Optimization of the metabolic stability of a fluorinated cannabinoid receptor subtype 2 (CB2) ligand designed for PET studies

The central CB2 receptor represents a promising target for the treatment of neuroinflammatory diseases as CB2 activation mediates anti-inflammatory effects. Recently, the F-18 labeled PET radiotracer [F-18]7a was reported, which shows high CB2 affinity and high selectivity over the CB1 subtype but low metabolic stability due to hydrolysis of the amide group. Based on these findings twelve bioisosteres of 7a were synthesized containing a non-hydrolysable functional group instead of the amide group. The secondary amine 23a (K-i = 7.9 nM) and the ketone 26a (K-i = 8.6 nM) displayed high CB2 affinity and CB2:CB1 selectivity in in vitro radioligand binding studies. Incubation of 7a, 23a and 26a with mouse liver microsomes and LC-quadrupole-MS analysis revealed a slightly higher metabolic stability of secondary amine 23a, but a remarkably higher stability of ketone 26a in comparison to amide 7a. Furthermore, a logD(7.4) value of 5.56 +/- 0.08 was determined for ketone 26a by micro shake-flask method and LC-MS quantification. (C) 2018 Elsevier Masson SAS. All rights reserved.Medicinal Chemistr

Quality of spirometry and related diagnosis in primary care with a focus on clinical use

Contains fulltext : 220998.pdf (publisher's version ) (Open Access

Overcoming establishment thresholds for peat mosses in human-made bog pools

Globally, peatlands have been affected by drainage and peat extraction, with adverse effects on their functioning and services. To restore peat‐forming vegetation, drained bogs are being rewetted on a large scale. Although this practice results in higher groundwater levels, unfortunately it often creates deep lakes in parts where peat was extracted to greater depths than the surroundings. Revegetation of these deeper waters by peat mosses appears to be challenging due to strong abiotic feedbacks that keep these systems in an undesired bare state. In this study, we theoretically explore if a floating peat mat and an open human‐made bog lake can be considered two alternative stable states using a simple model, and experimentally test in the field whether stable states are present, and whether a state shift can be accomplished using floating biodegradable structures that mimic buoyant peat. We transplanted two peat moss species into these structures (pioneer sp. Sphagnum cuspidatum and later‐successional sp. S. palustre) with and without additional organic substrate. Our model suggests that these open human‐made bog lakes and floating peat mats can indeed be regarded as alternative stable states. Natural recovery by spontaneous peat moss growth, i.e., a state shift from open water to floating mats, is only possible when the water table is sufficiently shallow to avoid light limitation (<0.29 m at our site). Our experiment revealed that alternative stable states are present and that the floating structures facilitated the growth of pioneer S. cuspidatum and vascular plants. Organic substrate addition particularly facilitated vascular plant growth, which correlated to higher moss height. The structures remained too wet for the late‐successional species S. palustre. We conclude that open water and floating peat mats in human‐made bog lakes can be considered two alternative stable states, and that temporary floating establishment structures can induce a state shift from the open water state to peat‐forming vegetation state. These findings imply that for successful restoration, there is a clear water depth threshold to enable peat moss growth and there is no need for addition of large amounts of donor‐peat substrate. Correct species selection for restoration is crucial for success

Three-Nucleon Force Effects in Nucleon Induced Deuteron Breakup: Comparison to Data (II)

Selected Nd breakup data over a wide energy range are compared to solutions of Faddeev equations based on modern high precision NN interactions alone and adding current three-nucleon force models. Unfortunately currently available data probe phase space regions for the final three nucleon momenta which are rather insensitive to 3NF effects as predicted by current models. Overall there is good to fair agreement between present day theory and experiment but also some cases exist with striking discrepancies. Regions in the phase space are suggested where large 3NF effects can be expected.Comment: 33 pages, 24 ps figures, 9 gif figure

Establishment of a canine model of cardiac memory using endocardial pacing via internal jugular vein

<p>Abstract</p> <p>Background</p> <p>Development of experimental animal models has played an important role in understanding the mechanisms of cardiac memory. The purpose of this study was to evaluate a new canine model of cardiac memory using endocardial ventricular pacing via internal jugular vein.</p> <p>Methods</p> <p>Twelve Beagle dogs underwent placement of a permanent ventricular pacemaker mimicking the use of pacemakers in humans and induction of cardiac memory by endocardial ventricular pacing.</p> <p>Results</p> <p>Cardiac memory was achieved in 11 of 12 attempts overall. Procedural mortality due to cardiac tamponade (n = 1) occurred in the first attempt. The T-wave memory persisted for 96 ± 17 minutes and 31 ± 6 days in the short-term and long-term cardiac memory groups, respectively. There were no significant differences in the heart rate, blood pressure and echocardiographic parameters in the animals between before and after ventricular pacing in the short-term and long-term cardiac memory groups. No significant pathologic changes with the light microscopy were found in the present study in all dogs.</p> <p>Conclusion</p> <p>The model does require surgery but is not as invasive as an open-chest model. This canine model can serve as a useful tool for studying mechanisms of cardiac memory.</p

Herstel van biodiversiteit en landschapsecologische relaties in het natte zandlandschap. Herkomst van CO2 voor hoogveengroei en basenverzadiging in hoogveentjes. Eindrapport deel 3

Contains fulltext : 91880.pdf (publisher's version ) (Open Access)76 p

Blocking of impulse conduction in peripheral nerves by local cooling as a routine in animal experimentation

Small thermodes, cooled by the Peltier effect and heated by transistor dissipation, were developed for reversible nerve blocking. Temperature control is achieved by an electronic feedback circuit for two thermodes independently. This enables simple operation of the cooling system during animal experimentation. Any nerve temperature between 0 and 37° C can be obtained within 90 s and maintained within 0.2° C. The instrument can be used both as a stand alone apparatus or under computer control. Effects of local cooling of the cervical vagus nerve of the rabbit on the A-wave of the compound action potential and on spontaneous activity are given as examples of application of the cooling system in biological experiments