The carbonate system of the NW European shelf: sensitivity and model validation

The ocean plays an important role in regulating the climate, acting as a sink for carbon dioxide, perturbing the carbonate system and resulting in a slow decrease of seawater pH. Understanding the dynamics of the carbonate system in shelf sea regions is necessary to evaluate the impact of Ocean Acidification (OA) in these societally important ecosystems. Complex hydrodynamic and ecosystem coupled models provide a method of capturing the significant heterogeneity of these areas. However rigorous validation is essential to properly assess the reliability of such models. The coupled model POLCOMS–ERSEM has been implemented in the North Western European shelf with a new parameterization for alkalinity explicitly accounting for riverine inputs and the influence of biological processes. The model has been validated in a like with like comparison with North Sea data from the CANOBA dataset. The model shows good to reasonable agreement for the principal variables, physical (temperature and salinity), biogeochemical (nutrients) and carbonate system (dissolved inorganic carbon and total alkalinity), but simulation of the derived variables, pH and pCO2, are not yet fully satisfactory. This high uncertainty is attributed mostly to riverine forcing and primary production. This study suggests that the model is a useful tool to provide information on Ocean Acidification scenarios, but uncertainty on pH and pCO2 needs to be reduced, particularly when impacts of OA on ecosystem functions are included in the model systems.

Empirically modelling the potential effects of changes in temperature and prey availability on the growth of cod larvae in UK shelf seas

It has been hypothesized that changes in zooplankton community structure over the past four decades led to reduced growth and survival of prerecruit Atlantic cod (Gadus morhua) and that this was a key factor underlying poor year classes, contributing to stock collapse, and inhibiting the recovery of stocks around the UK. To evaluate whether observed changes in plankton abundance, species composition and temperature could have led to periods of poorer growth of cod larvae, we explored the effect of prey availability and temperature on early larval growth using an empirical trophodynamic model. Prey availability was parameterized using species abundance data from the Continuous Plankton Recorder. Our model suggests that the observed changes in plankton community structure in the North Sea may have had less impact on cod larval growth, at least for the first 40 days following hatching, than previously suggested. At least in the short term, environmental and prey conditions should be able to sustain growth of cod larvae and environmental changes acting on this early life stage should not limit stock recovery.

Biophysical models of larval dispersal in the Benguela Current ecosystem

We synthesise and update results from the suite of biophysical, larval-dispersal models developed in the Benguela Current ecosystem. Biophysical models of larval dispersal use outputs of physical hydrodynamic models as inputs to individual-based models in which biological processes acting during the larval life are included. In the Benguela, such models were first applied to simulate the dispersal of anchovy Engraulis encrasicolus and sardine Sardinops sagax ichthyoplankton, and more recently of the early life stages of chokka-squid Loligo reynaudii and Cape hakes Merluccius spp. We identify how the models have helped advance understanding of key processes for these species. We then discuss which aspects of the early life of marine species in the Benguela Current ecosystem are still not well understood and could benefit from new modelling studies.

Potential impacts of climate change on the primary production of regional seas: A comparative analysis of five European seas

Regional seas are potentially highly vulnerable to climate change, yet are the most directly societally important regions of the marine environment. The combination of widely varying conditions of mixing, forcing, geography (coastline and bathymetry) and exposure to the open-ocean makes these seas subject to a wide range of physical processes that mediates how large scale climate change impacts on these seas’ ecosystems. In this paper we explore the response of five regional sea areas to potential future climate change, acting via atmospheric, oceanic and terrestrial vectors. These include the Barents Sea, Black Sea, Baltic Sea, North Sea, Celtic Seas, and are contrasted with a region of the Northeast Atlantic. Our aim is to elucidate the controlling dynamical processes and how these vary between and within these seas. We focus on primary production and consider the potential climatic impacts on: long term changes in elemental budgets, seasonal and mesoscale processes that control phytoplankton’s exposure to light and nutrients, and briefly direct temperature response. We draw examples from the MEECE FP7 project and five regional model systems each using a common global Earth System Model as forcing. We consider a common analysis approach, and additional sensitivity experiments. Comparing projections for the end of the 21st century with mean present day conditions, these simulations generally show an increase in seasonal and permanent stratification (where present). However, the first order (low- and mid-latitude) effect in the open ocean projections of increased permanent stratification leading to reduced nutrient levels, and so to reduced primary production, is largely absent, except in the NE Atlantic. Even in the two highly stratified, deep water seas we consider (Black and Baltic Seas) the increase in stratification is not seen as a first order control on primary production. Instead, results show a highly heterogeneous picture of positive and negative change arising from complex combinations of multiple physical drivers, including changes in mixing, circulation and temperature, which act both locally and non-locally through advection.

Linking Research and Marketing: A Pharmaceutical Innovation

This chapter describes in very general terms the integration of clinical research and marketing, drawing on books by marketers and recent cases that have come to the public eye. The tools that have been used to accomplish this integration over the past half-century are various, but they all stem from a realization that in a rational world centered on health there need be no intrinsic divide between research and marketing. Most obviously, marketing drugs to physicians, who are professionals acting within their own spheres, depends crucially on research. Physicians respond, and need to see themselves as responding, to fact, figures, and studies. The well-chosen images and vehicles for marketing campaigns must be subordinated to research. Yet at the same time research is a means of increasing sales.

The pathophysiology of eosinophilic esophagitis: Altered mechanisms of antigen detection in the esophagus

Recently, a chronic idiopathic disease of the esophagus has emerged, which is now known as eosinophilic esophagitis (EoE). Incomplete knowledge regarding the pathogenesis of EoE has limited treatment options. EoE is known to be a Th2-type immune-mediated disorder. Based on previous studies in both patients and experimental models, it is possible that an abnormal reaction to antigen mediates the pathophysiology of EoE. In this thesis, symptoms and signs unique to EoE were identified by an age-matched, case-controlled study of 326 patients with EoE and gastroesophageal reflux disease. The molecular mechanisms involved in antigen detection in the esophagus, in relation to EoE were then investigated. Esophageal epithelial cells were found, for the first time, to be capable of acting as non-professional antigen presenting cells, with the ability to engulf, process and present antigen on MHC class II to T helper lymphocytes. Antigen presentation by esophageal epithelial cells was induced by interferon-γ, which is increased in biopsies from patients with EoE. Next, it was discovered that esophageal epithelial cell lines expressed functional toll-like receptor (TLR) 2 and TLR3, but in esophageal mucosal biopsies only infiltrating immune cells (including eosinophils) expressed TLR2 and TLR3. Finally, the potential involvement of IgE in the pathogenesis of esophageal inflammation was investigated. IgE in the esophagus was found to be present on mast cells, which are increased in density in the esophageal mucosae of patients with EoE and especially those with a history of atopy. Mechanisms of antigen detection may mediate the pathophysiology of EoE in the esophagus through antigen presentation by epithelial cells, detection by TLRs on immune cells and detection through IgE on mucosal mast cells. Together, these findings demonstrate that mechanisms of antigen detection may actually contribute to the pathophysiology of EoE. Through increased understanding of the mechanisms of EoE, the results of this thesis may contribute to future therapy.

The Experience and Practice of Approved Social Workers in Northern Ireland

This article reports on the first extensive survey of Approved Social Worker (ASW) activity under the Mental Health (Northern Ireland) Order 1986. The integrated health and social services organizational structure, the adverse effects on individual mental health of the legacy of thirty years of civil conflict and the move from hospital to community care are significant features which have influenced the delivery of mental health social work services locally. The practice and experience of ASWs was surveyed by postal questionnaire and user and carer experience of compulsory hospital admission was investigated by a series of focus groups. The study revealed that two‐thirds of ASWs had experience of acting as an applicant in compulsory hospital admission during the past two years. Nearly half (42 per cent) of these ASWs had reported experience of between one and five admissions and one‐tenth had completed over twenty admissions in the two‐year period. In only a small minority of cases did joint face‐to‐face assessment with the General Practitioner (doctor) take place; nearly half of ASWs reported difficulties in obtaining transport; and only one‐fifth of ASWs had experience of acting as a second approved social worker. Half of ASWs reported experience of guardianship, either as applicant or in making the recommendation. Both service users and carers reported a lack of understanding about the role of the ASW and complained about the lack of alternative resources that ASWs could use to prevent hospital admissions. These findings are discussed and a number of recommendations are proposed for improvements to approved social worker practice.

Approved Social Work Training in Northern Ireland: Using Research to Examine Competence-Based Learning and Influence Policy Change

This article reports on how research activity helped describe and analyse ASW (Approved Social Worker) learning experience as well as acting as a catalyst for change and development in policy and practice in Northern Ireland. The paper contextualizes the study by outlining the legislation, the main features of the ASW role and the approach to ASW training in Northern Ireland, and by reviewing the literature on the efficacy and value of competence-based learning. While the findings do not provide conclusive evidence that a competence-based approach is inherently more effective than previous courses, they do indicate that candidates who were trained in this way were moderately more satisfied than those who had participated in non-competence based programmes. The research also highlights the importance of the interrelationship between training, practice experience and support in developing and sustaining competence. The paper concludes with a review of the recommendations arising from the study and an analysis of the developments in training and regulations relating to practice experience and re-approval of ASWs since publication of the research. The study is of contemporary interest given the proposed changes to the role of ASWs/Mental Health Officers in the context of the reviews of UK mental health law.

Multinational Management

This book is designed to help the reader understand the rationale of multinational corporations. Each of the nine central chapters focuses on the question of how a centrally directed multinational corporation (called a geocentric) can earn more profit than an identical corporation which lacks central direction (called a polycentric). Although some central direction is usually good, too much can be bad: Other multinationals (called ethnocentric) straitjacket their subsidiaries into acting in ways appropriate only in the headquarters' nation.

Drug Delivery of Aminolevulinic Acid from Topical Formulations Intended for Photodynamic Therapy

Topical photodynamic therapy is used for a variety of malignant and pre-malignant skin disorders, including Bowen's Disease and Superficial Basal Cell Carcinoma. A haem precursor, typically 5-aminolevulinic acid (ALA), acting as a prodrug, is absorbed and converted by the haem biosynthetic pathway to photoactive protoprophyrin IX (PpIX), which accumulates preferentially in rapidly dividing
cells. Cell destruction occurs when PpIx is activated by an intense light source of appropriate wavelength. Topical delivery of ALA avoids the prolonged photosensitivity reactions associated with systemic administration of photosensitisers but its clinical utility is influenced by the tissue penetration characteristics of the drug, its ease of application and the stability of the active agent in the applied dose. This review, therefore, focuses on drug delivery applications for topical, ALA-based PDT. Issues considered in detail include physical and chemical enhancement strategies for tissue penetration of ALA and subsequent intracellular accumulation of PpIX, together with formulation strategies and drug delivery design solutions appropriate to various clinical applications. The fundamental aspects of drug diffusion in
relation to the physicochemical properties of ALA are reviewed and specific consideration is given to the degradation pathways of ALA in formulated systems that, in turn, influence the design of stable topical formulations.

Biodegradation and Rhodococcus--masters of catabolic versatility.

The genus Rhodococcus is a very diverse group of bacteria that possesses the ability to degrade a large number of organic compounds, including some of the most difficult compounds with regard to recalcitrance and toxicity. They achieve this through their capacity to acquire a remarkable range of diverse catabolic genes and their robust cellular physiology. Rhodococcus appear to have adopted a strategy of hyperrecombination associated with a large genome. Notably, they harbour large linear plasmids that contribute to their catabolic diversity by acting as 'mass storage' for a large number of catabolic genes. In addition, there is increasing evidence that multiple pathways and gene homologues are present that further increase the catabolic versatility and efficiency of Rhodococcus.

Complex weathering in drylands: implications of 'stress' history for rock debris breakdown and sediment release

Weathering studies have often sought to explain features in terms of a prevailing set of environmental conditions. However, it is clear that in most present-day hot desert regions, the surface rock debris has been exposed to a range of weathering environments and processes. These different weathering conditions can arise in two ways, either from the effects of long-term climate change acting on debris that remains relatively static within the landscape or through the spatial relocation of debris from high to low altitude. Consequently, each fragment of rock may contain a unique weathering-related legacy of damage and alteration — a legacy that may greatly influence its response to present-day weathering activity. Experiments are described in which blocks of limestone, sandstone, granite and basalt are given ‘stress histories’ by subjecting them to varying numbers of heating and freezing cycles as a form of pre-treatment. These imposed stress histories act as proxies for a weathering history. Some blocks were used in a laboratory salt weathering simulation study while others underwent a 2 year field exposure trial at high, mid and low altitude sites in Death Valley, California. Weight loss and ultrasonic pulse velocity measurements suggest that blocks with stress histories deteriorate more rapidly than unstressed samples of the same rock type exposed to the same environmental conditions. Laboratory data also indicate that the result of imposing a known ‘weathering history’ on samples by pre-stressing them is an increase in the amount of fine sediment released during salt weathering over a given period of time in comparison to unstressed samples.

Effect of purinergic blockers on outward current in isolated smooth muscle cells of the sheep bladder

Freshly dispersed cells from sheep urinary bladder were voltage clamped using the whole cell and inside-out patch-clamp technique. Cibacron and Basilen blue increased outward current in a dose-dependent manner with a half-maximal response at 10(-5) M. Suramin, in concentrations to 10(-3) M, had no such effect. The Cibacron blue response was abolished in Ca2+-free physiological salt solution, suggesting that it was acting on a Ca2+-dependent current. Similarly, the Cibacron blue-sensitive current was significantly attenuated by charybdotoxin. Cibacron blue did not modulate inward current nor were its effects modified by caffeine or heparin, suggesting that its effect on outward current was not secondary to an increase in intracellular Ca2+. Application of 10(-4) M Cibacron blue to the inside membrane of excised patches caused a rapid increase in open probability of a large-conductance (300 pS) K+ channel. These results suggest that Cibacron blue is a potent activator of a Ca2+-dependent outward current in bladder smooth muscle cells in addition to its action as a purinergic blocker.

Rational design of a dual-mode optical and chemical prodrug

Purpose. The purpose of this study is to demonstrate the rational design and behaviour of the first dual mode optical and chemical prodrug, exemplified by an acetyl salicylic acid-based system. Methods. A cyclic 1,4-benzodioxinone prodrug was synthesised by reaction of 3,5-dimethoxybenzoin and acetyl salicoyl chloride with pyridine. After purification by column chromatography and recrystallization, characterization was achieved using infrared and NMR spectroscopies, mass spectrometry, elemental analysis and single crystal X-ray diffraction. Light-triggered drug liberation was characterised via UV-visible spectroscopy following low-power 365 nm irradiation for controlled times. Chemical drug liberation was characterised via UV-visible spectroscopy in pH 5.5 solution. Results. The synthetic method yielded pure prodrug, with full supporting characterisation. Light-triggered drug liberation proceeded at a rate of 8.30 10j2 sj1, while chemical, hydrolytic liberation proceeded independently at 1.89 10j3 sj1. The photochemical and hydrolytic reactions were both quantitative. Conclusions. This study demonstrates the first rational dual-mode optical and chemical prodrug, using acetyl salicylic acid as a model, acting as a paradigm for future dual-mode systems. Photochemical drug liberation proceeds 44 times faster than chemical liberation, suggesting potential use in drug-eluting medical devices where an additional burst of drug is required at the onset of infection.

Ca2+-independent phospholipase A2-dependent gating of TRPM8 by lysophospholipids

TRPM8 represents an ion channel activated by cold temperatures and cooling agents, such as menthol, that underlies the cold-induced excitation of sensory neurons. Interestingly, the only human tissue outside the peripheral nervous system, in which the expression of TRPM8 transcripts has been detected at high levels, is the prostate, a tissue not exposed to any essential temperature variations. Here we show that the TRPM8 cloned from human prostate and heterologously expressed in HEK-293 cells is regulated by the Ca(2+)-independent phospholipase A(2) (iPLA(2)) signaling pathway with its end products, lysophospholipids (LPLs), acting as its endogenous ligands. LPLs induce prominent prolongation of TRPM8 channel openings that are hardly detectable with other stimuli (e.g. cold, menthol, and depolarization) and that account for more than 90% of the total channel open time. Down-regulation of iPLA(2) resulted in a strong inhibition of TRPM8-mediated functional responses and abolished channel activation. The action of LPLs on TRPM8 channels involved either changes in the local lipid bilayer tension or interaction with the critical determinant(s) in the transmembrane channel core. Based on this, we propose a novel concept of TRPM8 regulation with the involvement of iPLA(2) stimulation. This mechanism employs chemical rather than physical (temperature change) signaling and thus may be the main regulator of TRPM8 activation in organs not exposed to any essential temperature variations, as in the prostate gland.