The rodent uterotrophic assay: Critical protocol features, studies with nonyl phenols, and comparison with a yeast estrogenicity assay

The major protocol features of the immature rat uterotrophic assay have been evaluated using a range of reference chemicals. The protocol variables considered include the selection of the test species and route of chemical administration, the age of the test animals, the maintenance diet used, and the specificity of the assay for estrogens. It is concluded that three daily oral administrations of test chemicals to 21- to 22-day-old rats, followed by determination of absolute uterus weights on the fourth day, provide a sensitive and toxicologically relevant in vivo estrogenicity assay. Rats are favored over mice for reasons of toxicological practice, but the choice of test species is probably not a critical protocol variable, as evidenced by the similar sensitivity of rats and mice to the uterotrophic activity of methoxychlor. Vaginal opening is shown to be a useful, but nondefinitive, adjunct to the uterotrophic assay. The ability of test chemicals to reduce or abolish the uterotrophic response of estradiol is suggested to provide a useful extension of the uterotrophic assay for the purpose of detecting antiestrogens. The results of a series of studies on the environmental estrogen nonyl phenol (NP), and its linear isomer n -nonyl phenol, confirm that branching of the aliphatic side chain is important for activity. 17beta-Desoxyestradiol is shown to be of similar activity to estradiol in the uterotrophic assay and is suggested to represent the "parent" estrogen of NP. Benzoylation of NP and 17-desoxyestradiol did not affect their uterotrophic activity, in contrast to the enhancing effect of benzoylation on estradiol. Selected chemicals shown to be active in the immature rat uterotrophic assay were also evaluated in an in vitro yeast human estrogen receptor transactivation assay. Most of the chemicals gave similar qualitative responses to those seen in the uterotrophic assay, and the detection of the estrogen methoxychlor by the yeast assay evidenced a degree of intrinsic metabolic competence. However, the assay had a reduced ability (compared to rodents) to hydrolyze the benzoate ester of estradiol, and the estrogenic benzoate derivative of NP was not active in the yeast assay. These last results indicate that current metabolic deficiencies of in vitro estrogenicity assays will limit the value of negative data for the immediate future. The results described illustrate the intrinsic complexity of evaluating chemicals for estrogenic activities and confirm the need for rigorous attention to experimental design and criteria for assessing estrogenic activity

Audit of healthcare provision for UK prisoners with suspected epilepsy

SummaryPurposeTo describe the prevalence and nature of epileptic seizure disorders in a typical UK prison and compare the care offered to prisoners to the recommendations of the National Institute for Clinical Excellence (NICE).MethodsOver a 14-month period, all prisoners identified as having epilepsy were registered by prison primary healthcare services at a category ‘C’ prison holding 640 male adults. Prison and National Health Service health records were reviewed, prisoners were re-assessed by members of a specialist secondary care service based in the local general hospital NHS.ResultsTwenty-six prisoners were thought to have epilepsy. 61.5% of diagnoses had not been made by epilepsy specialists, 73.1% had uncontrolled seizures, only 19.2% had had computed tomography, none magnetic resonance imaging. At review, 30.8% of prisoners were thought to require neuroimaging, 19.2% cardiac investigations. The diagnosis of epilepsy was confirmed in only 57.9% of those prisoners considered to have the condition by prison healthcare services. 53.8% of those prisoners confirmed as having epilepsy had not had a medical review in the past 12 months; 63.2% required a change in their antiepileptic drugs (AEDs).ConclusionAlthough the prevalence of epilepsy in this prison population appeared high at first sight, a critical review of the diagnoses reduced the difference to the prevalence of epilepsy in the population at large. Fewer prisoners than expected achieved seizure control. Collaboration with specialist epilepsy services was poor. There were significant discrepancies between the healthcare provision in prison and the NICE epilepsy guidelines

Inferred support for disturbance-recovery hypothesis of North Atlantic phytoplankton blooms

Analyses of satellite-derived chlorophyll data indicate that the phase of rapid phytoplankton population growth in the North Atlantic (the ‘spring bloom') is actually initiated in the winter rather than the spring, contradicting Sverdrup's Critical Depth Hypothesis. An alternative disturbance-recovery hypothesis (DRH) has been proposed to explain this discrepancy, in which the rapid deepening of the mixed layer reduces zooplankton grazing rates sufficiently to initiate the bloom. We use Bayesian parameter inference on a simple Nutrient-Phytoplankton-Zooplankton (NPZ) to investigate the DRH and also investigate how well the model can capture the multiyear and spatial dynamics of phytoplankton concentrations and population growth rates. Every parameter in our NPZ model was inferred as a probability distribution given empirical constraints, this provides a more objective method to identify a model parameterisation given available empirical evidence, rather than fixing or tuning individual parameter values. Our model explains around 75% of variation in the seasonal dynamics of phytoplankton concentrations, 30% of variation in their population rates of change, and correctly predicts the phases of population growth and decline. Our parameter-inferred model supports DRH, revealing the sustained reduction of grazing due to mixed layer deepening as the driving mechanism behind bloom initiation, with the relaxation of nutrient limitation being another contributory mechanism. Our results also show that the continuation of the bloom is caused in part by the maintenance of phytoplankton concentrations below a level that can support positive zooplankton population growth. Our approach could be employed to formally assess alternative hypotheses for bloom formatio

Non-linear changes in modelled terrestrial ecosystems subjected to perturbations

Perturbed ecosystems may undergo rapid and non-linear changes, resulting in ‘regime shifts’ to an entirely different ecological state. The need to understand the extent, nature, magnitude and reversibility of these changes is urgent given the profound effects that humans are having on the natural world. General ecosystem models, which simulate the dynamics of ecosystems based on a mechanistic representation of ecological processes, provide one novel way to project ecosystem changes across all scales and trophic levels, and to forecast impact thresholds beyond which irreversible changes may occur. We model ecosystem changes in four terrestrial biomes subjected to human removal of plant biomass, such as occurs through agricultural land-use change. We find that irreversible, non-linear responses commonly occur where removal of vegetation exceeds 80% (a level that occurs across nearly 10% of the Earth’s land surface), especially for organisms at higher trophic levels and in less productive ecosystems. Very large, irreversible changes to ecosystem structure are expected at levels of vegetation removal akin to those in the most intensively used real-world ecosystems. Our results suggest that the projected twenty-first century rapid increases in agricultural land conversion may lead to widespread trophic cascades and in some cases irreversible changes to ecosystem structure

Three Key considerations for biodiversity conservation in multilateral agreements

It is nearly three decades since the world recognized the need for a global multilateral treaty aiming to address accelerating biodiversity loss. However, biodiversity continues to decline at a concerning rate. Drawing on lessons from the implementation of the current strategic plan of the Convention on Biological Diversity and the 2010 Aichi Targets, we highlight three interlinked core areas, which require attention and improvement in the development of the post‐2020 Biodiversity Framework under the Convention on Biological Diversity. They are: (1) developing robust theories of change which define agreed, adaptive plans for achieving targets; (2) using models to evaluate assumptions and effectiveness of different plans and targets; and (3) identifying the common but differentiated responsibilities of different actors/states/countries within these plans. We demonstrate how future multilateral agreements must not focus only on what needs to be done but also on how it should be done, using measurable steps, which make sense at the scales at which biodiversity change happens

Emergent global patterns of ecosystem structure and function from a mechanistic general ecosystem model

Anthropogenic activities are causing widespread degradation of ecosystems worldwide, threatening the ecosystem services upon which all human life depends. Improved understanding of this degradation is urgently needed to improve avoidance and mitigation measures. One tool to assist these efforts is predictive models of ecosystem structure and function that are mechanistic: based on fundamental ecological principles. Here we present the first mechanistic General Ecosystem Model (GEM) of ecosystem structure and function that is both global and applies in all terrestrial and marine environments. Functional forms and parameter values were derived from the theoretical and empirical literature where possible. Simulations of the fate of all organisms with body masses between 10 µg and 150,000 kg (a range of 14 orders of magnitude) across the globe led to emergent properties at individual (e.g., growth rate), community (e.g., biomass turnover rates), ecosystem (e.g., trophic pyramids), and macroecological scales (e.g., global patterns of trophic structure) that are in general agreement with current data and theory. These properties emerged from our encoding of the biology of, and interactions among, individual organisms without any direct constraints on the properties themselves. Our results indicate that ecologists have gathered sufficient information to begin to build realistic, global, and mechanistic models of ecosystems, capable of predicting a diverse range of ecosystem properties and their response to human pressures

Integrating climate adaptation and biodiversity conservation in the global ocean

The impacts of climate change and the socioecological challenges they present are ubiquitous and increasingly severe. Practical efforts to operationalize climate-responsive design and management in the global network of marine protected areas (MPAs) are required to ensure long-term effectiveness for safeguarding marine biodiversity and ecosystem services. Here, we review progress in integrating climate change adaptation into MPA design and management and provide eight recommendations to expedite this process. Climate-smart management objectives should become the default for all protected areas, and made into an explicit international policy target. Furthermore, incentives to use more dynamic management tools would increase the climate change responsiveness of the MPA network as a whole. Given ongoing negotiations on international conservation targets, now is the ideal time to proactively reform management of the global seascape for the dynamic climate-biodiversity reality

Prescribing anti-epileptic drugs for people with epilepsy and intellectual disability

This report addresses the extremely important area of epilepsy in the field of intellectual disability (ID), also known as learning disability. Epilepsy and ID are two conditions that carry stigma and can lead to social isolation. An individual who experiences both these problems faces huge challenges. This report aims to provide epileptologists, psychiatrists, doctors and clinicians working with people with ID and epilepsy an overview of good practice prescribing. Its focus is on using current evidence and applying it to support practical prescribing for people with ID. The document is not a substitute for recognised prescribing guides such as the British National Formulary (BNF). It is not a complete or comprehensive overview of epilepsy management or of epilepsy service provision. The contents of this report need to be considered as guidance, especially where most practitioners struggle when the evidence does not inform the complex clinical challenges. The report is a consensus statement on the application of current evidence used in the general population to people with ID and should be used for the purpose of guiding holistic decision-making in prescribing AEDs. It is important that clinicians keep themselves up to date using the latest information on the subject as part of their continuing professional development, as the subject area covered by this report changes rapidly