Common Variants of TLR1 Associate with Organ Dysfunction and Sustained Pro- Inflammatory Responses during Sepsis

Background: Toll-like receptors (TLRs) are critical components for host pathogen recognition and variants in genes participating in this response influence susceptibility to infections. Recently, TLR1 gene polymorphisms have been found correlated with whole blood hyper-inflammatory responses to pathogen-associated molecules and associated with sepsis-associated multiorgan dysfunction and acute lung injury (ALI). We examined the association of common variants of TLR1 gene with sepsis-derived complications in an independent study and with serum levels for four inflammatory biomarker among septic patients. Methodology/Principal Findings: Seven tagging single nucleotide polymorphisms of the TLR1 gene were genotyped in samples from a prospective multicenter case-only study of patients with severe sepsis admitted into a network of intensive care units followed for disease severity. Interleukin (IL)-1 b, IL-6, IL-10, and C-reactive protein (CRP) serum levels were measured at study entry, at 48 h and at 7th day. Alleles -7202G and 248Ser, and the 248Ser-602Ile haplotype were associated with circulatory dysfunction among severe septic patients (0.001<=p <= 0.022), and with reduced IL-10 (0.012<= p <=0.047) and elevated CRP (0.011<= p <=0.036) serum levels during the first week of sepsis development. Additionally, the -7202GG genotype was found to be associated with hospital mortality (p =0.017) and ALI (p =0.050) in a combined analysis with European Americans, suggesting common risk effects among studies Conclusions/Significance: These results partially replicate and extend previous findings, supporting that variants of TLR1 gene are determinants of severe complications during sepsis.

Associative Issue Ownership as a Determinant of Voters' Campaign Attention

Campaigns raise public interest in politics and allow parties to convey their messages to voters. However, voters' exposure and attention during campaigns are biased towards parties and candidates they like. This hinders parties' ability to reach new voters. This paper theorises and empirically tests a simple way in which parties can break partisan selective attention: owning an issue. When parties own issues that are important for a voter, that voter is more likely to notice them. Using survey data collected prior to the 2009 Belgian regional elections it is shown that this effect exists independent of partisan preferences and while controlling for the absolute visibility of a party in the media. This indicates that issue ownership has an independent impact on voters' attention to campaigns. This finding shows that owning salient issues yields (potential) advantages for parties, since getting noticed is a prerequisite for conveying electoral messages and increasing electoral success.

Sustained CTL activation by murine pulmonary epithelial cells promotes the development of COPD-like disease

Chronic obstructive pulmonary disease (COPD) is a lethal progressive lung disease culminating in permanent airway obstruction and alveolar enlargement. Previous studies suggest CTL involvement in COPD progression; however, their precise role remains unknown. Here, we investigated whether the CTL activation receptor NK cell group 2D (NKG2D) contributes to the development of COPD. Using primary murine lung epithelium isolated from mice chronically exposed to cigarette smoke and cultured epithelial cells exposed to cigarette smoke extract in vitro, we demonstrated induced expression of the NKG2D ligand retinoic acid early tran - script 1 (RAET1)as well as NKG2D-mediated cytotoxicity. Furthermore, a genetic model of inducible RAET1 expression on mouse pulmonary epithelial cells yielded a severe emphysematous phenotype characterized by epithelial apoptosis and increased CTL activation, which was reversed by blocking NKG2D activation. We also assessed whether NKG2D ligand expression corresponded with pulmonary disease in human patients by staining airway and peripheral lung tissues from never smokers, smokers with normal lung function, and current and former smokers with COPD. NKG2D ligand expression was independent of NKG2D receptor expression in COPD patients, demonstrating that ligand expression is the limiting factor in CTL activation. These results demonstrate that aberrant, persistent NKG2D ligand expression in the pulmonary epithelium contributes to the development of COPD pathologies.

Sustained-release steroids for the treatment of diabetic macular edema.

Glucocorticoids have been used for decades in the treatment of ocular disorders via topical, periocular, and more recently intravitreal routes. However, their exact mechanisms of action on ocular tissues remain imperfectly understood. Fortunately, two recently approved intravitreal sustained-release drug delivery systems have opened new perspectives for these very potent drugs. To date, among other retinal conditions, their label includes diabetic macular edema, for which a long-lasting therapeutic effect has been demonstrated both morphologically and functionally in several randomized clinical trials. The rate of ocular complications of intravitreal sustained-release steroids, mainly cataract formation and intraocular pressure elevation, is higher than with anti-vascular endothelial growth factor agents. Yet, a better understanding of the mechanisms underlying these adverse effects and the search for the minimal efficient dose should help optimize their therapeutic window.

Ribavirin Concentrations Do Not Predict Sustained Virological Response in HIV/HCV-Coinfected Patients Treated with Ribavirin and Pegylated Interferon in the Swiss HIV Cohort Study.

BACKGROUND: Ribavirin (RBV) is an essential component of most current hepatitis C (HCV) treatment regimens and still standard of care in the combination with pegylated interferon (pegIFN) to treat chronic HCV in resource limited settings. Study results in HIV/HCV-coinfected patients are contradicting as to whether RBV concentration correlates with sustained virological response (SVR). METHODS: We included 262 HCV treatment naïve HIV/HCV-coinfected Swiss HIV Cohort Study (SHCS) participants treated with RBV and pegIFN between 01.01.2001-01.01.2010, 134 with HCV genotype (GT) 1/4, and 128 with GT 2/3 infections. RBV levels were measured retrospectively in stored plasma samples obtained between HCV treatment week 4 and end of therapy. Uni- and multivariable logistic regression analyses were used to evaluate the association between RBV concentration and SVR in GT 1/4 and GT 2/3 infections. The analyses were repeated stratified by treatment phase (week 4-12, 13-24, >24) and IL28B genotype (CC versus CT/TT). RESULTS: SVR rates were 35.1% in GT 1/4 and 70.3% in GT 2/3 infections. Overall, median RBV concentration was 2.0 mg/L in GT 1/4, and 1.9 mg/L in GT 2/3, and did not change significantly across treatment phases. Patients with SVR had similar RBV concentrations compared to patients without SVR in both HCV genotype groups. SVR was not associated with RBV levels ≥2.0 mg/L (GT 1/4, OR 1.19 [0.5-2.86]; GT 2/3, 1.94 [0.78-4.80]) and ≥2.5 mg/L (GT 1/4, 1.56 [0.64-3.84]; GT 2/3 2.72 [0.85-8.73]), regardless of treatment phase, and IL28B genotype. CONCLUSION: In HIV/HCV-coinfected patients treated with pegIFN/RBV, therapeutic drug monitoring of RBV concentrations does not enhance the chance of HCV cure, regardless of HCV genotype, treatment phase and IL28B genotype.

Pneumococcal polysaccharide vaccination in adults undergoing immunosuppressive treatment for inflammatory diseases - a longitudinal study.

INTRODUCTION: Patients undergoing immunosuppressive therapy are at increased risk of infection. Community-acquired pneumonia and invasive pneumococcal disease account for substantial morbidity and mortality in this population and may be prevented by vaccination. Ideally, immunization to pneumococcal antigens should take place before the start of immunosuppressive treatment. Often, however, the treatment cannot be delayed. Little is known about the efficacy of pneumococcal vaccines during immunosuppressive treatment. The objectives of this study were to determine the percentage of vaccine-naïve, immunosuppressed adults with inflammatory diseases seroprotected against Streptococcus pneumoniae and to assess factors associated with the immunogenicity, clinical impact and safety of 23-valent pneumococcal polysaccharide vaccine (PPV) in seronegative subjects. METHODS: This observational study included patients 18 years of age and older who were receiving prednisone ≥20 mg/day or other immunosuppressive drugs. Exclusion criteria were PPV administration in the previous 5 years, intravenous immunoglobulins and pregnancy. Serum immunoglobulin G (IgG) antibody levels against six pneumococcal serotypes were measured. Seropositivity was defined as IgG of 0.5 μg/ml or greater for at least four of six serotypes. Seronegative patients received PPV, and seropositive patients were included as a comparison group. Vaccine response and tolerance were assessed after 4-8 weeks. Disease activity was evaluated on the basis of the Physician Global Assessment scores. Serology was repeated after 1 year, and information on any kind of infection needing medical attention was collected. Outcomes were the proportion of seropositivity and infections between vaccinated and unvaccinated patients. RESULTS: Of 201 included patients, 35 received high-dose corticosteroids and 181 were given immunosuppressive drugs. Baseline seronegativity in 60 (30 %) patients was associated with corticotherapy and lower total IgG. After PPV, disease activity remained unchanged or decreased in 81 % of patients, and 87 % became seropositive. After 1 year, 67 % of vaccinated compared with 90 % of observed patients were seropositive (p < 0.001), whereas the rate of infections did not differ between groups. Those still taking prednisone ≥10 mg/day tended to have poorer serological responses and had significantly more infections. CONCLUSIONS: PPV was safe and moderately effective based on serological response. Seropositivity to pneumococcal antigens significantly reduced the risk of infections. Sustained high-dose corticosteroids were associated with poor vaccine response and more infections.

Macroinvertebrate assemblages on reed beds, with special attention to Chironomidae (Diptera), in Mediterranean shallow lakes.

Macroinvertebrates associated to reed-beds (Phragmites australis) in six shallow natural water bodies along the 220 km of coast of the Comunidad Valenciana (Spain) were studied. These sites were selected to reflect different trophic states, but also, and due to the natural variability of mediterranean wetlands, they greatly differ in salinity and hydroperiod. To unify the sampling, reed bed was chosen to provide data from a habitat common to all wetlands, including the most eutrophic ones where submerged macrophytes have disappeared due to water turbidity. Individual submerged stems of Phragmites australis were sampled along with the surrounding water. The animal density found refers to the available stem surface area for colonization. Forty-one taxa were recorded in total, finding Chironomidae to be the most important group, quantitatively and qualitatively. In freshwater sites it was observed an increase in macroinvertebrate"s density at higher trophic states. Nevertheless each studied region had a different fauna. The PCA analysis with macroinvertebrate groups distinguished three types of environment: freshwaters (characterized by swimming insect larvae, collectors and predators, oligochaetes and Orthocladiinae), saline waters (characterized by crustaceans and Chironominae) and the spring pool, which shares both taxa. Chironomids were paid special attention for being the most abundant. A DCA analysis based on the relative abundance of Chironomids reveals salinity as the main characteristic responsible for its distribution, but trophic state and hydrological regime were also shown to be important factors.

Making SENSE - Sustained Effort Network for treatment of Status Epilepticus as a multicenter prospective registry.

BACKGROUND: Evidence regarding the different treatment options of status epilepticus (SE) in adults is scarce. Large randomized trials cover only one treatment at early stage and suggest the superiority of benzodiazepines over placebo, of intravenous lorazepam over intravenous diazepam or over intravenous phenytoin alone, and of intramuscular midazolam over intravenous lorazepam. However, many patients will not be treated successfully with the first treatment step. A large randomized trial covering the treatment of established status (ESETT) has just been funded recently by the NIH and will not start before 2015, with expected results in 2018; a trial on the treatment of refractory status with general anesthetics was terminated early due to insufficient recruitment. Therefore, a prospective multicenter observational registry was set up; this may help in clinical decision-making until results from randomized trials are available. METHODS/DESIGN: SENSE is a prospective, multicenter registry for patients treated for SE. The primary objective is to document patient characteristics, treatment modalities and in-house outcome of consecutive adults admitted for SE treatment in each of the participating centres and to identify predictors of outcome. Pre-treatment, treatment-related and outcome variables are documented systematically. To allow for meaningful multivariate analysis in the patient subgroups with refractory SE, a cohort size of 1000 patients is targeted. DISCUSSION: The results of the study will provide information about risks and benefits of specific treatment steps in different patient groups with SE at different points of time. Thus, it will support clinical decision-making and, furthermore, it will be helpful in the planning of treatment trials. TRIAL REGISTRATION: DRKS00000725.

Braving the Storm: How Are Global Biofuel Policies Sustained Despite Being Contested? An Analysis of the Biofuel Discourses of the EU, Brazil and Mozambique

Considered as a remedy to multiple problems that our world is facing, biofuels are nowadays promoted on a global scale. Despite this globalised approach, however, biofuels are heavily contested. Not only the social implications of biofuels are disputed and uncertain, particularly in countries of the global South, but also their environmental and economic rationales. Given these huge controversies, policies promoting biofuels would seem difficult to maintain. Yet, support for them has been surprisingly well established on the political agendas. With the aim of understanding this puzzle, this study asks how the dominant approach to biofuels has been sustained on a global level. In order to answer this question, the meanings and assumptions in biofuel discourses are explored through the lens of Maarten Hajer’s “argumentative” discourse analysis. Based on the existence of a “partnership for sustainable bioenergy” between the EU, Brazil and Mozambique, the study takes these three locations as case studies. The analysis reveals that various discursive strategies, including a particular problem construction and the use of two main story-lines, have played an important role in ensuring the permanence of the global approach to biofuels. Moreover, while the discourse of critics against biofuels demonstrates that there is room for contestation, the analysis finds that the opponents’ discourse largely fails to target the most salient justification for biofuels. A more effective strategy for critics would therefore be to also question the problem constructions underpinning this main justification in the global discourse.

A role of Eye Vergence in Covert Attention

Covert spatial attention produces biases in perceptual and neural responses in the absence of overt orienting movements. The neural mechanism that gives rise to these effects is poorly understood. Here we report the relation between fixational eye movements, namely eye vergence, and covert attention. Visual stimuli modulate the angle of eye vergence as a function of their ability to capture attention. This illustrates the relation between eye vergence and bottom-up attention. In visual and auditory cue/no-cue paradigms, the angle of vergence is greater in the cue condition than in the no-cue condition. This shows a top-down attention component. In conclusion, observations reveal a close link between covert attention and modulation in eye vergence during eye fixation. Our study suggests a basis for the use of eye vergence as a tool for measuring attention and may provide new insights into attention and perceptual disorders.

E2F1 mediates sustained lipogenesis and contributes to hepatic steatosis.

E2F transcription factors are known regulators of the cell cycle, proliferation, apoptosis, and differentiation. Here, we reveal that E2F1 plays an essential role in liver physiopathology through the regulation of glycolysis and lipogenesis. We demonstrate that E2F1 deficiency leads to a decrease in glycolysis and de novo synthesis of fatty acids in hepatocytes. We further demonstrate that E2F1 directly binds to the promoters of key lipogenic genes, including Fasn, but does not bind directly to genes encoding glycolysis pathway components, suggesting an indirect effect. In murine models, E2F1 expression and activity increased in response to feeding and upon insulin stimulation through canonical activation of the CDK4/pRB pathway. Moreover, E2F1 expression was increased in liver biopsies from obese, glucose-intolerant humans compared with biopsies from lean subjects. Finally, E2f1 deletion completely abrogated hepatic steatosis in different murine models of nonalcoholic fatty liver disease (NAFLD). In conclusion, our data demonstrate that E2F1 regulates lipid synthesis and glycolysis and thus contributes to the development of liver pathology.

Determinants of the decision to appeal against motor bodily injury settlements awarded by Spanish trial courts

Automobile bodily injury disputes represent one of the main causes of litigation faced by Spanish Courts. In this paper a multinomial model is implemented to analyse which factors determine the decision to appeal against the verdicts of trial courts. Use of a dataset of motor insurance claims revealed differences between the determinants of a claimant’s decision to appeal and those of insurers. Among other results it is shown that discrepancies regarding the permanent disability sustained affect the insurer’s decision to appeal. In contrast, the claimant pays more attention to differences in the stated temporary disability. Conclusions are drawn regarding which factors could reduce the percentage of appealed cases.