A within farm clinical trial to compare two treatments (parenteral antibacterials and hoof trimming) for sheep lame with footrot

From observational studies, farmers who use parenteral antibacterials to promptly treat all sheep with footrot (FR) or interdigital dermatitis (ID) have a prevalence of lameness of <2% compared with a prevalence of 9% lameness reported by farmers who treat lame sheep by trimming affected feet. We tested the hypothesis that prompt treatment of sheep lame with naturally developing FR or ID with parenteral and topical antibacterials reduces the prevalence and incidence of lameness with these conditions compared with less frequent treatment with trimming of hoof horn and applying topical antibacterials. A further hypothesis was that reduction of ID and FR would improve productivity. A lowland sheep flock with 700 ewes was used to test these hypotheses in an 18-month within farm clinical trial with four groups of ewes: two intervention and two control. The duration and severity of lameness was used to categorise sheep into three weighted scores of lameness (WLS): never lame (WLS0), mildly lame/lame for <6 days (WLS1) and severely or chronically lame (WLS2). The intervention reduced the prevalence of lameness due to FR and ID in ewes and lambs and the incidence of lameness in ewes. The WLS was also significantly lower in sheep in the intervention groups. Ewes with a higher WLS were subsequently significantly more likely to have a body condition score <2.5 and to have lame lambs. Significantly more ewes lambed and successfully reared more lambs that were ready for slaughter at a younger age in the intervention versus control groups. There was an increase in the gross margin of £630/100 ewes mated in the intervention group, including the cost of treatment of £150/100 ewes mated. We conclude that prompt parenteral and topical antibacterial treatment of sheep lame with ID and FR reduced the prevalence and incidence of these infectious conditions and led to improved health, welfare and productivity

Pharmacological Validation of Trypanosoma brucei Phosphodiesterases as Novel Drug Targets

The development of drugs for neglected infectious diseases often uses parasite-specific enzymes as targets. We here demonstrate that parasite enzymes with highly conserved human homologs may represent a promising reservoir of new potential drug targets. The cyclic nucleotide-specific phosphodiesterases (PDEs) of Trypanosoma brucei, causative agent of the fatal human sleeping sickness, are essential for the parasite. The highly conserved human homologs are well-established drug targets. We here describe what is to our knowledge the first pharmacological validation of trypanosomal PDEs as drug targets. High-throughput screening of a proprietary compound library identified a number of potent hits. One compound, the tetrahydrophthalazinone compound A (Cpd A), was further characterized. It causes a dramatic increase of intracellular cyclic adenosine monophosphate (cAMP). Short-term cell viability is not affected, but cell proliferation is inhibited immediately, and cell death occurs within 3 days. Cpd A prevents cytokinesis, resulting in multinucleated, multiflagellated cells that eventually lyse. These observations pharmacologically validate the highly conserved trypanosomal PDEs as potential drug targets

The role of snow-surface coupling, radiation, and turbulent mixing in modeling a stable boundary layer over Arctic sea ice

To enhance the understanding of the impact of small-scale processes in the polar climate, this study focuses on the relative role of snow-surface coupling, radiation and turbulent mixing in an Arctic stable boundary layer. We extend the GABLS1 (GEWEX Atmospheric Boundary-Layer Study 1) model intercomparison for turbulent mixing with the other relevant physical processes in the stable boundary layer over sea ice. We use the Single Column Model (SCM) version of the Weather Research and Forecasting (WRF) mesoscale meteorological model and run different combinations of boundary layer and radiation schemes, using a state-of-the art land surface scheme. With this intercomparison of schemes, we confirm a wide variety in the state of the atmosphere and the surface variables for the selected parameterization schemes. To understand this variety, a sensitivity analysis for one particular combination of parameterization schemes is performed, using a novel analysis method of process diagrams. The variation between the sensitivity runs indicates a relative orientation of model sensitivities to variations in each of the overning processes and these can explain the variety of model results obtained in the intercomparison of different parameterization schemes. Moreover, we apply the same method for several geostrophic wind speeds to represent a large range of synoptic conditions. Results indicate a shift in process significance for different wind regimes. For low wind regimes, the model sensitivity is larger for surface coupling and radiation, while for high wind speeds, the largest sensitivity is found for the turbulent mixing process. An interesting non-linear feature was found for turbulent mixing for frequently occurring wind speeds and low wind speed cases, where the 2m temperature increases for decreased amounts of mixing

Unraveling the Role of Turbulent Mixing, Surface Coupling and Radiation in a Polar Stable Boundary Layer

Observations indicate that the Arctic regions are very sensitive to climate change and warm more rapidly than the global average in the last few decades, a feature known as ‘Arctic Amplification'. Global climate models reproduce a similar signal for the Arctic warming, though their magnitude varies substantially both in temporal and spatial patterns. Especially in wintertime, large biases are found, indicating the need for a better understanding of the stable boundary layer (SBL) coupled to the surface. The uncertainty may partly be caused by differences in model formulations for the most relevant snow/ice physics, atmospheric mixing and radiation used in the various models. This multiplicity of processes forces us to investigate which process has the relatively largest impact in determining the model behavior. This study focusses on the role of turbulent mixing, surface coupling and radiation in a polar boundary layer. The goal is to gain insight in the relative role of these small scale processes and how these processes can compensate each other. As such, we extend the GABLS1 model intercomparison for turbulent mixing (Cuxart et al., 2006) with the other relevant physical processes in the SBL over ice. We use the Single Column Model (SCM) version of the Weather Research and Forecasting (WRF) mesoscale meteorological model and run different combinations of boundary-layer and radiation schemes (using one state of the art surface scheme). As such, an intercomparison of schemes within a single model is obtained. We confirm a wide variety in the state of the atmosphere and the surface variables for the selected parameterization schemes. Subsequently, a sensitivity analysis for one particular combination of parameterization schemes is performed for the governing processes of turbulent mixing, surface coupling and radiation. Using a novel analysis method based on time-integrated SBL development, the variation between the sensitivity runs indicates the relative orientation of model sensitivities to variations in governing processes. Furthermore, this sensitivity can explain the variety of model results obtained in the intercomparison of different parameterization schemes. We apply the same method for several geostrophic wind speeds to represent a large range of synoptic conditions. Our preliminary results indicate a shift in process significance for different wind regimes. For low wind regimes, the model sensitivity is larger for coupling and radiation, while for high wind speeds, not surprisingly, the largest sensitivity is found for the turbulent mixing process. Additionally, for typical wind speeds we find that for the 2m temperature and net radiation budget, the orientations of the turbulent mixing and surface coupling overlap. This implies that compensating errors in the boundary-layer scheme and land-surface model can remain hidden and this may explain the relatively slow progress in model development

Synthesis and pharmacology of a series of new organic nitrate esters.

New organic nitrate esters, derived from structurally different (cyclo)aliphatic templates, were synthesized and pharmacologically investigated. Their in vitro vascular smooth muscle relaxing activities and, occasionally, in vivo haemodynamic profiles were studied and compared to those of the clinically important nitrates, glyceryl trinitrate, isosorbide dinitrate and isosorbide-5-mononitrate. A number of compounds appeared to be even more potent than glyceryl trinitrate. Qualitative structure-activity relationships within the series of new compounds are discussed. In flexible n-alkylene dinitrates, lipophilicity as well as chain length appears to affect in vitro activity. In semi-rigid cyclohexylene dinitrates, the number of atoms between and the configuration of the nitrate groups may play an important role. Finally, in cycloalkylene mononitrates neither the number of ring carbon atoms nor the lipophilicity clearly affects the in vitro activity. It is suggested that, apart from a limited involvement of compound lipophilicity, other factors such as differences in enzymatic conversion to a common putative bioactive species, nitric oxide, are responsible for the observed differences in activity. © 1995 Royal Dutch Association for Advancement of Pharmacy

Clear-sky stable boundary layers with low winds over snow-covered surfaces Part I: A WRF model evaluation

In this paper we evaluated the Weather Research and Forecasting (WRF) mesoscale meteorological model for stable conditions at clear skies with low wind speeds. Three contrasting terrains with snow covered surfaces are considered, namely Cabauw (Netherlands, snow over grass), Sodankylä (Finland, snow over a needle-leaf forest) and Halley (Antarctica, snow over an ice shelf). We used the full 3D model and the single-column versions of the WRF model. The SCM was driven by realistic forcings of the WRF-3D field. Several sets of SCM forcings were tested: A. no advection, B. varying geostrophic wind in time, C. momentum advection in addition to B, D. temperature and moisture advection in addition to C, and E. forcing the SCM field to the 3D field above a threshold height. The WRF-3D model produced overall good results for wind speed, but the near-surface temperatures and specific humidity were overestimated for Cabauw and Sodankylä, and underestimated for Halley. Prescribing advection for momentum, temperature and moisture gave the best results for the WRF-SCM, and simulations deviated strongly from reality without advection. Nudging the SCM field to the 3D field above a threshold height lead to an unrealistic behaviour of the variables below this height and is not recommended. Detailed prescription of the surface characteristics, e.g. adjusting the snow cover and vegetation fraction, improved the 2¿m temperature simulation. For all three sites, the simulated temperature and moisture inversion was underestimated, though this improved when prescribing advection. Overall, in clear-sky conditions, the stable boundary layer over snow and ice can be modelled to a good approximation if all processes are taken into account at high resolution, and if land surface properties are carefully prescribed