EC144, a synthetic inhibitor of heat shock protein 90, blocks innate and adaptive immune responses in models of inflammation and autoimmunity

Heat shock protein 90 (Hsp90) is a molecular chaperone involved in folding and stabilizing multiple intracellular proteins that have roles in cell activation and proliferation. Many Hsp90 client proteins in tumor cells are mutated or overexpressed oncogenic proteins driving cancer cell growth, leading to the acceptance of Hsp90 as a potential therapeutic target for cancer. Because several signal transduction molecules that are dependent on Hsp90 function are also involved in activation of innate and adaptive cells of the immune system, we investigated the mechanism by which inhibiting Hsp90 leads to therapeutic efficacy in rodent models of inflammation and autoimmunity. EC144, a synthetic Hsp90 inhibitor, blocked LPS-induced TLR4 signaling in RAW 264.7 cells by inhibiting activation of ERK1/2, MEK1/2, JNK, and p38 MAPK but not NF-κB. Ex vivo LPS-stimulated CD11b(+) peritoneal exudate cells from EC144-treated mice were blocked from phosphorylating tumor progression locus 2, MEK1/2, and ERK1/2. Consequently, EC144-treated mice were resistant to LPS administration and had suppressed systemic TNF-α release. Inhibiting Hsp90 also blocked in vitro CD4(+) T cell proliferation in mouse and human MLRs. In vivo, semitherapeutic administration of EC144 blocked disease development in rat collagen-induced arthritis by suppressing the inflammatory response. In a mouse collagen-induced arthritis model, EC144 also suppressed disease development, which correlated with a suppressed Ag-specific Ab response and a block in activation of Ag-specific CD4(+) T cells. Our results describe mechanisms by which blocking Hsp90 function may be applicable to treatment of autoimmune diseases involving inflammation and activation of the adaptive immune response.     

Contrasting diversity dynamics of phoretic mites and beetles associated with vertebrate carrion

Carrion is an ephemeral and nutrient-rich resource that attracts a diverse array of arthropods as it decomposes. Carrion-associated mites often disperse between animal carcasses using phoresy, the transport of one species by another. Yet few studies have contrasted the dynamics of mite assemblages with other insect taxa present at carrion. We examined and compared the changes in abundance, species richness and composition of mite and beetle assemblages sampled at kangaroo carcasses in a grassy eucalypt woodland at four different times over a 6-month period. We found that the majority of mites were phoretic, with the mesostigmatid genera Uroseius (Uropodidae), Macrocheles (Macrochelidae) and Parasitus (Parasitidae) the most abundant taxa (excluding astigmatid mites). Abundance and richness patterns of mites and beetles were very different, with mites reaching peak abundance and richness at weeks 6 and 12, and beetles at weeks 1 and 6. Both mites and beetles showed clear successional patterns via changes in species presence and relative abundance. Our study shows that mesostigmatid mite assemblages have a delay in peak abundance and richness relative to beetle assemblages. This suggests that differences in dispersal and reproductive traits of arthropods may contribute to the contrasting diversity dynamics of carrion arthropod communities, and further highlights the role of carrion as a driver of diversity and heterogeneity in ecosystems.     

Seasonal Variation in the Capacity for Plant Trait Measures to Predict Grassland Carbon and Water Fluxes

There is a need for accurate predictions of ecosystem carbon (C) and water fluxes in field conditions. Previous research has shown that ecosystem properties can be predicted from community abundance-weighted means (CWM) of plant functional traits and measures of trait variability within a community (FDvar). The capacity for traits to predict carbon (C) and water fluxes, and the seasonal dependency of these trait-function relationships has not been fully explored. Here we measured daytime C and water fluxes over four seasons in grasslands of a range of successional ages in southern England. In a model selection procedure, we related these fluxes to environmental covariates and plant biomass measures before adding CWM and FDvar plant trait measures that were scaled up from measures of individual plants grown in greenhouse conditions. Models describing fluxes in periods of low biological activity contained few predictors, which were usually abiotic factors. In more biologically active periods, models contained more predictors, including plant trait measures. Field-based plant biomass measures were generally better predictors of fluxes than CWM and FDvar traits. However, when these measures were used in combination traits accounted for additional variation. Where traits were significant predictors their identity often reflected seasonal vegetation dynamics. These results suggest that database derived trait measures can improve the prediction of ecosystem C and water fluxes. Controlled studies and those involving more detailed flux measurements are required to validate and explore these findings, a worthwhile effort given the potential for using simple vegetation measures to help predict landscape-scale fluxes.     

The effects of light and noise from urban development on biodiversity: Implications for protected areas in Australia

Global population growth and associated urban development are having profound effects on biodiversity. Two major outcomes of expanding development that affect wildlife are light and noise pollution. In this paper, we review literature reporting the effects of light and noise on biodiversity, and assess implications for conservation planning in Australia. Our results clearly indicate that light and noise pollution have the potential to affect the physiology, behaviour and reproduction of a range of animal taxa. Types of effects include changes in foraging and reproductive behaviours, reduction in animal fitness, increased risk of predation and reduced reproductive success. These could have flow‐on consequences at the population and ecosystem levels. We found a significant gap in knowledge of the impact of these pollutants on Australian fauna. To reduce the effect of light and noise pollution, there needs to be careful planning of urban areas in relation to protected areas, and for biodiversity more generally. Potential measures include strategically planning the types of development and associated human activities adjacent to protected areas, and the use of shields and barriers, such as covers for lights or the use of dense native vegetation screens, while still allowing movement of animals. Changes in government standards and regulations could also help to reduce the impacts of light and noise pollution.     

Cost-Effectiveness of Collaborative Care for Depression in UK Primary Care: Economic Evaluation of a Randomised Controlled Trial (CADET)

Background

Collaborative care is an effective treatment for the management of depression but evidence on its cost-effectiveness in the UK is lacking.

Aims

To assess the cost-effectiveness of collaborative care in a UK primary care setting.

Methods

An economic evaluation alongside a multi-centre cluster randomised controlled trial comparing collaborative care with usual primary care for adults with depression (n = 581). Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICER) were calculated over a 12-month follow-up, from the perspective of the UK National Health Service and Personal Social Services (i.e. Third Party Payer). Sensitivity analyses are reported, and uncertainty is presented using the cost-effectiveness acceptability curve (CEAC) and the cost-effectiveness plane.

Results

The collaborative care intervention had a mean cost of £272.50 per participant. Health and social care service use, excluding collaborative care, indicated a similar profile of resource use between collaborative care and usual care participants. Collaborative care offered a mean incremental gain of 0.02 (95% CI: –0.02, 0.06) quality-adjusted life-years over 12 months, at a mean incremental cost of £270.72 (95% CI: –202.98, 886.04), and resulted in an estimated mean cost per QALY of £14,248. Where costs associated with informal care are considered in sensitivity analyses collaborative care is expected to be less costly and more effective, thereby dominating treatment as usual.

Conclusion

Collaborative care offers health gains at a relatively low cost, and is cost-effective compared with usual care against a decision-maker willingness to pay threshold of £20,000 per QALY gained. Results here support the commissioning of collaborative care in a UK primary care setting.     

Bird community responses to the edge between suburbs and reserves

New insights into community-level responses at the urban fringe, and the mechanisms underlying them, are needed. In our study, we investigated the compositional distinctiveness and variability of a breeding bird community at both sides of established edges between suburban residential areas and woodland reserves in Canberra, Australia. Our goals were to determine if: (1) community-level responses were direct (differed with distance from the edge, independent of vegetation) or indirect (differed in response to edge-related changes in vegetation), and (2) if guild-level responses provided the mechanism underpinning community-level responses. We found that suburbs and reserves supported significantly distinct bird communities. The suburban bird community, characterised by urban-adapted native and exotic species, had a weak direct edge response, with decreasing compositional variability with distance from the edge. In comparison, the reserve bird community, characterised by woodland-dependent species, was related to local tree and shrub cover. This was not an indirect response, however, as tree and shrub cover was not related to edge distance. We found that the relative richness of nesting, foraging and body size guilds also displayed similar edge responses, indicating that they underpinned the observed community-level responses. Our study illustrates how community-level responses provide valuable insights into how communities respond to differences in resources between two contrasting habitats. Further, the effects of the suburban matrix penetrate into reserves for greater distances than previously thought. Suburbs and adjacent reserves, however, provided important habitat resources for many native species and the conservation of these areas should not be discounted from continued management strategies.     

Mapping and validation of chromosome regions conferring boron toxicity tolerance in wheat (Triticum aestivum)

Boron is an essential plant micro-nutrient which can be phytotoxic to plants if present in soils in high concentration. Boron toxicity has been recognised as an important problem limiting production in the low rainfall areas of southern Australia, West Asia and North Africa. Genetic variation for boron toxicity tolerance in wheat has been well-characterised. The efficiency of breeding for boron toxicity tolerance could be greatly enhanced by the development of molecular markers associated with QTLs for tolerance in wheat. A population of 161 doubled haploids from a cross between the tolerant cultivar Halberd and the moderately sensitive cultivar Cranbrook was used to identify chromosomal regions involved in boron tolerance. A combined RFLP and AFLP linkage map of the Cranbrook x Halberd population was used to identify chromosomal regions involved in the boron tolerance traits measured. Regions on chromosome 7B and 7D were associated with leaf symptom expression. The region on chromosome 7B was also associated with the control of boron uptake and with a reduction in the effect of boron toxicity on root-growth suppression. RFLP markers at the chromosome 7B and 7D loci were shown to be effective in selecting for improved boron tolerance in an alternative genetic background. Halberd alleles at the chromosome 7B locus were associated with the concentration of boron in whole shoots and grain. The concentration of boron in whole shoots and in grain were both related to grain yield in a field trial conducted on soil containing toxic levels of boron. Implications relating to marker-assisted selection for boron toxicity tolerance in wheat are discussed. Received: 3 September 1999 / Accepted: 12 February 2000     

The Wolff-Parkinson-White Pattern in Routine Electrocardiography

Fifteen thousand consecutive electrocardiograms on R.C.A.F. aircrew applicants aged 18 to 24 were studied from the standpoint of incidence, clinical findings and follow-up of the WPW pattern discovered because the ECG was taken as part of the selection procedure. Forty-six cases were discovered (0.3%). All were reviewed and passed as clinically fit except for one with asymptomatic rheumatic heart disease. Two others gave a history suggestive of paroxysmal rapid heart action. None of the 43 men on follow-up have developed evidence of arrhythmia. Thirteen of the 46 showed an intermittent pattern initially or on subsequent follow-up. Fifty to 80% of people with the WPW pattern experience tachycardia, according to the literature. The incidence of tachycardia in this study was much lower (2 in 46 or 4.3%). The WPW pattern is not synonymous with the WPW syndrome, and iatrogenic heart disease must be avoided in fit young men in whom the WPW pattern is discovered because of routine electrocardiography.