When therapy is freely provided, population-based survival for CML is similar to that reported in clinical trials, and age loses its prognostic significance. However, although most of the patients with CML now experience close to normal lifespans, those living in more deprived areas tend to have poorer outcomes, despite receiving the same clinical care. A significant improvement in overall population outcomes could be achieved if these socioeconomic differences, which may reflect the treatment compliance, could be eliminated

Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial.

BACKGROUND: Remote ischaemic conditioning with transient ischaemia and reperfusion applied to the arm has been shown to reduce myocardial infarct size in patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI). We investigated whether remote ischaemic conditioning could reduce the incidence of cardiac death and hospitalisation for heart failure at 12 months. METHODS: We did an international investigator-initiated, prospective, single-blind, randomised controlled trial (CONDI-2/ERIC-PPCI) at 33 centres across the UK, Denmark, Spain, and Serbia. Patients (age >18 years) with suspected STEMI and who were eligible for PPCI were randomly allocated (1:1, stratified by centre with a permuted block method) to receive standard treatment (including a sham simulated remote ischaemic conditioning intervention at UK sites only) or remote ischaemic conditioning treatment (intermittent ischaemia and reperfusion applied to the arm through four cycles of 5-min inflation and 5-min deflation of an automated cuff device) before PPCI. Investigators responsible for data collection and outcome assessment were masked to treatment allocation. The primary combined endpoint was cardiac death or hospitalisation for heart failure at 12 months in the intention-to-treat population. This trial is registered with ClinicalTrials.gov (NCT02342522) and is completed. FINDINGS: Between Nov 6, 2013, and March 31, 2018, 5401 patients were randomly allocated to either the control group (n=2701) or the remote ischaemic conditioning group (n=2700). After exclusion of patients upon hospital arrival or loss to follow-up, 2569 patients in the control group and 2546 in the intervention group were included in the intention-to-treat analysis. At 12 months post-PPCI, the Kaplan-Meier-estimated frequencies of cardiac death or hospitalisation for heart failure (the primary endpoint) were 220 (8·6%) patients in the control group and 239 (9·4%) in the remote ischaemic conditioning group (hazard ratio 1·10 [95% CI 0·91-1·32], p=0·32 for intervention versus control). No important unexpected adverse events or side effects of remote ischaemic conditioning were observed. INTERPRETATION: Remote ischaemic conditioning does not improve clinical outcomes (cardiac death or hospitalisation for heart failure) at 12 months in patients with STEMI undergoing PPCI. FUNDING: British Heart Foundation, University College London Hospitals/University College London Biomedical Research Centre, Danish Innovation Foundation, Novo Nordisk Foundation, TrygFonden

Biased Ghrelin Receptor Signaling and the Dopaminergic System as Potential Targets for Metabolic and Psychological Symptoms of Anorexia Nervosa

Anorexia Nervosa (AN) is a complex disease that impairs the metabolic, mental and physiological health of affected individuals in a severe and sometimes lethal way. Many of the common symptoms in AN patients, such as reduced food intake, anxiety, impaired gut motility or overexercising are connected to both the orexigenic gut hormone ghrelin and the dopaminergic system. Targeting the ghrelin receptor (GhrR) to treat AN seems a promising possibility in current research. However, GhrR signaling is highly complex. First, the GhrR can activate four known intracellular pathways Gαq, Gαi/o, Gα12/13 and the recruitment of β-arrestin. Biased signaling provides the possibility to activate or inhibit only one or a subset of the intracellular pathways of a pleiotropic receptor. This allows specific targeting of physiological functions without adverse effects. Currently little is known on how biased signaling could specifically modulate GhrR effects. Second, GhrR signaling has been shown to be interconnected with the dopaminergic system, particularly in the context of AN symptoms. This review highlights that a biased agonist for the GhrR may be a promising target for the treatment of AN, however extensive and systematic translational studies are still needed and the connection to the dopaminergic system has to be taken into account

Anxiolytic-Like Effects of Increased Ghrelin Receptor Signaling in the Amygdala

BACKGROUND: Besides the well-known effects of ghrelin on adiposity and food intake regulation, the ghrelin system has been shown to regulate aspects of behavior including anxiety and stress. However, the effect of virus-mediated overexpression of the ghrelin receptor in the amygdala has not previously been addressed directly. METHODS: First, we examined the acute effect of peripheral ghrelin administration on anxiety- and depression-like behavior using the open field, elevated plus maze, forced swim, and tail suspension tests. Next, we examined the effect of peripheral ghrelin administration and ghrelin receptor deficiency on stress in a familiar and social environment using the Intellicage system. Importantly, we also used a novel approach to study ghrelin receptor signaling in the brain by overexpressing the ghrelin receptor in the amygdala. We examined the effect of ghrelin receptor overexpression on anxiety-related behavior before and after acute stress and measured the modulation of serotonin receptor expression. RESULTS: We found that ghrelin caused an anxiolytic-like effect in both the open field and elevated plus maze tests. Additionally, it attenuated air-puff–induced stress in the social environment, while the opposite was shown in ghrelin receptor deficient mice. Finally, we found that overexpression of the ghrelin receptor in the basolateral division of the amygdala caused an anxiolytic-like effect and decreased the 5HT1a receptor expression. CONCLUSIONS: Ghrelin administration and overexpression of the ghrelin receptor in the amygdala induces anxiolytic-like behavior. Since the ghrelin receptor has high constitutive activity, ligand-independent signaling in vivo may be important for the observed anxiolytic-like effects. The anxiolytic effects seem to be mediated independently from the HPA axis, potentially engaging the central serotonin system