Establishing gold standard approaches to rapid tranquillisation: a review and discussion of the evidence on the safety and efficacy of medications currently used

Background: Rapid tranquillisation is used when control of agitation, aggression or excitement is required. Throughout the UK there is no consensus over the choice of drugs to be used as first line treatment. The NICE guideline on the management of violent behaviour involving psychiatric inpatients conducted a systematic examination of the literature relating to the effectiveness and safety of rapid tranquillisation (NICE, 2005). This paper presents the key findings from that review and key guideline recommendations generated, and discusses the implications for practice of more recent research and information. Aims: To examine the evidence on the efficacy and safety of medications used for rapid tranquillisation in inpatient psychiatric settings. Method: Systematic review of current guidelines and phase III randomised, controlled trials of medication used for rapid tranquillisation. Formal consensus methods were used to generate clinically relevant recommendations to support safe and effective prescribing of rapid tranquillisation in the development of a NICE guideline. Findings: There is a lack of high quality clinical trial evidence in the UK and therefore a ‘gold standard’ medication regime for rapid tranquillisation has not been established. Rapid tranquillisation and clinical practice: The NICE guideline produced 35 recommendations on rapid tranquillisation practice for the UK, with the primary aim of calming the service user to enable the use of psychosocial techniques. Conclusions and implications for clinical practice: Further UK specific research is urgently needed that provides the clinician with a hierarchy of options for the clinical practice of rapid tranquillisation

A quantum molecular dynamics study of aqueous solvation dynamics

Ring polymer molecular dynamics experiments have been carried out to examine effects derived from nuclear quantum fluctuations at ambient conditions on equilibrium and non-equilibrium dynamical characteristics of charge solvation by a popular simple, rigid, water model, SPC/E , and for a more recent, and flexible, q-TIP4P/F model, to examine the generality of conclusions. In particular, we have recorded the relaxation of the solvent energy gap following instantaneous, ±e charge jumps in an initially uncharged Lennard-Jones-like solute. In both charge cases, quantum effects are reflected in sharper decays at the initial stages of the relaxation, which produce up to a ∼20% reduction in the characteristic timescales describing the solvation processes. For anionic solvation, the magnitude of polarization fluctuations controlling the extent of the water proton localization in the first solvation shell is somewhat more marked than for cations, bringing the quantum solvation process closer to the classical case. Effects on the solvation response from the explicit incorporation of flexibility in the water Hamiltonian are also examined. Predictions from linear response theories for the overall relaxation profile and for the corresponding characteristic timescales are reasonably accurate for the solvation of cations, whereas we find that they are much less satisfactory for the anionic case.Fil: Videla, Pablo Ernesto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina. Universidad de Buenos Aires; ArgentinaFil: Rossky, Peter J.. University of Texas at Austin; Estados UnidosFil: Laria, Daniel Hector. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Química, Física de los Materiales, Medioambiente y Energía; Argentina. Universidad de Buenos Aires; Argentina. Comision Nacional de Energia Atomica. Gerencia Quimica. CAC; Argentin

Promotion of germination using hydroxamic acid inhibitors of 9-cis-epoxycarotenoid dioxygenase

Abscisic acid (ABA) inhibits seed germination and the regulation of ABA biosynthesis has a role in maintenance of seed dormancy. The key rate-limiting step in ABA biosynthesis is catalysed by 9-cis-epoxycarotenoid dioxygenase (NCED). Two hydroxamic acid inhibitors of carotenoid cleavage dioxygenase (CCD), D4 and D7, previously found to inhibit CCD and NCED in vitro, are shown to have the novel property of decreasing mean germination time of tomato (Solanum lycopersicum L.) seeds constitutively overexpressing LeNCED1. Post-germination, D4 exhibited no negative effects on tomato seedling growth in terms of height, dry weight and fresh weight. Tobacco (Nicotiana tabacum L.) seeds containing a tetracycline-inducible LeNCED1 transgene were used to show that germination could be negatively and positively controlled through the chemical induction of gene expression and the chemical inhibition of the NCED protein: application of tetracycline increased mean germination time and delayed hypocotyl emergence in a similar manner to that observed when exogenous ABA was applied and this was reversed by D4 when NCED expression was induced at intermediate levels. D4 also improved germination in lettuce (Lactuca sativa L.) seeds under thermoinhibitory temperatures and in tomato seeds imbibed in high osmolarity solutions of polyethylene glycol. D4 reduced ABA and dihydrophaseic acid accumulation in tomato seeds overexpressing LeNCED1 and reduced ABA accumulation in wild type tomato seeds imbibed on polyethylene glycol. The evidence supports a mode of action of D4 through NCED inhibition, and this molecule provides a lead compound for the design of NCED inhibitors with greater specificity and potency

Modeling parasite dynamics on farmed salmon for precautionary conservation management of wild salmon

Conservation management of wild fish may include fish health management in sympatric populations of domesticated fish in aquaculture. We developed a mathematical model for the population dynamics of parasitic sea lice (Lepeophtheirus salmonis) on domesticated populations of Atlantic salmon (Salmo salar) in the Broughton Archipelago region of British Columbia. The model was fit to a seven-year dataset of monthly sea louse counts on farms in the area to estimate population growth rates in relation to abiotic factors (temperature and salinity), local host density (measured as cohort surface area), and the use of a parasiticide, emamectin benzoate, on farms. We then used the model to evaluate management scenarios in relation to policy guidelines that seek to keep motile louse abundance below an average three per farmed salmon during the March-June juvenile wild Pacific salmon (Oncorhynchus spp.) migration. Abiotic factors mediated the duration of effectiveness of parasiticide treatments, and results suggest treatment of farmed salmon conducted in January or early February minimized average louse abundance per farmed salmon during the juvenile wild salmon migration. Adapting the management of parasites on farmed salmon according to migrations of wild salmon may therefore provide a precautionary approach to conserving wild salmon populations in salmon farming regions

Isomerization dynamics of a buckled nanobeam

We analyze the dynamics of a model of a nanobeam under compression. The model is a two mode truncation of the Euler-Bernoulli beam equation subject to compressive stress. We consider parameter regimes where the first mode is unstable and the second mode can be either stable or unstable, and the remaining modes (neglected) are always stable. Material parameters used correspond to silicon. The two mode model Hamiltonian is the sum of a (diagonal) kinetic energy term and a potential energy term. The form of the potential energy function suggests an analogy with isomerisation reactions in chemistry. We therefore study the dynamics of the buckled beam using the conceptual framework established for the theory of isomerisation reactions. When the second mode is stable the potential energy surface has an index one saddle and when the second mode is unstable the potential energy surface has an index two saddle and two index one saddles. Symmetry of the system allows us to construct a phase space dividing surface between the two "isomers" (buckled states). The energy range is sufficiently wide that we can treat the effects of the index one and index two saddles in a unified fashion. We have computed reactive fluxes, mean gap times and reactant phase space volumes for three stress values at several different energies. In all cases the phase space volume swept out by isomerizing trajectories is considerably less than the reactant density of states, proving that the dynamics is highly nonergodic. The associated gap time distributions consist of one or more `pulses' of trajectories. Computation of the reactive flux correlation function shows no sign of a plateau region; rather, the flux exhibits oscillatory decay, indicating that, for the 2-mode model in the physical regime considered, a rate constant for isomerization does not exist.Comment: 42 pages, 6 figure

Manipulating Gibberellin Control Over Growth and Fertility as a Possible Target for Managing Wild Radish Weed Populations in Cropping Systems

Wild radish is a major weed of Australian cereal crops. A rapid establishment, fast growth, and abundant seed production are fundamental to its success as an invasive species. Wild radish has developed resistance to a number of commonly used herbicides increasing the problem. New innovative approaches are needed to control wild radish populations. Here we explore the possibility of pursuing gibberellin (GA) biosynthesis as a novel molecular target for controlling wild radish, and in doing so contribute new insights into GA biology. By characterizing ga 3-oxidase (ga3ox) mutants in Arabidopsis, a close taxonomic relative to wild radish, we showed that even mild GA deficiencies cause considerable reductions in growth and fecundity. This includes an explicit requirement for GA biosynthesis in successful female fertility. Similar defects were reproducible in wild radish via chemical inhibition of GA biosynthesis, confirming GA action as a possible new target for controlling wild radish populations. Two possible targeting approaches are considered; the first would involve developing a species-specific inhibitor that selectively inhibits GA production in wild radish over cereal crops. The second, involves making crop species insensitive to GA repression, allowing the use of existing broad spectrum GA inhibitors to control wild radish populations. Toward the first concept, we cloned and characterized two wild radish GA3OX genes, identifying protein differences that appear sufficient for selective inhibition of dicot over monocot GA3OX activity. We developed a novel yeast-based approach to assay GA3OX activity as part of the molecular characterization, which could be useful for future screening of inhibitory compounds. For the second approach, we demonstrated that a subset of GA associated sln1/Rht-1 overgrowth mutants, recently generated in cereals, are insensitive to GA reductions brought on by the general GA biosynthesis inhibitor, paclobutrazol. The location of these mutations within sln1/Rht-1, offers additional insight into the functional domains of these important GA signaling proteins. Our early assessment suggests that targeting the GA pathway could be a viable inclusion into wild radish management programs that warrants further investigation. In drawing this conclusion, we provided new insights into GA regulated reproductive development and molecular characteristics of GA metabolic and signaling proteins.The work was supported by the CRC for Australian Weed Management and the Australian Research Council Centre of Excellence for Translational Photosynthesis (CE140100015)

Assembly of infectious enteroviruses depends on multiple, conserved genomic RNA-coat protein contacts.

Picornaviruses are important viral pathogens, but despite extensive study, the assembly process of their infectious virions is still incompletely understood, preventing the development of anti-viral strategies targeting this essential part of the life cycle. We report the identification, via RNA SELEX and bioinformatics, of multiple RNA sites across the genome of a typical enterovirus, enterovirus-E (EV-E), that each have affinity for the cognate viral capsid protein (CP) capsomer. Many of these sites are evolutionarily conserved across known EV-E variants, suggesting they play essential functional roles. Cryo-electron microscopy was used to reconstruct the EV-E particle at ~2.2 Å resolution, revealing extensive density for the genomic RNA. Relaxing the imposed symmetry within the reconstructed particles reveals multiple RNA-CP contacts, a first for any picornavirus. Conservative mutagenesis of the individual RNA-contacting amino acid side chains in EV-E, many of which are conserved across the enterovirus family including poliovirus, is lethal but does not interfere with replication or translation. Anti-EV-E and anti-poliovirus aptamers share sequence similarities with sites distributed across the poliovirus genome. These data are consistent with the hypothesis that these RNA-CP contacts are RNA Packaging Signals (PSs) that play vital roles in assembly and suggest that the RNA PSs are evolutionarily conserved between pathogens within the family, augmenting the current protein-only assembly paradigm for this family of viruses

Rapid development and persistence of efficient subglacial drainage under 900 m-thick ice in Greenland

Intensive study of the Greenland Ice Sheet's (GrIS) subglacial drainage has been motivated by its importance for ice dynamics and for nutrient/sediment export to coastal ecosystems. This has revealed consistent seasonal development of efficient subglacial drainage in the lower ablation area. While some hydrological models show qualitative agreement with field data, conflicting evidence (both field- and model-based) maintains uncertainty in the extent and rate of efficient drainage development under thick (∼1 km) ice. Here, we present the first simultaneous time series of directly-observed subglacial drainage evolution, supraglacial hydrology and ice dynamics over 11 weeks in a large GrIS catchment. We demonstrate development of a fast/efficient subglacial drainage system extending from the margin to beneath ice >900 m thick, which then persisted with little response to highly variable moulin inputs including extreme melt events and extended periods (2 weeks) of low melt input. This efficient system evolved within ∼3 weeks at a moulin initiated when a fracture intersected a supraglacial river (rather than hydrofracture and lake drainage). Ice flow response to surface melt inputs at this site follows a pattern commonly observed in the lower GrIS ablation area, and by assuming a strong relationship between ice dynamics and subglacial hydrology, we infer that efficient subglacial drainage evolution is widespread under 900 m-thick ice in west Greenland. This time series of tracer transit characteristics through a developing and then persistent efficient drainage system provides a unique data set with which to validate and constrain existing numerical drainage system models, extending their capability for simulating drainage system evolution under current and future conditionspublishedVersio

Long term follow up of high risk children: who, why and how?

Background: Most babies are born healthy and grow and develop normally through childhood. There are, however, clearly identifiable high-risk groups of survivors, such as those born preterm or with ill-health, who are destined to have higher than expected rates of health or developmental problems, and for whom more structured and specialised follow-up programs are warranted. Discussion This paper presents the results of a two-day workshop held in Melbourne, Australia, to discuss neonatal populations in need of more structured follow-up and why, in addition to how, such a follow-up programme might be structured. Issues discussed included the ages of follow-up, and the personnel and assessment tools that might be required. Challenges for translating results into both clinical practice and research were identified. Further issues covered included information sharing, best practice for families and research gaps. Summary A substantial minority of high-risk children has long-term medical, developmental and psychological adverse outcomes and will consume extensive health and education services as they grow older. Early intervention to prevent adverse outcomes and the effective integration of services once problems are identified may reduce the prevalence and severity of certain outcomes, and will contribute to an efficient and effective use of health resources. The shared long-term goal for families and professionals is to work toward ensuring that high risk children maximise their potential and become productive and valued members of society. Electronic supplementary material The online version of this article (doi:10.1186/1471-2431-14-279) contains supplementary material, which is available to authorized users