The use of mechanisms and modes of toxic action in integrated testing strategies: the report and recommendations of a workshop held as part of the European Union OSIRIS Integrated Project

This report on The Potential of Mode of Action (MoA) Information Derived from Non-testing and Screening Methodologies to Support Informed Hazard Assessment, resulted from a workshop organised within OSIRIS (Optimised Strategies for Risk Assessment of Industrial Chemicals through Integration of Non-test and Test Information), a project partly funded by the EU Commission within the Sixth Framework Programme. The workshop was held in Liverpool, UK, on 30 October 2008, with 35 attendees. The goal of the OSIRIS project is to develop integrated testing strategies (ITS) fit for use in the REACH system, that would enable a significant increase in the use of non-testing information for regulatory decision making, and thus minimise the need for animal testing. One way to improve the evaluation of chemicals may be through categorisation by way of mechanisms or modes of toxic action. Defining such groups can enhance read-across possibilities and priority settings for certain toxic modes or chemical structures responsible for these toxic modes. Overall, this may result in a reduction of in vivo testing on organisms, through combining available data on mode of action and a focus on the potentially most-toxic groups. In this report, the possibilities of a mechanistic approach to assist in and guide ITS are explored, and the differences between human health and environmental areas are summarised.

Attitudes and Beliefs of Pig Farmers and Wild Boar Hunters Towards Reporting of African Swine Fever in Bulgaria, Germany and the Western Part of the Russian Federation

This study investigated the attitudes and beliefs of pig farmers and hunters in Germany, Bulgaria and the western part of the Russian Federation towards reporting suspected cases of African swine fever (ASF). Data were collected using a web-based questionnaire survey targeting pig farmers and hunters in these three study areas. Separate multivariable logistic regression models identified key variables associated with each of the three binary outcome variables whether or not farmers would immediately report suspected cases of ASF, whether or not hunters would submit samples from hunted wild boar for diagnostic testing and whether or not hunters would report wild boar carcasses. The results showed that farmers who would not immediately report suspected cases of ASF are more likely to believe that their reputation in the local community would be adversely affected if they were to report it, that they can control the outbreak themselves without the involvement of veterinary services and that laboratory confirmation would take too long. The modelling also indicated that hunters who did not usually submit samples of their harvested wild boar for ASF diagnosis, and hunters who did not report wild boar carcasses are more likely to justify their behaviour through a lack of awareness of the possibility of reporting. These findings emphasize the need to develop more effective communication strategies targeted at pig farmers and hunters about the disease, its epidemiology, consequences and control methods, to increase the likelihood of early reporting, especially in the Russian Federation where the virus circulates

Suprasellar chordoid neoplasm with expression of thyroid transcription factor 1: evidence that chordoid glioma of the third ventricle and pituicytoma may form part of a spectrum of lineage-related tumors of the basal forebrain.

Chordoid glioma of the third ventricle is a rare neuroepithelial tumor characterized by a unique histomorphology and exclusive association with the suprasellar/third ventricular compartment. Variously interpreted as either astrocytic- or ependymal-like, and speculatively ascribed to the lamina terminalis/subcommissural organ, its histogenesis remains, nevertheless, unsettled. Here, we report on a suprasellar chordoid glioma occurring in a 52-year-old man. Although displaying otherwise typical morphological features, the tumor was notable for expression of thyroid transcription factor 1, a marker of tumors of pituicytic origin in the context of the sellar region. We furthermore found overlapping immunoprofiles of this example of chordoid glioma and pituicytic tumors (pituicytoma and spindle cell oncocytoma), respectively. Specifically, phosphorylated ribosomal protein S6, a marker of mTOR pathway activation, was expressed in both groups. Based on these findings, we suggest that chordoid glioma and pituicytic tumors may form part of a spectrum of lineage-related neoplasms of the basal forebrain.

Assertive community treatment as part of integrated care versus standard care: a 12-month trial in patients with first- and multiple-episode schizophrenia spectrum disorders treated with quetiapine immediate release (ACCESS trial)

The ACCESS trial examined the 12-month effectiveness of continuous therapeutic assertive community treatment (ACT) as part of integrated care compared to standard care in a catchment area comparison design in patients with schizophrenia spectrum disorders treated with quetiapine immediate release.

Cost-effectiveness of 12-month therapeutic assertive community treatment as part of integrated care versus standard care in patients with schizophrenia treated with quetiapine immediate release (ACCESS trial)

To compare the 1-year cost-effectiveness of therapeutic assertive community treatment (ACT) with standard care in schizophrenia. ACT was specifically developed for patients with schizophrenia, delivered by psychosis experts highly trained in respective psychotherapies, and embedded into an integrated care system.

The exchange of radiotherapy data as part of an electronic patient-referral system

PURPOSE: To describe the implementation and use of an electronic patient-referral system as an aid to the efficient referral of patients to a remote and specialized treatment center. METHODS AND MATERIALS: A system for the exchange of radiotherapy data between different commercial planning systems and a specially developed planning system for proton therapy has been developed through the use of the PAPYRUS diagnostic image standard as an intermediate format. To ensure the cooperation of the different TPS manufacturers, the number of data sets defined for transfer has been restricted to the three core data sets of CT, VOIs, and three-dimensional dose distributions. As a complement to the exchange of data, network-wide application-sharing (video-conferencing) technologies have been adopted to provide methods for the interactive discussion and assessment of treatments plans with one or more partner clinics. RESULTS: Through the use of evaluation plans based on the exchanged data, referring clinics can accurately assess the advantages offered by proton therapy on a patient-by-patient basis, while the practicality or otherwise of the proposed treatments can simultaneously be assessed by the proton therapy center. Such a system, along with the interactive capabilities provided by video-conferencing methods, has been found to be an efficient solution to the problem of patient assessment and selection at a specialized treatment center, and is a necessary first step toward the full electronic integration of such centers with their remotely situated referral centers.

Olfactory bulb interneurons releasing NO exhibit the Reelin receptor ApoEr2 and part of those targeted by NO express Reelin

Nitric oxide (NO) and Reelin both modulate neuronal plasticity in developing and mature synaptic networks. We recently showed a loss of neuronal nitric oxide synthase (nNOS) protein in the olfactory bulb of reeler mutants and advanced the hypothesis that the Reelin and NO signalling pathways may influence each other. We now studied the distribution of NO sensitive guanylyl cyclase (NOsGC), Reelin and its receptor Apolipoprotein E2 (ApoEr2) in the olfactory bulb by multiple fluorescence labelling and tested whether nNOS and ApoEr2 colocalize in this area. We also essayed the protein content of NOsGC in the reeler olfactory bulb and tested whether there are any changes in nNOS and NOsGC protein in other reeler brain areas. Olfactory bulb interneurons expressing ApoEr2 and nNOS are only few in the glomerular layer but represent the large majority of granule cell layer interneurons. Conversely, NOsGC interneurons are rare in the granule cell layer and abundant as periglomerular cells. Reelin containing periglomerular cells almost entirely belong to the NOsGC subset. These data further support the hypothesis of a reciprocal signalling between Reelin/NOsGC and ApoEr2/nNOS expressing neurons to affect olfactory bulb activity. We also show that a significant rise in NOsGC content accompanies the decrease of nNOS protein in the reeler olfactory bulb. The same reciprocal changes present in the cortex/striatum and the hippocampus of reeler mice. Thus, the influence that the deficit of extracellular Reelin seems to exert on nNOS and its receptor is not limited to the olfactory bulb but is a general feature of the reeler brain.

Chemokine receptor 4 (CXCR4) is part of the lipopolysaccharide "sensing apparatus"

Recognition of bacterial lipopolysaccharide (LPS) by the innate immune system involves at least three receptor molecules: CD14, TLR4 and MD-2. Additional receptor components such as heat shock proteins, chemokine receptor 4 (CXCR4), or CD55 have been suggested to be part of this activation cluster; possibly acting as additional LPS transfer molecules. Our group has previously identified CXCR4 as a component of the "LPS-sensing apparatus". In this study we aimed to elucidate the role that CXCR4 plays in innate immune responses to LPS. Here we demonstrate that CXCR4 transfection results in responsiveness to LPS. Fluorescence correlation spectroscopy experiments further showed that LPS directly interacts with CXCR4. Our data suggest that CXCR4 is not only involved in LPS binding but is also responsible for triggering signalling, especially mitogen-activated protein kinases in response to LPS. Finally, co-clustering of CXCR4 with other LPS receptors seems to be crucial for LPS signalling, thus suggesting that CXCR4 is a functional part of the multimeric LPS "sensing apparatus".

Summer temperature in the eastern part of southern South America: its variability in the twentieth century and a teleconnection with Oceania

The 1907–2001 summer-to-summer surface air temperature variability in the eastern part of southern South America (SSA, partly including Patagonia) is analysed. Based on records from instruments located next to the Atlantic Ocean (36°S–55°S), we define indices for the interannual and interdecadal timescales. The main interdecadal mode reflects the late-1970s cold-to-warm climate shift in the region and a warm-to-cold transition during early 1930s. Although it has been in phase with the Pacific Decadal Oscillation (PDO) index since the 1960s, they diverged in the preceding decades. The main interannual variability index exhibits high spectral power at ~3.4 years and is representative of temperature variability in a broad area in the southern half of the continent. Eleven-years running correlation coefficients between this index and December-to-February (DJF) Niño3.4 show significant decadal fluctuations, out-of-phase with the running correlation with a DJF index of the Southern Annular Mode. The main interannual variability index is associated with a barotropic wavetrain-like pattern extending over the South Pacific from Oceania to SSA. During warm (cold) summers in SSA, significant anticyclonic (cyclonic) anomalies tend to predominate over eastern Australia, to the north of the Ross Sea, and to the east of SSA, whereas anomalous cyclonic (anticyclonic) circulation is observed over New Zealand and west of SSA. This teleconnection links warm (cold) SSA anomalies with dry (wet) summers in eastern Australia. The covariability seems to be influenced by the characteristics of tropical forcing; indeed, a disruption has been observed since late 1970s, presumably due to the PDO warm phase.

Integration through Land Improvment – Internal Colonization in Switzerland During the First Part of the 20th Century

Internal colonization in Switzerland is often seen in connection with the battle for cultivation in the Second World War, but the history of internal colonization in Switzerland is more complex. The food crisis in the First World War formed the horizon of experience for various actors from industry, consumer protection, the urban population and agriculture to start considering practical strategies for managing agricultural production. In this way, traditional spaces, such as rural and urban areas and economic roles, such as food producer, consumer and trader, overlapped and were newly conceived to some extent: people started thinking about utopias and how a modern society could be designed to be harmonious and resistant to crisis. The aim of this article is to trace some of the key points in this process for the interwar years in neutral Switzerland. In the process, the focus must be on the context of people’s mentalities in the past, although the relationships between the actors of internal colonization and the state also need to be considered. Internal colonization in Switzerland in the twentieth century can be understood as an open process. In principle, the project was driven by private actors, but in times of crisis, the project was claimed by the state as a possible tool for social and economic intervention. In addition, as a result of the planned dissolution of urban and rural spaces, it will be shown that modern societies in the interwar period were on an existential search to overcome the problems of the modern age. Internal colonization can therefore be seen as an attempt to find a third way between a world characterized by an agrarian society and a modern industrial nation.