Reappraisal of the mechanism of cardiovascular responses to sympathomimetic amines in anaesthetised rats: dual α-adrenoceptor and trace amine receptor mechanisms.

Established dogma is that sympathomimetic amines, including β-phenylethylamine (PEA), increase blood pressure by releasing noradrenaline from sympathetic neurons. Recent evidence allowing longer contact with isolated immersed tissues indicates other mechanisms. The present study re-evaluates the mechanism of pressor responses to PEA in anaesthetised rats with longer exposure to infusions.

Trace amine-induced vasoconstriction of human mammary artery and saphenous vein.

Sympathomimetic amines, including β-phenylethylamine (PEA), constrict animal blood vessels but their mechanism of action is not now thought to be through α-adrenoceptors and release of noradrenaline but via trace amine-associated receptors (TAARs). This information is not available for human blood vessels. Functional studies were therefore performed on human arteries and veins to establish whether they constrict to PEA and whether any constrictions are adrenoceptor-mediated.

The Utility of Oncology Information Systems for Prognostic Modelling in Head and Neck Cancer.

Cancer centres rely on electronic information in oncology information systems (OIS) to guide patient care. We investigated the completeness and accuracy of routinely collected head and neck cancer (HNC) data sourced from an OIS for suitability in prognostic modelling and other research. Three hundred and fifty-three adults diagnosed from 2000 to 2017 with head and neck squamous cell carcinoma, treated with radiotherapy, were eligible.

Evaluation of an automated Presidio anonymisation model for unstructured radiation oncology electronic medical records in an Australian setting.

Background: Electronic medical records (EMRs) contain valuable information for clinical research, however, the presence of personally identifying information (PII) restricts their use. Anonymisation of PII from EMRs enables clinical information to be shared for research purposes. Since there is limited research relating to the anonymisation of Australian EMRs, the performance of Microsoft Presidio with customisation on clinical documents from an Australian radiation oncology information system (OIS) was evaluated.

Density-dependent space use affects interpretation of camera trap detection rates.

Camera traps (CTs) are an increasingly popular tool for wildlife survey and monitoring. Estimating relative abundance in unmarked species is often done using detection rate as an index of relative abundance, which assumes that detection rate has a positive linear relationship with true abundance. This assumption may be violated if movement behavior varies with density, but the degree to which movement behavior is density-dependent across taxa is unclear.

Modulation of vascular responses of guinea-pig aorta by non-endothelial nitric oxide: A minor role for the endothelium.

Acetylcholine (Ach) causes vasodilatation by nitric oxide (NO) release from the vascular endothelium. Vasoconstrictors such as α-adrenoceptor agonists (phenylephrine) or thromboxane TxA mimetics (U46619) also release endothelial NO. Inhibition of nitric oxide synthase (NOS) with N-nitro-L-arginine (L-NAME) potentiates vasoconstriction by phenylephrine and the trace amine, β-phenylethylamine (PEA), indicating underlying opposing vasodilatation.

Quantifying fear effects on prey demography in nature.

In recent years, it has been argued that the effect of predator fear exacts a greater demographic toll on prey populations than the direct killing of prey. However, efforts to quantify the effects of fear have primarily relied on experiments that replace predators with predator cues. Interpretation of these experiments must consider two important caveats: (1) the magnitude of experimenter-induced predator cues may not be realistically comparable to those of the prey's natural sensory environment, and (2) given functional predators are removed from the treatments, the fear effect is measured in the absence of any consumptive effects, a situation which never occurs in nature.

Non-adrenergic vasoconstriction and vasodilatation of guinea-pig aorta by β-phenylethylamine and amphetamine - Role of nitric oxide determined with L-NAME and NO scavengers.

Sympathomimetic and trace amines, including β-phenylethylamine (PEA) and amphetamine, increase blood pressure and constrict isolated blood vessels. By convention this is regarded as a sympathomimetic response, however, recent studies suggest trace amine-associated receptor (TAAR) involvement. There is also uncertainty whether these amines also release nitric oxide (NO) causing opposing vasodilatation.

Death Receptor 3 regulates distinct pathological attributes of acute versus chronic murine allergic lung inflammation.

The Death Receptor 3 (DR3)/Tumour Necrosis Factor-like cytokine 1A (TL1A) axis stimulates effector T cells and type 2 innate lymphocytes (ILC2) that trigger cytokine release and drive disease pathology in several inflammatory and autoimmune diseases, including murine models of acute allergic lung inflammation (ALI). The aim of this study was to elucidate the role of DR3 in chronic ALI compared to acute ALI, using mice genetically deficient in the DR3 gene (DR3). Results showed DR3 expression in the lungs of wild-type mice was up-regulated following induction of acute ALI and this increased expression was maintained in chronic disease.

Route of Administration Affects Corticosteroid Sensitivity of a Combined Ovalbumin and Lipopolysaccharide Model of Asthma Exacerbation in Guinea Pigs.

Lipopolysaccharide (LPS) contributes to asthma exacerbations and development of inhaled corticosteroid insensitivity. Complete resistance to systemic corticosteroids is rare, and most patients lie on a continuum of steroid responsiveness. This study aimed to examine the sensitivity of combined ovalbumin- (Ova) and LPS-induced functional and inflammatory responses to inhaled and systemic corticosteroid in conscious guinea pigs to test the hypothesis that the route of administration affects sensitivity.

Effects of nebulised magnesium sulphate on inflammation and function of the guinea-pig airway.

Magnesium sulphate is a potential treatment for acute severe asthma. However, the mechanisms and dose-response relationships are poorly understood. The first objective of this study was to examine whether inhaled magnesium sulphate exerts bronchodilator activity measured as bronchoprotection against histamine-induced bronchoconstriction in conscious guinea-pigs alone and combined with salbutamol.

Iterative sorting reveals CD133+ and CD133- melanoma cells as phenotypically distinct populations.

Background: The heterogeneity and tumourigenicity of metastatic melanoma is attributed to a cancer stem cell model, with CD133 considered to be a cancer stem cell marker in melanoma as well as other tumours, but its role has remained controversial.

Methods: We iteratively sorted CD133+ and CD133- cells from 3 metastatic melanoma cell lines, and observed tumourigenicity and phenotypic characteristics over 7 generations of serial xeno-transplantation in NOD/SCID mice.

Results: We demonstrate that iterative sorting is required to make highly pure populations of CD133+ and CD133- cells from metastatic melanoma, and that these two populations have distinct characteristics not related to the cancer stem cell phenotype.

The synthesis of a series of adenosine A3 receptor agonists.

A series of 1'-(6-aminopurin-9-yl)-1'-deoxy-N-methyl-β-d-ribofuranuronamides that were characterised by 2-dialkylamino-7-methyloxazolo[4,5-b]pyridin-5-ylmethyl substituents on N6 of interest for screening as selective adenosine A3 receptor agonists, have been synthesised. This work involved the synthesis of 2-dialkylamino-5-aminomethyl-7-methyloxazolo[4,5-b]pyridines and analogues that were coupled with the known 1'-(6-chloropurin-9-yl)-1'-deoxy-N-methyl-β-d-ribofuranuronamide. The oxazolo[4,5-b]pyridines were synthesized by regioselective functionalisation of 2,4-dimethylpyridine N-oxides.

Stereoselective synthesis of oxazolidinonyl-fused piperidines of interest as selective muscarinic (M1) receptor agonists: a novel M1 allosteric modulator.

Syntheses of (1RS,2SR,6SR)-2-alkoxymethyl-, 2-hetaryl-, and 2-(hetarylmethyl)-7-arylmethyl-4,7-diaza-9-oxabicyclo[4.3.0]nonan-8-ones, of interest as potential muscarinic M1 receptor agonists, are described.

The vascular Ca2+-sensing receptor regulates blood vessel tone and blood pressure.

The extracellular calcium-sensing receptor CaSR is expressed in blood vessels where its role is not completely understood. In this study, we tested the hypothesis that the CaSR expressed in vascular smooth muscle cells (VSMC) is directly involved in regulation of blood pressure and blood vessel tone. Mice with targeted CaSR gene ablation from vascular smooth muscle cells (VSMC) were generated by breeding exon 7 LoxP-CaSR mice with animals in which Cre recombinase is driven by a SM22α promoter (SM22α-Cre).

Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma.

Airway hyperresponsiveness and inflammation are fundamental hallmarks of allergic asthma that are accompanied by increases in certain polycations, such as eosinophil cationic protein. Levels of these cations in body fluids correlate with asthma severity. We show that polycations and elevated extracellular calcium activate the human recombinant and native calcium-sensing receptor (CaSR), leading to intracellular calcium mobilization, cyclic adenosine monophosphate breakdown, and p38 mitogen-activated protein kinase phosphorylation in airway smooth muscle (ASM) cells.

Pulmonary edema measured by MRI correlates with late-phase response to allergen challenge.

Purpose: Asthma is associated with reversible airway obstruction, leucocyte infiltration, airways hyperresponsiveness (AHR), and airways remodeling. Fluid accumulation causes pulmonary edema contributing to airways obstruction. We examined the temporal relationship between the late asthmatic response (LAR) following allergen challenge of sensitized guinea-pigs and pulmonary edema measured by magnetic resonance imaging (MRI).

LPS exacerbates functional and inflammatory responses to ovalbumin and decreases sensitivity to inhaled fluticasone propionate in a guinea pig model of asthma.

Background And Purpose: Asthma exacerbations contribute to corticosteroid insensitivity. LPS is ubiquitous in the environment. It causes bronchoconstriction and airway inflammation and may therefore exacerbate allergen responses.

Adjustment of sensitisation and challenge protocols restores functional and inflammatory responses to ovalbumin in guinea-pigs.

Introduction: Inhalation of antigen in atopic asthma induces early (EAR) and late asthmatic responses (LARs), inflammatory cell infiltration and airways hyperresponsiveness (AHR). Previously, we have established a protocol of sensitisation and subsequent ovalbumin (Ova) inhalation challenge in guinea-pigs which induced these 4 features (Smith & Broadley, 2007). However, the responses of guinea-pigs to Ova challenge have recently declined, producing no LAR or AHR and diminished EAR and cells.

Enhanced immunosuppression by therapy-exposed glioblastoma multiforme tumor cells.

Glioblastoma multiforme (GBM) is a highly malignant brain tumor with an extremely short time to relapse following standard treatment. Since recurrent GBM is often resistant to subsequent radiotherapy and chemotherapy, immunotherapy has been proposed as an alternative treatment option. Although it is well established that GBM induces immune suppression, it is currently unclear what impact prior conventional therapy has on the ability of GBM cells to modulate the immune environment.

Functional evaluation of the receptors mediating vasoconstriction of rat aorta by trace amines and amphetamines.

Trace amines including β-phenylethylamine (β-PEA) and amphetamines classically exert pharmacological actions via indirect sympathomimetic mechanisms. However, there is evidence for other mechanisms and this study explores the receptors mediating vasoconstriction in rat aorta. β-PEA, d-amphetamine, MDMA, cathinone and methylphenidate caused concentration-dependent contractions of rat isolated aortic rings which were unaffected by prazosin (1 μM), ICI-118,551 (1 μM), cocaine (10 μM) and pargyline (10 μM), to inhibit α1- and β2-adrenoceptors, neuronal transport and monoamine oxidase (MAO), respectively.