IL-1ß induces changes in expression of core circadian clock components PER2 and BMAL1 in primary human chondrocytes through the NMDA receptor/CREB and NF-κB signalling pathways.

The circadian clock is a specialised cell signalling circuit present in almost all cells. It controls the timing of key cell activities such as proliferation and differentiation. In osteoarthritis, expression of two components of the circadian clock, BMAL1 and PER2 is altered in chondrocytes and this change has been causally linked with the increase in proliferation and altered chondrocyte differentiation in disease. IL-1ß, an inflammatory cytokine abundant in OA joints, has previously been shown to induce changes in BMAL1 and PER2 expression in chondrocytes. The purpose of this study is to identify the mechanism involved. We found IL-1ß treatment of primary human chondrocytes led to activation of NMDA receptors as evidenced by an increase in phosphorylation of GluN1 and an increase in intracellular calcium which was blocked by the NMDAR antagonist MK801. Levels of phosphorylated CREB were also elevated in IL-1ß treated cells and this effect was blocked by co-treatment of cells with IL-1ß and the NMDAR antagonist MK-801. Knockdown of CREB or inhibition of CREB activity prevented the IL-1ß induced increase in PER2 expression in chondrocytes but had no effect on BMAL1. Phosphorylated p65 levels were elevated in IL-1ß treated chondrocytes indicating increased NF-κB activation. Inhibition of NF-κB activity prevented the IL-1ß induced reduction in BMAL1 expression and partially mitigated the IL-1ß induced increase in PER2 expression in chondrocytes. These data indicate that the NMDAR/CREB and NF-κB signalling pathways regulate the core circadian clock components PER2 and BMAL1 in chondrocytes. Given that changes in expression of these clock components have been observed in a wide range of diseases, these findings may be broadly relevant for understanding the mechanism leading to circadian clock changes in pathology.

Marine macrofaunal traits responses to dredged material disposal.

Currently, our understanding of the mechanisms for, and potential functional implications of, changes in seabed assemblages resulting from dredged material disposal is relatively unknown. Based on empirical data from 17 disposal sites, we address this by quantifying the nature and magnitude of shifts in the relative composition of response and effects traits within disposal site assemblages relative to their reference assemblages. Differing shifts in both response and effects traits were observed across sites, regardless of the trait composition of the reference assemblages. Notable differences in the magnitude of traits changes were also observed for both trait types. Traits shifts are difficult to predict as they appear to reflect both environmental conditions and disposal regime. Temporal data revealed that some sites display relatively consistent responses while others presented large inter-annual variability. These findings are discussed in relation to dredged material monitoring and with respect to conservation objectives of marine protected areas.

Differences in biological traits composition of benthic assemblages between unimpacted habitats.

There is an implicit requirement under contemporary policy drivers to understand the characteristics of benthic communities under anthropogenically-unimpacted scenarios. We used a trait-based approach on a large dataset from across the European shelf to determine how functional characteristics of unimpacted benthic assemblages vary between different sedimentary habitats. Assemblages in deep, muddy environments unaffected by anthropogenic disturbance show increased proportions of downward conveyors and surface deposit-feeders, while burrowing, diffusive mixing, scavenging and predation traits assume greater numerical proportions in shallower habitats. Deep, coarser sediments are numerically more dominated by sessile, upward conveyors and suspension feeders. In contrast, unimpacted assemblages of coarse sediments in shallower regions are proportionally dominated by the diffusive mixers, burrowers, scavengers and predators. Finally, assemblages of gravelly sediments exhibit a relatively greater numerical dominance of non-bioturbators and asexual reproducers. These findings may be used to form the basis of ranking habitats along a functional sensitivity gradient.

An approach for the identification of exemplar sites for scaling up targeted field observations of benthic biogeochemistry in heterogeneous environments.

Continental shelf sediments are globally important for biogeochemical activity. Quantification of shelf-scale stocks and fluxes of carbon and nutrients requires the extrapolation of observations made at limited points in space and time. The procedure for selecting exemplar sites to form the basis of this up-scaling is discussed in relation to a UK-funded research programme investigating biogeochemistry in shelf seas. A three-step selection process is proposed in which (1) a target area representative of UK shelf sediment heterogeneity is selected, (2) the target area is assessed for spatial heterogeneity in sediment and habitat type, bed and water column structure and hydrodynamic forcing, and (3) study sites are selected within this target area encompassing the range of spatial heterogeneity required to address key scientific questions regarding shelf scale biogeochemistry, and minimise confounding variables. This led to the selection of four sites within the Celtic Sea that are significantly different in terms of their sediment, bed structure, and macrofaunal, meiofaunal and microbial community structures and diversity, but have minimal variations in water depth, tidal and wave magnitudes and directions, temperature and salinity. They form the basis of a research cruise programme of observation, sampling and experimentation encompassing the spring bloom cycle. Typical variation in key biogeochemical, sediment, biological and hydrodynamic parameters over a pre to post bloom period are presented, with a discussion of anthropogenic influences in the region. This methodology ensures the best likelihood of site-specific work being useful for up-scaling activities, increasing our understanding of benthic biogeochemistry at the UK-shelf scale.

The effect of sewage pollution on the feeding behaviour and diet of Hediste (Nereis diversicolor (O.F. Müller, 1776)) in three estuaries in south-east England, with implications for saltmarsh erosion.

Stable isotope analyses of the abundant infaunal polychaete Hediste diversicolor, recognised as an indicator of sewage pollution, support the hypothesis that nutrient enrichment promotes surface deposit feeding, over suspension feeding and predation. At sewage-polluted sites in three estuaries in SE England Hediste mainly consumed microphytobenthos, sediment organic matter and filamentous macroalgae Ulva spp. At cleaner sites Hediste relied more on suspension feeding and consumption of Spartina anglica. There were no consistent differences in Hediste densities between the polluted and cleaner sites, probably because of increased densities at the cleaner sites too, facilitated by the planting of Spartina and nitrogen enrichment there too, including from agricultural run-off. Increased nutrient enrichment and the artificial availability of Spartina have probably increased densities of, and deposit-feeding by, Hediste in the past half-century and contributed indirectly to saltmarsh losses, since deposit-feeding by Hediste has been implicated in recent saltmarsh erosion in SE England.

Application of biological traits to further our understanding of the impacts of dredged material disposal on benthic assemblages.

While the effects of coastal disposal of dredged material on benthic assemblage structure have been well studied, our understanding of the mechanism of such responses, and their potential ecological implications, remain relatively unknown. Data from a licenced disposal site off the northeast coast of England are analysed to address this and improve our ability to make informed licencing decisions for this activity. Assemblages within the disposal site displayed reduced number of species and total invertebrate density, an altered assemblage taxonomic structure, and a shift towards a greater numerical dominance of less-productive individuals. Following separate analyses of biological response and effect traits, a novel approach for marine benthic trait analysis, we identify the traits responsible (i.e. response traits) for the observed structural alterations. Furthermore, analysis of the effect traits revealed that the assemblages characterising the disposal site possess a greater bioturbative capability compared to those not directly impacted by disposal.

Macrofaunal recovery following the intertidal recharge of dredged material: a comparison of structural and functional approaches.

There is a growing need to understand the functional implications of anthropogenic pressures, such as those following coastal disposal of dredged material. Current assessments, based on taxonomic structure of benthic organisms, only provide a limited capacity to determine functional impacts or recovery. This study assesses recovery of two intertidal dredged material recharge schemes, comparing results obtained based on taxonomic structure (univariate and multivariate approaches) and function (biological trait composition, functional diversity, secondary production) of the benthic assemblages. The assemblages recolonising both schemes were consistently less speciose, less densely-populated and exhibited multivariate community structures that differed from those of the reference areas. However, for both schemes metrics of functionality converged to those of reference areas, although some differences in trait composition persisted for up to 3 years. These data support the proposition that impacts of, and recovery from, anthropogenic disturbance should be assessed using a combination of both functional and taxonomic structural approaches.

Impacts of maintenance dredged material disposal on macrobenthic structure and secondary productivity.

The results of a monitoring programme to assess the spatial impacts associated with ongoing dredged material disposal activity at a dispersive, coastal disposal site (southwest UK) are described. Benthic impacts were assessed using benthic community structure and secondary productivity estimates. Analyses of univariate indices (including secondary production) and multivariate community structure revealed differences between stations inside and those outside the disposal site were minimal. Generally, stations within and outside the disposal site were characterised by the same species. Regression models indicated that the variability in biological structure and secondary production was predominantly accounted for by natural variables (e.g., depth, sediment granulometry) with only a small amount of residual variability being due to contaminant variables. Thus, the elevated levels of certain contaminants in the vicinity of the disposal area were not sufficient to result in significant ecological or ecotoxicological changes. We ascribe such findings partly to the dispersive nature of the disposal site.

Response of intertidal macrofauna to multiple disturbance types and intensities - an experimental approach.

Two of the best-supported theories which describe the effects of disturbance within marine benthic habitats are the organic enrichment 'Successional Model' and the 'Intermediate Disturbance Hypothesis'. Underlying these models, biological mechanisms thought to drive community change include competition, facilitation, inhibition, tolerance and random colonisation. To further examine the effects of disturbance an experimental test of the effects of different types (burial, raking and organic enrichment) and intensities of disturbance on infaunal intertidal communities at two different sites with similar suites of species was carried out. The same type and frequency of disturbance, applied to the two different sites, produced different responses at the species, community and trophic group level. In models that assume a linear relationship between disturbance intensity and effect, knowledge of the intensity of any novel disturbance, combined with the original disturbance regime experienced by a community (i.e. its 'starting point'), should be sufficient to predict final community characteristics. The current results do not conform to such a linear interpretation, as at both sites the intensity of treatments did not always predict the degree of disturbance. Therefore the response to disturbance may depend on site-specific factors such as the history of prior disturbance and the inherent ecological plasticity exhibited by many benthic species. Whilst current models perform well in predicting benthic responses to gross disturbance, detecting subtler effects requires a recognition that community response may depend on the site, the species and the sources of disturbance.

Macrofaunal recovery following TBT ban. Long-term recovery of subtidal macrofaunal communities in relation to declining levels of TBT contamination.

In the United Kingdom, the use of TBT-based anti-fouling paints on small vessels was banned in 1987, and a biological study of the Crouch Estuary, a yachting centre on the south-eastern coast of the UK, was conducted in order to determine the ecological improvements resulting from this legislation. We present the changes in the macro-infaunal communities along the estuary in relation to declining TBT concentrations between 1987 and 2005. Although the major changes in response to the ban were observed within the first 3 years (primarily an increase in the number of crustacean taxa and a shift in community structure), with changes still apparent between three and 5 years, the temporal duration of this study allowed the rapidity of the response to be truly determined.

Macro- and meiofaunal recolonisation of dredged material used for habitat enhancement: temporal patterns in community development.

In recent years, dredged material has become regarded as a potential resource and used to create and/or improve intertidal habitats (i.e., beneficial use). This paper presents the results of a sampling programme to investigate the long-term (42 months post-recharge) macro- and meiofaunal recolonisation processes of a beneficial use scheme in south-east England. While univariate indices of community structure indicated that the scheme's meiofaunal community was never significantly different from that of a nearby reference area, such attributes for macrofauna were continually significantly below those of the reference area, although this was not the case for all reference stations. Multivariate analyses revealed that macro- and meiofaunal community structures were always significantly different from those of the reference communities. We discuss the factors responsible for these observations and propose that assessing recovery of a beneficial use scheme should be undertaken using pre-defined criteria in addition to comparisons with a reference site.

Ecological consequences of dredged material disposal in the marine environment: a holistic assessment of activities around the England and Wales coastline.

This study provides a holistic perspective on the ecological effects of dredged material disposal, both intertidally and subtidally. A number of numerical techniques (univariate, distributional, multivariate and meta-analysis) were used to assess impacts at 18 different disposal sites. The analyses revealed that ecological effects associated with dredged material disposal were dependent on the numerical techniques used, and that impacts were disposal-site specific. Disposal-site communities were generally faunistically impoverished to varying degrees, and impacts following intertidal placement were comparable to those of subtidal placement. We conclude that any assessment of the consequences of dredged material disposal to the coastal environment must take account of site-specific variation in prevailing hydrographic regimes and in ecological status, along with information on the disposal activity itself (mode, timing, quantity, frequency and type of material). As would be expected, variability in the latter presents a significant challenge in attempts to generalise about environmental and ecological impacts.

Slide session, British Society for Haematology, 45th Annual Scientific Meeting, Manchester, 2005.

Each year at the Annual Scientific Meeting of the British Society for Haematology, there is a slide session in which microscopic slides of six patients with haematological disorders are discussed by two experts. Further data and the final diagnosis are then provided. The slide session is presented here, as it occurred at the meeting.

Development of macrofaunal communities on dredged material used for mudflat enhancement: a comparison of three beneficial use schemes after one year.

In recent years, dredged material has become regarded as a potential resource and used to create and/or improve intertidal habitats ('beneficial use' schemes). This paper presents the results of a sampling programme to investigate the short-term macrofaunal recovery of three beneficial use schemes in south-east England in terms of species and functional diversity. Environmental parameters (sediment redox potential, and water, organic carbon and silt/clay contents) and univariate community attributes (total individuals and species, diversity, evenness and biomass) at the recharge sites had attained reference levels at two schemes while assemblages differed significantly in terms of species composition at all three schemes. While trophic group proportionality had re-established at one scheme, an increased grazer dominance was apparent at another while the proportion of sub-surface deposit feeders decreased at the third. Total individuals and species number of the developing communities were negatively correlated with sediment redox potential at 4 cm and % silt/clay, respectively. The implications of these results for monitoring the recovery of future fine-grained beneficial use schemes are discussed.

The development of targeted chemotherapy for CNS lymphoma-a pilot study of the IDARAM regimen.

PURPOSE: We have developed and evaluated a CNS-targeted chemotherapy regimen based on the pharmacokinetic properties of the individual drugs in the combination. PATIENTS AND METHODS: In a twin-track study, 16 patients with secondary CNS lymphoma (SCNSL) and 8 with primary CNS lymphoma (PCNSL) were treated with IDARAM which comprised idarubicin 10 mg/m(2) i.v., days 1 and 2; dexamethasone 100 mg, 12-h infusion, days 1, 2 and 3; cytosine arabinoside (ARA-C) 1.0 g/m(2), 1-h infusion, days 1 and 2; methotrexate 2.0 g/m(2), 6-h infusion, day 3 (with folinic acid rescue); and cytosine arabinoside 70 mg plus methotrexate 12 mg, intrathecally, days 1 and 8. Two cycles were delivered at 3-weekly intervals. After response assessment, patients received adjuvant cranial radiotherapy (40 Gy over 20 fractions). RESULTS: The series comprised 24 patients, 11 male and 13 female. Their median age was 53 years (range 21 to 73 years). Grade 4 neutropenia and thrombocytopenia occurred in the majority of patients treated. Of the eight PCNSL patients, seven achieved complete remission (CR). Four remained in CR at the time of this report with a median duration of follow-up of 25 months (range 11 to 42 months). Of the 16 SCNSL patients, 12 achieved CR. Seven patients remained in CR at the time of this report with a median duration of follow-up of 24 months (range 18 to 57 months). CONCLUSION: This study suggests that IDARAM is an effective regimen in both PCNSL and SCNSL and is suitable for further development and evaluation.

Colony-stimulating factors in the treatment of older patients with acute myelogenous leukaemia.

The treatment of acute myelogenous leukaemia (AML) in the elderly is a difficult and increasing problem. The elderly are generally less able to tolerate the intensive chemotherapy required to achieve a sustained remission, and there is an increased incidence of resistant disease in this age group. Granulocyte- and granulocyte-macrophage colony-stimulating factors have been demonstrated to shorten the duration of severe neutropenia following chemotherapy for solid tumours and after bone marrow/peripheral blood stem cell transplantation, and the effect of these growth factors in the treatment of AML has been investigated in a number of trials using 2 distinct strategies. Growth factors may be administered following chemotherapy in an attempt to accelerate neutrophil recovery, and they may be given before and during chemotherapy with the aim to increase the number of leukaemic blast cells in cell cycle and enhance their responsiveness to chemotherapy. Both of these approaches have proved safe despite initial theoretical concerns regarding the expression of receptors for these growth factors on leukaemic cells. The results of trials using these growth factors in the treatment of AML in the elderly generally show a significant reduction in the duration of neutropenia following induction chemotherapy. However, consistent benefits with respect to morbidity and early mortality together with improvements in long term disease outcome have not been observed. The 'priming' approach using growth factors before and during induction chemotherapy has proved equally disappointing in failing to improve response rates or survival. The routine use of these growth factors in the treatment of AML in the elderly population as a whole would, therefore, not seem to be cost effective.

Association of myelodysplastic changes with purine analogues.

We describe the occurrence of myelodysplastic changes (hypogranular myeloid series and Pelger cells, dyserythropoiesis with ring sideroblasts) in five of 31 patients with chronic lymphoproliferative disorders after treatment with purine analogues. The bone marrows of 31 patients with chronic lymphoproliferative disorders before and after treatment with purine analogues were reviewed. The majority of patients had received extensive prior treatment, but none had dysplastic changes prior to treatment with purine analogues. We suggest that a purine analogue may have been responsible for dysplastic change and that further follow-up of this phenomenon is warranted.

Fludarabine is effective in the treatment of splenic lymphoma with villous lymphocytes.

We report on the use of fludarabine in four patients with splenic lymphoma with villous lymphocytes (SLVL). All four had relapsed after, or failed to respond to, recommended first-line therapies. In each case fludarabine resulted in a complete clinico-haematological response with minimal toxicity, which, in the two patients with long-term follow-up, proved durable. Fludarabine is effective in the treatment of SLVL and should be considered as both a first-line therapeutic option as well as salvage therapy in this condition.