Seasonal and dietary influences on adipose tissue and systemic gene expression in control and previously laminitic ponies

The aims of the study were to determine whether adipose tissue global gene expression (i) differs between never laminitic (NL) and previously laminitic (PL) ponies; (ii) is influenced by season and/or a diet designed to simulate spring grass and (iii) differences seen also occur systemically in peripheral blood mononuclear cells (PBMCs). Subcutaneous adipose tissue and PBMCs were obtained from six NL and six PL ponies on three occasions; summer, winter (season study) and in winter after consuming a diet simulating spring grass for seven days (diet study). Adipose tissue global gene expression was determined using a 44K equine specific microarray, validated using multiplex quantitative real time PCR (qRT-PCR) and analysed using GeneSpring software and Ingenuity Pathway Analysis. PBMC gene expression was quantified using qRT-PCR. The total number of genes whose expression differed (=2-fold change, p=0.01) between PL and NL ponies was greater in summer (192 genes) compared to winter (58 genes); 40/192 genes influenced by disease in the summer were also seasonally regulated and were predominantly associated with inflammation. The genes modified by dietary intervention and PBMC gene expression did not follow the same pattern as the season study. Thus, adipose tissue global gene expression differed between NL and PL ponies most in summer compared to winter, and these differentially expressed genes predominantly related to inflammation

Steady-state modulation of voltage-gated K+ channels in rat arterial smooth muscle by cyclic AMP-dependent protein kinase and protein phosphatase 2B

Voltage-gated potassium channels (Kv) are important regulators of membrane potential in vascular smooth muscle cells, which is integral to controlling intracellular Ca2+ concentration and regulating vascular tone. Previous work indicates that Kv channels can be modulated by receptor-driven alterations of cyclic AMP-dependent protein kinase (PKA) activity. Here, we demonstrate that Kv channel activity is maintained by tonic activity of PKA. Whole-cell recording was used to assess the effect of manipulating PKA signalling on Kv and ATP-dependent K+ channels of rat mesenteric artery smooth muscle cells. Application of PKA inhibitors, KT5720 or H89, caused a significant inhibition of Kv currents. Tonic PKA-mediated activation of Kv appears maximal as application of isoprenaline (a β-adrenoceptor agonist) or dibutyryl-cAMP failed to enhance Kv currents. We also show that this modulation of Kv by PKA can be reversed by protein phosphatase 2B/calcineurin (PP2B). PKA-dependent inhibition of Kv by KT5720 can be abrogated by pre-treatment with the PP2B inhibitor cyclosporin A, or inclusion of a PP2B auto-inhibitory peptide in the pipette solution. Finally, we demonstrate that tonic PKA-mediated modulation of Kv requires intact caveolae. Pre-treatment of the cells with methyl-β-cyclodextrin to deplete cellular cholesterol, or adding caveolin-scaffolding domain peptide to the pipette solution to disrupt caveolae-dependent signalling each attenuated PKA-mediated modulation of the Kv current. These findings highlight a novel, caveolae-dependent, tonic modulatory role of PKA on Kv channels providing new insight into mechanisms and the potential for pharmacological manipulation of vascular tone

Preformulated Implementation Intentions to Promote Colorectal Cancer Screening: A Cluster-Randomized Trial

Objective: To evaluate an intervention based on implementation intention principles designed to increase uptake of colorectal cancer screening, and to examine differential efficacy by socioeconomic deprivation. Method: In England, adults aged between 60 and 69 years are invited for biennial fecal occult blood testing. A test kit and an information leaflet are mailed to each individual by the "Hubs" that deliver the national screening program. In the intervention group, three preformulated implementation intentions, based on known barriers to carrying out the test, were added to the information leaflet. Over a 12-week period, each week was randomly allocated to either the intervention (n = 12,414 invitations) or the control condition (n = 10,768), with uptake recorded at the Hub. Socioeconomic deprivation of each individual's area of residence was categorized into tertiles. Results: There was no overall difference in uptake between control (40.4%) and intervention (39.7%) conditions, odds ratio (OR) = 0.97, 95% confidence interval (CI) [0.91, 1.04]. There was an interaction with deprivation, OR = 1.11, 95% CI [1.04, 1.18], but the positive effect observed in the lowest socioeconomic status (SES) tertile was small (35.2% vs. 33.0%), OR = 1.103, 95% CI [1.01, 1.21], and offset by a negative effect in the least deprived tertile (45.6% vs. 48.2%), OR = 0.90, 95% CI [0.82, 0.99]. The intervention had no significant effect in the middle tertile (38.9% vs. 40.8%), OR = 0.92, 95% CI [0.81, 1.04]. Conclusion: Preformulated implementation intentions did not increase overall colorectal cancer screening uptake and failed to make a sufficiently large impact on uptake among lower SES groups to merit their future use in this context. (PsycINFO Database Record (c) 2013 APA, all rights reserved)

The Ecological Impacts of Contaminated Sediment from Abandoned Metal Mines

Contains public sector information licensed under the Open Government Licence v3.0. The OGL requires that users acknowledge the information provider and/or source of the information with an attribution statement.Pollution from abandoned non-coal (i.e. metal) mines is a serious impediment to rivers meeting the water quality targets set out in River Basin Management Plans. Recent work has identified the mines most likely to be causing a significant environmental impact and hence where efforts to prevent pollution need to be focussed. Yet, it is not clear to what extent rivers, and the animal and plant life they support, are impacted by the legacy of past pollution still bound up in river sediments. Work will be undertaken to reduce toxic metals in mine waters before they enter the river. However, if riverbed sediments are already contaminated and affecting life in rivers, the planned clean-up of mine water sources may not result in recovery of ecological condition. A controlled laboratory experiment was undertaken where river invertebrates (mayfly larvae) from an uncontaminated site were incubated with contaminated riverbed sediment collected downstream of an abandoned metal mine. Concentrations of metals in the tissues of the mayflies increased over the duration of the incubation, particularly those metals that were in high concentrations in the sediment, i.e. cadmium, copper and zinc. As the sediment was the only substantial source of metals in the experiment, it is apparent that the contaminated riverbed sediment was acting as a source of bioavailable metals. It is likely that contaminated sediments, including riverbed sediment, will act as a source of bioavailable metals, at least to benthic organisms, even where mine drainage water is treated to reduce metal concentrations. Metal toxicity occurs when the rate of metal uptake into an organism exceeds the combined rates of excretion and physiological detoxification. Current tests of metal toxicity on biota typically do not match in scale (temporal, spatial and taxonomic range) with assessments of ecological quality undertaken for management, which raises questions regarding the adequacy of environmental limits based on laboratory testing. Existing data were compiled describing geochemistry of riverbed sediment and the Biological Quality Elements invertebrates, diatoms, macrophytes and fish, collected by the regulatory authorities to assess the condition of rivers. As toxic effects of trace metals were not expected at low concentrations, the biological response to sediment metal concentration was determined using a threshold model. Thresholds were found for biotic metrics based on species richness, but other metrics (diatom EQR, macrophyte EQR and invertebrate ASPT) displayed implausible positive relationships with sediment metal concentrations and should not be relied upon for classification of ecological status in waterbodies affected by mining. New data were collected from 20 spatially-independent river catchments in areas affected by metal mine facilities, including samples of the macroinvertebrate community, bioavailability of metals (assessed as metal concentrations in the body tissue of tolerant taxa), and sediment metal concentrations. There were strong correlations between sediment metal concentrations and measured bioavailability, particularly for copper and lead. Measurements of bioavailable metals were related to changes in taxon richness in the invertebrate samples. The data were used to develop a new biotic index (MetTol), which can be used to assess the extent of ecological damage from metal contamination using standard invertebrate monitoring data, and to construct dose response curves based on species sensitivities. A number of approaches were used to establish tolerable limits for sediment metal concentrations based on ecological data, and the results compared with existing Canadian sediment quality guidelines. The limits for copper derived from ecological data were most consistent with existing sediment guidelines. The limits for other metals (silver, arsenic, cadmium, nickel, lead and zinc) derived from ecological data were up to an order of magnitude above the Canadian interim sediment quality guidelines. These existing guidelines, based on toxicological data, may be too precautionary, and we suggest that guideline sediment concentrations based on ecological data may provide a more appropriate level of protection for the environment

Risk factors for high anti-HHV-8 antibody titers (≥1:51,200) in black, HIV-1 negative South African cancer patients: a case control study

Background: Infection with human herpesvirus 8 (HHV-8) is the necessary causal agent in the development of Kaposi's sarcoma (KS). Infection with HIV-1, male gender and older age all increase risk for KS. However, the geographic distribution of HHV-8 and KS both prior to the HIV/AIDS epidemic and with HIV/AIDS suggest the presence of an additional co-factor in the development of KS. Methods: Between January 1994 and October 1997, we interviewed 2576 black in-patients with cancer in Johannesburg and Soweto, South Africa. Blood was tested for antibodies against HIV-1 and HHV-8 and the study was restricted to 2191 HIV-1 negative patients. Antibodies against the latent nuclear antigen of HHV-8 encoded by orf73 were detected with an indirect immunofluorescence assay. We examined the relationship between high anti-HHV-8 antibody titers (≥1:51,200) and sociodemographic and behavioral factors using unconditional logistic regression models. Variables that were significant at p = 0.10 were included in multivariate analysis. Results: Of the 2191 HIV-1 negative patients who did not have Kaposi's sarcoma, 854 (39.0%) were positive for antibodies against HHV-8 according to the immunofluorescent assay. Among those seropositive for HHV-8, 530 (62.1%) had low titers (1:200), 227 (26.6%) had medium titers (1:51,200) and 97 (11.4%) had highest titers (1:204,800). Among the 2191 HIV-1 negative patients, the prevalence of high anti-HHV-8 antibody titers (≥1:51,200) was independently associated with increasing age (ptrend = 0.04), having a marital status of separated or divorced (p = 0.003), using wood, coal or charcoal as fuel for cooking 20 years ago instead of electricity (p = 0.02) and consuming traditional maize beer more than one time a week (p = 0.02; p-trend for increasing consumption = 0.05) although this may be due to chance given the large number of predictors considered in this analysis. Conclusions: Among HIV-negative subjects, patients with high anti-HHV-8 antibody titers are characterized by older age. Other associations that may be factors in the development of high anti- HHV-8 titers include exposure to poverty or a low socioeconomic status environment and consumption of traditional maize beer. The relationship between these variables and high anti- HHV-8 titers requires further, prospective study

Spatial variation of trace metals within intertidal beds of native mussels (Mytilus edulis) and non-native Pacific oysters (Crassostrea gigas): implications for the food web?

Abstract Pollution is of increasing concern within coastal regions and the prevalence of invasive species is also rising. Yet the impact of invasive species on the distribution and potential trophic transfer of metals has rarely been examined. Within European intertidal areas, the non-native Pacific oyster (Crassostrea gigas) is becoming established, forming reefs and displacing beds of the native blue mussel (Mytilus edulis). The main hypothesis tested is that the spatial pattern of metal accumulation within intertidal habitats will change should the abundance and distribution of C. gigas continue to increase. A comparative analysis of trace metal content (cadmium, lead, copper and zinc) in both species was carried out at four shores in south-east England. Metal concentrations in bivalve and sediment samples were determined after acid digestion by inductively coupled plasma-optical emission spectrometry. Although results showed variation in the quantities of zinc, copper and lead (mg m-2) in the two bivalve species, differences in shell thickness are also likely to influence the feeding behaviour of predators and intake of metals. The availability and potential for trophic transfer of metals within the coastal food web, should Pacific oysters transform intertidal habitats, is discussed

Evaluation of a service intervention to improve awareness and uptake of bowel cancer screening in ethnically-diverse areas

The Policy Research Unit in Cancer Awareness, Screening and Early Diagnosis receives funding for a research programme from the UK Department of Health Policy Research Programme (grant no. 106/0001). It is a collaboration between researchers from seven institutions (the Queen Mary University of London, the UCL, the King’s College London, the London School of Hygiene and Tropical Medicine, the Hull York Medical School, the Durham University and the Peninsula Medical School)

GDF15 linked to maternal risk of nausea and vomiting during pregnancy

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy (NVP) including its most severe form, Hyperemesis Gravidarum (HG), but a full mechanistic understanding is lacking [1-4]. Here we report that fetal production of GDF15, and maternal sensitivity to it, both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally-labelled GDF15 variant we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with beta-thalassemia, a condition where GDF15 levels are chronically high [5], report very low levels of NVP. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally-derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by pre-pregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.</p

Genetic and functional data identifying Cd101 as a type 1 diabetes (T1D) susceptibility gene in nonobese diabetic (NOD) mice

Type 1 diabetes (T1D) is a chronic multi-factorial disorder characterized by the immune-mediated destruction of insulin-producing pancreatic beta cells. Variations at a large number of genes influence susceptibility to spontaneous autoimmune T1D in non-obese diabetic (NOD) mice, one of the most frequently studied animal models for human disease. The genetic analysis of these mice allowed the identification of many insulin-dependent diabetes (Idd) loci and candidate genes, one of them being Cd101. CD101 is a heavily glycosylated transmembrane molecule which exhibits negative-costimulatory functions and promotes regulatory T (Treg) function. It is abundantly expressed on subsets of lymphoid and myeloid cells, particularly within the gastrointestinal tract. We have recently reported that the genotype-dependent expression of CD101 correlates with a decreased susceptibility to T1D in NOD.B6 Idd10 congenic mice compared to parental NOD controls. Here we show that the knockout of CD101 within the introgressed B6-derived Idd10 region increased T1D frequency to that of the NOD strain. This loss of protection from T1D was paralleled by decreased Gr1-expressing myeloid cells and FoxP3+ Tregs and an enhanced accumulation of CD4-positive over CD8-positive T lymphocytes in pancreatic tissues. As compared to CD101+/+ NOD.B6 Idd10 donors, adoptive T cell transfers from CD101−/− NOD.B6 Idd10 mice increased T1D frequency in lymphopenic NOD scid and NOD.B6 Idd10 scid recipients. Increased T1D frequency correlated with a more rapid expansion of the transferred CD101−/− T cells and a lower proportion of recipient Gr1-expressing myeloid cells in the pancreatic lymph nodes. Fewer of the Gr1+ cells in the recipients receiving CD101−/− T cells expressed CD101 and the cells had lower levels of IL-10 and TGF-β mRNA. Thus, our results connect the Cd101 haplotype-dependent protection from T1D to an anti-diabetogenic function of CD101-expressing Tregs and Gr1-positive myeloid cells and confirm the identity of Cd101 as Idd10