Severe trauma continues to represent a global public health issue and mortality and morbidity in trauma patients remains substantial. A number of initiatives have aimed to provide guidance on the management of trauma patients. This document focuses on the management of major bleeding and coagulopathy following trauma and encourages adaptation of the guiding principles to each local situation and implementation within each institution. The pan-European, multidisciplinary Task Force for Advanced Bleeding Care in Trauma was founded in 2004 and included representatives of six relevant European professional societies. The group used a structured, evidence-based consensus approach to address scientific queries that served as the basis for each recommendation and supporting rationale. Expert opinion and current clinical practice were also considered, particularly in areas in which randomised clinical trials have not or cannot be performed. Existing recommendations were reconsidered and revised based on new scientific evidence and observed shifts in clinical practice; new recommendations were formulated to reflect current clinical concerns and areas in which new research data have been generated. This guideline represents the fourth edition of a document first published in 2007 and updated in 2010 and 2013. The guideline now recommends that patients be transferred directly to an appropriate trauma treatment centre and encourages use of a restricted volume replacement strategy during initial resuscitation. Best-practice use of blood products during further resuscitation continues to evolve and should be guided by a goal-directed strategy. The identification and management of patients pre-treated with anticoagulant agents continues to pose a real challenge, despite accumulating experience and awareness. The present guideline should be viewed as an educational aid to improve and standardise the care of the bleeding trauma patients across Europe and beyond. This document may also serve as a basis for local implementation. Furthermore, local quality and safety management systems need to be established to specifically assess key measures of bleeding control and outcome. A multidisciplinary approach and adherence to evidence-based guidance are key to improving patient outcomes. The implementation of locally adapted treatment algorithms should strive to achieve measureable improvements in patient outcome.

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The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition

Danshen, the dried root of Salvia miltiorrhiza, has been widely used in China and, to a lesser extent, in Japan, the United States, and other European countries for the treatment of cardiovascular and cerebrovascular diseases. In China, the specific clinical use is angina pectoris, hyperlipidemia, and acute ischemic stroke. The current review covers its traditional uses, chemical constituents, pharmacological activities, pharmacokinetics, clinical applications, and potential herb-drug interactions based on information obtained in both the English and Chinese literature. Although numerous clinical trials have demonstrated that certain Danshen products in China are effective and safe for the treatment of cardiovascular diseases, most of these lack sufficient quality. Therefore, large randomized clinical trials and further scientific research to determine its mechanism of actions will be necessary to ensure the safety, effectiveness, and better understanding of its action.

Danshen: an overview of its chemistry, pharmacology, pharmacokinetics, and clinical use.

Superoxide dismutases (SODs) are universal enzymes of organisms that live in the presence of oxygen. They catalyze the conversion of superoxide into oxygen and hydrogen peroxide. Superoxide anions are the intended product of dedicated signaling enzymes as well as the byproduct of several metabolic processes including mitochondrial respiration. Through their activity, SOD enzymes control the levels of a variety of reactive oxygen species (ROS) and reactive nitrogen species, thus both limiting the potential toxicity of these molecules and controlling broad aspects of cellular life that are regulated by their signaling functions. All aerobic organisms have multiple SOD proteins targeted to different cellular and subcellular locations, reflecting the slow diffusion and multiple sources of their substrate superoxide. This compartmentalization also points to the need for fine local control of ROS signaling and to the possibility for ROS to signal between compartments. In this review, we discuss studies in model organisms and humans, which reveal the dual roles of SOD enzymes in controlling damage and regulating signaling.

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Superoxide dismutases: Dual roles in controlling ROS damage and regulating ROS signaling.

Introduction: Evidence-based recommendations are needed to guide the acute management of the bleeding trauma patient. When these recommendations are implemented patient outcomes may be improved. Methods: The multidisciplinary Task Force for Advanced Bleeding Care in Trauma was formed in 2005 with the aim of developing a guideline for the management of bleeding following severe injury. This document represents an updated version of the guideline published by the group in 2007 and updated in 2010. Recommendations were formulated using a nominal group process, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) hierarchy of evidence and based on a systematic review of published literature. Results: Key changes encompassed in this version of the guideline include new recommendations on the appropriate use of vasopressors and inotropic agents, and reflect an awareness of the growing number of patients in the population at large treated with antiplatelet agents and/or oral anticoagulants. The current guideline also includes recommendations and a discussion of thromboprophylactic strategies for all patients following traumatic injury. The most significant addition is a new section that discusses the need for every institution to develop, implement and adhere to an evidence-based clinical protocol to manage traumatically injured patients. The remaining recommendations have been re-evaluated and graded based on literature published since the last edition of the guideline. Consideration was also given to changes in clinical practice that have taken place during this time period as a result of both new evidence and changes in the general availability of relevant agents and technologies. Conclusions: A comprehensive, multidisciplinary approach to trauma care and mechanisms with which to ensure that established protocols are consistently implemented will ensure a uniform and high standard of care across Europe and beyond.

/pdf/management-of-bleeding-and-coagulopathy-following-major-127uh3smia.pdf

Management of bleeding and coagulopathy following major trauma: an updated European guideline

IntroductionEvidence-based recommendations are needed to guide the acute management of the bleeding trauma patient. When these recommendations are implemented patient outcomes may be improved.MethodsThe multidisciplinary Task Force for Advanced Bleeding Care in Trauma was formed in 2005 with the aim of developing a guideline for the management of bleeding following severe injury. This document represents an updated version of the guideline published by the group in 2007 and updated in 2010. Recommendations were formulated using a nominal group process, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) hierarchy of evidence and based on a systematic review of published literature.ResultsKey changes encompassed in this version of the guideline include new recommendations on the appropriate use of vasopressors and inotropic agents, and reflect an awareness of the growing number of patients in the population at large treated with antiplatelet agents and/or oral anticoagulants. The current guideline also includes recommendations and a discussion of thromboprophylactic strategies for all patients following traumatic injury. The most significant addition is a new section that discusses the need for every institution to develop, implement and adhere to an evidence-based clinical protocol to manage traumatically injured patients. The remaining recommendations have been re-evaluated and graded based on literature published since the last edition of the guideline. Consideration was also given to changes in clinical practice that have taken place during this time period as a result of both new evidence and changes in the general availability of relevant agents and technologies.ConclusionsA comprehensive, multidisciplinary approach to trauma care and mechanisms with which to ensure that established protocols are consistently implemented will ensure a uniform and high standard of care across Europe and beyond.http://ccforum.com/content/17/4/442

This Provisional PDF corresponds to the article as it appeared upon acceptance. Copyedited and fully formatted PDF and full text (HTML) versions will be made available soon. Management of bleeding and coagulopathy following major trauma: an updated European guideline

Discovered a little over two decades ago, small interfering RNAs (siRNAs) and microRNAs (miRNAs) are noncoding RNAs with important roles in gene regulation. They have recently been investigated as novel classes of therapeutic agents for the treatment of a wide range of disorders including cancers and infections. Clinical trials of siRNA- and miRNA-based drugs have already been initiated. siRNAs and miRNAs share many similarities, both are short duplex RNA molecules that exert gene silencing effects at the post-transcriptional level by targeting messenger RNA (mRNA), yet their mechanisms of action and clinical applications are distinct. The major difference between siRNAs and miRNAs is that the former are highly specific with only one mRNA target, whereas the latter have multiple targets. The therapeutic approaches of siRNAs and miRNAs are therefore very different. Hence, this review provides a comparison between therapeutic siRNAs and miRNAs in terms of their mechanisms of action, physicochemical properties, delivery, and clinical applications. Moreover, the challenges in developing both classes of RNA as therapeutics are also discussed.

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siRNA Versus miRNA as Therapeutics for Gene Silencing

http://hub.hku.hk/bitstream/10722/226382/1/content.pdf

Vascular nitric oxide: Beyond eNOS

Endothelial cells control vascular tone by releasing nitric oxide (NO) produced by endothelial NO synthase. The activity of endothelial NO synthase is modulated by the calcium concentration and by post-translational modifications (eg, phosphorylation). When NO reaches vascular smooth muscle, soluble guanylyl cyclase is its primary target producing cGMP. NO production is stimulated by circulating substances (eg, catecholamines), platelet products (eg, serotonin), autacoids formed in (eg, bradykinin) or near (eg, adiponectin) the vascular wall and physical factors (eg, shear stress). NO dysfunction can be caused, alone or in combination, by abnormal coupling of endothelial cell membrane receptors, insufficient supply of substrate (l-arginine) or cofactors (tetrahydrobiopterin), endogenous inhibitors (asymmetrical dimethyl arginine), reduced expression/presence/dimerization of endothelial NO synthase, inhibition of its enzymatic activity, accelerated disposition of NO by reactive oxygen species and abnormal responses (eg, biased soluble guanylyl cyclase activity producing cyclic inosine monophosphate) of the vascular smooth muscle. Major culprits causing endothelial dysfunction, irrespective of the underlying pathological process (aging, obesity, diabetes mellitus, and hypertension), include stimulation of mineralocorticoid receptors, activation of endothelial Rho-kinase, augmented presence of asymmetrical dimethyl arginine, and exaggerated oxidative stress. Genetic and pharmacological interventions improve dysfunctional NO-mediated vasodilatations if protecting the supply of substrate and cofactors for endothelial NO synthase, preserving the presence and activity of the enzyme and reducing reactive oxygen species generation. Common achievers of such improvement include maintained levels of estrogens and increased production of adiponectin and induction of silent mating-type information regulation 2 homologue 1. Obviously, endothelium-dependent relaxations are not the only beneficial action of NO in the vascular wall. Thus, reduced NO-mediated responses precede and initiate the atherosclerotic process.

Thirty Years of Saying NO: Sources, Fate, Actions, and Misfortunes of the Endothelium-Derived Vasodilator Mediator.

Structure-activity relationships of flavonoids for vascular relaxation in porcine coronary artery

Puerarin, an isoflavonoid derived from Radix puerariae, potentiates endothelium-independent relaxation via the cyclic AMP pathway in porcine coronary artery.

Susan W.S. Leung

Papers

siRNA Versus miRNA as Therapeutics for Gene Silencing

Vascular nitric oxide: Beyond eNOS

Thirty Years of Saying NO: Sources, Fate, Actions, and Misfortunes of the Endothelium-Derived Vasodilator Mediator.

Structure-activity relationships of flavonoids for vascular relaxation in porcine coronary artery

Puerarin, an isoflavonoid derived from Radix puerariae, potentiates endothelium-independent relaxation via the cyclic AMP pathway in porcine coronary artery.