Clustering of equine grass sickness cases in the United Kingdom: a study considering the effect of position-dependent reporting on the space-time K-function

Equine grass sickness (EGS) is a largely fatal, pasture-associated dysautonomia. Although the aetiology of this disease is unknown, there is increasing evidence that Clostridium botulinum type C plays an important role in this condition. The disease is widespread in the United Kingdom, with the highest incidence believed to occur in Scotland. EGS also shows strong seasonal variation (most cases are reported between April and July). Data from histologically confirmed cases of EGS from England and Wales in 1999 and 2000 were collected from UK veterinary diagnostic centres. The data did not represent a complete census of cases, and the proportion of all cases reported to the centres would have varied in space and, independently, in time. We consider the variable reporting of this condition and the appropriateness of the space–time K-function when exploring the spatial-temporal properties of a ‘thinned’ point process. We conclude that such position-dependent under-reporting of EGS does not invalidate the Monte Carlo test for space–time interaction, and find strong evidence for space–time clustering of EGS cases (P<0.001). This may be attributed to contagious or other spatially and temporally localized processes such as local climate and/or pasture management practices

Impact of polymorphic variants on the molecular pharmacology of the two-agonist conformations of the human β1-adrenoceptor

β-blockers are widely used to improve symptoms and prolong life in heart disease primarily by inhibiting the actions of endogenous catecholamines at the β1-adrenoceptor. There are two common naturally occurring polymorphisms within the human β1-adrenoceptor sequence: Ser or Gly at position 49 in the N-terminus and Gly or Arg at position 389 in the C-terminus and some clinical studies have suggested that expression of certain variants may be associated with disease and affect response to treatment with β-blockers. The β1-adrenoceptor also exists in two agonist conformations - a high affinity catecholamine conformation and a low affinity secondary agonist conformation. Receptor-effector coupling and intracellular signalling from the different conformations may be affected by the polymorphic variants. Here, we examine in detail the molecular pharmacology of the β1-adrenoceptor polymorphic variants with respect to ligand affinity, efficacy, activation of the different agonist conformations and signal transduction and determine whether the polymorphic variants do indeed affect this secondary conformation. Stable cell lines expressing the wildtype and polymorphic variants were constructed and receptor pharmacology examined using whole cell binding and intracellular secondary messenger techniques. There was no difference in affinity for agonists and antagonists at the human wildtype β1-adrenoceptor (Ser49/Gly389) and the polymorphic variants Gly49/Gly389 and Ser49/Arg389. Furthermore, the polymorphic variant receptors both have two active agonist conformations with pharmacological properties similar to the wildtype receptor. Although the polymorphism at position 389 is thought to occur in an intracellular domain important for Gs-coupling, the two agonist conformations of the polymorphic variants stimulate intracellular signalling pathways, including Gs-cAMP intracellular signalling, in a manner very similar to that of the wildtype receptor

Fish oil: what the prescriber needs to know

There is a general belief among doctors, in part grounded in experience, that patients with arthritis need nonsteroidal anti-inflammatory drugs (NSAIDs). Implicit in this view is that these patients require the symptomatic relief provided by inhibiting synthesis of nociceptive prostaglandin E(2), a downstream product of the enzyme cyclo-oxygenase (COX), which is inhibited by NSAIDs. However, the concept of 'safe' NSAIDs has collapsed following a multiplicity of observations establishing increased risk for cardiovascular events associated with NSAID use, especially but not uniquely with the new COX-2-selective NSAIDs. This mandates greater parsimony in the use of these agents. Fish oils contain a natural inhibitor of COX, reduce reliance on NSAIDs, and reduce cardiovascular risk through multiple mechanisms. Fish oil thus warrants consideration as a component of therapy for arthritis, especially rheumatoid arthritis, in which its symptomatic benefits are well established. A major barrier to the therapeutic use of fish oil in inflammatory diseases is ignorance of its mechanism, range of beneficial effects, safety profile, availability of suitable products, effective dose, latency of effects and instructions for administration. This review provides an evidence-based resource for doctors and patients who may choose to prescribe or take fish oil

Recent developments in research into the Cyathostominae and Anoplocephala perfoliata

Intestinal helminths are an important cause of equine disease. Of these parasites, the Cyathostominae are the commonest group that infect horses. These nematodes consist of a complex tribe of 51 species, although individual horses tend to harbour 10 or so common species, in addition to a few rarer species. The Cyathostominae can be extremely pathogenic, and high levels of infection result in clinical symptoms ranging from chronic weight loss to colic, diarrhoea and death. As part of their life cycle, immature cyathostomins penetrate the large intestinal wall, where they can enter a state of inhibited larval development. These larvae can exist in this state for months to years, after which they subsequently re-emerge. If larvae re-emerge in large numbers (i.e. several million), severe pathological consequences ensue. The inhibited larvae are also relatively refractory to several of the currently available anthelmintics, so that horses treated previously with anthelmintics can still carry life-threatening burdens of these parasitic stages. Little is known about the cyathostomin larvae during their mucosal phase, and current research efforts are focused on investigating the biology of these stages. Much of the research described here highlights this area of research and details studies aimed at investigating the host immune responses that the mucosal larvae invoke. As part of this research effort, molecular tools have been developed to facilitate the identification of larval and egg stages of cyathostomins. These molecular tools are now proving very useful in the investigation of the relative contributions that individual, common cyathostomin species make to the pathology and epidemiology of mixed helminth infections. At the more applied level, research is also in progress to develop an immunodiagnostic test that will allow numbers of mucosal larvae to be estimated. This test utilises antigen-specific IgG(T) serum antibody responses as markers of infection. As anthelmintic resistance will be the major constraint on the future control of the Cyathostominae, researchers are now actively investigating this area and studies aimed at elucidating the molecular mechanisms of drug resistance are described. Another parasite which has assumed a clinically important role in horses is the tapeworm, Anoplocephala perfoliata. This parasite is prevalent world-wide and has been shown to be a significant cause of equine colic. Because previous methods of estimating the infection intensity of tapeworm were inaccurate, recent research has been directed at developing an immunodiagnostic ELISA for these cestodes. Specific IgG(T) responses to antigens secreted by adult tapeworms have been shown to provide a reasonable indication of infection intensity. An ELISA based on these responses is now commercially available. The steps involved in the development of this ELISA are described here. In addition to these recent advances in research, this review also outlines the principle areas for future research into these important equine parasites

The Effect of Moxidectin Treatment on the Equine Hind Gut Microbiome, Metabonome and Feed Fermentation Kinetics in Horses with Very Low Parasite Burdens

Seventeen horses, mean 12 ± 3.5 years, kept at pasture, with haylage provided and no concentrates. Faecal Egg Counts were conducted September 2015‐March 2016, no eggs seen, no anthelmintic given. Sampling commenced March 2016, points were 0 (prior), 16, 48 and 168 hours post anthelmintic. Treatments were randomized, nine animals dosed orally with Moxidectin 18.92 mg/g at 0.4 mg/kg bw and eight controls. Three horses from each group were randomly assigned for fermentation kinetics. Sequencing of the 16S rRNA gene was conducted on extracted faecal bacterial DNA, bioinformatics using QIIME assigning operational taxonomic units (OTUs). LEfSe (Segata et al., 2011) was used to identify differentially abundant OTUs. Bacterial metabolic profiles were characterized by 1H NMR spectroscopy (Escalona et al., 2015), from urine, analysed by Principal Components Analysis. Fermentation of hay and oats, separately, were measured by in vitro gas production (Murray et al., 2006), data were analysed by repeated measures ANOVA

Reduction of mean-square advection in turbulent passive scalar mixing

Direct numerical simulation data show that the variance of the coupling term in passive scalar advection by a random velocity field is smaller than it would be if the velocity and scalar fields were statistically independent. This effect is analogous to the "depression of nonlinearity" in hydrodynamic turbulence. We show that the trends observed in the numerical data are qualitatively consistent with the predictions of closure theories related to Kraichnan's direct interaction approximation. The phenomenon is demonstrated over a range of Prandtl numbers. In the inertial-convective range the depletion is approximately constant with respect to wavenumber. The effect is weaker in the Batchelor range

Is equine colic seasonal? Novel application of a model based approach

BACKGROUND: Colic is an important cause of mortality and morbidity in domesticated horses yet many questions about this condition remain to be answered. One such question is: does season have an effect on the occurrence of colic? Time-series analysis provides a rigorous statistical approach to this question but until now, to our knowledge, it has not been used in this context. Traditional time-series modelling approaches have limited applicability in the case of relatively rare diseases, such as specific types of equine colic. In this paper we present a modelling approach that respects the discrete nature of the count data and, using a regression model with a correlated latent variable and one with a linear trend, we explored the seasonality of specific types of colic occurring at a UK referral hospital between January 1995–December 2004. RESULTS: Six- and twelve-month cyclical patterns were identified for all colics, all medical colics, epiploic foramen entrapment (EFE), equine grass sickness (EGS), surgically treated and large colon displacement/torsion colic groups. A twelve-month cyclical pattern only was seen in the large colon impaction colic group. There was no evidence of any cyclical pattern in the pedunculated lipoma group. These results were consistent irrespective of whether we were using a model including latent correlation or trend. Problems were encountered in attempting to include both trend and latent serial dependence in models simultaneously; this is likely to be a consequence of a lack of power to separate these two effects in the presence of small counts, yet in reality the underlying physical effect is likely to be a combination of both. CONCLUSION: The use of a regression model with either an autocorrelated latent variable or a linear trend has allowed us to establish formally a seasonal component to certain types of colic presented to a UK referral hospital over a 10 year period. These patterns appeared to coincide with either times of managemental change or periods when horses are more likely to be intensively managed. Further studies are required to identify the determinants of the observed seasonality. Importantly, this type of regression model has applications beyond the study of equine colic and it may be useful in the investigation of seasonal patterns in other, relatively rare, conditions in all species

The association of low complement with disease activity in systemic sclerosis: a prospective cohort study

Background: In some rheumatic diseases such as systemic lupus erythematosus (SLE), low serum complement ('hypocomplementaemia') is a feature of active disease. However, the role of hypocomplementaemia in systemic sclerosis (SSc) is unknown. We sought to determine the frequency, clinical associations and relationship to disease activity of hypocomplementaemia in SSc. Methods: The study included 1140 patients fulfilling the 2013 American College of Rheumatology criteria for SSc. Demographic, serological and clinical data, obtained prospectively through annual review, were analysed using univariable methods. Linear and logistic regression, together with generalised estimating equations, were used to determine the independent correlates of hypocomplementaemia ever, and at each visit, respectively. Results: At least one episode of hypocomplementaemia (low C3 and/or low C4) occurred in 24.1 % of patients over 1893 visits; these patients were more likely to be seropositive for anti-ribonucleoprotein (OR = 3.8, p = 0.002), anti-Ro (OR = 2.2, p = 0.002), anti-Smith (OR = 6.3, p = 0.035) and anti-phospholipid antibodies (OR = 1.4, p = 0.021) and were more likely to display features of overlap connective tissue disease, in particular polymyositis (OR = 16.0, p = 0.012). However, no association was found between hypocomplementaemia and either the European Scleroderma Study Group disease activity score or any of its component variables (including erythrocyte sedimentation rate) in univariate analysis. Among patients with SSc overlap disease features, those who were hypocomplementaemic were more likely to have digital ulcers (OR = 1.6, p = 0.034), tendon friction rubs (OR = 2.4, p = 0.037), forced vital capacity <80 % predicted (OR = 2.9, p = 0.008) and lower body mass index (BMI) (OR for BMI = 0.9, p < 0.0005) at that visit, all of which are features associated with SSc disease activity and/or severity. Conclusions: While hypocomplementaemia is not associated with disease activity in patients with non-overlap SSc, it is associated with some features of increased SSc disease activity in patients with overlap disease features.James Esposito, Zoe Brown, Wendy Stevens, Joanne Sahhar, Candice Rabusa, Jane Zochling, Janet Roddy, Jennifer Walker, Susanna M. Proudman, and Mandana Nikpo