Studies on the role of GPR55 in cardiovascular physiology and pathophysiology.

Atherosclerosis is a multifactorial, chronic inflammatory condition characterised by endothelial dysfunction, hyperlipidaemia and the accumulation of fatty deposits within the tunica intima of medium-to-large sized muscular arteries. This disease can prove fatal with patients suffering lethal myocardial infarction or stroke. Recently, two studies investigating the role of G-protein-coupled receptor 55 (GPR55) in atherosclerosis reported conflicting results; one reported a pro-atherogenic role for GPR55 and the other, an anti-atherogenic role for this receptor. Interestingly, another study demonstrated that the activation of GPR55 by lysophosphatidylinositol (LPI) in cultured rat neonatal ventricular cardiomyocytes provokes distinct cellular functions that are dependent on the location of GPR55, leading to suggestions that GPR55 may regulate cardiomyocyte function at two cellular sites and be a potential therapeutic target for cardiac disorders. While it has been demonstrated that GPR55 is important in the maintenance of cardiac function of healthy mice, what is currently unknown is if GPR55 has a role in the cardiovascular remodelling and cardiac function of atherosclerosis prone mice. To address this, the present studies were conducted to investigate 1) the role of GPR55 in atherogenesis, 2) if GPR55 has a role in the cardiac function of mice suffering from atherosclerosis, 3) the signalling pathway by which LPI activates cardiomyocytes, 4) the impact of GPR55 activation on the outcome of myocardial ischaemia/reperfusion (I/R) injury and, 5) the signalling mechanisms by which GPR55 elicits any observed effects on the myocardium in response to such injury. Using C57BL/6 (wildtype; WT), apolipoprotein E knockout (ApoE-/-; mouse model of atherosclerosis), GPR55 knockout (GPR55-/-) and novel ApoE-/-/GPR55-/- mice, this study has established that in the presence of high fat feeding (to accelerate atherosclerosis), GPR55 has a complex role whereby it both regulates risk factors associated with atherosclerosis (i.e. body weight and fat mass) yet promotes the development of fatty streaks within the vasculature, via a lipid independent mechanism. In terms of cardiac function, GPR55 exerted a protective role by maintaining the systolic function of high fat fed ApoE-/- mice, yet negatively affected the contractile reserve of these mice. With regard to infarct size, the present study established that LPI-induced activation of GPR55 (pre-global ischaemia) exacerbates myocardial tissue injury via a Rho-associated protein kinase (ROCK) dependent mechanism. Finally, this study established that LPI signals through the same signalling pathway as it did in the isolated heart, in both mouse and human-induced pluripotent stem cell-derived cardiomyocytes thus suggesting a translational role for GPR55 in the human heart. In conclusion, despite further research being required, the data presented within this thesis provides evidence that GPR55 may have the potential to be targeted for therapeutic gains in atherosclerosis and myocardial I/R injury

Cyclophilin D palmitoylation and permeability transition: a new twist in the tale of myocardial ischaemia-reperfusion injury

No abstract available

Screening for congenital cytomegalovirus in North Carolina

The authors are full-time graduate students in UNC’s Doctor of Audiology (AuD) program. They are conducting this investigation in conjunction with their participation as audiology trainees in the North Carolina LEND Program (Leadership Education in Neurodevelopmental and Related Disabilities). The findings reported here are part of an ongoing investigation and represent current work in progress

The Cardiff self‐injury inventory (English version): convergent validity and psychometric properties

Background and Aims: The Cardiff Self‐Injury Inventory (CSII) is a short (1 min), relatively nonintrusive, measure of previous self‐injury behaviors written in English. It measures self‐injury with suicidal intent and without such intent, covers actions versus thoughts, and has two time periods (lifetime vs recent [defined as the last 3 months]). The study aimed to examine its psychometric properties and its relationship to more well‐established measures. Methods: A UK community sample of 184 participants completed the CSII and two other measures of self‐harming (Deliberate Self‐Harm Inventory [DSHI] and Suicidal Behaviors Questionnaire–Revised [SBQ‐R]) in March 2020–May 2020. Fifty participants also repeated these measurements 1–2 weeks later. Results: The CSII showed strong psychometric properties with internal reliability of 0.87 and a test–retest of 0.82. The subscales also showed strong psychometric properties. The CSII showed strong concurrent validity to the other measures of self‐injury (SBQ‐R, r = 0.70; DSHI, r = 0.81). A factor analysis supported the idea that there are two distinct components to the overall CSII score arising due to the distinction between suicidal and nonsuicidal behaviors. Conclusion: The CSII has good psychometric properties in this population and can be used as a fast, nonintrusive, measure of different self‐injurious behaviors for clinical or research purposes

l-α-Lysophosphatidylinositol (LPI) aggravates myocardial ischemia/reperfusion injury via a GPR55/ROCK-dependent pathway

The phospholipid l-α-lysophosphatidylinositol (LPI), an endogenous ligand for GPR55, is elevated in patients with acute coronary syndrome, and a GPR55 antagonist cannabidiol (CBD) reduces experimental ischemia/reperfusion (I/R) injury. While LPI activates multiple signaling pathways, little is known about which ones are important in cardiomyocytes. In this study we explored whether activation of the Rho kinase/ROCK/p38 MAPK pathway is responsible for LPI-induced extension of I/R injury. Using a high-throughput screening method (dynamic mass redistribution; DMR), mouse- and human-induced pluripotent stem cell (iPSC) cardiomyocytes exposed to LPI were shown to exhibit a rapid, sustained, and concentration‐dependent (1 nmol L−1‐30 μmol L−1) cellular response. Y‐27632 (ROCK inhibitor; 10 & 50 μmol L−1) and CBD (1 μmol L−1) both abolished the DMR response to LPI (10 μmol L−1). In murine iPSC cardiomyocytes, LPI-induced ROCK and p38 MAPK phosphorylation, both of which were prevented by Y-27632 and CBD, but did not induce JNK activation or cleavage of caspase-3. In hearts isolated from wild type (WT) mice subjected to 30 minutes global I/R, LPI (10 μmol L−1) administered via the coronary circulation increased infarct size when applied prior to ischemia onset, but not when given at the time of reperfusion. The exacerbation of tissue injury by LPI was not seen in hearts from GPR55−/− mice or in the presence of Y-27632, confirming that injury is mediated via the GPR55/ROCK/p38 MAPK pathway. These findings suggest that raised levels of LPI in the vicinity of a developing infarct may worsen the outcome of AMI

Have e-cigarettes renormalised or displaced youth smoking? Results of a segmented regression analysis of repeated cross-sectional survey data in England, Scotland and Wales

Objectives: To examine whether during a period of limited e-cigarette regulation and rapid growth in their use, smoking began to become renormalised among young people. Design: Interrupted time-series analysis of repeated cross-sectional time-series data. Setting: Great Britain Participants: 248 324 young people aged approximately 13 and 15 years, from three national surveys during the years 1998–2015. Intervention Unregulated growth of e-cigarette use (following the year 2010, until 2015). Outcome measures: Primary outcomes were prevalence of self-reported ever smoking and regular smoking. Secondary outcomes were attitudes towards smoking. Tertiary outcomes were ever use of cannabis and alcohol. Results: In final models, no significant change was detected in the pre-existing trend for ever smoking (OR 1.01, CI 0.99 to 1.03). There was a marginally significant slowing in the rate of decline for regular smoking (OR 1.04, CI 1.00 to 1.08), accompanied by a larger slowing in the rate of decline of cannabis use (OR 1.21, CI 1.18 to 1.25) and alcohol use (OR 1.17, CI 1.14 to 1.19). In all models and subgroup analyses for smoking attitudes, an increased rate of decline was observed after 2010 (OR 0.88, CI 0.86 to 0.90). Models were robust to sensitivity analyses. Conclusions: There was a marginal slowing in the decline in regular smoking during the period following 2010, when e-cigarettes were emerging but relatively unregulated. However, these patterns were not unique to tobacco use and the decline in the acceptability of smoking behaviour among youth accelerated during this time. These analyses provide little evidence that renormalisation of youth smoking was occurring during a period of rapid growth and limited regulation of e-cigarettes from 2011 to 2015

Has increased clinical experience with methotrexate reduced the direct costs of medical management of ectopic pregnancy compared to surgery?

<p>Abstract</p> <p>Background</p> <p>There is a debate about the cost-efficiency of methotrexate for the management of ectopic pregnancy (EP), especially for patients presenting with serum human chorionic gonadotrophin levels of >1500 IU/L. We hypothesised that further experience with methotrexate, and increased use of guideline-based protocols, has reduced the direct costs of management with methotrexate.</p> <p>Methods</p> <p>We conducted a retrospective cost analysis on women treated for EP in a large UK teaching hospital to (1) investigate whether the cost of medical management is less expensive than surgical management for those patients eligible for both treatments and (2) to compare the cost of medical management for women with hCG concentrations 1500–3000 IU/L against those with similar hCG concentrations that elected for surgery. Three distinct treatment groups were identified: (1) those who had initial medical management with methotrexate, (2) those who were eligible for initial medical management but chose surgery (‘elected’ surgery) and (3) those who initially ‘required’ surgery and did not meet the eligibility criteria for methotrexate. We calculated the costs from the point of view of the National Health Service (NHS) in the UK. We summarised the cost per study group using the mean, standard deviation, median and range and, to account for the skewed nature of the data, we calculated 95% confidence intervals for differential costs using the nonparametric bootstrap method.</p> <p>Results</p> <p>Methotrexate was £1179 (CI 819–1550) per patient cheaper than surgery but there were no significant savings with methotrexate in women with hCG >1500 IU/L due to treatment failures.</p> <p>Conclusions</p> <p>Our data support an ongoing unmet economic need for better medical treatments for EP with hCG >1500 IU/L.</p