Characterization of the insulin sensitivity of ghrelin receptor KO mice using glycemic clamps

<p>Abstract</p> <p>Background</p> <p>We and others have demonstrated previously that ghrelin receptor (<it>GhrR</it>) knock out (KO) mice fed a high fat diet (HFD) have increased insulin sensitivity and metabolic flexibility relative to WT littermates. A striking feature of the HFD-fed <it>GhrR </it>KO mouse is the dramatic decrease in hepatic steatosis. To characterize further the underlying mechanisms of glucose homeostasis in <it>GhrR </it>KO mice, we conducted both hyperglycemic (HG) and hyperinsulinemic-euglycemic (HI-E) clamps. Additionally, we investigated tissue glucose uptake and specifically examined liver insulin sensitivity.</p> <p>Results</p> <p>Consistent with glucose tolerance-test data, in HG clamp experiments, <it>GhrR </it>KO mice showed a reduction in glucose-stimulated insulin release relative to WT littermates. Nevertheless, a robust 1^stphase insulin secretion was still achieved, indicating that a healthy β-cell response is maintained. Additionally, <it>GhrR </it>KO mice demonstrated both a significantly increased glucose infusion rate and significantly reduced insulin requirement for maintenance of the HG clamp, consistent with their relative insulin sensitivity. In HI-E clamps, both LFD-fed and HFD-fed <it>GhrR </it>KO mice showed higher peripheral insulin sensitivity relative to WT littermates as indicated by a significant increase in insulin-stimulated glucose disposal (Rd), and decreased hepatic glucose production (HGP). HFD-fed <it>GhrR </it>KO mice showed a marked increase in peripheral tissue glucose uptake in a variety of tissues, including skeletal muscle, brown adipose tissue and white adipose tissue. <it>GhrR </it>KO mice fed a HFD also showed a modest, but significant decrease in conversion of pyruvate to glucose, as would be anticipated if these mice displayed increased liver insulin sensitivity. Additionally, the levels of UCP2 and UCP1 were reduced in the liver and BAT, respectively, in <it>GhrR </it>KO mice relative to WT mice.</p> <p>Conclusions</p> <p>These results indicate that improved glucose homeostasis of <it>GhrR </it>KO mice is characterized by robust improvements of glucose disposal in both normal and metabolically challenged states, relative to WT controls. <it>GhrR </it>KO mice have an intact 1^stphase insulin response but require significantly less insulin for glucose disposal. Our experiments reveal that the insulin sensitivity of <it>GhrR </it>KO mice is due to both BW independent and dependent factors. We also provide several lines of evidence that a key feature of the <it>GhrR </it>KO mouse is maintenance of hepatic insulin sensitivity during metabolic challenge.</p

Spectrum of mutational signatures in T-cell lymphoma reveals a key role for UV radiation in cutaneous T-cell lymphoma

Funder: Galderma; doi: http://dx.doi.org/10.13039/501100009754Funder: NIHR-BRC Cambridge core grantFunder: National Institute for Health Research; doi: http://dx.doi.org/10.13039/501100000272Funder: NHS EnglandAbstract: T-cell non-Hodgkin’s lymphomas develop following transformation of tissue resident T-cells. We performed a meta-analysis of whole exome sequencing data from 403 patients with eight subtypes of T-cell non-Hodgkin’s lymphoma to identify mutational signatures and associated recurrent gene mutations. Signature 1, indicative of age-related deamination, was prevalent across all T-cell lymphomas, reflecting the derivation of these malignancies from memory T-cells. Adult T-cell leukemia-lymphoma was specifically associated with signature 17, which was found to correlate with the IRF4 K59R mutation that is exclusive to Adult T-cell leukemia-lymphoma. Signature 7, implicating UV exposure was uniquely identified in cutaneous T-cell lymphoma (CTCL), contributing 52% of the mutational burden in mycosis fungoides and 23% in Sezary syndrome. Importantly this UV signature was observed in CD4 + T-cells isolated from the blood of Sezary syndrome patients suggesting extensive re-circulation of these T-cells through skin and blood. Analysis of non-Hodgkin’s T-cell lymphoma cases submitted to the national 100,000 WGS project confirmed that signature 7 was only identified in CTCL strongly implicating UV radiation in the pathogenesis of cutaneous T-cell lymphoma

Percutaneous revascularization for ischemic left ventricular dysfunction: Cost-effectiveness analysis of the REVIVED-BCIS2 trial

BACKGROUND: Percutaneous coronary intervention (PCI) is frequently undertaken in patients with ischemic left ventricular systolic dysfunction. The REVIVED (Revascularization for Ischemic Ventricular Dysfunction)-BCIS2 (British Cardiovascular Society-2) trial concluded that PCI did not reduce the incidence of all-cause death or heart failure hospitalization; however, patients assigned to PCI reported better initial health-related quality of life than those assigned to optimal medical therapy (OMT) alone. The aim of this study was to assess the cost-effectiveness of PCI+OMT compared with OMT alone. METHODS: REVIVED-BCIS2 was a prospective, multicenter UK trial, which randomized patients with severe ischemic left ventricular systolic dysfunction to either PCI+OMT or OMT alone. Health care resource use (including planned and unplanned revascularizations, medication, device implantation, and heart failure hospitalizations) and health outcomes data (EuroQol 5-dimension 5-level questionnaire) on each patient were collected at baseline and up to 8 years post-randomization. Resource use was costed using publicly available national unit costs. Within the trial, mean total costs and quality-adjusted life-years (QALYs) were estimated from the perspective of the UK health system. Cost-effectiveness was evaluated using estimated mean costs and QALYs in both groups. Regression analysis was used to adjust for clinically relevant predictors. RESULTS: Between 2013 and 2020, 700 patients were recruited (mean age: PCI+OMT=70 years, OMT=68 years; male (%): PCI+OMT=87, OMT=88); median follow-up was 3.4 years. Over all follow-ups, patients undergoing PCI yielded similar health benefits at higher costs compared with OMT alone (PCI+OMT: 4.14 QALYs, £22 352; OMT alone: 4.16 QALYs, £15 569; difference: −0.015, £6782). For both groups, most health resource consumption occurred in the first 2 years post-randomization. Probabilistic results showed that the probability of PCI being cost-effective was 0. CONCLUSIONS: A minimal difference in total QALYs was identified between arms, and PCI+OMT was not cost-effective compared with OMT, given its additional cost. A strategy of routine PCI to treat ischemic left ventricular systolic dysfunction does not seem to be a justifiable use of health care resources in the United Kingdom

Arrhythmia and death following percutaneous revascularization in ischemic left ventricular dysfunction: Prespecified analyses from the REVIVED-BCIS2 trial

BACKGROUND: Ventricular arrhythmia is an important cause of mortality in patients with ischemic left ventricular dysfunction. Revascularization with coronary artery bypass graft or percutaneous coronary intervention is often recommended for these patients before implantation of a cardiac defibrillator because it is assumed that this may reduce the incidence of fatal and potentially fatal ventricular arrhythmias, although this premise has not been evaluated in a randomized trial to date. METHODS: Patients with severe left ventricular dysfunction, extensive coronary disease, and viable myocardium were randomly assigned to receive either percutaneous coronary intervention (PCI) plus optimal medical and device therapy (OMT) or OMT alone. The composite primary outcome was all-cause death or aborted sudden death (defined as an appropriate implantable cardioverter defibrillator therapy or a resuscitated cardiac arrest) at a minimum of 24 months, analyzed as time to first event on an intention-to-treat basis. Secondary outcomes included cardiovascular death or aborted sudden death, appropriate implantable cardioverter defibrillator (ICD) therapy or sustained ventricular arrhythmia, and number of appropriate ICD therapies. RESULTS: Between August 28, 2013, and March 19, 2020, 700 patients were enrolled across 40 centers in the United Kingdom. A total of 347 patients were assigned to the PCI+OMT group and 353 to the OMT alone group. The mean age of participants was 69 years; 88% were male; 56% had hypertension; 41% had diabetes; and 53% had a clinical history of myocardial infarction. The median left ventricular ejection fraction was 28%; 53.1% had an implantable defibrillator inserted before randomization or during follow-up. All-cause death or aborted sudden death occurred in 144 patients (41.6%) in the PCI group and 142 patients (40.2%) in the OMT group (hazard ratio, 1.03 [95% CI, 0.82–1.30]; P =0.80). There was no between-group difference in the occurrence of any of the secondary outcomes. CONCLUSIONS: PCI was not associated with a reduction in all-cause mortality or aborted sudden death. In patients with ischemic cardiomyopathy, PCI is not beneficial solely for the purpose of reducing potentially fatal ventricular arrhythmias. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920048

Is rural Ireland a good place in which to grow old?

The theme of ageing in rural areas has gained increasing attention from policy makers and researchers in the last few decades in a situation where older people now often comprise a disproportionately larger share of those living in rural areas (see for example, Lowe and Speakman, 2006; Heenan, 2010.). This recognition is important because many stereotypes have evolved about rural ageing. Rural families, communities and places are often idealised, contributing to a tendency to romanticise age and ageing in rural settings. This is exacerbated by the difficulty of identifying social exclusion in rural environments simply because deprivation is not easily found in concentrated clusters of people, as is often the case in urban neighbourhoods. Sometimes older people in rural areas qualify their experience of poverty and isolation by drawing attention to the more positive aspects of rural life. The result is that rural older people are sometimes portrayed as being more resilient and self-sufficient and which may, in turn, be used to justify public policy inaction. This paper critically examines the notion of a rural idyll as it relates to the lived experiences of older people and presents some of the key findings that have emerged from a baseline research project conducted in 2010 across the island of Ireland

Incidence of mild traumatic brain injury: A prospective hospital, emergency room and general practitioner-based study

Background: There are no recent estimates of incidence rates of mild traumatic brain injury (MTBI) from Norway. Moreover, reported incidence rates rarely comprise cases of MTBI evaluated in the primary care setting. In this study, we utilized existing data collected as part of the recruitment to a large, follow-up study of patients with MTBI. We estimated the incidence rate of MTBI, including patients who visited outpatient clinics, in the age group 16–59 years in a Norwegian region. Methods: During 81 weeks in 2014 and 2015, all persons aged 16–59 years, presenting with possible MTBI to the emergency department (ED) at St. Olavs Hospital, Trondheim University Hospital or to the general practitioner (GP)-run Trondheim municipal outpatient ED, were evaluated for a diagnosis of MTBI. Patients were identified by computerized tomography (CT) referrals and patient lists. Patients referred to acute CT from their primary GP with suspicion of MTBI were also recorded. This approach identified 732 patients with MTBI. Age- and sex-specific incidence rates of MTBI were calculated using population figures from the regional catchment area. Results: Overall incidence of MTBI in people between 16 and 59 years was 302 per 100,000 person-years (95% confidence interval 281–324). The incidence rate was highest in the age group 16–20 years, where rates were 835 per 100,000 person-years in males and 726 in females. Conclusion: The overall incidence rate of MTBI was lower than expected from existing estimates. Like other reports, the incidence was highest in the late teens

The epidemiology of mild traumatic brain injury: The Trondheim MTBI follow-up study

ackground Mild traumatic brain injury (MTBI) is a frequent medical condition, and some patients report long-lasting problems after MTBI. In order to prevent MTBI, knowledge of the epidemiology is important and potential bias in studies should be explored. Aims of this study were to describe the epidemiological characteristics of MTBI in a Norwegian area and to evaluate the representativeness of patients successfully enrolled in the Trondheim MTBI follow-up study. Methods During 81 weeks in 2014 and 2015, all persons aged 16–60 years, presenting with possible MTBI to the emergency department (ED) at St. Olavs Hospital, Trondheim University Hospital or to Trondheim municipal outpatient ED, were evaluated for participation in the follow-up study. Patients were identified by CT referrals and patient lists. Patients who were excluded or missed for enrolment in the follow-up study were recorded. Results We identified 732 patients with MTBI. Median age was 28 years, and fall was the most common cause of injury. Fifty-three percent of injuries occurred during the weekend. Only 29% of MTBI patients were hospitalised. Study specific exclusion criteria were present in 23%. We enrolled 379 in the Trondheim MTBI follow-up study. In this cohort, Glasgow Coma Scale score was 15 at presentation in 73%; 45% of patients were injured under the influence of alcohol. Patients missed for inclusion were significantly more often outpatients, females, injured during the weekend, and suffering violent injuries, but differences between enrolled and not enrolled patients were small. Conclusion Two thirds of all patients with MTBI in the 16–60 age group were treated without hospital admission, patients were often young, and half of the patients presented during the weekend. Fall was the most common cause of injury, and patients were commonly injured under the influence of alcohol, which needs to be addressed when considering strategies for prevention. The Trondheim MTBI follow-up study comprised patients who were highly representative for the underlying epidemiology of MTBI.publishedVersion© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/