Lipoprotein‐Associated Phospholipase A2 Activity Is a Marker of Risk But Not a Useful Target for Treatment in Patients With Stable Coronary Heart Disease

Background: We evaluated lipoprotein‐associated phospholipase A2 (Lp‐PLA2) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp‐PLA2 inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial. Methods and Results: Plasma Lp‐PLA2 activity was determined at baseline (n=14 500); at 1 month (n=13 709); serially (n=100) at 3, 6, and 18 months; and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp‐PLA2 activity levels and outcomes. At baseline, the median Lp‐PLA2 level was 172.4 μmol/min per liter (interquartile range 143.1–204.2 μmol/min per liter). Comparing the highest and lowest Lp‐PLA2 quartile groups, the hazard ratios were 1.50 (95% CI 1.23–1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29–2.93) for hospitalization for heart failure, 1.42 (1.07–1.89) for cardiovascular death, and 1.37 (1.03–1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a ≈65% persistent reduction in median Lp‐PLA2 activity. There were no associations between on‐treatment Lp‐PLA2 activity or changes of Lp‐PLA2 activity and outcomes, and there were no significant interactions between baseline and on‐treatment Lp‐PLA2 activity or changes in Lp‐PLA2 activity levels and the effects of darapladib on outcomes. Conclusions: Although high Lp‐PLA2 activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp‐PLA2 activity by ≈65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp‐PLA2 activity

Design and synthesis of steroid mimetic libraries using solid phase techniques

This thesis deals with the design and synthesis of biologically active ligands for nuclear hormone receptors using combinatorial techniques. In the first part, a 5,6,6a,7,8,9,10,10a-octahydrobenzo[f]quinolin-3(4H)-one tricyclic core structure was designed mimicking the ABC-rings of a steroid. The core structure was synthesized from 7,8-dihydroquinoline-2,5(1H,6H)-dione with the AB-rings already in place. Two different approaches towards the preparation of the C-ring were tested, i.e. using either a Robinson annulation or a Diels-Alder cyclization where only the latter accomplished the formation of the C-ring. The ligands prepared showed low affinity for the nuclear hormone receptors AR, ER, GR, MR, PR, however, and this core structure was therefore abandoned. The second part consists of a study of selective N-alkylation of 2-pyridones. A solid phase method was developed where 2-halopyridines were attached to a Wang-resin and subsequently treated with alkyl halides to alkylate and cleave the substrate in tandem, thus generating N-alkylated-pyridones. In the third part, a 6-phenylquinolin-2(1H)-one core structure is mimicking the ABD-rings of a steroid. The core structure was prepared from from 6-bromo2chloroquinoline and subsequently attached to a Wang-resin, whereupon the Dring was added to the 6-bromo moiety of the quinoline via a Suzuki-coupling. The phenolic position was alkylated, and the product was cleaved from the resin using the tandem alkylation cleavage method described earlier to generate N-alkylated 6-phenyl-quinolones. This library showed moderate to high affinity towards nuclear hormone receptors. In the final section, a new core structure was designed, fusing a pyrazole-ring onto the Aring on an AB-steroid ring system to generate a benzoindazole scaffold. Buchwald's palladium catalyzed alpha-arylation method was initially employed to derivatize the scaffold at the 6-position, but the reaction failed when transferred to solid phase. The 6phenyl-benzoindazole core structure was then redesigned to a benzoindazole-5hydrazone scaffold, introducing diversity at the hydrazone moiety. Best results were obtained using a solid phase approach, and the scope and limitations in terms of the substituents was thus investigated

Development of a Semicontinuous Spray Process for the Production of Superhydrophobic Coatings from Supercritical Carbon Dioxide Solutions

Superhydrophobic surfaces have been fabricated in a continuous spray process, where an alkyl ketene dimer (AKD) wax is dissolved in supercritical carbon dioxide (scCO(2)) and sprayed onto the substrate. The mass of extracted AKD from scCO2 has been investigated as well as the pressure, temperature, and flow of CO2 at the steady-state spray conditions. Several different substrates such as glass, aluminum, paper, poly(ethylene terephthalate) (PET), and polytetrafluoroethylene (PTFE) have been successfully coated, and the superhydrophobic properties have been evaluated by measurement of water contact angle, water drop friction, scanning electron microscopy (SEM), and surface topography. The most efficient spray process, considering surface properties and mass of extracted AKD, is obtained at the lowest temperature investigated, 67 degrees C, and the highest pressure evaluated in this study, 25 MPa. We also show that the influence of preexpansion conditions (p, T) on the surface temperature at the selected spray distance (3 cm) is negligible by measurement with an infrared camera during spraying

Xyloglucan-Functional Latex Particles via RAFT-Mediated Emulsion Polymerization for the Biomimetic Modification of Cellulose

Herein, we report a novel class of latex particles composed of a hemicellulose, xyloglucan (XG), and poly­(methyl methacrylate) (PMMA), specially designed to enable a biomimetic modification of cellulose. The formation of the latex particles was achieved utilizing reversible addition–fragmentation chain transfer (RAFT) mediated surfactant-free emulsion polymerization employing XG as a hydrophilic macromolecular RAFT agent (macroRAFT). In an initial step, XG was functionalized at the reducing chain end to bear a dithioester. This XG macroRAFT was subsequently utilized in water and chain extended with methyl methacrylate (MMA) as hydrophobic monomer, inspired by a polymerization-induced self-assembly (PISA) process. This yielded latex nanoparticles with a hydrophobic PMMA core stabilized by the hydrophilic XG chains at the corona. The molar mass of PMMA targeted was varied, resulting in a series of stable latex particles with hydrophobic PMMA content between 22 and 68 wt % of the total solids content (5–10%). The XG-PMMA nanoparticles were subsequently adsorbed to a neutral cellulose substrate (filter paper), and the modified surfaces were analyzed by FT-IR and SEM analyses. The adsorption of the latex particles was also investigated by quartz crystal microbalance with dissipation monitoring (QCM-D), where the nanoparticles were adsorbed to negatively charged model cellulose surfaces. The surfaces were analyzed by atomic force microscopy (AFM) and contact angle (CA) measurements. QCM-D experiments showed that more mass was adsorbed to the surfaces with increasing molar mass of the PMMA present. AFM of the surfaces after adsorption showed discrete particles, which were no longer present after annealing (160 °C, 1 h) and the roughness (<i>R</i>_q) of the surfaces had also decreased by at least half. Interestingly, after annealing, the surfaces did not all become more hydrophobic, as monitored by CA measurements, indicating that the surface roughness was an important factor to consider when evaluating the surface properties following particle adsorption. This novel class of latex nanoparticles provides an excellent platform for cellulose modification via physical adsorption. The utilization of XG as the anchoring molecule to cellulose provides a versatile methodology, as it does not rely on electrostatic interactions for the physical adsorption, enabling a wide range of cellulose substrates to be modified, including neutral sources such as cotton and bacterial nanocellulose, leading to new and advanced materials

Two-year outcomes in patients admitted with non-ST elevation acute coronary syndrome:results of the OASIS registry 1 and 2

Acute coronary syndrome continues to have significant long-term morbidity and mortality. This study sought to compare baseline characteristics, practice patterns and clinical outcomes for patients with non-ST elevation acute coronary syndrome from a broad range of low-, middle- and high-income countries

Building Custom Polysaccharides in Vitro with an Efficient, Broad-Specificity Xyloglucan Glycosynthase and a Fucosyltransferase

The current drive for applications of biomass-derived compounds, for energy and advanced materials, has led to a resurgence of interest in the manipulation of plant polymers. The xyloglucans, a family of structurally complex plant polysaccharides, have attracted significant interest due to their intrinsic high affinity for cellulose, both in muro and in technical applications. Moreover, current cell wall models are limited by the lack of detailed structure–property relationships of xyloglucans, due to a lack of molecules with well-defined branching patterns. Here, we have developed a new, broad-specificity “xyloglucan glycosynthase”, selected from active-site mutants of a bacterial endoxyloglucanase, which catalyzed the synthesis of high molar mass polysaccharides, with complex side-chain structures, from suitable glycosyl fluoride donor substrates. The product range was further extended by combination with an Arabidopsis thaliana α(1→2)-fucosyltransferase to achieve the in vitro synthesis of fucosylated xyloglucans typical of dicot primary cell walls. These enzymes thus comprise a toolkit for the controlled enzymatic synthesis of xyloglucans that are otherwise impossible to obtain from native sources. Moreover, this study demonstrates the validity of a chemo-enzymatic approach to polysaccharide synthesis, in which the simplicity and economy of glycosynthase technology is harnessed together with the exquisite specificity of glycosyltransferases to control molecular complexity