GEF-H1-RhoA signaling pathway mediates LPS-induced NF-κB transactivation and IL-8 synthesis in endothelial cells

Secretion of proinflammatory cytokines by LPS activated endothelial cells contributes substantially to the pathogenesis of sepsis. However, the mechanism involved in this process is not well understood. In the present study, we determined the roles of GEF-H1 (Guanine-nucleotide exchange factor-H1)-RhoA signalling in LPS-induced interleukin-8 (IL-8, CXCL8) production in endothelial cells. First, we observed that GEF-H1 expression was upregulated in a dose- and time-dependent manner as consistent with TLR4 (Toll-like receptor 4) expression after LPS stimulation. Afterwards, Clostridium difficile toxin B-10463 (TcdB-10463), an inhibitor of Rho activities, reduced LPS-induced NF-κB phosphorylation. Inhibition of GEF-H1 and RhoA expression reduced LPS-induced NF-κB and p38 phosphorylation. TLR4 knockout blocked LPS-induced activity of RhoA, however, MyD88 knockout did not impair the LPS-induced activity of RhoA. Nevertheless, TLR4 and MyD88 knockout both significantly inhibited transactivation of NF-κB. GEF-H1-RhoA and MyD88 both induced significant changes in NF-κB transactivation and IL-8 synthesis. Co-inhibition of GEF-H1-RhoA and p38 expression produced similar inhibitory effects on LPS-induced NF-κB transactivation and IL-8 synthesis as inhibition of p38 expression alone, thus confirming that activation of p38 was essential for the GEF-H1-RhoA signalling pathway to induce NF-κB transactivation and IL-8 synthesis. Taken together, these results demonstrate that LPS-induced NF-κB activation and IL-8 synthesis in endothelial cells are regulated by the MyD88 pathway and GEF-H1-RhoA pathway.

Theoretical and experimental characterisation of energy in an electrostatic discharge

Electrostatic discharges have been identified as the most likely cause in a number of incidents of fire and explosion with unexplained ignitions. The lack of data and suitable models for this ignition mechanism creates a void in the analysis to quantify the importance of static electricity as a credible ignition mechanism. Quantifiable hazard analysis of the risk of ignition by static discharge cannot, therefore, be entirely carried out with our current understanding of this phenomenon. The study of electrostatics has been ongoing for a long time. However, it was not until the wide spread use of electronics that research was developed for the protection of electronics from electrostatic discharges. Current experimental models for electrostatic discharge developed for intrinsic safety with electronics are inadequate for ignition analysis and typically are not supported by theoretical analysis. A preliminary simulation and experiment with low voltage was designed to investigate the characteristics of energy dissipation and provided a basis for a high voltage investigation. It was seen that for a low voltage the discharge energy represents about 10% of the initial capacitive energy available and that the energy dissipation was within 10 ns of the initial discharge. The potential difference is greatest at the initial break down when the largest amount of the energy is dissipated. The discharge pathway is then established and minimal energy is dissipated as energy dissipation becomes greatly influenced by other components and stray resistance in the discharge circuit. From the initial low voltage simulation work, the importance of the energy dissipation and the characteristic of the discharge were determined. After the preliminary low voltage work was completed, a high voltage discharge experiment was designed and fabricated. Voltage and current measurement were recorded on the discharge circuit allowing the discharge characteristic to be recorded and energy dissipation in the discharge circuit calculated. Discharge energy calculations show consistency with the low voltage work relating to discharge energy with about 30-40% of the total initial capacitive energy being discharged in the resulting high voltage arc. After the system was characterised and operation validated, high voltage ignition energy measurements were conducted on a solution of n-Pentane evaporating in a 250 cm3 chamber. A series of ignition experiments were conducted to determine the minimum ignition energy of n-Pentane. The data from the ignition work was analysed with standard statistical regression methods for tests that return binary (yes/no) data and found to be in agreement with recent publications. The research demonstrates that energy dissipation is heavily dependent on the circuit configuration and most especially by the discharge circuit's capacitance and resistance. The analysis established a discharge profile for the discharges studied and validates the application of this methodology for further research into different materials and atmospheres; by systematically looking at discharge profiles of test materials with various parameters (e.g., capacitance, inductance, and resistance). Systematic experiments looking at the discharge characteristics of the spark will also help understand the way energy is dissipated in an electrostatic discharge enabling a better understanding of the ignition characteristics of materials in terms of energy and the dissipation of that energy in an electrostatic discharge.

Critical factors for sustainable reconstruction of post natural disasters

While scientists are still debating the level of climate change impact to new weather patterns, there have been some devastating natural disasters worldwide in the last decade. From cyclones to earthquakes and from Tsunamis to landslides, these disasters occur with formidable forces and crushing effects. As one of the most important arrangements to erase the negative influence of natural disasters and help with the recovery and redevelopment of the hit area, reconstruction is of utmost importance in light of sustainable objectives. However, current reconstruction practice confronts quite a lot of criticisms for focusing on providing short-term necessities. How to conduct the post disaster reconstruction in a long-term perspective and achieve sustainable development is thereby a highlight for industry practice and research. This paper introduced an on-going research project which is aimed at establishing an operational framework for improving sustainability performance of post disaster reconstruction by identifying critical sustainable factors and exploring their internal relationships. The research reported in this paper is part of the project. After a comprehensive literature review, 17 potential critical sustainability factors for post disaster reconstruction were identified. Preliminary examination and discussion of the factors was conducted.

Research trends of post disaster reconstruction : the past and the future

Natural disasters can have adverse effect on human lives. To raise the awareness of research and better combat future events, it is important to identify recent research trends in the area of post disaster reconstruction (PDR). The authors used a three-round literature review strategy to study journal papers published in the last decade that are related to PDR with specific conditions using the Scopus search engine. A wide range of PDR related papers from a general perspective was examined in the first two rounds while the final round established 88 papers as target publications through visual examination of the abstracts, keywords and as necessary, main texts. These papers were analysed in terms of research origins, active researchers, research organisations, most cited papers, regional concerns, major themes and deliverables, for clues of the past trends and future directions. The need for appropriate PDR research is increasingly recognised. The publication number multiplied 5 times from 2002 to 2012. For PDR research with a construction perspective, the increase is sixfold. Developing countries such as those in Asia attract almost 50% researchers' attention for regional concerns while the US is the single most concentrated (24%) country. Africa is hardly represented. Researchers in developed countries lead in worldwide PDR research. This contrasts to the need for expertise in developing countries. Past works focused on waste management, stakeholder analysis, resourcing, infrastructure issue, resilience and vulnerability, reconstruction approach, sustainable reconstruction and governance issues. Future research should respond to resourcing, integrated development, sustainability and resilience building to cover the gaps. By means of a holistic summary and structured analysis of key patterns, the authors hope to provide a streamlined access to existing research findings and make predictions of future trends. They also hope to encourage a more holistic approach to PDR research and international collaborations.

Analysis on causes of death of rural residents in Shouguang City [寿光市农村人群慢性病死因分析]

Among people living in rural areas of Shouguang City, Shandong, China, 88% of deaths were caused by chronic non-communicable diseases. Cardiovascular diseases, respiratory diseases and cancers accounted for 97% of all chronic disease causes and 85% of all causes of death. The proportion of chronic causes increased by 27% from 1993 to 2000. However, the mortality of respiratory diseases showed a decreasing trend over time. Abstract in Chinese 篇首： 随着生活水平的提高,慢性非传染性疾病在居民死因谱中所占比重越来越大,为准确反映居民的死因状况,为农村地区慢性病的控制工作提供科学依据,本文对寿光市农村疾病监测点1993～2000年居民的慢性病死因进行了分析.

Defining mega project success in Australian defence : a relation-based framework for value co-creation with project stakeholders

Defining success in mega projects has been a challenging exercise for Australian Defence. The inherent conflict between nation capability building and cost efficiency raises questions about how to appropriately define mega project success. Contrary to the traditional output-focused project methodology, the value creation perspective argues for the importance of creating new knowledge, processes, and systems for suppliers and customers. Stakeholder involvement is important in this new perspective, as the balancing of competing needs of stakeholders in mega projects becomes a major challenge in managing the value co-creation process. In our earlier study reported interview data from three Australian defence mega projects and reported that those senior executives have a more complex understanding of project success than traditional iron triangle measures. In these mega defence projects, customers and other stakeholders actively engage in the value creation process, and over time both content and process value are created to increase defence and national capability. Value created and captured during and post projects are the key to true success. We aim to develop a comprehensive theoretical model the capture the value co-creation process as a way of re-conceptualising success in mega projects. We propose a new framework redefine project value as multi-dimensional, contextual and temporal construct that emerges from the interactions among multiple stake holders over the complete project life cycle. The framework distinguishes between exploitation and exploration types of projects, and takes into consideration the requisite governance structures.

Shrinkage empirical likelihood estimator in longitudinal analysis with time-dependent covariates-application to modeling the health of Filipino children

The method of generalized estimating equations (GEE) is a popular tool for analysing longitudinal (panel) data. Often, the covariates collected are time-dependent in nature, for example, age, relapse status, monthly income. When using GEE to analyse longitudinal data with time-dependent covariates, crucial assumptions about the covariates are necessary for valid inferences to be drawn. When those assumptions do not hold or cannot be verified, Pepe and Anderson (1994, Communications in Statistics, Simulations and Computation 23, 939–951) advocated using an independence working correlation assumption in the GEE model as a robust approach. However, using GEE with the independence correlation assumption may lead to significant efficiency loss (Fitzmaurice, 1995, Biometrics 51, 309–317). In this article, we propose a method that extracts additional information from the estimating equations that are excluded by the independence assumption. The method always includes the estimating equations under the independence assumption and the contribution from the remaining estimating equations is weighted according to the likelihood of each equation being a consistent estimating equation and the information it carries. We apply the method to a longitudinal study of the health of a group of Filipino children.

Crizotinib versus chemotherapy in advanced ALK-positive lung cancer

BACKGROUND: In single-group studies, chromosomal rearrangements of the anaplastic lymphoma kinase gene (ALK ) have been associated with marked clinical responses to crizotinib, an oral tyrosine kinase inhibitor targeting ALK. Whether crizotinib is superior to standard chemotherapy with respect to efficacy is unknown. METHODS: We conducted a phase 3, open-label trial comparing crizotinib with chemotherapy in 347 patients with locally advanced or metastatic ALK-positive lung cancer who had received one prior platinum-based regimen. Patients were randomly assigned to receive oral treatment with crizotinib (250 mg) twice daily or intravenous chemotherapy with either pemetrexed (500 mg per square meter of body-surface area) or docetaxel (75 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to crizotinib as part of a separate study. The primary end point was progression-free survival. RESULTS: The median progression-free survival was 7.7 months in the crizotinib group and 3.0 months in the chemotherapy group (hazard ratio for progression or death with crizotinib, 0.49; 95% confidence interval [CI], 0.37 to 0.64; P<0.001). The response rates were 65% (95% CI, 58 to 72) with crizotinib, as compared with 20% (95% CI, 14 to 26) with chemotherapy (P<0.001). An interim analysis of overall survival showed no significant improvement with crizotinib as compared with chemotherapy (hazard ratio for death in the crizotinib group, 1.02; 95% CI, 0.68 to 1.54; P=0.54). Common adverse events associated with crizotinib were visual disorder, gastrointestinal side effects, and elevated liver aminotransferase levels, whereas common adverse events with chemotherapy were fatigue, alopecia, and dyspnea. Patients reported greater reductions in symptoms of lung cancer and greater improvement in global quality of life with crizotinib than with chemotherapy. CONCLUSIONS: Crizotinib is superior to standard chemotherapy in patients with previously treated, advanced non-small-cell lung cancer with ALK rearrangement. (Funded by Pfizer; ClinicalTrials.gov number, NCT00932893.) Copyright © 2013 Massachusetts Medical Society.

Prevalence of childhood sexual abuse among 2508 college students in 6 provinces of China [中国6省市2508名大学生儿童期性虐待经历回顾性调查]

OBJECTIVE To assess the prevalence of childhood sexual abuse (CSA) in college students and to explore the association of CSA with youth mental health problem. METHODS A retrospective survey was conducted among 2508 students (females 1360, males 1148) in Nov. 2003 to Mar. 2004. The students were from 6 colleges/universities in Beijing, Hebei, Shanxi, Jiangsu, Shaanxi and Anhui provinces of China. RESULTS Of the 2508 students, 24.8% of females and 17.6% of males reported one or more types of nonphysical contact CSA (females 20.0% vs. males 14.6%) or/and physical contact CSA (females 14.1% vs. males 7.8%) before the age of 16 years. Risk of any CSA was not associated with the existence of siblings (one-child vs. two-or more child families), rural/non-rural residence during childhood, or parental education. Compared with their peers who had no CSA, the students with CSA showed significantly higher mean scores of psychological symptoms of somatization, obsessiveness, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation and psychoticism. CONCLUSION The problem of CSA was not uncommon and there was a significant correlation between CSA experience and students mental health problems. More attention should be paid on CSA prevention and provision of health services for the victims.

Scrub typhus in mainland China, 2006–2012 : the need for targeted public health interventions

Scrub typhus is a vector-borne disease carried by the chigger mite. The aetiological agent is the rickettsia Orientia tsutsugamushi, which is endemic to several countries in the Asia-Pacific region, including China [1]. It is also a travel-associated disease [2] and of great importance among military personnel [3], [4]. During the Second World War, scrub typhus was associated with a higher case fatality ratio than any other infectious disease in the China-Burma-India theatre of operations 1,3. Clinical presentation in patients varies from asymptomatic to life-threatening disease [5], including acute hearing loss and multiple organ failure [6], [7]. To date, there is still no effective and reliable human vaccine against scrub typhus and no point-of-care diagnostics available [1].

Spatiotemporal patterns of Japanese Encephalitis in China, 2002–2010

OBJECTIVE The aim of the study is to examine the spatiotemporal pattern of Japanese Encephalitis (JE) in mainland China during 2002-2010. Specific objectives of the study were to quantify the temporal variation in incidence of JE cases, to determine if clustering of JE cases exists, to detect high risk spatiotemporal clusters of JE cases and to provide evidence-based preventive suggestions to relevant stakeholders. METHODS Monthly JE cases at the county level in mainland China during 2002-2010 were obtained from the China Information System for Diseases Control and Prevention (CISDCP). For the purpose of the analysis, JE case counts for nine years were aggregated into four temporal periods (2002; 2003-2005; 2006; and 2007-2010). Local Indicators of Spatial Association and spatial scan statistics were performed to detect and evaluate local high risk space-time clusters. RESULTS JE incidence showed a decreasing trend from 2002 to 2005 but peaked in 2006, then fluctuated over the study period. Spatial cluster analysis detected high value clusters, mainly located in Southwestern China. Similarly, we identified a primary spatiotemporal cluster of JE in Southwestern China between July and August, with the geographical range of JE transmission increasing over the past years. CONCLUSION JE in China is geographically clustered and its spatial extent dynamically changed during the last nine years in mainland China. This indicates that risk factors for JE infection are likely to be spatially heterogeneous. The results may assist national and local health authorities in the development/refinement of a better preventive strategy and increase the effectiveness of public health interventions against JE transmission.

Isolation of human lymphatic malformation endothelial cells, their in vitro characterization and in vivo survival in a mouse xenograft model

Human lymphatic vascular malformations (LMs), also known as cystic hygromas or lymphangioma, consist of multiple lymphatic endothelial cell-lined lymph-containing cysts. No animal model of this disease exists. To develop a mouse xenograft model of human LM, CD34NegCD31Pos LM lymphatic endothelial cells (LM-LEC) were isolated from surgical specimens and compared to foreskin CD34NegCD31Pos lymphatic endothelial cells (LECs). Cells were implanted into a mouse tissue engineering model for 1, 2 and 4 weeks. In vitro LM-LECs showed increased proliferation and survival under starvation conditions (P < 0.0005 at 48 h, two-way ANOVA), increased migration (P < 0.001, two-way ANOVA) and formed fewer (P = 0.029, independent samples t test), shorter tubes (P = 0.029, independent samples t test) than foreskin LECs. In vivo LM-LECs implanted into a Matrigel™-containing mouse chamber model assembled to develop vessels with dilated cystic lumens lined with flat endothelium, morphology similar to that of clinical LMs. Human foreskin LECs failed to survive implantation. In LM-LEC implanted chambers the percent volume of podoplaninPos vessels was 1.18 ± 2.24 % at 1 week, 6.34 ± 2.68 % at 2 weeks and increasing to 7.67 ± 3.60 % at 4 weeks. In conclusion, the significantly increased proliferation, migration, resistance to apoptosis and decreased tubulogenesis of LM-LECs observed in vitro is likely to account for their survival and assembly into stable LM-like structures when implanted into a mouse vascularised chamber model. This in vivo xenograft model will provide the basis of future studies of LM biology and testing of potential pharmacological interventions for patients with lymphatic malformations.