Characterization of a daptomycin-nonsusceptible vancomycin-intermediate Staphylococcus aureus strain in a patient with endocarditis

We analyzed the emergence of daptomycin nonsusceptibility in a patient with persistent vancomycin-intermediate Staphylococcus aureus (VISA) bacteremia. The daptomycin-nonsusceptible VISA's cell wall demonstrated a reduction in muramic acid O-acetylation, a phenotypic parameter not previously reported for VISA; some isolates also contained a single point mutation in the mprF gene.     

Incidence and characteristics of vancomycin nonsusceptible strains of methicillin-resistant Staphylococcus aureus at Hershey Medical Center

All 982 methicillin-resistant Staphylococcus aureus strains collected from August 2006 to December 2007 were tested for vancomycin susceptibility by using 3-μg/ml vancomycin brain heart infusion screening plates, a vancomycin Etest, and a vancomycin/teicoplanin macro Etest. Three vancomycin-intermediate Staphylococcus aureus (VISA) (0.3%) and two heterogeneous VISA (0.2%) isolates were identified. The screening method yielded 895 cases of ≤1 colony and 87 positive results (with growth of >1 colony after 48 h); further Etests showed 82/87 isolates with growth on screening plates to be false positive. Repeat testing showed a false-positivity rate of only 15 of the original 87 isolates by plate screening.     

Cross-linguistic adaptations of The Comprehensive Aphasia Test: Challenges and solutions

ABSTRACT

Comparative research on aphasia and aphasia rehabilitation is challenged by the lack of comparable assessment tools across different languages. In English, a large array of tools is available, while in most other languages, the selection is more limited. Importantly, assessment tools are often simple translations and do not take into consideration specific linguistic and psycholinguistic parameters of the target languages. As a first step in meeting the needs for comparable assessment tools, the Comprehensive Aphasia Test is currently being adapted into a number of languages spoken in Europe. In this article, some key challenges encountered in the adaptation process and the solutions to ensure that the resulting assessment tools are linguistically and culturally equivalent, are proposed. Specifically, we focus on challenges and solutions related to the use of imageability, frequency, word length, spelling-to-sound regularity and sentence length and complexity as underlying properties in the selection of the testing material.     

Discovery of substituted maleimides as liver X receptor agonists and determination of a ligand-bound crystal structure

Substituted 3-(phenylamino)-1H-pyrrole-2,5-diones were identified from a high throughput screen as inducers of human ATP binding cassette transporter A1 expression. Mechanism of action studies led to the identification of GSK3987 as an LXR ligand. GSK3987 recruits the steroid receptor coactivator-1 to human LXRalpha and LXRbeta with EC(50)s of 40 nM, profiles as an LXR agonist in functional assays, and activates LXR though a mechanism that is similar to first generation LXR agonists.     

Blockage of intermediate-conductance Ca2+-activated K+ channels inhibit human pancreatic cancer cell growth in vitro

Ion channels are important in controlling cell cycle progression and proliferation in a variety of cell types. Using the whole-cell recording mode of the patch-clamp technique, functional ion channels were electrophysiologically characterized in PANC-1 (K-ras G12D (+/-), p53 R273C, Deltap16), BxPC-3 (smad4-, p53 Y220C, Deltap16), and MiaPaCa-2 [transforming growth factor-beta receptor type II defect, K-ras G12C(-/-), p53 R248W, Deltap16] human pancreatic cancer cell lines. In BxPC-3 and the MiaPaCa-2 cells, we could identify approximately 600 or approximately 1200 functional Ca2+-activated K+ channels (IK) per cell, respectively, whereas PANC-1 cells expressed approximately 200 functional IK channels per cell. These channels were observed by using pipette solutions buffering [Ca2+]i to 1 microM. The channels were voltage-independent, blocked by charybdotoxin, clotrimazole, 1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34), and blocked by Ba2+ in a voltage-dependent manner. In the presence of 10 microM clotrimazole or TRAM-34, proliferation of the BxPC-3 as well as the MiaPaCa-2 cells was completely stopped. In contrast, proliferation of PANC-1 cells was hardly affected by clotrimazole or TRAM-34. Proliferation in all three cell lines could be inhibited in the presence of the Ca2+ channel antagonists verapamil, diltiazem, and nifedipine. By quantitative RT-PCR, we could show that MiaPaCa-2 cells exhibit a 2.8-fold and BxPC3 cells a more than 8-fold elevated level of IK mRNA level compared with PANC-1 cells. Interestingly, in primary pancreatic tumors we found a tremendous up-regulation of IK mRNA. In eight of nine (or 89%) primary pancreatic tumor tissues, we found a 6- to 66-fold increase in IK mRNA. Our findings suggest that a certain amount of functional IK channels is crucial for the proliferation of some pancreatic cancer types. The blockade of IK channels may ultimately prove useful as a therapeutic option for some patients with ductal adenocarcinoma of the pancreas with an up-regulated IK channel expression.     

Luminescence Properties of Nano Zinc Oxide Doped with Al(III) Ions Obtained in Microwave-Assisted Hydrothermal Synthesis

The hydrothermal method of obtaining nano zinc oxide doped with different contents of aluminum ions (III) was presented and discussed in this paper. Aqueous solution of Zn(NO₃)₂*6H₂O and Al(NO₃)₃*9H₂O salts mixture were used as the synthesis precursor. In order to reduce the process time all reactions were performed in a microwave reactor. The influence of process parameters and the content of impurity ions on the properties of synthesized nano zinc oxide were analyzed. In addition to zinc oxide doped with Al(III) ions, an additional spinel phase (ZnAl₂O₄) was obtained. The luminescent properties of nano zinc oxide as a function of the dopant ions were also discussed. Based on the luminescence measurements results, it was found that the luminescence intensity decreases with the increasing dopant content. The obtained materials are aimed to be implemented as luminescent materials in optoelectronic and sensors.     

Efficacy and Safety of Solifenacin Plus Tamsulosin OCAS in Men with Voiding and Storage Lower Urinary Tract Symptoms: Results from a Phase 2, Dose-finding Study (SATURN)

Background

Storage symptoms are often undertreated in men with lower urinary tract symptoms (LUTS).

Objective

To evaluate the combination of an antimuscarinic (solifenacin) with an α-blocker (tamsulosin) versus tamsulosin alone in the treatment of men with LUTS.

Design, setting, and participants

A double-blind, 12-wk, phase 2 study in 937 men with LUTS (≥3 mo, total International Prostate Symptom Score [IPSS] ≥13, and maximum urinary flow rate 4.0–15.0 ml/s).

Intervention

Eight treatment groups: tamsulosin oral controlled absorption system (OCAS) 0.4 mg; solifenacin 3, 6, or 9 mg; solifenacin 3, 6 or 9 mg plus tamsulosin OCAS 0.4 mg; or placebo.

Outcome measurements and statistical analysis

The primary efficacy end point was change from baseline in total IPSS. Secondary end points included micturition diary and quality-of-life (QoL) parameters. Post hoc subgroup analyses were performed by severity of baseline storage symptoms, with statistical comparisons presented only for tamsulosin OCAS alone versus combination therapy, due to the small sample size of the solifenacin monotherapy and placebo subgroups.

Results and limitations

Combination therapy was associated with significant improvements in micturition frequency and voided volume versus tamsulosin OCAS alone in the total study population; improvements in total IPSS were not significant. Statistically significant improvements in urgency episodes, micturition frequency, total urgency score, voided volume, IPSS storage subscore, IPSS-QoL index, and Patient Perception of Bladder Condition were observed in a subpopulation of men with two or more urgency episodes per 24 h (Patient Perception of Intensity of Urgency Scale grade 3 or 4) and eight or more micturitions per 24 h at baseline (storage symptoms subgroup) with combination therapy versus tamsulosin OCAS alone (p ≤ 0.05 for the dose–response slope, all variables). Combination therapy was well tolerated, and adverse events were consistent with the safety profiles of both compounds.

Conclusions

Solifenacin plus tamsulosin OCAS did not significantly improve IPSS in the total study population but offered significant efficacy and QoL benefits over tamsulosin OCAS monotherapy in men with both voiding and storage symptoms at baseline. Combination therapy was well tolerated.

ClinicalTrials.gov identifier

NCT00510406