Synthesis and Redox and Photophysical Properties of Benzodifuran-Spiropyran Ensembles

Two benzodifuran (BDF)-coupled spiropyran (SP) systems and their BDF reference compounds were obtained in good yields through HuisgenMeldalSharpless click chemistry and then subjected to investigation of their electrochemical and photophysical properties. In both SP and merocyanine (MC) forms of the coupled molecules, the BDF-based emission is quenched to around 1 of the quantum yield of emission from the BDF reference compounds. Based on electrochemical data, this quenching is attributed to oxidative electron-transfer quenching. Irradiation at 366nm results in ring opening to the MC forms of the BDF-coupled SP compounds and the SP reference compound with a quantum efficiency of about 50. The rate constants for the thermal ring closing are approximately 3.4x103s1. However, in the photostationary states the MC fractions of the coupled molecules are substantially lower than that of the reference SP compound, attributed to the observed acceleration of the ring-closing reaction upon irradiation. As irradiation at 366nm invariably also excites higher-energy transitions of the BDF units in the coupled compounds, the ring-opening reaction is accelerated relative to the SP reference, which results in lower MC fractions in the photostationary state. Reversible photochromism of these BDF-coupled SP compounds renders them promising in the field of molecular switches.

Intra- and interlaboratory reliability of a cryopreserved trout hepatocyte assay for the prediction of chemical bioaccumulation potential

Measured rates of intrinsic clearance determined using cryopreserved trout hepatocytes can be extrapolated to the whole animal as a means of improving modeled bioaccumulation predictions for fish. To date, however, the intra- and interlaboratory reliability of this procedure has not been determined. In the present study, three laboratories determined in vitro intrinsic clearance of six reference compounds (benzo[a]pyrene, 4-nonylphenol, di-tert-butyl phenol, fenthion, methoxychlor and o-terphenyl) by conducting substrate depletion experiments with cryopreserved trout hepatocytes from a single source. O-terphenyl was excluded from the final analysis due to nonfirst-order depletion kinetics and significant loss from denatured controls. For the other five compounds, intralaboratory variability (% CV) in measured in vitro intrinsic clearance values ranged from 4.1 to 30%, while interlaboratory variability ranged from 27 to 61%. Predicted bioconcentration factors based on in vitro clearance values exhibited a reduced level of interlaboratory variability (5.3-38% CV). The results of this study demonstrate that cryopreserved trout hepatocytes can be used to reliably obtain in vitro intrinsic clearance of xenobiotics, which provides support for the application of this in vitro method in a weight-of-evidence approach to chemical bioaccumulation assessment.

Similarity Mapplet: Interactive Visualization of the Directory of Useful Decoys and ChEMBL in High Dimensional Chemical Spaces

An Internet portal accessible at www.gdb.unibe.ch has been set up to automatically generate color-coded similarity maps of the ChEMBL database in relation to up to two sets of active compounds taken from the enhanced Directory of Useful Decoys (eDUD), a random set of molecules, or up to two sets of user-defined reference molecules. These maps visualize the relationships between the selected compounds and ChEMBL in six different high dimensional chemical spaces, namely MQN (42-D molecular quantum numbers), SMIfp (34-D SMILES fingerprint), APfp (20-D shape fingerprint), Xfp (55-D pharmacophore fingerprint), Sfp (1024-bit substructure fingerprint), and ECfp4 (1024-bit extended connectivity fingerprint). The maps are supplied in form of Java based desktop applications called “similarity mapplets” allowing interactive content browsing and linked to a “Multifingerprint Browser for ChEMBL” (also accessible directly at www.gdb.unibe.ch) to perform nearest neighbor searches. One can obtain six similarity mapplets of ChEMBL relative to random reference compounds, 606 similarity mapplets relative to single eDUD active sets, 30 300 similarity mapplets relative to pairs of eDUD active sets, and any number of similarity mapplets relative to user-defined reference sets to help visualize the structural diversity of compound series in drug optimization projects and their relationship to other known bioactive compounds.

Performance of different polishing techniques for direct CAD/CAM ceramic restorations

This in vitro study evaluated the performance of three ceramic and two commonly used polishing methods on two CAD/CAM ceramics. Surface roughness and quality were compared. A glazed group (GLGR) of each ceramic material served as reference. One-hundred and twenty specimens of VITABLOCS Mark II (VITA) and 120 specimens of IPS Empress CAD (IPS) were roughened in a standardized manner. Twenty VITA and 20 IPS specimens were glazed (VITA Akzent Glaze/Empress Universal Glaze). Five polishing methods were investigated (n=20/group): 1) EVE Diacera W11DC-Set (EVE), 2) JOTA 9812-Set (JOTA), 3) OptraFine-System (OFI), 4) Sof-Lex 2382 discs (SOF) and 5) Brownie/Greenie/Occlubrush (BGO). Polishing quality was measured with a surface roughness meter (Ra and Rz values). The significance level was set at alpha=0.05. Kruskal Wallis tests and pairwise Wilcoxon rank sum tests with Bonferroni-Holm adjustment were used. Qualitative surface evaluation of representative specimens was done with SEM. On VITA ceramics, SOF produced lower Ra (p<0.00001) but higher Rz values than GLGR (p=0.003); EVE, JOTA, OFI and BGO yielded significantly higher Ra and Rz values than GLGR. On IPS ceramics, SOF and JOTA exhibited lower Ra values than GLGR (p<0.0001). Equivalent Ra but significantly higher Rz values occurred between GLGR and EVE, OFI or BGO. VITA and IPS exhibited the smoothest surfaces when polished with SOF. Nevertheless, ceramic polishing systems are still of interest to clinicians using CAD/CAM, as these methods are universally applicable and showed an increased durability compared to the investigated silicon polishers.

Diagnostic performance and accuracy of 3-D spoiled gradient-dual-echo MRI with water- and fat-signal separation in liver-fat quantification: comparison to liver biopsy

To prospectively evaluate a 3-dimensional spoiled gradient-dual-echo (3D SPGR-DE) magnetic resonance imaging (MRI) sequence for the qualitative and quantitative analysis of liver fat content (LFC) in patients with the suspicion of fatty liver disease using histopathology as the standard of reference.

Simultaneous determination of 3-hydroxyanthranilic and cinnabarinic acid by high-performance liquid chromatography with photometric or electrochemical detection

A convenient and rapid method for the simultaneous determination by HPLC of 3-hydroxyanthranilic acid and the dimer derived by its oxidation, cinnabarinic acid, is described. Buffers or biological samples containing these two Trp metabolites were acidified to pH 2.0 and extracted with ethyl acetate with recoveries of 96.5 +/- 0.5 and 93.4 +/- 3.7% for 3-hydroxyanthranilic and cinnabarinic acid, respectively. The two compounds were separated on a reversed-phase (C18) column combined with ion-pair chromatography and detected photometrically or electrochemically. The method was applied successfully to biological systems in which formation of either 3-hydroxyanthranilic or cinnabarinic acid had been described previously. Thus, interferon-gamma-treated human peripheral blood mononuclear cells formed and released significant amounts of 3-hydroxyanthranilic acid into the culture medium and mouse liver nuclear fraction possessed high "cinnabarinic acid synthase" activity. In contrast, addition of 3-hydroxyanthranilic acid to human erythrocytes resulted in only marginal formation of cinnabarinic acid. We conclude that the method described is specific, sensitive, and suitable for the detection of the two Trp metabolites in biological systems.

Clinical performance of a new laser fluorescence device for detection of occlusal caries lesions in permanent molars

OBJECTIVES: To determine the clinical performance of a laser fluorescence device (DIAGNOdent pen, KaVo) to discriminate between different occlusal caries depths (D(0)-D(1-4); D(0-2)-D(3,4)) in permanent molars. METHODS: In this prospective, randomized two-centre-study 120 sound/uncavitated carious sites in 120 patients were measured after visual and radiographic caries assessment. In cases of operative intervention (n=86), the lesion depths after caries removal were recorded (reference). In cases of preventive intervention (n=34), the sites were reassessed visually/radiographically after 12 months to verify the status assessed before (reference). The discrimination performance was determined statistically (Mann-Whitney test, Spearman's rho coefficient, and areas under the receiver operating characteristic curves (AUCs)). Sensitivities (SE) and specificities (SP) were plotted as a function of the measured values and cut-off values for the mentioned thresholds suggested. RESULTS: Sound sites (n=13) had significantly minor fluorescence values than carious sites (n=107) (P<0.0001) as had sites with no/enamel caries (n=63) compared to dentinal caries (n=57). The AUCs for the same discriminations were 0.92 and 0.78 (P<0.001). For the D(0)-D(1-4) threshold, a cut-off at a value of 12 (SE: 0.88, SP: 0.85) and for the D(0-2)-D(3,4) threshold at 25 (SE: 0.67, SP: 0.79) can be suggested. A moderate positive correlation between the measurements and the caries depths was calculated (rho=+0.57, P=0.01). CONCLUSION: Within this study, the device's discrimination performance for different caries depths was moderate to very good and it may be recommended as adjunct tool in the diagnosis of occlusal caries.

Call for a reference model of chronic hind limb ischemia to investigate therapeutic angiogenesis

A large number of studies utilize animal models to investigate therapeutic angiogenesis. However, the lack of a standardized experimental model leaves the comparison of different studies problematic. To establish a reference model of prolonged moderate tissue ischemia, we created unilateral hind limb ischemia in athymic rnu-rats by surgical excision of the femoral vessels. Blood flow of the limb was monitored for 60 days by laser Doppler imaging. Following a short postoperative period of substantially depressed perfusion, the animals showed a status of moderate hind limb ischemia from day 14 onwards. Thereafter, the perfusion remained at a constant level (55.5% of normal value) until the end of the observation period. Histopathological assessment of the ischemic musculature on postoperative days 28 and 60 showed essentially no inflammatory cell infiltrate or fibrosis. However, the mitochondrial activity and capillary-to-fiber ratio of the muscular tissue was reduced to 52.7% of normal, presenting with a significant weakness of the ischemic limb evidenced by a progressive decline in performance. Intramuscular injection of culture-expanded human endothelial progenitor cells (EPC) resulted in a significant increase in blood flow (82.0+/-3.5% of normal), capillary density (1.60+/-0.08/muscle fiber) and smooth muscle covered arterioles (8.0+/-0.6/high power field) in the ischemic hind limb as compared to controls (55.0+/-3.1%; 0.99+/-0.03; 5.0+/-0.2). In conclusion, chronic, moderate hind limb ischemia with consistently reduced perfusion levels persisting over a prolonged period can be established reliably in rnu athymic nude rats and is responsive to pro-angiogenic treatments such as EPC transplantation. This study provides a detailed protocol of a highly reproducible reference model to test novel therapeutic options for limb ischemia.

A robust reference signal generator for synchronized ventricular assist devices

Ventricular assist devices (VADs) are blood pumps that offer an option to support the circulation of patients with severe heart failure. Since a failing heart has a remaining pump function, its interaction with the VAD influences the hemodynamics. Ideally, the heart's action is taken into account for actuating the device such that the device is synchronized to the natural cardiac cycle. To realize this in practice, a reliable real-time algorithm for the automatic synchronization of the VAD to the heart rate is required. This paper defines the tasks such an algorithm needs to fulfill: the automatic detection of irregular heart beats and the feedback control of the phase shift between the systolic phases of the heart and the assist device. We demonstrate a possible solution to these problems and analyze its performance in two steps. First, the algorithm is tested using the MIT-BIH arrhythmia database. Second, the algorithm is implemented in a controller for a pulsatile and a continuous-flow VAD. These devices are connected to a hybrid mock circulation where three test scenarios are evaluated. The proposed algorithm ensures a reliable synchronization of the VAD to the heart cycle, while being insensitive to irregularities in the heart rate.

First intercomparison study on the analysis of oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs) and nitrogen heterocyclic polycyclic aromatic compounds (N-PACs) in contaminated soil

Oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs) and nitrogen heterocyclic polycyclic aromatic compounds (N-PACs) are toxic, highly leachable and often abundant at sites that are also contaminated with PAHs. However, due to lack of regulations and standardized methods for their analysis, they are seldom included in monitoring and risk-assessment programs. This intercomparison study constitutes an important step in the harmonization of the analytical methods currently used, and may also be considered a first step towards the certification of reference materials for these compounds. The results showed that the participants were able to determine oxy-PAHs with accuracy similar to PAHs, with average determined mass fractions agreeing well with the known levels in a spiked soil and acceptable inter- and intra-laboratory precisions for all soils analyzed. For the N-PACs, the results were less satisfactory, and have to be improved by using analytical methods more specifically optimized for these compounds.

Performance of the resolute zotarolimus-eluting stent in small vessels.

BACKGROUND Drug eluting stents for the treatment of small vessel coronary artery disease have traditionally yielded inferior clinical outcomes compared to the use of DES in large vessels. The benefit of the second-generation Resolute zotarolimus-eluting stent (R-ZES) in small vessels was examined. METHODS Two-year clinical outcomes from five combined R-ZES studies were compared between patients with small (reference vessel diameter [RVD] ≤2.5 mm; n = 1,956) and large (RVD >2.5 mm; n = 3174) vessels. RESULTS Despite a higher incidence of comorbidities in the small vessel group, there was no significant difference in target lesion failure (TLF) (10.1% vs. 8.7%; P = 0.54) at 2 years. When the subgroup of patients with diabetes was examined (n = 1,553) there was no significant difference in 2-year TLF in small compared to large vessels (11.2% vs. 11.1%; P = 0.17). Similarly, within the small vessel cohort, no significant difference was seen regarding TLF at 2 years between people with and without diabetes (11.2% vs 9.6%; P = 0.28). CONCLUSION When used for the treatment of small vessels, the R-ZES appears to provide acceptable clinical results at 2 years when compared to its performance in large vessels.

Neural patterns underlying social comparisons of personal performance

Humans often evaluate their abilities by comparing their personal performance with that of others. For this process, it is critical whether the comparison turns out in one's favor or against it. Here, we investigate how social comparisons of performance are encoded and integrated on the neural level. We collected functional magnetic resonance images while subjects answered questions in a knowledge quiz that was related to their profession. After each question, subjects received a feedback about their personal performance, followed by a feedback about the performance of a reference group who had been quizzed beforehand. Based on the subjects' personal performance, we divided trials in downward and upward comparisons. We found that upward comparisons correlated with activity in the dorsolateral prefrontal cortex and the anterior insula. Downward comparisons were associated with increased activation in the ventral striatum (VS), the medial orbitofrontal cortex and the ventral anterior cingulate cortex (ACC). The extent to which subjects outperformed the reference group modulated the activity in the VS and in the dorsal ACC. We suggest that the co-activation of the VS and the dorsal ACC contributes to the integration of downward comparisons into the evaluation of personal performance.