cGMP signaling inhibits platelet shape change through regulation of the RhoA-Rho Kinase-MLC phosphatase signaling pathway

Background: Platelet shape change, spreading and thrombus stability require activation of the actin cytoskeleton contractile machinery. The mechanisms controlling actin assembly to prevent unwanted platelet activation are unclear. Objectives: We examined the effects of nitric oxide on the signaling pathways regulating platelet actinmyosin activation. Results: S-nitrosoglutathione (GSNO) inhibited thrombin-induced platelet shape change and myosin phosphorylation of the myosin light chain (MLC). Because thrombin stimulates phospho-MLC through the RhoA/ ROCK dependent inhibition of MLC phosphatase (MLCP) we examined the effects of NO on this pathway. Thrombin caused the GTP loading and activation of RhoA, leading to the ROCK-mediated phosphorylation of MLCP on threonine 853 (thr853), which is known to inhibit phosphatase activity. Treatment of platelets with GSNO blocked ROCK-mediated increases in phosphoMLCPthr853 induced by thrombin. This effect was mimicked by the direct activator of protein kinase G, 8-pCPT-PET-cGMP, and blocked by the inhibition of guanylyl cyclase, but not inhibitors of protein kinase A. Further exploration of the mechanism demonstrated that GSNO stimulated the association of RhoA with protein kinase G (PKG) and the inhibitory phosphorylation (serine188) of RhoA in a cGMP-dependent manner. Consistent with these observations, in vitro experiments revealed that recombinant PKG caused direct phosphorylation of RhoA. The inhibition of RhoA by GSNO prevented ROCK-mediated phosphorylation and inhibition of MLCP activity. Conclusions: These data suggest novel crosstalk between the NO-cGMP-PKG and RhoA/ROCK signaling pathways to control platelet actin remodeling

An extraoral approach to intraoral cooling–a feasibility study in non-cancer patients

Abstract Background Cryotherapy, using ice chips (IC) is an effective strategy to prevent chemotherapy-induced oral mucositis (OM) in selected cancer patient cohorts. However, although effective, use of IC may cause adverse reactions, e.g., nausea, numbness, and shooting pain in the teeth, which could have an adverse impact on the medical treatment. Furthermore, IC requires water of good quality to minimize risk of serious systemic infections. To eliminate these disadvantages, novel cooling devices have emerged as alternative cooling modalities. Thus, the aim was to evaluate the efficacy and tolerability profile of extraoral cooling for intraoral temperature reduction. Subjects and Methods This experimental pilot study was conducted at the Institute of Odontology, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. In total, six healthy volunteers were enrolled in this study. At baseline and following 30-, and 60 min of cooling with the extraoral cooling device, intraoral mucosal temperatures were measured using a thermographic camera, and a questionnaire related to tolerability was completed. Results Following 30-, and 60 min of cooling, the intraoral temperature decreased with 2.0 °C and 2.3 °C, respectively. Extraoral cooling was well tolerated, and all subjects endured the entire cooling session of 60 min. Conclusion Extraoral cooling reduces intraoral mucosal temperatures and is a well-tolerated cooling modality

Achieving harmonized port security training in Europe : a critical review of EU legislative frameworks

Abstract Ports are complex, multiple-stakeholder environments representing the entrance point of intercontinental sea shipments into a country. Because ports are areaswhere large amounts of goods converge, they play a strategic role in a country’s securityand economic sustenance. Consequently different stakeholders interact to ensure thatcargo handling operations are optimized and cost-effective, e.g. international shipping,logistics companies, trading communities, and regulatory bodies. In this context securitythreats assume a special relevance, since ports could be exploited by criminal organizations to smuggle illicit goods into a country or by terrorists planning an attack. Toeliminate or mitigate these risks human resources need to be correctly trained andeducated. In addition, the competent authorities need to ensure that the same level andquality of training is delivered to all port facilities providing access to a country or acontinent. Unfortunately, experts believe that in the EU there is a lack of harmonizationof courses and quality assurance systems. Hence, the aim of this study is to reviewexisting regulatory frameworks and assess whether guidance is provided to harmonizesecurity training and education in port facilities. Thereafter, based on the experiencedeveloped within other sectors, where harmonization of training and education coursesin the EU has been successfully achieved, we make recommendations for improvementof the existing frameworks. The article concludes by summarizing the findings andindicating implications for managers and researchers.Sponsorship:EU Leonardo Da Vinci</p