MRSA decolonization failure - are biofilms the missing link?

Background: Device-associated infections due to biofilm-producing methicillin-resistant Staphylococcus aureus (MRSA) have been recently associated with the failure of antibiotic treatment and decolonization measures. The goal of our study was to evaluate the extent to which the formation of biofilms influenced the efficacy of topical decolonization agents or disinfectants such as mupirocin (MUP), octenidine (OCT), chlorhexidine (CHG), polyhexanide (POL), and chloroxylenol (CLO). Methods: Bacterial killing in biofilms by the disinfectants and MUP was determined as the reduction [%] in metabolic activity determined by a biofilm viability assay that uses kinetic analysis of metabolic activity. The test substances were diluted in water with standardized hardness (WSH) at 25 °C at the standard concentration as well as half the standard concentration to demonstrate the dilution effects in a practical setting. The tested concentrations were: CHG 1%, 2%; OCT 0.1%, 0.05%; PH 0.04%, 0.02%; and CLO 0.12%, 0.24%. A test organism suspension, 1 mL containing ~1 × 109 bacterial cells/mL, and 1 mL of sterile WSH were mixed and incubated for six different exposure times (15 s, 1, 3, 5, 10 and 20 min) after the test substance was added. Additionally, the bactericidal effects of all substances were tested on planktonic bacteria and measured as the log10 reduction. Results: The disinfectants OCT and CHG showed good efficacy in inhibiting MRSA in biofilms with reduction rates of 94 ± 1% and 91 ± 1%, respectively. POL, on the other hand, had a maximum efficacy of only 81 ± 7%. Compared to the tested disinfectants, MUP showed a significantly lower efficacy with <20% inhibition (p < .05). Bactericidal effects were the greatest for CHG (log10 reduction of 9.0), followed by OCT (7.7), POL (5.1), and CLO (6.8). MUP, however, showed a very low bactericidal effect of only 2.1. Even when the exposure time was increased to 24 h, 2% MUP did not show sufficient bactericidal effect. Conclusions: Our data provide evidence that OCT and CHG are effective components for disinfection of MRSA-biofilms. On the other hand, exposure to MUP at the standard concentrations in topical preparations did not effectively inhibit MRSA-biofilms and also did not show adequate bactericidal effects. Combining an MUP-based decolonization regimen with a disinfectant such as OCT or CHG could decrease decolonization failure

The β-blocker Nebivolol Is a GRK/β-arrestin Biased Agonist

Nebivolol, a third generation β-adrenoceptor (β-AR) antagonist (β-blocker), causes vasodilation by inducing nitric oxide (NO) production. The mechanism via which nebivolol induces NO production remains unknown, resulting in the genesis of much of the controversy regarding the pharmacological action of nebivolol. Carvedilol is another β-blocker that induces NO production. A prominent pharmacological mechanism of carvedilol is biased agonism that is independent of Gαs and involves G protein-coupled receptor kinase (GRK)/β-arrestin signaling with downstream activation of the epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase (ERK). Due to the pharmacological similarities between nebivolol and carvedilol, we hypothesized that nebivolol is also a GRK/β-arrestin biased agonist. We tested this hypothesis utilizing mouse embryonic fibroblasts (MEFs) that solely express β2-ARs, and HL-1 cardiac myocytes that express β1- and β2-ARs and no detectable β3-ARs. We confirmed previous reports that nebivolol does not significantly alter cAMP levels and thus is not a classical agonist. Moreover, in both cell types, nebivolol induced rapid internalization of β-ARs indicating that nebivolol is also not a classical β-blocker. Furthermore, nebivolol treatment resulted in a time-dependent phosphorylation of ERK that was indistinguishable from carvedilol and similar in duration, but not amplitude, to isoproterenol. Nebivolol-mediated phosphorylation of ERK was sensitive to propranolol (non-selective β-AR-blocker), AG1478 (EGFR inhibitor), indicating that the signaling emanates from β-ARs and involves the EGFR. Furthermore, in MEFs, nebivolol-mediated phosphorylation of ERK was sensitive to pharmacological inhibition of GRK2 as well as siRNA knockdown of β-arrestin 1/2. Additionally, nebivolol induced redistribution of β-arrestin 2 from a diffuse staining pattern into more intense punctate spots. We conclude that nebivolol is a β2-AR, and likely β1-AR, GRK/β-arrestin biased agonist, which suggests that some of the unique clinically beneficial effects of nebivolol may be due to biased agonism at β1- and/or β2-ARs. © 2013 Erickson et al

Crystal structure of bis-[3-meth-oxy-17β-estra-1,3,5(10)-trien-17-yl] oxalate.

In the title compound, C40H50O6, a symmetrical steroid oxalate diester, the dihedral angle between the CO2 planes of the oxalate linker is 61.5 (5)° and the C-C bond length is 1.513 (6) Å. The steroid B, C and D rings adopt half-chair, chair and envelope conformations, respectively, in both halves of the mol-ecule, which adopts an overall shallow V-shaped conformation. In the crystal, mol-ecules are linked by weak C-H⋯O inter-actions, forming a three-dimensional network

Malate as a key carbon source of leaf dark-respired CO2 across different environmental conditions in potato plants

Dissimilation of carbon sources during plant respiration in support of metabolic processes results in the continuous release of CO(2). The carbon isotopic composition of leaf dark-respired CO(2) (i.e. δ (13) C (R)) shows daily enrichments up to 14.8‰ under different environmental conditions. However, the reasons for this (13)C enrichment in leaf dark-respired CO(2) are not fully understood, since daily changes in δ(13)C of putative leaf respiratory carbon sources (δ (13) C (RS)) are not yet clear. Thus, we exposed potato plants (Solanum tuberosum) to different temperature and soil moisture treatments. We determined δ (13) C (R) with an in-tube incubation technique and δ (13) C (RS) with compound-specific isotope analysis during a daily cycle. The highest δ (13) C (RS) values were found in the organic acid malate under different environmental conditions, showing less negative values compared to δ (13) C (R) (up to 5.2‰) and compared to δ (13) C (RS) of soluble carbohydrates, citrate and starch (up to 8.8‰). Moreover, linear relationships between δ (13) C (R) and δ (13) C (RS) among different putative carbon sources were strongest for malate during daytime (r(2)=0.69, P≤0.001) and nighttime (r(2)=0.36, P≤0.001) under all environmental conditions. A multiple linear regression analysis revealed δ (13) C (RS) of malate as the most important carbon source influencing δ (13) C (R). Thus, our results strongly indicate malate as a key carbon source of (13)C enriched dark-respired CO(2) in potato plants, probably driven by an anapleurotic flux replenishing intermediates of the Krebs cycle

Linguistic Landscape of Religious Signboards in Ado Ekiti, Nigeria: Culture, Identity and Globalisation

This paper focuses on the linguistic landscape (LL) of religious signboards in select areas of Ado Ekiti, Nigeria with a view of establishing the relationship between the languages used on these signboards and the implication for identity, globalisation and culture. Fifty-three LL items were photographed for the study. The areas selected were based on activity level and the number of religious signboards they featured. The data were analysed both quantitatively and qualitatively. The findings revealed the dominance and the pervasiveness of the English language over and across the other languages in the public space. The use of Yoruba texts across the items revealed religio-cultural and loyalist reasons while the use of Arabic confirmed the inherent attachment of the language to Islamic religion, and fostered a religion-based collective identity between the sign writer and the sign reader

Testing variational estimation of process parameters and initial conditions of an earth system model

We present a variational assimilation system around a coarse resolution Earth System Model (ESM) and apply it for estimating initial conditions and parameters of the model. The system is based on derivative information that is efficiently provided by the ESM's adjoint, which has been generated through automatic differentiation of the model's source code. In our variational approach, the length of the feasible assimilation window is limited by the size of the domain in control space over which the approximation by the derivative is valid. This validity domain is reduced by non-smooth process representations. We show that in this respect the ocean component is less critical than the atmospheric component. We demonstrate how the feasible assimilation window can be extended to several weeks by modifying the implementation of specific process representations and by switching off processes such as precipitation

Production of Biodiesel from Soybean Oil Using Calcium Oxide and Cow Bone as Catalysts

Biodiesel was produced from the transesterification of soybean oil using calcium oxide and cow bone (an animal waste bone that contains hydroxyapatite, a calcium phosphate mineral) as heterogeneous catalysts. The soybean oil used was characterized using gas chromatography mass spectrometer (GCMS) and the cow bone catalyst produced was characterized using X-ray diffractometer (XRD) and X-ray fluorescence (XRF) spectrometer. The effects of the variation of methanol/oil mole ratio (9–15), catalyst concentration (10–20 wt/wt%) and reaction temperature (55–65 °C) on biodiesel yield during the transesterification of soybean oil with methanol was investigated. Reaction time of 3 hours and stirring rate of 500 rpm were kept constant. It was observed that the calcination of cow bone catalyst (at 800 °C) enhanced its conversion to apatite [Ca5(PO4)3OH] and increased the yield of biodiesel obtained. Biodiesel yield results revealed an optimum condition of methanol/oil mole ratio of 9, catalyst concentration of 15 wt/wt% and reaction temperature of 55 °C. Also, the results obtained showed that the performance trends of the two catalysts used were similar. And the close values of highest biodiesel yields obtained when the two heterogenous catalysts were used separately (yields of 94.8 and 92.2% using calcium oxide and calcined cow bone catalysts respectively) implies that the use of low-cost and readily available calcined cow bone catalyst is a promising alternative to CaO catalyst

Epidermal Growth Factor–PEG Functionalized PAMAM-Pentaethylenehexamine Dendron for Targeted Gene Delivery Produced by Click Chemistry

Aim of this study was the site-specific conjugation of an epidermal growth factor (EGF)-polyethylene glycol (PEG) chain by click chemistry onto a poly(amido amine) (PAMAM) dendron, as a key step toward defined multifunctional carriers for targeted gene delivery. For this purpose, at first propargyl amine cored PAMAM dendrons with ester ends were synthesized. The chain terminal ester groups were then modified by oligoamines with different secondary amino densities. The oligoamine-modified PAMAM dendrons were well biocompatible, as demonstrated in cytotoxicity assays. Among the different oligoamine-modified dendrons, PAMAM-pentaethylenehexamine (PEHA) dendron polyplexes displayed the best gene transfer ability. Conjugation of PAMAM-PEHA dendron with PEG spacer was conducted via click reaction, which was performed before amidation with PEHA. The resultant PEG-PAMAM-PEHA copolymer was then coupled with EGF ligand. pDNA transfections in HuH-7 hepatocellular carcinoma cells showed a 10-fold higher efficiency with the polyplexes containing conjugated EGF as compared to the ligand-free ones, demonstrating the concept of ligand targeting. Overall gene transfer efficiencies, however, were moderate, suggesting that additional measures for overcoming subsequent intracellular bottlenecks in delivery have to be taken

Limits on WWgamma and WWZ Couplings from W Boson Pair Production

The results of a search for W boson pair production in pbar-p collisions at sqrt{s}=1.8 TeV with subsequent decay to emu, ee, and mumu channels are presented. Five candidate events are observed with an expected background of 3.1+-0.4 events for an integrated luminosity of approximately 97 pb^{-1}. Limits on the anomalous couplings are obtained from a maximum likelihood fit of the E_T spectra of the leptons in the candidate events. Assuming identical WWgamma and WWZ couplings, the 95 % C.L. limits are -0.62<Delta_kappa<0.77 (lambda = 0) and -0.53<lambda<0.56 (Delta_kappa = 0) for a form factor scale Lambda = 1.5 TeV.Comment: 10 pages, 1 figure, submitted to Physical Review

Measurement of the W boson mass

We present a measurement of the W boson mass in W -> ev decays using 1 fb^-1 of data collected with the D0 detector during Run II of the Fermilab Tevatron collider. With a sample of 499830 W -> ev candidate events, we measure M_W = 80.401 +- 0.043 GeV. This is the most precise measurement from a single experiment.Comment: As published in PR