FTY720 and two novel butterfly derivatives exert a general anti-inflammatory potential by reducing immune cell adhesion to endothelial cells through activation of S1P3 and phosphoinositide 3-kinase

Sphingosine-1-phosphate (S1P) is a key lipid regulator of a variety of cellular responses including cell proliferation and survival, cell migration, and inflammatory reactions. Here, we investigated the effect of S1P receptor activation on immune cell adhesion to endothelial cells under inflammatory conditions. We show that S1P reduces both tumor necrosis factor (TNF)-α- and lipopolysaccharide (LPS)-stimulated adhesion of Jurkat and U937 cells to an endothelial monolayer. The reducing effect of S1P was reversed by the S1P1+3 antagonist VPC23019 but not by the S1P1 antagonist W146. Additionally, knockdown of S1P3, but not S1P1, by short hairpin RNA (shRNA) abolished the reducing effect of S1P, suggesting the involvement of S1P3. A suppression of immune cell adhesion was also seen with the immunomodulatory drug FTY720 and two novel butterfly derivatives ST-968 and ST-1071. On the molecular level, S1P and all FTY720 derivatives reduced the mRNA expression of LPS- and TNF-α-induced adhesion molecules including ICAM-1, VCAM-1, E-selectin, and CD44 which was reversed by the PI3K inhibitor LY294002, but not by the MEK inhibitor U0126.In summary, our data demonstrate a novel molecular mechanism by which S1P, FTY720, and two novel butterfly derivatives acted anti-inflammatory that is by suppressing gene transcription of various endothelial adhesion molecules and thereby preventing adhesion of immune cells to endothelial cells and subsequent extravasation.

Comparing expectations and experiences of care for sexually transmitted infections in general practice: a qualitative study

Background A key aim of England's National Strategy for Sexual Health is to extend high-quality sexual health services in primary care. Objectives To explore the expectations and experiences of men and women who initially presented at their general practice with a suspected sexually transmitted infection in order to identify areas where change could improve service delivery. Methods Semi-structured interviews were carried out in six general practices and two genitourinary medicine (GUM) clinics in Brent primary care trust (London) and Bristol (southwest England). Patients within general practice, and GUM patients who had initially attended general practice were eligible to participate. Interview transcripts were analysed using thematic analysis. Results 49 patients (29 women, 20 men) were interviewed. Patients approaching their GP practice typically expected written referral or in-house care, but this expectation was often not met. Absence of formal referral, lack of information and perceived avoidance of sexual health matters by practitioners were commonly cited as reasons for disappointment. However, a dedicated service within general practice met expectations well. Conclusion Purchasers and providers of all general practice services should ensure that any patient consulting in primary care with a suspected sexually transmitted infection can either receive appropriate care there, or a formal and supported referral to a specialised GUM clinic or primary care service.

Avoidance of Long Mononucleotide Repeats in Codon Pair Usage

Protein is an essential component for life, and its synthesis is mediated by codons in any organisms on earth. While some codons encode the same amino acid, their usage is often highly biased. There are many factors that can cause the bias, but a potential effect of mononucleotide repeats, which are known to be highly mutable, on codon usage and codon pair preference is largely unknown. In this study we performed a genomic survey on the relationship between mononucleotide repeats and codon pair bias in 53 bacteria, 68 archaea, and 13 eukaryotes. By distinguishing the codon pair bias from the codon usage bias, four general patterns were revealed: strong avoidance of five or six mononucleotide repeats in codon pairs; lower observed/expected (o/e) ratio for codon pairs with C or G repeats (C/G pairs) than that with A or T repeats (A/T pairs); a negative correlation between genomic GC contents and the o/e ratios, particularly for C/G pairs; and avoidance of C/G pairs in highly conserved genes. These results support natural selection against long mononucleotide repeats, which could induce frameshift mutations in coding sequences. The fact that these patterns are found in all kingdoms of life suggests that this is a general phenomenon in living organisms. Thus, long mononucleotide repeats may play an important role in base composition and genetic stability of a gene and gene functions.

What is the incidence of intracranial bleeding in patients with mild traumatic brain injury? A retrospective study in 3088 Canadian CT head rule patients

OBJECTIVE Only limited data exists in terms of the incidence of intracranial bleeding (ICB) in patients with mild traumatic brain injury (MTBI). METHODS We retrospectively identified 3088 patients (mean age 41 range (7-99) years) presenting with isolated MTBI and GCS 14-15 at our Emergency Department who had undergone cranial CT (CCT) between 2002 and 2011. Indication for CCT was according to the "Canadian CT head rules." Patients with ICB were either submitted for neurosurgical treatment or kept under surveillance for at least 24 hours. Pearson's correlation coefficient was used to correlate the incidence of ICB with age, gender, or intake of coumarins, platelet aggregation inhibitors, or heparins. RESULTS 149 patients (4.8%) had ICB on CCT. No patient with ICB died or deteriorated neurologically. The incidence of ICB increased with age and intake of anticoagulants without clinically relevant correlation (R = 0.11; P < 0.001; R = -0.06; P < 0.001). CONCLUSION Our data show an incidence of 4.8% for ICB after MTBI. However, neurological deterioration after MTBI seems to be rare, and the need for neurosurgical intervention is only required in selected cases. The general need for CCT in patients after MTBI is therefore questionable, and clinical surveillance may be sufficient when CCT is not available.

The response of four winter wheat (Triticum aestivum L.) varieties to field water deficit: leaf anti-oxidative protection and proteolytic activity

Introduction: Drought is one of the most significant factors that limit plant productivity. Oxidative stress is a secondary event in many unfavorable environmental conditions. Intracellular proteases have a role in the metabolism reorganisation and nutrient remobilization under stress. In order to under stand the relative significance of oxidative stress and proteolysis in the yield reduction under drought, four varieties of Triticum aestivum L. with different field drought resistance were examined. Methods: A two-year field experiment was conducted. Analyses were performed on the upper most leaf of control plants and plants under water deficitat the stages most critical for yield reduction under drought (from jointing till milk ripeness). Leaf water deficit and electrolyte leakage, malondyaldehyde level, activities and isoenzymes of superoxide dismutase, catalase and peroxidase, leaf protein content and proteolytic activity were studied. Yield components were analyzed. Results: A general trend of increasing the membrane in stability and accumulation of lipid hydroperoxides was observed with some differences among varieties, especially under drought. The anti-oxidative enzyme activities were progressively enhanced, as well as the azocaseinolytic activities. The leaf protein content decreased under drought at the last phase. Differences among varieties were observed in the parameters under study. They were compared to yield components` reduction under water deprivation.

Organoleptic assessment of halitosis for dental professionals - general recommendations

An organoleptic assessment of an odor is defined as a method that can measure the strength of target odors and expresses the value in terms of a point or number with reference to a pre-defined organoleptic scale. Organoleptic assessments are performed using different scales and are used widely in industry (e.g. for measuring the effectiveness of anti-odor agents), in research (to discover relationships between bad breath and microbiology of the tongue, or the generation of particular volatile compounds), but it is also a prerequisite for the diagnosis of halitosis in individual patients required before directing appropriate treatment. An organoleptic assessment of halitosis patients may be carried out in specialized institutions but--based on the fact that in most cases the odor originates from oral structures--also by dental professionals including general dental practitioners (GDPs). Thus, this paper describes the scientific background for recommendations on how a GDP or dental hygienist or general practitioner with cases of bad breath should use organoleptic methods as a valid approach to assess malodor in patients, with a view to diagnosis and treatment, and subsequent treatment monitoring.

Later Wittgenstein's Anti-Philosophical Therapy

The object of this essay is to discuss Ludwig Wittgenstein's remarks in Philosophical Investigations and elsewhere in the posthumously published writings concerning the role of therapy in relation to philosophy. Wittgenstein's reflections seem to suggest that there is a kind of philosophy or mode of investigation targeting the philosophical grammar of language uses that gratuitously give rise to philosophical problems, and produce in many thinkers philosophical anxieties for which the proper therapy is intended to offer relief. Two possible objectives of later Wittgensteinian therapy are proposed, for subjective psychological versus objective semantic symptoms of ailments that a therapy might address for the sake of relieving philosophical anxieties. The psychological in its most plausible form is rejected, leaving only the semantic. Semantic therapy in the sense defined and developed is more general and long-lasting, and more in the spirit of Wittgenstein's project on a variety of levels. A semantic approach treats language rather than the thinking, language-using subject as the patient needing therapy, and directs its attention to the treatment of problems in language and the conceptual framework a language game use expresses in its philosophical grammar, rather than to soothing unhappy or socially ill-adjusted individual psychologies.

Reconciling Perspectives on Blame Avoidance Behaviour

Blame avoidance behaviour (BAB) has become an increasingly popular topic in political science. However, the preconditions of BAB, its presence and consequences in various areas and in different political systems largely remain a black box. In order to generate a better understanding of BAB and its importance for the workings of democratic political systems, the scattered literature on BAB needs to be assessed and structured. This article offers a comprehensive review of the literature on blame avoidance. It departs from Weaver’s concept of blame avoidance and subsequently differentiates between work on BAB in comparative welfare state research and work on BAB in public policy and administration. It is argued that between these two strands of literature a bifurcation exists since both perspectives rarely draw on each other to create a more general understanding of BAB. Advantages from existing approaches must be combined to assess the phenomenon of blame avoidance in a more comprehensive way.

Anticipatory and reactive forms of blame avoidance: of foxes and lions

Blame avoidance behavior (BAB) encompasses all kinds of integrity-protecting activities by officeholders in the face of potentially blame-attracting events. Although considered essential for a realistic understanding of politics and policymaking, a general understanding of this multi-faceted behavioral phenomenon and its implications has been lacking to date. We argue that this is due to the lack of careful conceptualization of various forms of BAB. Crucially, the difference between anticipatory and reactive forms of BAB is largely neglected in the literature. This paper links anticipatory and reactive forms of BAB as two consecutive decision situations. It exposes dependence relationships between the situations that trigger BAB, the rationalities at work, the resources and strategies applied by blame-avoiding actors, and the various consequences thereof. The paper concludes that anticipatory and reactive BAB are distinct phenomena that require specific research approaches to assess their relevance for the workings of polities.