Observational constraints on the chemistry of isoprene nitrates over the eastern United States

The formation of organic nitrates during the oxidation of the biogenic hydrocarbon isoprene can strongly affect boundary layer concentrations of ozone and nitrogen oxides (NOx = NO + NO2). We constrain uncertainties in the chemistry of these isoprene nitrates using chemical transport model simulations in conjunction with observations over the eastern United States from the International Consortium for Atmospheric Research on Transport and Transformation (ICARTT) field campaign during summer 2004. The model best captures the observed boundary layer concentrations of organic nitrates and their correlation with ozone using a 4% yield of isoprene nitrate production from the reaction of isoprene hydroxyperoxy radicals with NO, a recycling of 40% NOx when isoprene nitrates react with OH and ozone, and a fast dry deposition rate of isoprene nitrates. Simulated boundary layer concentrations are only weakly sensitive to the rate of photochemical loss of the isoprene nitrates. An 8% yield of isoprene nitrates degrades agreement with the observations somewhat, but concentrations are still within 50% of observations and thus cannot be ruled out by this study. Our results indicate that complete recycling of NOx from the reactions of isoprene nitrates and slow rates of isoprene nitrate deposition are incompatible with the observations. We find that ∼50% of the isoprene nitrate production in the model occurs via reactions of isoprene (or its oxidation products) with the NO3 radical, but note that the isoprene nitrate yield from this pathway is highly uncertain. Using recent estimates of rapid reaction rates with ozone, 20–24% of isoprene nitrates are lost via this pathway, implying that ozonolysis is an important loss process for isoprene nitrates. Isoprene nitrates are shown to have a major impact on the nitrogen oxide (NOx = NO + NO2) budget in the summertime U.S. continental boundary layer, consuming 15–19% of the emitted NOx, of which 4–6% is recycled back to NOx and the remainder is exported as isoprene nitrates (2–3%) or deposited (8–10%). Our constraints on reaction rates, branching ratios, and deposition rates need to be confirmed through further laboratory and field measurements. The model systematically underestimates free tropospheric concentrations of organic nitrates, indicating a need for future investigation of the processes controlling the observed distribution

Cholinergic modulation of disorder-relevant human defensive behaviour in generalised anxiety disorder

Drugs that are clinically effective against anxiety disorders modulate the innate defensive behaviour of rodents, suggesting these illnesses reflect altered functioning in brain systems that process threat. This hypothesis is supported in humans by the discovery that the intensity of threat-avoidance behaviour is altered by the benzodiazepine anxiolytic lorazepam. However, these studies used healthy human participants, raising questions as to their validity in anxiety disorder patients, as well as their generalisability beyond GABAergic benzodiazepine drugs. BNC210 is a novel negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor and we recently used functional Magnetic Resonance Imaging to show it reduced amygdala responses to fearful faces in generalised anxiety disorder patients. Here we report the effect of BNC210 on the intensity of threat-avoidance behaviour in 21 female GAD patients from the same cohort. We used the Joystick Operated Runway Task as our behavioural measure, which is a computerised human translation of the Mouse Defense Test Battery, and the Spielberger state anxiety inventory as our measure of state affect. Using a repeated-measures, within-subjects design we assessed the effect of BNC210 at two dose levels versus placebo (300 mg and 2000 mg) upon two types of threat-avoidance behaviour (Flight Intensity and Risk Assessment Intensity). We also tested the effects of 1.5 mg of the benzodiazepine lorazepam as an active control. BNC210 significantly reduced Flight Intensity relative to placebo and the low dose of BNC210 also significantly reduced self-reported state anxiety. Risk Assessment Intensity was not significantly affected. Results show both human defensive behaviour and state anxiety are influenced by cholinergic neurotransmission and there provide converging evidence that this system has potential as a novel target for anxiolytic pharmacotherapy

Preclinical Strategies to Identify Off-Target Toxicity of High-Affinity TCRs

Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Development of a sustained-release voriconazole-containing thermogel for subconjunctival injection in horses

PURPOSE. To determine in vitro release profiles, transcorneal permeation, and ocular injection characteristics of a voriconazole-containing thermogel suitable for injection into the subconjunctival space (SCS). METHODS. In vitro release rate of voriconazole (0.3% and 1.5%) from poly (DL-lactide-coglycolide-b-ethylene glycol-b-DL-lactide-co-glycolide) (PLGA-PEG-PLGA) thermogel was determined for 28 days. A Franz cell diffusion chamber was used to evaluate equine transcorneal and transscleral permeation of voriconazole (1.5% topical solution, 0.3% and 1.5% voriconazole-thermogel) for 24 hours. Antifungal activity of voriconazole released from the 1.5% voriconazole-thermogel was determined via the agar disk diffusion method. Ex vivo equine eyes were injected with liquid voriconazole-thermogel (4°C). Distension of the SCS was assessed ultrasonographically and macroscopically. SCS voriconazole-thermogel injections were performed in a horse 1 week and 2 hours before euthanasia and histopathologic analysis of ocular tissues performed. RESULTS. Voriconazole was released from the PLGA-PEG-PLGA thermogel for more than 21 days in all groups. Release followed first-order kinetics. Voriconazole diffused through the cornea and sclera in all groups. Permeation was greater through the sclerae than corneas. Voriconazole released from the 1.5% voriconazole-thermogel showed antifungal activity in vitro. Voriconazole-thermogel was easily able to be injected into the dorsal SCS where it formed a discrete gel deposit. Voriconazole-thermogel was easily injected in vivo and did not induce any adverse reactions. CONCLUSIONS. Voriconazole-containing thermogels have potential application in treatment of keratomycosis. Further research is required to evaluate their performance in vivo

Does the perception of fairness and standard of care in the health system depend on the field of study? Results of an empirical analysis

Background: The main challenge in the context of health care reforms and priority setting is the establishment and/or maintenance of fairness and standard of care. For the political process and interdisciplinary discussion, the subjective perception of the health care system might even be as important as potential objective criteria. Of special interest are the perceptions of academic disciplines, whose representatives act as decision makers in the health care sector. The aim of this study is to explore and compare the subjective perception of fairness and standard of care in the German health care system among students of medicine, law, economics, philosophy, and religion. Methods: Between October 2011 and January 2012, we asked freshmen and advanced students of the fields mentioned above to participate in a paper and pencil survey. Prior to this, we formulated hypotheses. The data were analysed by micro econometric regression techniques. Results: Data from 1,088 students were included in the study. Medical students, freshmen, and advanced students perceive the standard of care significantly as being better than non-medical students. Differences in the perception of fairness are not significant between the freshmen of the academic disciplines; however, they increase with the number of study terms. Besides the field of study, further variables such as gender and health status have a significant impact on perceptions. Conclusions: Our results show that there are differences in the perception of fairness and standard of care between academic disciplines, which might influence the interdisciplinary discussion on health care reforms and priority setting.Leibniz University Hannover/Wege in die Forschung I

Direct Measurements of the Convective Recycling of the Upper Troposphere

We present a statistical representation of the aggregate effects of deep convection on the chemistry and dynamics of the Upper Troposphere (UT) based on direct aircraft observations of the chemical composition of the UT over the Eastern United States and Canada during summer. These measurements provide new and unique observational constraints on the chemistry occurring downwind of convection and the rate at which air in the UT is recycled, previously only the province of model analyses. These results provide quantitative measures that can be used to evaluate global climate and chemistry models