When do combinations of diuretics make sense?

Diuretics are commonly prescribed by physicians to contract the ECF volume. In two clinical situations combining different classes of diuretics make sense: First, if a loop diuretic at maximal dose alone does not lead to sufficient diuresis or second, if the side effect of a diuretic needs to be corrected by adding a diuretic of another class. The latter is clinically often used to counteract loop or thiazide diuretic-induced hypokalemia by the addition of a potassium sparing diuretic. Key to a reasonable combination of diuretics is understanding of the pharmaco-kinetics and knowledge of the molecular targets of the diuretics involved.

Does emergency vaccination make sense as a supporting element in control of foot-and-mouth disease in Switzerland

The outbreak of foot and mouth disease (FMD) in Great Britain in 2001 let to discussions and especially emergency vaccination was deemed as an alternative to the culling of vast numbers of healthy animals. The project emergency vaccination for FMD in Switzerland was conducted to compare the effectiveness of conventional control strategies during a FMD outbreak alone and with ring vaccination of 3 km and 10 km, respectively. The results of this project showed that emergency vaccination conducted at the beginning of an epidemic was not favorable compared to conventional disease control strategy in Switzerland. In case of an advanced FMD epidemic, a 10 km ring vaccination could support the disease control in a positive way. However, the goal of emergency vaccination to save animal live can hardly be achieved due to actual legal basis and the consequent restriction measures within vaccination zones which will lead to welfare culling.

Who’s to blame? How narcissists and ex-partners of narcissists make sense of romantic breakup

Objective: past research has shown relationship problems associated with narcissists’ excessive self-centeredness and lacking concern for others. Using romantic relationships as opportunities to self-enhance rather than caring about intimacy, narcissists are sensitive to shortcomings in their partners and quick to withdraw investment once relationships turn out to be less than perfect. Our research aimed to reveal whether narcissists are aware of their destructive relationship behavior or tend to put the blame for a failed relationship on their ex-partners. Conversely, do ex-partners of narcissists take the blame and feel responsible for the breakup or walk away convinced their narcissistic ex-partners’ behavior was just too unbearable? Method: 120 participants (19-59 yrs) who reported a recent romantic breakup completed a battery of questionnaires online, including measures of narcissism and self-esteem, as well as newly created scales assessing attributions for breakup. In addition to self-reports, participants retrospectively rated their ex-partners on adapted versions of the same measures. Results: narcissists made attributions to lacking relationship investment mostly in themselves and to a lesser extent in their partners. However, this pattern was reversed when self-esteem was controlled, with attributions to partner shortcomings outnumbering aspects of own destructive behavior. Narcissism perceived in the ex-partner was related to reports of lacking investment in oneself as well as the ex-partner, but controlling for self-esteem reduced the number of attributions to own shortcomings. Conclusion: our analyses revealed that narcissists do show some awareness of their contribution to a failed relationship, although controlling for self-esteem increased their blame of the ex-partner. In contrast, associations between perceived partner-narcissism and aspects of own lacking relationship investment became fewer when self-esteem was controlled for.

[Sense and nonsense of toxicological analyses in the daily clinical routine]

Screening tests for drugs of abuse are regularly used in the clinical routine. These tests identify the targeted substances very differently if tests from different manufacturers are used and sometimes also react positive after the intake of drugs which are not intended to be detected. Therefore, implausible results have to be questioned. A test result can be falsely negative, if a patient has taken a compound which is not detected by the antibody used in the test system. Chromatographic confirmation and screening assays are more laborious to perform and more demanding for the interpretation and are therefore only offered by several specialized clinical laboratories. However, their specificity is excellent and many different compounds can be detected depending on the number of compounds which are part of the mass spectra library used. If the clinical evaluation results in the differential diagnosis of an acute intoxication, screening tests for drugs of abuse can help to identify a single compound or a group of substances. The clinical picture, however, can usually not been explained by a qualitative test result. In addition, there are no published data demonstrating that these tests meaningfully influence triage, treatment, diagnosis or further therapy of a poisoned patient. The quantitative determination of specific compounds in the blood allows for example an appraisal of the prognosis and helps to indicate a specific therapy after intake of acetaminophen or methanol. New designer drugs can not at all be detected by the classic screening tests for drugs of abuse. The have to be identified by chromatographic methods.

PLASMACYTOID DENDRITIC CELLS SENSE SKIN INJURY AND PROMOTE WOUND HEALING THROUGH TYPE I INTERFERONS

Plasmacytoid dendritic cells (pDCs) are a rare population of circulating cells, which selectively express intracellular Toll-like receptors (TLR)-7 and TLR-9 and have the capacity to produce large amounts of type I IFNs (IFN-a/b) in response to viruses or host derived nucleic acid containing complexes. pDCs are normally absent in skin but accumulate in the skin of psoriasis patients where their chronic activation to produce IFN-a/b drives the disease formation. Whether pDCs and their activation to produce IFN-a/b play a functional role in healthy skin is unknown. Here we show that pDCs are rapidly and transiently recruited into healthy human and mouse skin upon epidermal injury. Infiltrating pDCs were found to sense nucleic acids in wounded skin via TLRs, leading to the production of IFN-a/b. The production of IFN-a/b was paralleled by a short lived expression of cathelicidins, which form complexes with extracellular nucleic acids and activated pDCs to produce IFN-a/b in vitro. In vivo, cathelicidins were sufficient but not necessary for the induction of IFN-a/b in wounded skin, suggesting redundancy of this pathway. Depletion of pDCs or inhibition of IFN-a/bR signaling significantly impaired the inflammatory response and delayed re-epithelialization of skin wounds. Thus we uncover a novel role of pDCs in sensing skin injury via TLR mediated recognition of nucleic acids and demonstrate their involvement in the early inflammatory process and wound healing response through the production of IFN-a/b.

In What Sense Are Emotions Evaluations?

Abstract: In this chapter, we first introduce the idea that emotions are evaluations. Next, we explore two approaches attempting to account for this idea in terms of attitudes that are alleged to become emotional when taking evaluative contents. According to the first approach, emotions are evaluative judgments. According to the second, emotions are perceptual experiences of evaluative properties. We explain why this theory remains unsatisfactory insofar as it shares with the evaluative judgement theory the idea that emotions are evaluations in virtue of their contents. We then outline an alternative – the attitudinal theory of emotions. It parts with current theorizing about the emotions in elucidating the fact that emotions are evaluations not in terms of what they represent, but in terms of the attitude subjects take towards what they represent. We explore what sorts of attitudes emotions are and claim that they are felt bodily attitudes.

Trying to make sense in nonsense-mediated mRNA decay

Despite over 30 years of research, the molecular mechanisms of nonsense-mediated mRNA decay (NMD) are still not well understood. NMD appears to exist in most eukaryotes and is intensively studied in S. cerevisiae, C. elegans, D. melanogaster and in mammalian cells. Current evidence suggests that the core of NMD – involving UPF1, UPF2 and UPF3 – is evolutionarily conserved, but that different species may have evolved slightly different ways to identify target mRNAs for NMD and to degrade them. Our lab has shown that the exon junction complex (EJC) is not absolutely required for NMD in human cells (Bühler et al., NSMB 2006) and that it is neither restricted to CBP80-bound mRNAs as classical models claim (Rufener & Mühlemann, NSMB 2013). Together with the finding that long 3’ UTRs often are an NMD-inducing feature (Eberle et al, PLoS Biol 2008; Yepiskoposyan et al., RNA 2011), our data is consistent with much of the data from other species and hence has led to a “unified” working model for NMD (Stalder & Mühlemann, Trends Cell Biol 2008; Schweingruber et al., Biochim Biophys Acta 2013). Our recent iCLIP experiments with endogenous UPF1 indicate that UPF1 binds mRNAs indiscriminately with respect to being an NMD target or not before they engage with ribosomes (Zünd et al., NSMB 2013). After onset of translation, UPF1 is cleared from the coding region but remains bound to the 3’ UTR of mRNAs. Why this 3’ UTR-associated in some cases induces NMD and in others not is currently being investigated and not yet understood. Following assembly of a phospho-UPF1-containing NMD complex, decay adaptors (SMG5, SMG7, PNRC2) and/or the endonuclease SMG6 are recruited. While the latter cleaves the mRNA in the vicinity of the termination codon, the former proteins induce deadenylation, decapping and exonucleolytic degradation of the mRNA. In my talk, I will give an overview about the latest developments in NMD – with a focus on our own work – and try to integrate the bits and pieces into a somewhat coherent working model.