Time-Dependent Vascular Effects of Endocannabinoids Mediated by Peroxisome Proliferator-Activated Receptor Gamma (PPARγ)

The aim of the present study was to examine whether endocannabinoids cause PPARγ-mediated vascular actions. Functional vascular studies were carried out in rat aortae. Anandamide and N-arachidonoyl-dopamine (NADA), but not palmitoylethanolamide, caused significant vasorelaxation over time (2 hours). Vasorelaxation to NADA, but not anandamide, was inhibited by CB1 receptor antagonism (AM251, 1 μM), and vasorelaxation to both anandamide and NADA was inhibited by PPARγ antagonism (GW9662, 1 μM). Pharmacological inhibition of de novo protein synthesis, nitric oxide synthase, and super oxide dismutase abolished the responses to anandamide and NADA. Removal of the endothelium partly inhibited the vasorelaxant responses to anandamide and NADA. Inhibition of fatty acid amide hydrolase (URB597, 1 μM) inhibited the vasorelaxant response to NADA, but not anandamide. These data indicate that endocannabinoids cause time-dependent, PPARγ-mediated vasorelaxation. Activation of PPARγ in the vasculature may represent a novel mechanism by which endocannabinoids are involved in vascular regulation

Pterosauria of the Great Oolite Group (Middle Jurassic, Bathonian) of Oxfordshire and Gloucestershire, England

The current understanding of UK Middle Jurassic pterosaur taxonomy is under-developed, leading to it being previously considered a time of low diversity. This is despite the presence of a productive but under-studied pterosaur-bearing horizon extending over parts of Oxfordshire and Gloucestershire. This unit, informally called the Stonesfield Slate, is part of the Great Oolite Group and it produces the largest number of Middle Jurassic pterosaurs. There are over 200 specimens distributed across museums in the United Kingdom, America, and Australia, almost all of which are accessioned under the genus Rhamphocephalus and referred to three species: the type species Rhamphocephalus prestwichi, Rhamphocephalus bucklandi, and Rhamphocephalus depressirostris. This study reviews the British Middle Jurassic Pterosauria assemblage, evaluating both their systematics and taxonomic diversity. The holotype of Rhamphocephalus, an isolated skull table, is found to be a misidentified crocodylomorph skull and the genus is considered a nomen dubium. The holotype of Rhamphocephalus bucklandi is identified as missing and that of Rhamphocephalus depressirostris has characters diagnostic at a family level, not a generic or specific one. Both species are considered dubious. Detailed examination of the entire assemblage shows that rather than being monogeneric, the assemblage contains at least five pterosaur taxa, representing three families. This diversity includes the potential earliest occurrences of both Monofenestrata and Pterodactyloidea. A new genus, Klobiodon rochei gen. et sp. nov. is described based on a well-preserved mandible. The English Bathonian pterosaur assemblage is shown to be diverse and indicates that, as has been suggested in other studies, the low-diversity signal in the Middle Jurassic is at least partially artificial

Oleoylethanolamine and palmitoylethanolamine modulate intestinal permeability in vitro via TRPV1 and PPARα

Cannabinoids modulate intestinal permeability through cannabinoid receptor 1 (CB1). The endocannabinoid-like compounds oleoylethanolamine (OEA) and palmitoylethanolamine (PEA) play an important role in digestive regulation, and we hypothesized they would also modulate intestinal permeability. Transepithelial electrical resistance (TEER) was measured in human Caco-2 cells to assess permeability after application of OEA and PEA and relevant antagonists. Cells treated with OEA and PEA were stained for cytoskeletal F-actin changes and lysed for immunoassay. OEA and PEA were measured by liquid chromatography–tandem mass spectrometry. OEA (applied apically, logEC50 −5.4) and PEA (basolaterally, logEC50 −4.9; apically logEC50 −5.3) increased Caco-2 resistance by 20–30% via transient receptor potential vanilloid (TRPV)-1 and peroxisome proliferator-activated receptor (PPAR)-α. Preventing their degradation (by inhibiting fatty acid amide hydrolase) enhanced the effects of OEA and PEA. OEA and PEA induced cytoskeletal changes and activated focal adhesion kinase and ERKs 1/2, and decreased Src kinases and aquaporins 3 and 4. In Caco-2 cells treated with IFNγ and TNFα, OEA (via TRPV1) and PEA (via PPARα) prevented or reversed the cytokine-induced increased permeability compared to vehicle (0.1% ethanol). PEA (basolateral) also reversed increased permeability when added 48 or 72 h after cytokines (P < 0.001, via PPARα). Cellular and secreted levels of OEA and PEA (P < 0.001–0.001) were increased in response to inflammatory mediators. OEA and PEA have endogenous roles and potential therapeutic applications in conditions of intestinal hyperpermeability and inflammation

Stunning and Cumulative Left Ventricular Dysfunction Occurs Late After Coronary Balloon Occlusion in Humans Insights From Simultaneous Coronary and Left Ventricular Hemodynamic Assessment

ObjectivesWe aimed to investigate whether left ventricular (LV) stunning could be detected late after coronary occlusion when coronary flow has normalized.BackgroundStunning and cumulative LV dysfunction after ischemia reperfusion has been clearly demonstrated in animal models but has been refuted in several angioplasty models in humans. However, these studies have assessed LV function early, during the reactive hyperemic phase, which might have augmented LV function.MethodsWe recruited 20 male subjects with single-vessel, type A coronary disease, and normal ventricular function. We simultaneously measured LV function with a conductance catheter and coronary flow velocity with a Combowire (Volcano Therapeutics, Inc., Rancho Cordova, California) at baseline (BL), for 30 s after a low-pressure coronary balloon occlusion for 1 min and again after 30 min, before a second balloon occlusion.ResultsStunning was detected at 30 min after a 1-min balloon occlusion: stroke volume (ml) BL1: 88.4 (22.8) versus BL2: 79.4 (24.0), p = 0.04; τ (ms) BL1: 49.8 (9.0) versus BL2: 52.5 (8.9), p = 0.02, despite full recovery of coronary average peak velocity (p = 0.62). A second balloon occlusion caused cumulative LV dysfunction: stroke volume (ml) BO1: 77.3 (34.6) versus BO2 64.9 (22.9), p = 0.01. Reactive hyperemia significantly augmented early recovery systolic function: dP/dt max 30 s: +5.8% versus 30 min − 5.4%, p = 0.0009.ConclusionsCoronary occlusion for 1-min results in late stunning and cumulative LV dysfunction after 30 min. Reactive hyperemia augments stunned LV systolic function in early recovery

Warm H2_2 as a probe of massive accretion and feedback through shocks and turbulence across cosmic time

Galaxy formation depends on a complex interplay between gravitational collapse, gas accretion, merging, and feedback processes. Yet, after many decades of investigation, these concepts are poorly understood. This paper presents the argument that warm H$_2$ can be used as a tool to unlock some of these mysteries. Turbulence, shocks and outflows, driven by star formation, AGN activity or inflows, may prevent the rapid buildup of star formation in galaxies. Central to our understanding of how gas is converted into stars is the process by which gas can dissipate its mechanical energy through turbulence and shocks in order to cool. H$_2$ lines provide direct quantitative measurements of kinetic energy dissipation in molecular gas in galaxies throughout the Universe. Based on the detection of very powerful H$_2$ lines from z = 2 galaxies and proto-clusters at the detection limits of {\it Spitzer}, we are confident that future far-IR and UV H$_2$ observations will provide a wealth of new information and insight into galaxy evolution to high-z. Finally, at the very earliest epoch of star and galaxy formation, warm H$_2$ may also provide a unique glimpse of molecular gas collapse at 7 $<$ z $<$ 12 in massive dark matter (DM) halos on their way to forming the very first galaxies. Such measurements are beyond the reach of existing and planned observatories.Comment: Submitted as a science White Paper to the Astronomy and Astrophysics Astro 2020 Decadal Survey call issued by the National Academies of Sciences, Engineering and Medicine (March 11 2019

Glucagon-like peptide-1 derived cardioprotection does not utilize a KATP-channel dependent pathway: mechanistic insights from human supply and demand ischemia studies.

BACKGROUND: Glucagon-like peptide-1 (7-36) amide (GLP-1) protects against stunning and cumulative left ventricular dysfunction in humans. The mechanism remains uncertain but GLP-1 may act by opening mitochondrial K-ATP channels in a similar fashion to ischemic conditioning. We investigated whether blockade of K-ATP channels with glibenclamide abrogated the protective effect of GLP-1 in humans. METHODS: Thirty-two non-diabetic patients awaiting stenting of the left anterior descending artery (LAD) were allocated into 4 groups (control, glibenclamide, GLP-1, and GLP-1 + glibenclamide). Glibenclamide was given orally prior to the procedure. A left ventricular conductance catheter recorded pressure-volume loops during a 1-min low-pressure balloon occlusion (BO1) of the LAD. GLP-1 or saline was then infused for 30-min followed by a further 1-min balloon occlusion (BO2). In a non-invasive study, 10 non-diabetic patients were randomized to receive two dobutamine stress echocardiograms (DSE) during GLP-1 infusion with or without oral glibenclamide pretreatment. RESULTS: GLP-1 prevented stunning even with glibenclamide pretreatment; the Δ % dP/dtmax 30-min post-BO1 normalized to baseline after GLP-1: 0.3 ± 6.8 % (p = 0.02) and GLP-1 + glibenclamide: -0.8 ± 9.0 % (p = 0.04) compared to control: -11.5 ± 10.0 %. GLP-1 also reduced cumulative stunning after BO2: -12.8 ± 10.5 % (p = 0.02) as did GLP-1 + glibenclamide: -14.9 ± 9.2 % (p = 0.02) compared to control: -25.7 ± 9.6 %. Glibenclamide alone was no different to control. Glibenclamide pretreatment did not affect global or regional systolic function after GLP-1 at peak DSE stress (EF 74.6 ± 6.4 vs. 74.0 ± 8.0, p = 0.76) or recovery (EF 61.9 ± 5.7 vs. 61.4 ± 5.6, p = 0.74). CONCLUSIONS: Glibenclamide pretreatment does not abrogate the protective effect of GLP-1 in human models of non-lethal myocardial ischemia. Trial registration Clinicaltrials.gov Unique Identifier: NCT02128022

11 C-Metomidate PET/CT is a useful adjunct for lateralization of primary aldosteronism in routine clinical practice.

OBJECTIVE: To describe clinical practice experience of 11 C-Metomidate PET/CT as an adjunct to adrenal vein sampling (AVS) in the lateralization of aldosterone-producing adenomas (APA) in primary aldosteronism (PA). CONTEXT: Accurate lateralization of APA in the setting of PA offers the potential for surgical cure and improved long-term cardiovascular outcomes. Challenges associated with AVS, the current gold standard lateralization modality, mean that only a small proportion of potentially eligible patients currently make it through to surgery. This has prompted consideration of alternative strategies for lateralization, including the application of novel molecular PET tracers such as 11 C-Metomidate. DESIGN: Clinical Service Evaluation/Retrospective audit. PATIENTS: Fifteen individuals with a confirmed diagnosis of PA, undergoing lateralization with 11 C-Metomidate PET/CT prior to final clinical decision on surgical vs medical management. MEASUREMENTS: All patients underwent screening aldosterone renin ratio (ARR), followed by confirmatory testing with the seated saline infusion test, according to Endocrine Society Clinical Practice Guidelines. Adrenal glands were imaged using dedicated adrenal CT. 11 C-Metomidate PET/CT was undertaken due to equivocal or failed AVS. Management outcomes were assessed by longitudinal measurement of blood pressure, ARR, number of hypertensive medications following adrenalectomy or institution of medical therapy. RESULTS: We describe the individual lateralization and clinical outcomes for 15 patients with PA. CONCLUSION: 11 C-Metomidate PET/CT in conjunction with adrenal CT and AVS provided useful information which aided clinical decision-making for PA within a multidisciplinary hypertension clinic

Genome sequencing with gene panel-based analysis for rare inherited conditions in a publicly funded healthcare system: implications for future testing

Acknowledgements This study would not be possible without the families, patients, clinicians, nurses, research scientists, laboratory staff, informaticians and the wider Scottish Genomes Partnership team to whom we give grateful thanks. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health). The Scottish Genomes Partnership was funded by the Chief Scientist Office of the Scottish Government Health Directorates (SGP/1) and The Medical Research Council Whole Genome Sequencing for Health and Wealth Initiative (MC/PC/15080). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure.Peer reviewedPublisher PD