The influence of cannabis smoke and cannabis vapour on simulated lung surfactant function under physiologically relevant conditions

The use of cannabis for medicinal/recreational purposes is widespread throughout the world. Smoke inhalation is known to cause airway irritation due to noxious substances (ie, benzene) within the mix. Thus, advanced vaporisation platforms (eg, Davinci IQ) have been developed to circumvent negative health implications. Here, we consider the impact that cannabis smoke and cannabis vapour have on simulated lung surfactant performance within a model pulmonary space (ie, 37°C, elevated humidity and related fluid hydrodynamics). In total, 50 mg of herbal material was ignited or placed within a Davinci IQ vaporiser with subsequent activation. The aliquots were collected and then analysed using gas chromatography‐mass spectroscopy for composition and cannabinoid (eg, Δ9‐tetrahydrocannabinol [Δ9‐THC]) concentration. The average content within cannabis smoke was 2.84% (0.07%, SD) Δ9‐THC, with the same for cannabis vapour being 0.88% (0.14%, SD). Aerosolised samples were transferred to the lung biosimulator. When compared with the pristine Curosurf system, challenge with cannabis smoke and cannabis vapour reduced the surface pressure term by 26% and 7% and increased film compressibility by 60% and 15% at 80% trough area, respectively. The net effect would be enhanced film elasticity and an increased work of breathing, being more pronounced on cannabis smoke inhalation. The trends noted were ascribed to two factors operating synergistically, namely the amount of Δ9‐THC (plus others) within the aerosolised samples and the associated toxicity profile. Further research is required to establish mass‐balance effects (ie, titrated outputs) along with detailed chemical profiling of material generated from the unrelated cannabis activation pathways

A physiological increase in maternal cortisol alters uteroplacental metabolism in the pregnant ewe

Fetal nutrition is determined by maternal availability, placental transport and uteroplacental metabolism of carbohydrates. Cortisol affects maternal and fetal metabolism, but whether maternal cortisol concentrations within the physiological range regulate uteroplacental carbohydrate metabolism remains unknown. This study determined the effect of maternal cortisol infusion (1.2 mg kg−1 day−1 I.V. for 5 days, n = 20) on fetal glucose, lactate and oxygen supplies in pregnant ewes on day 130 of pregnancy (term = 145 days). Compared to saline infusion (n = 21), cortisol infusion increased maternal, but not fetal, plasma cortisol (P < 0.05). Cortisol infusion also raised maternal insulin, glucose and lactate concentrations, and blood pH, PCO2 and HCO3 − concentration. Although total uterine glucose uptake determined by Fick’s principle was unaffected, a greater proportion was consumed by the uteroplacental tissues, so net fetal glucose uptake was 29% lower in cortisol-infused than control ewes (P < 0.05). Concomitantly, uteroplacental lactate production was > 2-fold greater in cortisol- than saline-treated ewes (P < 0.05), although uteroplacental O2 consumption was unaffected by maternal treatment. Materno-fetal clearance of non-metabolizable [3H]methyl-D-glucose and placental SLC2A8 (glucose transporter 8) gene expression were also greater with cortisol treatment. Fetal plasma glucose, lactate or α-amino nitrogen concentrations were unaffected by treatment although fetal plasma fructose and hepatic lactate dehydrogenase activity were greater in cortisol- than saline-treated ewes (P < 0.05). Fetal plasma insulin levels and body weight were also unaffected by maternal treatment. During stress, cortisol-dependent regulation of uteroplacental glycolysis may allow increased maternal control over fetal nutrition and metabolism. However, when maternal cortisol concentrations are raised chronically, prolonged elevation of uteroplacental lactate production may compromise fetal wellbeing

A physiological increase in maternal cortisol alters uteroplacental metabolism in the pregnant ewe.

KEY POINTS: Fetal nutrient supply is dependent, in part, upon the transport capacity and metabolism of the placenta. The stress hormone, cortisol, alters metabolism in the adult and fetus but it is not known whether cortisol in the pregnant mother affects metabolism of the placenta. In this study, when cortisol concentrations were raised in pregnant sheep by infusion, proportionately more of the glucose taken up by the uterus was consumed by the uteroplacental tissues while less was transferred to the fetus, despite an increased placental glucose transport capacity. Concomitantly, the uteroplacental tissues produced lactate at a greater rate. The results show that maternal cortisol concentrations regulate uteroplacental glycolytic metabolism, producing lactate for use in utero. Prolonged increases in placental lactate production induced by cortisol overexposure may contribute to the adverse effects of maternal stress on fetal wellbeing. ABSTRACT: Fetal nutrition is determined by maternal availability, placental transport and uteroplacental metabolism of carbohydrates. Cortisol affects maternal and fetal metabolism, but whether maternal cortisol concentrations within the physiological range regulate uteroplacental carbohydrate metabolism remains unknown. This study determined the effect of maternal cortisol infusion (1.2 mg kg(-1)  day(-1) i.v. for 5 days, n = 20) on fetal glucose, lactate and oxygen supplies in pregnant ewes on day ∼130 of pregnancy (term = 145 days). Compared to saline infusion (n = 21), cortisol infusion increased maternal, but not fetal, plasma cortisol (P  2-fold greater in cortisol- than saline-treated ewes (P < 0.05), although uteroplacental O2 consumption was unaffected by maternal treatment. Materno-fetal clearance of non-metabolizable [(3) H]methyl-d-glucose and placental SLC2A8 (glucose transporter 8) gene expression were also greater with cortisol treatment. Fetal plasma glucose, lactate or α-amino nitrogen concentrations were unaffected by treatment although fetal plasma fructose and hepatic lactate dehydrogenase activity were greater in cortisol- than saline-treated ewes (P < 0.05). Fetal plasma insulin levels and body weight were also unaffected by maternal treatment. During stress, cortisol-dependent regulation of uteroplacental glycolysis may allow increased maternal control over fetal nutrition and metabolism. However, when maternal cortisol concentrations are raised chronically, prolonged elevation of uteroplacental lactate production may compromise fetal wellbeing

Histone deacetylase adaptation in single ventricle heart disease and a young animal model of right ventricular hypertrophy.

BackgroundHistone deacetylase (HDAC) inhibitors are promising therapeutics for various forms of cardiac diseases. The purpose of this study was to assess cardiac HDAC catalytic activity and expression in children with single ventricle (SV) heart disease of right ventricular morphology, as well as in a rodent model of right ventricular hypertrophy (RVH).MethodsHomogenates of right ventricle (RV) explants from non-failing controls and children born with a SV were assayed for HDAC catalytic activity and HDAC isoform expression. Postnatal 1-day-old rat pups were placed in hypoxic conditions, and echocardiographic analysis, gene expression, HDAC catalytic activity, and isoform expression studies of the RV were performed.ResultsClass I, IIa, and IIb HDAC catalytic activity and protein expression were elevated in the hearts of children born with a SV. Hypoxic neonatal rats demonstrated RVH, abnormal gene expression, elevated class I and class IIb HDAC catalytic activity, and protein expression in the RV compared with those in the control.ConclusionsThese data suggest that myocardial HDAC adaptations occur in the SV heart and could represent a novel therapeutic target. Although further characterization of the hypoxic neonatal rat is needed, this animal model may be suitable for preclinical investigations of pediatric RV disease and could serve as a useful model for future mechanistic studies

A Single Bolus of Docosahexaenoic Acid Promotes Neuroplastic Changes in the Innervation of Spinal Cord Interneurons and Motor Neurons and Improves Functional Recovery after Spinal Cord Injury

This work was supported by Chang GungMemorialHospital, Taiwan CMRPG3A1051–1054to Z.-H.L., CMDRP and Barts and the London Charity to P.K.Y. and A.T.M.-T., and the Nathalie Rose Barr PhD Studentship ISRT to L.A. andJ.V.P

Feedback from supermassive black holes transforms centrals into passive galaxies by ejecting circumgalactic gas

Davies et al. (2019) established that for L^* galaxies the fraction of baryons in the circumgalactic medium (CGM) is inversely correlated with the mass of their central supermassive black holes (BHs) in the EAGLE hydrodynamic simulation. The interpretation is that, over time, a more massive BH has provided more energy to transport baryons beyond the virial radius, which additionally reduces gas accretion and star formation. We continue this research by focusing on the relationship between the 1) BH masses, 2) physical and observational properties of the CGM, and 3) galaxy colours for Milky Way-mass systems. The ratio of the cumulative BH feedback energy over the gaseous halo binding energy is a strong predictor of the CGM gas content, with BHs injecting >~10x the binding energy resulting in gas-poor haloes. Observable tracers of the CGM, including CIV, OVI, and HI absorption line measurements, are found to be effective tracers of the total z~0 CGM halo mass. We use high-cadence simulation outputs to demonstrate that BH feedback pushes baryons beyond the virial radius within 100 Myr timescales, but that CGM metal tracers take longer (0.5-2.5 Gyr) to respond. Secular evolution of galaxies results in blue, star-forming or red, passive populations depending on the cumulative feedback from BHs. The reddest quartile of galaxies with M_*=10^{10.2-10.7} M_solar (median u-r = 2.28) has a CGM mass that is 2.5x lower than the bluest quartile (u-r=1.59). We propose strategies for observing the predicted lower CGM column densities and covering fractions around galaxies hosting more massive BHs using the Cosmic Origins Spectrograph on Hubble

Supply-chain modelling and control under proportional inventory-replenishment policies

A novel state-space model of a multi-node supply chain is presented, controlled via local proportional inventory-replenishment policies. The model is driven by a stochastic sequence representing customer demand. The model is analysed under stationarity conditions and a simple recursive scheme is developed for updating its covariance matrix. This allows us to characterise the ‘bullwhip effect’ (demand amplification) in the chain and to solve an optimisation problem for a three-node model involving the minimisation of inventory subject to a probabilistic constraint on downstream demand. Finally, issues related to estimation schemes based on local historical data are briefly discussed

Water diffusion in atmospherically relevant α-pinene secondary organic material

Secondary organic material (SOM) constitutes a large mass fraction of atmospheric aerosol particles. Understanding its impact on climate and air quality relies on accurate models of interactions with water vapour. Recent research shows that SOM can be highly viscous and can even behave mechanically like a solid, leading to suggestions that particles exist out of equilibrium with water vapour in the atmosphere. In order to quantify any kinetic limitation we need to know water diffusion coefficients for SOM, but this quantity has, until now, only been estimated and has not yet been measured. We have directly measured water diffusion coefficients in the water soluble fraction of α-pinene SOM between 240 and 280 K. Here we show that, although this material can behave mechanically like a solid, at 280 K water diffusion is not kinetically limited on timescales of 1 s for atmospheric-sized particles. However, diffusion slows as temperature decreases. We use our measured data to constrain a Vignes-type parameterisation, which we extend to lower temperatures to show that SOM can take hours to equilibrate with water vapour under very cold conditions. Our modelling for 100 nm particles predicts that under mid to upper tropospheric conditions radial inhomogeneities in water content produce a low viscosity surface region and more solid interior, with implications for heterogeneous chemistry and ice nucleation