A meta-analysis of remote ischaemic conditioning in experimental stroke

Remote ischaemic conditioning (RIC) is achieved by repeated transient ischaemia of a distant organ/limb and is neuroprotective in experimental ischaemic stroke. However, the optimal time and methods of administration are unclear. Systematic review identified relevant preclinical studies; two authors independently extracted data on infarct volume, neurological deficit, RIC method (administration time, site, cycle number, length of limb occlusion (dose)), species and quality. Data were analysed using random effects models; results expressed as standardised mean difference (SMD). In 57 publications incorporating 99 experiments (1406 rats, 101 mice, 14 monkeys), RIC reduced lesion volume in transient (SMD −2.0; 95% CI −2.38, −1.61; p

A novel transwell blood brain barrier model using primary human cells

© 2019 Stone, England and O’Sullivan. Structural alterations and breakdown of the blood brain barrier (BBB) is often a primary or secondary consequence of disease, resulting in brain oedema and the transport of unwanted substances into the brain. It is critical that effective in vitro models are developed to model the in vivo environment to aid in clinically relevant research, especially regarding drug screening and permeability studies. Our novel model uses only primary human cells and includes four of the key cells of the BBB: astrocytes, pericytes, brain microvascular endothelial cells (HBMEC) and neurons. We show that using a larger membrane pore size (3.0 μM) there is an improved connection between the endothelial cells, astrocytes and pericytes. Compared to a two and three cell model, we show that when neurons are added to HBMECs, astrocytes and pericytes, BBB integrity was more sensitive to oxygen-glucose deprivation evidenced by increased permeability and markers of cell damage. Our data also show that a four cell model responds faster to the barrier tightening effects of glucocorticoid dexamethasone, when compared to a two cell and three cell model. These data highlight the important role that neurons play in response to ischaemia, particularly how they contribute to BBB maintenance and breakdown. We consider that this model is more representative of the interactions at the neurovascular unit than other transwell models and is a useful method to study BBB physiology

A systematic review and meta-analysis of the in vivo haemodynamic effects of Δ9-Tetrahydrocannabinol

∆9-Tetrahydrocannabinol (THC) has complex effects on the cardiovascular system. We aimed to systematically review studies of THC and haemodynamic alterations. PubMed, Medline, and EMBASE were searched for relevant studies. Changes in blood pressure (BP), heart rate (HR), and blood flow (BF) were analysed using the Cochrane Review Manager Software. Thirty-one studies met the eligibility criteria. Fourteen publications assessed BP (number, n = 541), 22 HR (n = 567), and 3 BF (n = 45). Acute THC dosing reduced BP and HR in anaesthetised animals (BP, mean difference (MD) −19.7 mmHg, p < 0.00001; HR, MD −53.49 bpm, p < 0.00001), conscious animals (BP, MD −12.3 mmHg, p = 0.0007; HR, MD −30.05 bpm, p < 0.00001), and animal models of stress or hypertension (BP, MD −61.37 mmHg, p = 0.03) and increased cerebral BF in murine stroke models (MD 32.35%, p < 0.00001). Chronic dosing increased BF in large arteries in anaesthetised animals (MD 21.95 mL/min, p = 0.05) and reduced BP in models of stress or hypertension (MD −22.09 mmHg, p < 0.00001). In humans, acute administration increased HR (MD 8.16 bpm, p < 0.00001). THC acts differently according to species and experimental conditions, causing bradycardia, hypotension and increased BF in animals; and causing increased HR in humans. Data is limited, and further studies assessing THC-induced haemodynamic changes in humans should be considered

A Systematic Review of Minor Phytocannabinoids with Promising Neuroprotective Potential

Embase and Pubmed were systematically searched for articles addressing the neuroprotective properties of phytocannabinoids, aside from cannabidiol and Δ9‐tetrahydrocannabinol, including Δ9‐tetrahydrocannabinolic acid (Δ9‐THCA), Δ9‐tetrahydrocannabivarin (Δ9‐THCV), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabichromene (CBC), cannabichromenic acid (CBCA), cannabichromevarin (CBCV), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabigerivarin (CBGV), cannabigerovarinic acid (CBGVA), cannabichromevarinic acid (CBCVA) cannabidivarinic acid (CBDVA) and cannabinol (CBN). Out of 2,341 studies, 31 articles met inclusion criteria. CBG (range 5 mg.kg‐1 to 20 mg.kg‐1) and CBDV (range 0.2 mg.kg‐1 to 400 mg.kg‐1) displayed efficacy in models of Huntington’s disease and epilepsy. CBC (10‐75 mg.kg‐1), Δ9‐THCA (20 mg.kg‐1) and Δ9‐THCV (range 0.025‐2.5 mg.kg‐1) showed promise in models of seizure and hypomobility, Huntington’s and Parkinson’s disease. Limited mechanistic data showed CBG, VCE.003, VCE.003.2 and Δ9‐THCA mediated some of their effects through PPARy, but no other receptors were probed. Further studies with these phytocannabinoids, and their combinations, are warranted across a range of neurodegenerative disorders

Tissue phantoms in multicenter clinical trials for diffuse optical technologies

Tissue simulating phantoms are an important part of instrumentation validation, standardization/training and clinical translation. Properly used, phantoms form the backbone of sound quality control procedures. We describe the development and testing of a series of optically turbid phantoms used in a multi-center American College of Radiology Imaging Network (ACRIN) clinical trial of Diffuse Optical Spectroscopic Imaging (DOSI). The ACRIN trial is designed to measure the response of breast tumors to neoadjuvant chemotherapy. Phantom measurements are used to determine absolute instrument response functions during each measurement session and assess both long and short-term operator and instrument reliability

Estimating upper limb discomfort level due to intermittent isometric pronation torque with various combinations of elbow angles, forearm rotation angles, force and frequency with upper arm at 90 degrees abduction

peer-reviewedIndustrial jobs involving upper arm abduction have a strong association with musculoskeletal disorders and injury. But there is still paucity of data on the different risk factors that are responsible for the genesis of such disorders or injuries. The current laboratory study is an attempt in that direction. Thirty-six right-handed male university students participated in a full factorial model of three forearm rotation angles (60% prone and supine and neutral range of motion), three elbow angles (45 degrees, 90 degrees and 135 degrees), two exertion frequencies (10 and 20/min) and two levels of pronation torque (10% and 20% MVC). Discomfort rating after each five-minute treatment was recorded on a visual analogue scale. Repeated measures ANCOVA with grip endurance time as a covariate indicated that forearm rotation angle (p = 0.001), elbow flexion angle (p = 0.016), MVC torque (p = 0.001) and frequency (p = 0.049) were significant. Grip endurance time was not significant (p = 0.74). EMG activity of the Pronator Teres (PT) and the Extensor Carpi Radialis Brevis (ECRB) revealed that both muscles were affected by forearm rotation and level of MVC torque. A supplementary experiment in which MVC pronation torque at different articulations was measured showed that some of the increased discomfort appeared to be due to increased relative NIVC at some of the extreme articulations. The findings indicated that, with the upper arm in abduction, an elbow angle of 45 degrees and forearm prone, are a posture vulnerable to injury and should be avoided. Grip endurance time as a covariate warrants further investigation. Relevance to industry There is still a paucity of data on risk factors for musculoskeletal disorders for upper arm articulations typical of industrial jobs, especially postures involving upper arm abduction. Industrial jobs involving upper arm abduction have a strong association with injury as operators must often maintain static upper arm abduction while performing tasks for long durations. This study presents discomfort and pronation torque MVC data at different upper arm articulations to identify and control high-risk tasks in industry well before they develop into Musculoskeletal Disorders, especially at the design stage when using biomechanical models. (c) 2007 Elsevier B.V. All rights reserved.ACCEPTEDpeer-reviewe

Magnetic Nested-wind Scenarios for Bipolar Outflows: Pre-planetary and YSO nebular shaping

We present results of a series of magnetohydrodynamic (MHD) and hydro- dynamic (HD) 2.5D simulations of the morphology of outflows driven by nested wide-angle winds - i.e. winds which eminate from a central star as well as from an orbiting accretion disk. While our results are broadly relevent to nested wind systems we have tuned the parameters of the simulations to touch on issues in both Young Stellar Objects and Planetary Nebula studies. In particular our studies connect to open issues in the early evolution of Planetary Nebulae. We find that nested MHD winds exhibit marked morphological differences from the single MHD wind case along both dimensions of the flow. Nested HD winds on the other hand give rise mainly to geometric distortions of an outflow that is topologically similar to the flow arising from a single stellar HD wind. Our MHD results are insensitive to changes in ambient temperature between ionized and un-ionized circumstellar environments. The results are sensitive to the relative mass-loss rates, and to the relative speeds of the stellar and disk winds. We also present synthetic emission maps of both nested MHD and HD simulations. We find that nested MHD winds show knots of emission appearing on-axis that do not appear in the HD case.Comment: 28 pages, 8 figure

Ascorbic acid supplementation attenuates exercise-induced bronchoconstriction in patients with asthma

SummaryBackgroundPrevious research has shown that diet can modify the bronchoconstrictor response to exercise in asthmatic subjects.ObjectiveDetermine the effect of ascorbic acid supplementation on pulmonary function and several urinary markers of airway inflammation in asthmatic subjects with exercise-induced bronchoconstriction (EIB).MethodsEight asthmatic subjects with documented EIB participated in a randomized, placebo controlled double-blind crossover trial. Subjects entered the study on their usual diet and were placed on either 2 weeks of ascorbic acid supplementation (1500mg/day) or placebo, followed by a 1-week washout period, before crossing over to the alternative diet. Pre- and post-exercise pulmonary function, asthma symptom scores, fraction of exhaled nitric oxide (FENO), and urinary leukotriene (LT) C4–E4 and 9α, 11β-prostagladin (PG)F2] were assessed at the beginning of the trial (usual diet) and at the end of each treatment period.Results: The ascorbic acid diet significantly reduced (p<0.05) the maximum fall in post-exercise FEV1 (−6.4±2.4%) compared to usual (−14.3±1.6%) and placebo diet (−12.9±2.4%). Asthma symptoms scores significantly improved (p<0.05) on the ascorbic acid diet compared to the placebo and usual diet. Post-exercise FENO, LTC4–E4 and 9α, 11β-PGF2 concentration was significantly lower (p<0.05) on the ascorbic acid diet compared to the placebo and usual diet.ConclusionAscorbic acid supplementation provides a protective effect against exercise-induced airway narrowing in asthmatic subjects

Assessing Model Predictions of Carbon Dynamics in Global Drylands

Drylands cover ca. 40% of the land surface and are hypothesised to play a major role in the global carbon cycle, controlling both long-term trends and interannual variation. These insights originate from land surface models (LSMs) that have not been extensively calibrated and evaluated for water-limited ecosystems. We need to learn more about dryland carbon dynamics, particularly as the transitory response and rapid turnover rates of semi-arid systems may limit their function as a carbon sink over multi-decadal scales. We quantified aboveground biomass carbon (AGC; inferred from SMOS L-band vegetation optical depth) and gross primary productivity (GPP; from PML-v2 inferred from MODIS observations) and tested their spatial and temporal correspondence with estimates from the TRENDY ensemble of LSMs. We found strong correspondence in GPP between LSMs and PML-v2 both in spatial patterns (Pearson’s r = 0.9 for TRENDY-mean) and in inter-annual variability, but not in trends. Conversely, for AGC we found lesser correspondence in space (Pearson’s r = 0.75 for TRENDY-mean, strong biases for individual models) and in the magnitude of inter-annual variability compared to satellite retrievals. These disagreements likely arise from limited representation of ecosystem responses to plant water availability, fire, and photodegradation that drive dryland carbon dynamics. We assessed inter-model agreement and drivers of long-term change in carbon stocks over centennial timescales. This analysis suggested that the simulated trend of increasing carbon stocks in drylands is in soils and primarily driven by increased productivity due to CO$_2$ enrichment. However, there is limited empirical evidence of this 50-year sink in dryland soils. Our findings highlight important uncertainties in simulations of dryland ecosystems by current LSMs, suggesting a need for continued model refinements and for greater caution when interpreting LSM estimates with regards to current and future carbon dynamics in drylands and by extension the global carbon cycle

Cancer immunoediting by the innate immune system in the absence of adaptive immunity

Cancer immunoediting is the process whereby immune cells protect against cancer formation by sculpting the immunogenicity of developing tumors. Although the full process depends on innate and adaptive immunity, it remains unclear whether innate immunity alone is capable of immunoediting. To determine whether the innate immune system can edit tumor cells in the absence of adaptive immunity, we compared the incidence and immunogenicity of 3'methylcholanthrene-induced sarcomas in syngeneic wild-type, RAG2, and RAG2x γc mice. We found that innate immune cells could manifest cancer immunoediting activity in the absence of adaptive immunity. This activity required natural killer (NK) cells and interferon γ (IFN-γ), which mediated the induction of M1 macrophages. M1 macrophages could be elicited by administration of CD40 agonists, thereby restoring editing activity in RAG2x γc mice. Our results suggest that in the absence of adaptive immunity, NK cell production of IFN-γ induces M1 macrophages, which act as important effectors during cancer immunoediting