Search

Objective: Recent studies suggest many patients with non‐specific low back pain presenting to public hospital EDs receive low‐value care. The primary aim was to describe management of patients presenting with low back pain to the ED of a private hospital in Melbourne, Australia, and received a final ED diagnosis of non‐specific low back pain. We also determined predictors of hospital admission. Methods: Retrospective review of patients who presented with low back pain and received a final ED diagnosis of non‐specific low back pain to Cabrini Malvern ED in 2015. Demographics, lumbar spinal imaging, pathology tests and medications were extracted from hospital records. Multivariate logistic regression was used to determine independent predictors of hospital admission. Results: Four hundred and fifty presentations were included (60% female); 238 (52.9%) were admitted to hospital. One hundred and seventy‐seven (39.3%) patients received lumbar spine imaging. Two hundred and eighty (62.2%) patients had pathology tests and 391 (86.9%) received medications, which included opioids (n = 298, 66.2%), paracetamol (n = 219, 48.7%), NSAIDs (n = 161, 35.8%), benzodiazepines (n = 118, 26.2%) and pregabalin (n = 26, 5.8%). Predictors of hospital admission included older age (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.02–1.05), arrival by ambulance (OR 2.03, 95% CI 1.06–3.90) and receipt of pathology tests (OR 3.32, 95% CI 2.01–5.49) or computed tomography scans (OR 1.86, 95% CI 1.12–3.11). Conclusion: We observed high rates of imaging, pathology tests and hospital admissions compared with previous public hospital studies, while medication use was similar. Implementation of strategies to optimise evidence‐based ED care is needed to reduce low‐value care and improve patient outcomes. [ABSTRACT FROM AUTHOR]

The Australia and New Zealand Musculoskeletal (ANZMUSC) Clinical Trials Network was formed to build capacity and infrastructure for high‐quality musculoskeletal clinical trials in our region. The purpose of this paper is to describe the steps taken in its formation to help others interested in establishing similar networks. In particular, we describe the steps taken to form the collaboration and our progress in achieving our vision and mission. Our aim is to focus on trials of highest importance and quality to provide definitive answers to the most pressing questions in our field. [ABSTRACT FROM AUTHOR]

BACKGROUND A disintegrin and metalloprotease 17 (ADAM17) is a membrane-spanning metalloprotease overexpressed in various cardiovascular diseases such as hypertension and atherosclerosis. However, little is known regarding the regulation of ADAM17 expression in the cardiovascular system. Here, we test our hypothesis that angiotensin II induces ADAM17 expression in the vasculature. METHODS Cultured vascular smooth muscle cells were stimulated with 100nM angiotensin II. Mice were infused with 1 μg/kg/minute angiotensin II for 2 weeks. ADAM17 expression was evaluated by a promoter–reporter construct, quantitative polymerase chain reaction, immunoblotting, and immunohistochemistry. RESULTS In vascular smooth muscle cells, angiotensin II increased ADAM17 protein expression, mRNA, and promoter activity. We determined that the angiotensin II response involves hypoxia inducible factor 1α and a hypoxia responsive element. In angiotensin II–infused mice, marked induction of ADAM17 and hypoxia inducible factor 1α was seen in vasculatures in heart and kidney, as well as in aortae, by immunohistochemistry. CONCLUSIONS Angiotensin II induces ADAM17 expression in the vasculatures through a hypoxia inducible factor 1α–dependent transcriptional upregulation, potentially contributing to end-organ damage in the cardiovascular system. [ABSTRACT FROM PUBLISHER]

In this article the author discusses the study of Hitomi and colleagues on the influence of angiotensin II in the insulin resistance of vascular smooth muscle cells (VSMCs). It is notes the physiological roles of insulin receptors (IR) expressed in VSMCs which include promotion of differentiation, and suppression of proliferation. It also outlines the importance of angiotensin II in switching the insulin signaling from glucose metabolism to pathophysiological remodeling in VSMCs.

siRNA mediated gene silencing has been recently utilized as a powerful molecular tool to study the functional significance of a specific protein. However, due to the transient nature of silencing and insufficient transfection efficiency, this approach can be problematic in primary cell culture. To overcome such weakness of the siRNA based silencing and in order to establish reliable gene silencing in vascular cells, we devised an adenoviral-encoded miRNA based gene silencing system. Here we report the results of silencing ADAM17 in cultured rat vascular smooth muscle cells (VSMCs) and its functional consequences in angiotensin II (AngII) signal transduction. Four distinct miRNA sequences targeting rat ADAM17 were chosen based on recommendations from Invitrogen’s Block-iT RNAi Designer algorithm. The miRNA sequences were inserted into a mammalian expression vector, pcDNA 6.2-GW/EmGFP-miR, and the effective silencing by these vectors was confirmed in HEK cells expressing HA-tagged rat ADAM17. The 4 cassettes carrying the miRNAs were inserted into pAd/CMV/V5-DEST and adenoviral solutions were obtained. Greater than 95% silencing of ADAM17 was achieved when VSMC were infected with 100-200 moi of the ADAM17 miRNA encoding adeonvirus for 72 h with enhancement of infection by fugene6. Relatively linear time and concentration dependencies were observed between 1 to 3 days and 10 to 100 moi of the infection. A miR-ADAM17 (100 moi) but not miR-control (100 moi) completely inhibited 100 nM AngII-induced HB-EGF shedding in VSMCs as assessed by a reporter assay. A miR-ADAM17 but not miR-control also inhibited AngII-induced EGF receptor transactivation and subsequent ERK1/2 activation in VSMCs as assessed by immunoblotting with phospho-selective antibodies. In conclusion, ADAM17 was found to be a major sheddase for HB-EGF contributing to the growth promoting signals induced by AngII in VSMCs. An artificial miRNA-base adenoviral approach appears to be a reliable gene-silencing strategy for signal transduction research in primary cultured vascular cells. [ABSTRACT FROM AUTHOR]

ADAM17 has been shown to play critical roles in angiotensin II (AngII)-dependent as well as independent types of pathophysiological vascular remodeling in vitro and in vivo. Enzymatic activation of ADAM17 by AngII has been described, however, little is known regarding regulation of ADAM17 protein expression in the cardiovascular system. Here we test our hypothesis that AngII induces ADAM17 protein expression to originate a feed forward loop of ADAM17 activation/induction in the vasculature. 8 week old control mice were infused with 1000 ng/kg/min AngII for 2 weeks via osmotic minipump. Serum starved rat VSMCs were stimulated with 100 nM AngII. ADAM17 expression was evaluated by immunohistochemistry and immunoblotting, respectively. In AngII-infused mice, marked ADAM17 induction was seen in vasculatures in heart and kidney, and carotid arteries and aortae. In VSMCs, AngII as well as PDGF-BB (50 ng/mL) time-dependently induced ADAM17 expression up to 24 hours (AngII 24h: 2.34±0.25 fold induction). Both AngII and PDGF-BB also stimulated ADAM17 promoter activity in VSMCs (AngII 24h: 2.90±0.17 fold induction). The ADAM17 promoter contains 6 typical hypoxia responsible elements (HREs). By using deletion and mutation constructs, the PDGF-BB response seems to require HRE4 located between -991 to -410 of the promoter. AngII-induced promoter activation was also lost in the HRE4 mutant. Moreover, both AngII and PDGF-BB stimulated HIF-1alpha protein expression in VSMCs at 4-8 hours. From these data, we conclude that AngII and PDGF induce ADAM17 expression in VSMCs via HIF1alpha/HRE-dependent transcriptional upregulation. The induction of ADAM17 via the HIF1/HRE-dependent mechanism likely promotes a feed-forward loop of ADAM17 activation/induction under a variety of pathophysiological conditions including hypoxia/ischemia leading to end organ damages in the cardiovascular system. [ABSTRACT FROM AUTHOR]