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A case of ureteric metastasis of pancreatic carcinoma is discussed. Metastatic disease of the ureter is very rare and only 9 other cases of pancreatic carcinoma metastasizing to the ureter have been published. A lack of continuous longitudinal blood and lymphatic vasculature is a possible explanation for the low incidence. Diagnosis of ureteric metastasis can be difficult and a combination of radiographic imaging and histologic evaluation is often required. Treatment of ureteric metastasis depends on the primary tumor. Metastasectomy can be considered in a select number of patients. When urinary obstruction is caused by the ureteric mass, urine drainage can be considered.

Anaemia is highly prevalent at the time of intensive care unit discharge and is persistent for a high proportion of intensive care unit survivors. Whether anaemia is a driver of impaired recovery after critical illness is uncertain. The aim of this study was to test the hypothesis that, in adult intensive care survivors, anaemia at the time of intensive care unit discharge independently predicts decreased days at home-90. This retrospective cohort study was conducted in a tertiary intensive care unit in Perth, Western Australia. All patients aged ≥ 16 years, discharged alive from their index intensive care unit admission and without documented treatment limitations were included. Median (IQR [range]) age of the 6358 participants was 61 (46-72 [16-95]) years and included 3385 (53.2%) unplanned admissions. Intensive care unit discharge with a haemoglobin concentration

Endoscopic resection (ER) is an important diagnostic step in management of patients with early Barrett’s esophagus (BE) neoplasia. Based on ER specimens, an accurate histological diagnosis can be made, which guides further treatment. Based on depth of tumor invasion, differentiation grade, lymphovascular invasion, and margin status, the risk of lymph node metastases and local recurrence is judged to be low enough to justify endoscopic management, or high enough to warrant invasive surgical esophagectomy. Adequate assessment of these histological risk factors is therefore of the utmost importance. Aim of this study was to assess pathologist concordance on these histological features on ER specimens and evaluate causes of discrepancy. Of 62 challenging ER cases, one representative H&E slide and matching desmin and endothelial marker were digitalized and independently assessed by 13 dedicated GI pathologists from 8 Dutch BE expert centers, using an online assessment module. For each histological feature, concordance and discordance were calculated. Clinically relevant discordances were observed for all criteria. Grouping depth of invasion categories according to expanded endoscopic treatment criteria (T1a and T1sm1 vs. T1sm2/3), ≥1 pathologist was discrepant in 21% of cases, increasing to 45% when grouping diagnoses according to the traditional T1a versus T1b classification. For differentiation grade, lymphovascular invasion, and margin status, discordances were substantial with 27%, 42%, and 32% of cases having ≥1 discrepant pathologist, respectively. In conclusion, histological assessment of ER specimens of early BE cancer by dedicated GI pathologists shows significant discordances for all relevant histological features. We present propositions to improve definitions of diagnostic criteria.

A method has been developed to screen large numbers (~103–104 per sample) of coarse airborne dust particles for the occurrence of Pb-rich phases, together with quantification of the particles’ mineralogy, chemistry, and inferred provenance. Using SEM-EDS spectral imaging (SI) at 15 kV, and processing with the custom software PARC, screening of individual SI pixels is performed for Pb at the concentration level of ~10% at a length-scale of ~1 µm. The issue of overlapping Pb-Mα and S-Kα signal is resolved by exploiting peak shape criteria. The general efficacy of the method is demonstrated on a set of NIST particulate dust standard reference materials (SRMs 1649b, 2580, 2584 and 2587) with variable total Pb concentrations, and applied to a set of 31 dust samples taken in the municipalities surrounding the integrated steelworks of Tata Steel in IJmuiden, the Netherlands. The total abundances of Pb-rich pixels in the samples range from none to 0.094 area % of the (total) particle surfaces. Overall, out of ca. 92k screened particles, Pb was found in six discrete Pb-phase dominated particles and, more commonly, as superficial sub-particles (sub-micron to 10 µm) adhering to coarser particles of diverse and Pb-unrelated provenance. No relationship is apparent between the samples’ Pb-rich pixel abundance and their overall composition in terms of particle provenance.

Treatment-emergent depression is a common complication in patients with chronic hepatitis C virus (HCV) infection undergoing antiviral combination therapy with IFN-α and ribavirin. It has recently been shown that changes in A-to-I RNA editing rates are associated with various pathologies such as inflammatory disorders, depression and suicide. Interestingly, IFN-α induces gene expression of the RNA editing enzyme ADAR1-1 (ADAR1a-p150) and alters overall RNA editing activity. In this study, we took advantage of the high prevalence of pharmacologically induced depression in patients treated with IFN-α and ribavirin to test the interest of RNA editing–related biomarkers in white blood cells of patients. In this 16-week longitudinal study, a small cohort of patients was clinically evaluated using standard assessment methods prior to and during antiviral therapy and blood samples were collected to analyse RNA editing modifications. A-I RNA editing activity on the phosphodiesterase 8A (PDE8A) gene, a previously identified RNA editing hotspot in the context of lupus erythematosus, was quantified by using an ultra-deep next-generation sequencing approach. We also monitored gene expression levels of the ADAR enzymes and the PDE8A gene during treatment by qPCR. As expected, psychiatric evaluation could track treatment-emergent depression, which occurred in 30% of HCV patients. We show that PDE8A RNA editing is increased in all patients following interferon treatment, but differently in 30% of patients. This effect was mimicked in a cellular model using SHSY-5Y neuroblastoma cells. By combining the data of A-I RNA editing and gene expression, we generated an algorithm that allowed discrimination between the group of patients who developed a treatment-emergent depression and those who did not. The current model of drug-induced depression identified A-I RNA editing biomarkers as useful tools for the identification of individuals at risk of developing depression in an objective, quantifiable biological blood test. Electronic supplementary material The online version of this article (10.1007/s13365-019-00772-9) contains supplementary material, which is available to authorized users.

Introduction Metagenomics is increasingly considered for clinical diagnostics. In order for this technology to become integrated in the clinical microbiology laboratory, process controls are required. Molecular diagnostic tests typically integrate an internal control (IC) to detect potential sources of variation and technical failure. However, few studies report on the integration of an IC in metagenomics. Aim We aimed to develop an easy-to-use IC method for the process control of library preparation and sequencing applied to metagenomics in clinical microbiology diagnostics using Thermus thermophilus DNA. Methodology DNA was extracted from urine samples and sequenced on the Ion Torrent Proton in the absence and presence of incremental concentrations (0.5–2-5%) of IC. Between aliquots of each sample, we compared the IC relative abundance (RA), and after in silico subtraction of IC reads, analysed microbial composition and the RA of pathogens. The optimal IC concentration was defined as the lowest concentration still detectable in all samples with the smallest impact on the microbial composition. Results The RA of IC correlated linearly with the spiked IC concentration (r2 = 0.99). IC added in a concentration of 0.5% of the total DNA concentration was detectable in all sample aliquots, regardless of human-bacterial DNA proportion, and after in silico removal gave the smallest difference in RA of pathogens compared to the sample aliquot sequenced in the absence of IC. The microbial composition in the presence and absence of IC was highly similar after in silico removal of IC reads (median BC-dissimilarity per sample: 0.059), provided samples had a mean of >10,000 bacterial reads. Conclusion T. thermophilus DNA at a percentage of 0.5% of the total DNA concentration was successfully applied for the process control of metagenomics of urine samples. We demonstrated negligible alterations in sample microbial composition after in silico subtraction of IC reads. This approach contributes toward implementation of metagenomics in the clinical microbiology laboratory.

BackgroundProcess control for clinical metagenomic next-generation sequencing (mNGS) is not yet widely applied, while technical sources of bias are plentiful. We present an easy-to-use internal control (IC) method focussing on technical process control applied to metagenomics in clinical diagnostics.MethodsDNA of nine urine samples was sequenced in the absence and presence of Thermus thermophilus DNA as IC in incremental concentrations (0.5-2-5%). Between aliquots of each sample, we compared the IC relative abundance (RA), and after in silico subtraction of IC reads, the microbiota and the RA of pathogens. The optimal IC spike-in concentration was defined as the lowest concentration still detectable in all samples.ResultsThe RA of IC correlated linearly with the spiked IC concentration (r2=0.99). IC added in a concentration of 0.5% of total DNA concentration was detectable in all samples, regardless of human/bacterial composition and after in silico removal gave the smallest difference in RA of pathogens compared to the unspiked aliquot of the sample. The microbiota of sample aliquots sequenced in the presence and absence of IC was highly similar after in silico removal of IC reads (median BC-dissimilarity per sample of 0.059), provided samples had sufficient bacterial read counts.ConclusionT. thermophilus DNA at a percentage of 0.5% of the total DNA concentration can be applied for the process control of mNGS of urine samples. We demonstrated negligible alterations in sample microbial composition after in silico subtraction of IC sequence reads. This approach contributes toward implementation of mNGS in the clinical microbiology laboratory.

Background: Dysplasia assessment of Barrett's esophagus biopsies is associated with low observer agreement; guidelines advise expert review. We have developed a web-based review panel for dysplastic Barrett's esophagus biopsies.Objective: The purpose of this study was to test if 10 gastrointestinal pathologists working at Dutch Barrett's esophagus expert centres met pre-set benchmark scores for quality criteria.Methods: Ten gastrointestinal pathologists twice assessed 60 digitalized Barrett's esophagus cases, enriched for dysplasia; then randomised (7520 assessments). We tested predefined benchmark quality criteria: (a) percentage of 'indefinite for dysplasia' diagnoses, benchmark score ≤14% for all cases, ≤16% for dysplastic subset, (b) intra-observer agreement; benchmark score ≥0.66/≥0.39, (c) percentage agreement with 'gold standard diagnosis'; benchmark score ≥82%/≥73%, (d) proportion of cases with high-grade dysplasia underdiagnosed as non-dysplastic Barrett's esophagus; benchmark score ≤1/78 (≤1.28%) assessments for dysplastic subset.Results: Gastrointestinal pathologists had seven years' Barrett's esophagus-experience, handling seven Barrett's esophagus-cases weekly. Three met stringent benchmark scores; all cases and dysplastic subset, three met extended benchmark scores. Four pathologists lacked one quality criterion to meet benchmark scores.Conclusion: Predefined benchmark scores for expert assessment of Barrett's esophagus dysplasia biopsies are stringent and met by some gastrointestinal pathologists. The majority of assessors however, only showed limited deviation from benchmark scores. We expect further training with group discussions will lead to adherence of all participating gastrointestinal pathologists to quality criteria, and therefore eligible to join the review panel.

Since 2004, atmospheric carbon dioxide (CO2) is being measured at the High Altitude Research Station Jungfraujoch by the division of Climate and Environmental Physics at the University of Bern (KUP) using a nondispersive infrared gas analyzer (NDIR) in combination with a paramagnetic O2 analyzer. In January 2010, CO2 measurements based on cavity ring-down spectroscopy (CRDS) as part of the Swiss National Air Pollution Monitoring Network were added by the Swiss Federal Laboratories for Materials Science and Technology (Empa). To ensure a smooth transition – a prerequisite when merging two data sets, e.g., for trend determinations – the two measurement systems run in parallel for several years. Such a long-term intercomparison also allows the identification of potential offsets between the two data sets and the collection of information about the compatibility of the two systems on different time scales. A good agreement of the seasonality, short-term variations and, to a lesser extent mainly due to the short common period, trend calculations is observed. However, the comparison reveals some issues related to the stability of the calibration gases of the KUP system and their assigned CO2 mole fraction. It is possible to adapt an improved calibration strategy based on standard gas determinations, which leads to better agreement between the two data sets. By excluding periods with technical problems and bad calibration gas cylinders, the average hourly difference (CRDS – NDIR) of the two systems is −0.03 ppm ± 0.25 ppm. Although the difference of the two data sets is in line with the compatibility goal of ±0.1 ppm of the World Meteorological Organization (WMO), the standard deviation is still too high. A significant part of this uncertainty originates from the necessity to switch the KUP system frequently (every 12 min) for 6 min from ambient air to a working gas in order to correct short-term variations of the O2 measurement system. Allowing additional time for signal stabilization after switching the sample, an effective data coverage of only one-sixth for the KUP system is achieved while the Empa system has a nearly complete data coverage. Additionally, different internal volumes and flow rates may affect observed differences.

Radiocarbon dioxide (14CO2, reported in Δ14CO2) can be used to determine the fossil fuel CO2 addition to the atmosphere, since fossil fuel CO2 no longer contains any 14C. After the release of CO2 at the source, atmospheric transport causes dilution of strong local signals into the background and detectable gradients of Δ14CO2 only remain in areas with high fossil fuel emissions. This fossil fuel signal can moreover be partially masked by the enriching effect that anthropogenic emissions of 14CO2 from the nuclear industry have on the atmospheric Δ14CO2 signature. In this paper, we investigate the regional gradients in 14CO2 over the European continent and quantify the effect of the emissions from nuclear industry. We simulate the emissions and transport of fossil fuel CO2 and nuclear 14CO2 for Western Europe using the Weather Research and Forecast model (WRF-Chem) for a period covering 6 summer months in 2008. We evaluate the expected CO2 gradients and the resulting Δ14CO2 in simulated integrated air samples over this period, as well as in simulated plant samples. We find that the average gradients of fossil fuel CO2 in the lower 1200 m of the atmosphere are close to 15 ppm at a 12 km × 12 km horizontal resolution. The nuclear influence on Δ14CO2 signatures varies considerably over the domain and for large areas in France and the UK it can range from 20 to more than 500% of the influence of fossil fuel emissions. Our simulations suggest that the resulting gradients in Δ14CO2 are well captured in plant samples, but due to their time-varying uptake of CO2, their signature can be different with over 3‰ from the atmospheric samples in some regions. We conclude that the framework presented will be well-suited for the interpretation of actual air and plant 14CO2 samples.

The 222Radon tracer method is a powerful tool to estimate local and regional surface emissions of, e.g., greenhouse gases. In this paper we demonstrate that in practice, the method as it is commonly used, produces inaccurate results in case of nonhomogeneously spread emission sources, and we propose a different approach to account for this. We have applied the new methodology to ambient observations of CO2 and 222Radon to estimate CO2 surface emissions for the city of Bern, Switzerland. Furthermore, by utilizing combined measurements of CO2 and δ(O2/N2) we obtain valuable information about the spatial and temporal variability of the main emission sources. Mean net CO2 emissions based on 2 years of observations are estimated at (11.2 ± 2.9) kt km−2 a−1. Oxidative ratios indicate a significant influence from the regional biosphere in summer/spring and fossil fuel combustion processes in winter/autumn. Our data indicate that the emissions from fossil fuels are, to a large degree, related to the combustion of natural gas which is used for heating purposes.

We present results from an intercomparison program of CO2, δ(O2/N2) and δ13CO2 measurements from atmospheric flask samples. Flask samples are collected on a bi-weekly basis at the High Altitude Research Station Jungfraujoch in Switzerland for three European laboratories: the University of Bern, Switzerland, the University of Groningen, the Netherlands and the Max Planck Institute for Biogeochemistry in Jena, Germany. Almost 4 years of measurements of CO2, δ(O2/N2) and δ13CO2 are compared in this paper to assess the measurement compatibility of the three laboratories. While the average difference for the CO2 measurements between the laboratories in Bern and Jena meets the required compatibility goal as defined by the World Meteorological Organization, the standard deviation of the average differences between all laboratories is not within the required goal. However, the obtained annual trend and seasonalities are the same within their estimated uncertainties. For δ(O2/N2) significant differences are observed between the three laboratories. The comparison for δ13CO2 yields the least compatible results and the required goals are not met between the three laboratories. Our study shows the importance of regular intercomparison exercises to identify potential biases between laboratories and the need to improve the quality of atmospheric measurements.

IntroductionPredicting suicidal behaviors is one of the most complex challenges of daily psychiatric practices. Alterations of RNA editing of neurotransmitter receptors and other proteins have been shown to be involved in etiology of different psychiatric disorders and linked to suicidal behavior. Additionally, an increase in expression levels of ADARs, the RNA editing enzymes, has also been observed.ObjectiveThe objective of the present study was to test whether modifications in RNA editing profile of prime targets allow identifying disease-relevant blood biomarkers and evaluating suicide risk in patients.MethodsA clinical study was performed to identify an RNA editing signature in blood of depressed patients with and without history of suicide attempts. Patient's samples were drawn in PAXgene tubes and analyzed on Alcediag's proprietary RNA editing platform using NGS. In addition, gene expression analysis by quantitative PCR was performed.ResultsWe generated a predictive algorithm comprising various selected biomarkers to detect patients with a high risk to attempt suicide. We evaluated the diagnostic performance using the relative proportion of the phosphodiesterase 8A (PDE8A) mRNA editing at different sites as well as the expression of PDE8A and the ADARs. The significance of these biomarkers for suicidality was evaluated using the receiver–operating characteristic (ROC) curve. The generated algorithm comprising the biomarkers was found to have strong diagnostic performances with high specificity and sensitivity.ConclusionsWe developed tools to measure disease–specific biomarkers in blood samples of patients for identifying individuals at the greatest risk for future suicide attempts.Disclosure of interestThe authors have not supplied their declaration of competing interest.

We report results from our atmospheric flask sampling network for three European sites: Lutjewad in the Netherlands, Mace Head in Ireland and the North Sea F3 platform. The air samples from these stations are analyzed for their CO2 and O2 concentrations. In this paper we present the CO2 and O2 data series from these sites between 1998 and 2009, as well as the atmospheric potential oxygen (APO). The seasonal pattern and long term trends agree to a large extent between our three measurement locations. We however find a changing gradient between Mace Head and Lutjewad, both for CO2 and O2. To explain the potential contribution of fossil fuel emissions to this changing gradient we use an atmospheric transport model in combination with CO2 emission data and information on the fossil fuel mix per region. Using the APO trend from Mace Head we obtain an estimate for the global oceanic CO2 uptake of 1.8 ± 0.8 PgC/year.

We present an estimate of net ecosystem exchange (NEE) of CO2 in Europe for the years 2001-2007. It is derived with a data assimilation that uses a large set of atmospheric CO2 mole fraction observations (∼70 000) to guide relatively simple descriptions of terrestrial and oceanic net exchange, while fossil fuel and fire emissions are prescribed. Weekly terrestrial sources and sinks are optimized (i.e., a flux inversion) for a set of 18 large ecosystems across Europe in which prescribed climate, weather, and surface characteristics introduce finer scale gradients. We find that the terrestrial biosphere in Europe absorbed a net average of -165 Tg C yr-1 over the period considered. This uptake is predominantly in non-EU countries, and is found in the northern coniferous (-94 Tg C yr-1) and mixed forests (-30 Tg C yr-1) as well as the forest/field complexes of eastern Europe (-85 Tg C yr-1). An optimistic uncertainty estimate derived using three biosphere models suggests the uptake to be in a range of -122 to -258 Tg C yr-1, while a more conservative estimate derived from the a-posteriori covariance estimates is -165±437 Tg C yr-1. Note, however, that uncertainties are hard to estimate given the nature of the system and are likely to be significantly larger than this. Interannual variability in NEE includes a reduction in uptake due to the 2003 drought followed by 3 years of more than average uptake. The largest anomaly of NEE occurred in 2005 concurrent with increased seasonal cycles of observed CO2. We speculate these changes to result from the strong negative phase of the North Atlantic Oscillation in 2005 that lead to favorable summer growth conditions, and altered horizontal and vertical mixing in the atmosphere. All our results are available through http://www.carbontracker.eu. © 2009 Blackwell Publishing Ltd.

We present net emission estimates of CH4 and N2O of The Netherlands based on measurements conducted during the period of May 2006 to April 2009 at station Lutjewad, The Netherlands (6°21' E, 53°24' N, 1 m a.s.l.). 222Radon mixing ratios were applied as an indicator for vertical mixing and long-range air mass transport and used to calculate the net surface fluxes from atmospheric mixing ratios of CH4 and N2O. Our study shows that our measurement site Lutjewad is well-suited to measure emissions from The Netherlands and validation of the national inventories using the 222Radon flux method. Since this study is purely observation-based it is independent from inventories or atmospheric models. Our results are compared to the national inventories as reported to the UNFCCC. We found net emissions of: (15.2±5.3) t km−2 a−1 for CH4 and (0.9±0.3) t km−2 a−1 for N2O. These values are lower than the inventory-based emissions (2006-2008 averages) of (18.3±3.3) t km−2 a−1 for CH4, and (1.3±0.6) t km−2 a−1 for N2O, but the differences are insignificant.

We present an adapted gas chromatograph capable of measuring simultaneously and semi-continuously the atmospheric mixing ratios of the greenhouse gases CO2, CH4, N2O and SF6 and the trace gas CO with high precision and long-term stability. The novelty of our design is that all species are measured with only one device, making it a very cost-efficient system. No time lags are introduced between the measured mixing ratios. The system is designed to operate fully autonomously which makes it ideal for measurements at remote and unmanned stations. Only a small amount of sample air is needed, which makes this system also highly suitable for flask air measurements. In principle, only two reference cylinders are needed for daily operation and only one calibration per year against international WMO standards is sufficient to obtain high measurement precision and accuracy. The system described in this paper is in use since May 2006 at our atmospheric measurement site Lutjewad near Groningen, The Netherlands at 6°21' E, 53°24' N, 1 m a.s.l. Results show the long-term stability of the system. Observed measurement precisions at our remote research station Lutjewad were: ±0.04 ppm for CO2, ±0.8 ppb for CH4, ±0.8 ppb for CO, ±0.3 ppb for N2O, and ±0.1 ppt for SF6. The ambient mixing ratios of all measured species as observed at station Lutjewad for the period of May 2007 to August 2008 are presented as well.

Representation of atmospheric transport is a major source of error in the estimation of greenhouse gas sources and sinks by inverse modelling. Here we assess the impact on trace gas mole fractions of the new physical parameterizations recently implemented in the atmospheric global climate model LMDz to improve vertical diffusion, mesoscale mixing by thermal plumes in the planetary boundary layer (PBL), and deep convection in the troposphere. At the same time, the horizontal and vertical resolution of the model used in the inverse system has been increased. The aim of this paper is to evaluate the impact of these developments on the representation of trace gas transport and chemistry, and to anticipate the implications for inversions of greenhouse gas emissions using such an updated model. Comparison of a one-dimensional version of LMDz with large eddy simulations shows that the thermal scheme simulates shallow convective tracer transport in the PBL over land very efficiently, and much better than previous versions of the model. This result is confirmed in three-dimensional simulations, by a much improved reproduction of the radon-222 diurnal cycle. However, the enhanced dynamics of tracer concentrations induces a stronger sensitivity of the new LMDz configuration to external meteorological forcings. At larger scales, the inter-hemispheric exchange is slightly slower when using the new version of the model, bringing them closer to observations. The increase in the vertical resolution (from 19 to 39 layers) significantly improves the representation of stratosphere/troposphere exchange. Furthermore, changes in atmospheric thermodynamic variables, such as temperature, due to changes in the PBL mixing modify chemical reaction rates, which perturb chemical equilibriums of reactive trace gases. One implication of LMDz model developments for future inversions of greenhouse gas emissions is the ability of the updated system to assimilate a larger amount of highfrequency data sampled at high-variability stations. Others implications are discussed at the end of the paper., JRC.H.2-Air and Climate

Glucocorticoid hormones modulate brain function and as such are crucial for responding and adjusting to physical and psychological stressors. Their effects are mediated via mineralo- and glucocorticoid receptors, which in large measure act as transcription factors to modulate transcription of target genes, in a receptor-, cell-, and state-specific manner. The nature and magnitude of these transcriptional effects depend on the presence and activity of downstream proteins, such as steroid receptor coactivators and corepressors (together: coregulators), many of which are expressed in the brain. We address the role of coregulators for mineralo- and glucocorticoid receptor-mediated modulation of gene transcription. We first address evidence from cell lines for the importance of coregulator stoichiometry for steroid signaling. The in vivo importance of coregulators-when possible specifically for glucocorticoid signaling in the brain-is discussed based on knockout mice, transient knockdown of steroid receptor coactivators, and distribution and regulation of coactivator expression in the brain. We conclude that for a better understanding of modulation of brain function by glucocorticoids, it is necessary to take into account the role of coregulators, and to assess their importance relative to changes in hormone levels and receptor expression.

The two structurally related nuclear receptor corepressor (N-CoR) and silencing mediator of retinoid and thyroid receptors (SMRT) proteins have been found to differentially affect the transcriptional activity of numerous nuclear receptors, such as thyroid hormone, retinoic acid and steroid receptors. Because of the numerous effects mediated by nuclear receptors in brain, it is of interest to extend these in vitro data and to explore the cellular distribution of both corepressors in brain tissue. We therefore examined, using in situ hybridisation, whether the relative abundance of these two functionally distinct corepressors differed in rat brain and pituitary. We find that although both N-CoR and SMRT transcripts are ubiquitously expressed in brain, striking differences in their respective levels of expression could be observed in discrete areas of brain stem, thalamus, hypothalamus and hippocampus. Using dual-label immunofluorescence, we examined in selected glucocorticoid sensitive areas involved in the regulation of the hypothalamus-pituitary-adrenal axis activity, the respective protein abundance of N-CoR and SMRT. Protein abundance was largely concurrent with the mRNA expression levels, with SMRT relatively more abundant in hypothalamus and brain stem areas. Colocalisation of N-CoR and SMRT was demonstrated by confocal microscopy in most areas studied. Taken together, these findings are consistent with the idea that the uneven neuroanatomical distribution of N-CoR and SMRT protein may contribute to the site-specific effects exerted by hormones, such as glucocorticoids, in the brain.

Expression profiling in the hippocampus is hampered by its cellular heterogeneity. The aim of this study was to evaluate the feasibility of using laser-microdissected hippocampal subregions for expression profiling to improve detection of transcripts with a subregion-specific expression. Cornu ammonis (CA)3 and dentate gyrus (DG) subregions were isolated from rat brain slices using laser microdissection, subjected to two rounds of linear amplification and hybridized to rat GeneChips containing approximately 8000 transcripts (RG_U34A; Affymetrix). Analysis of the data using significance analysis of microarrays revealed 724 genes with a significant difference in expression between CA3 and DG with a false discovery rate of 2.1%, of which 264 had higher expression in DG and 460 in CA3. Several transcripts with known differential expression between the subregions were included in the dataset, as well as numerous novel mRNAs and expressed sequence tags. Sorting of the differentially expressed genes according to gene ontology classification revealed that genes involved in glycolysis and general metabolism, neurogenesis and cell adhesion were consistently expressed at higher levels in CA3. Conversely, a large cluster of genes involved in protein biosynthesis were expressed at higher levels in DG. In situ hybridization was used to validate differential expression of a selection of genes. The results of this study demonstrate that the combination of laser microdissection and GeneChip technology is both technically feasible and very promising. Besides providing an extensive inventory of genes showing differential expression between CA3 and DG, this study supports the idea that profiling in hippocampal subregions should improve detection of genes with a subregion-specific expression or regulation.

Azobenzenes substituted with two urea groups, and especially the 2,2‘-disubstituted azobenzenes, form thermoreversible gels with a wide range of organic solvents at concentrations which are in some cases even as low as 0.2 mM. Most remarkably, the 2,2‘-disubstituted azobenzene gelator can form two different morphs, which is governed by the properties of the solvent and kinetic factors.

Since 2004, atmospheric carbon dioxide (CO2) is measured at the High Altitude Research Station Jungfraujoch by the division of Climate and Environmental Physics at the University of Bern (KUP) using a nondispersive infrared gas analyzer (NDIR) in combination with a paramagnetic O2 analyzer. In January 2010, CO2 measurements based on cavity ring down spectroscopy (CRDS) as part of the Swiss National Air Pollution Monitoring Network have been added by the Swiss Federal Laboratories for Materials Science and Technology (Empa). To ensure a smooth transition – a prerequisite when merging two datasets e.g. for trend determinations – the two measurement systems run in parallel for several years. Such a long-term intercomparison also allows identifying potential offsets between the two datasets and getting information about the compatibility of the two systems on different time scales. A good agreement of the seasonality as well as for the short-term variations was observed and to a lesser extent for trend calculations mainly due to the short common period. However, the comparison revealed some issues related to the stability of the calibration gases of the KUP system and their assigned CO2 mole fraction. It was possible to adapt an improved calibration strategy based on standard gas determinations, which lead to better agreement between the two data sets. By excluding periods with technical problems and bad calibration gas cylinders, the average hourly difference (CRDS − NDIR) of the two systems is −0.03 ppm ± 0.25 ppm. Although the difference of the two datasets is in line with the compatibility goal of ±0.1 ppm of the World Meteorological Organization (WMO), the standard deviation is still too high. A significant part of this uncertainty originates from the necessity to switch the KUP system frequently (every 12 min) for 6 min from ambient air to a working gas in order to correct short-term variations of the O2 measurement system. Allowing additionally for signal stabilization after switching the sample, an effective data coverage of only 1/6 for the KUP system is achieved while the Empa system has a nearly complete data coverage. Additionally, different internal volumes and flow rates between the two systems may affect observed differences.

We present atmospheric CO2 and delta(O-2/N-2) from flask samples taken on board aircraft over Fyodorovskoye (56 degrees 27'N, 32 degrees 55'E) at heights of 3000 m and 100 m between 1998 and 2008. The long-term trends for CO2 and delta(O-2/N-2) are similar for both sampling heights, and also similar to observations from marine background station Mace Head (Ireland) and coastal station Lutjewad (the Netherlands). The seasonal CO2 amplitude at 100 m was almost twice as large as at 3000 m and a phase shift in the seasonality of about two weeks between both sampling heights was observed. This indicates a dominant influence on CO2 in the boundary layer from the regional biosphere which is confirmed by analysis of the delta(O-2/N-2) to CO2 oxidative ratio (OR). Together with simulations with the TM3 model, our data suggest that the observed OR of -1.7 +/- 0.2 in the free troposphere is mainly driven by exchange processes with the ocean. Within the boundary layer an OR of -0.89 +/- 0.12 was observed which supports the results of other recent studies suggesting the commonly used value of -1.1 for biospheric OR is likely too low. (C) 2014 Elsevier Ltd. All rights reserved.

Radiocarbon dioxide (14CO2, reported in Δ14CO2) can be used to determine the fossil fuel CO2 addition to the atmosphere, since fossil fuel CO2 no longer contains any 14C. After the release of CO2 at the source, atmospheric transport causes dilution of strong local signals into the background and detectable gradients of Δ14CO2 only remain in areas with high fossil fuel emissions. This fossil fuel signal can moreover be partially masked by the enriching effect that anthropogenic emissions of 14CO2 from the nuclear industry have on the atmospheric Δ14CO2 signature. In this paper, we investigate the regional gradients in 14CO2 over the European continent and quantify the effect of the emissions from nuclear industry. We simulate the emissions and transport of fossil fuel CO2 and nuclear 14CO2 for Western Europe using the Weather Research and Forecast model (WRF-Chem) for a period covering 6 summer months in 2008. We evaluate the expected CO2 gradients and the resulting Δ14CO2 in simulated integrated air samples over this period, as well as in simulated plant samples. We find that the average gradients of fossil fuel CO2 in the lower 1200 m of the atmosphere are close to 15 ppm at a 12 km × 12 km horizontal resolution. The nuclear influence on Δ14CO2 signatures varies considerably over the domain and for large areas in France and the UK it can range from 20 to more than 500% of the influence of fossil fuel emissions. Our simulations suggest that the resulting gradients in Δ14CO2 are well captured in plant samples, but due to their time-varying uptake of CO2, their signature can be different with over 3‰ from the atmospheric samples in some regions. We conclude that the framework presented will be well-suited for the interpretation of actual air and plant 14CO2 samples.

Radiocarbon dioxide (14CO2, reported in Δ14CO2) can be used to determine the fossil fuel CO2 addition to the atmosphere, since fossil fuel CO2 no longer contains any 14C. After release of CO2 at the source, atmospheric transport causes dilution of strong local signals into the background and detectable gradients of Δ14CO2 only remain in areas with high fossil fuel emissions. This fossil fuel signal can moreover be partially masked by the enriching effect that anthropogenic emissions of 14CO2 from the nuclear industry have on the atmospheric Δ14CO2 signature. In this paper, we investigate the regional gradients in 14CO2 over the European continent and quantify the effect of the emissions from nuclear industry. We simulate the emissions of fossil fuel CO2 and nuclear 14CO2 for Western Europe for a period covering 6 months in 2008 and their transport using the Weather Research and Forecast model (WRF-Chem). We evaluate the expected CO2 gradients and the resulting Δ14CO2 in simulated integrated air samples over this period, as well as in simulated plant samples. We find that the average gradients of fossil fuel CO2 in the lower 1200 m of the atmosphere are close to 15 ppm at a 12 km × 12 km horizontal resolution. The nuclear influence on Δ14CO2 signatures varies considerably over the domain and for large areas in France and UK it can range from 20% to more than 500% of the influence of fossil fuel emissions. Our simulations suggest that the resulting gradients in Δ14CO2 are well captured in plant samples, but due to their time-varying uptake of CO2 their signature can be different with over 3‰ from the atmospheric samples in some regions. We conclude that the framework presented will be well-suited for the interpretation of actual air and plant 14CO2 samples.

For what is now an extended period of time, a number of researchers have been working in what could bedescribed as “an isolated, very small and persecuted community… seeking to reify this mysterious oddity thatwas social accounting (emphasis in original)” (Gray, 2007, p. 2). However, with increasing commercial andregulatory emphasis globally on environmental degradation and rehabilitation, climate change and the socialresponsibilities of the corporate world, this isolated, small community has not only gained a voice, but anincreased profile and credibility for researchers in the area. As such, social and environmental accounting(SEA) research (as it is now known) boasts both a history and a future as a stand-alone sub-discipline ofaccounting research. More and more emerging scholars are opting for research programs that encompass orengage with SEA issues. Indeed, many major accounting conferences (such as the European AccountingAssociation (EAA) and Accounting and Finance Association of Australian and New Zealand (AFAANZ))offer dedicated SEA streams. SEA is no longer a special issue! But as noted above, this was not always thecase…..

Brain region-specific abnormalities in serotonergic transmission appear to underlie suicidal behavior. Alterations of RNA editing on the serotonin receptor 2C (HTR2C) pre-mRNA in the brain of suicides produce transcripts that attenuate 5-HT2CR signaling by impairing intracellular G-protein coupling and subsequent intracellular signal transduction. In brain, the distribution of RNA-editing enzymes catalyzing deamination (A-to-I modification) shows regional variation, including within the cerebral cortex. We tested the hypothesis that altered pre-mRNA 5-HT2CR receptor editing in suicide is region-specific. To this end, we investigated the complete 5-HT2CR mRNA-editing profile in two architectonically distinct cortical areas involved in mood regulation and decision-making in a clinically well-characterized cohort of age- and sex-matched non-psychiatric drug-free controls and depressed suicides. By using an original biochemical detection method, that is, capillary electrophoresis single-stranded conformational polymorphism (CE-SSCP), we corroborated the 5-HT2CR mRNA-editing profile previously described in the dorsolateral prefrontal cortex (Brodmann area 9 (BA9)). Editing of 5-HT2CR mRNA displayed clear regional difference when comparing dorsolateral prefrontal cortex (BA9) and anterior cingulate cortex (BA24). Compared with non-psychiatric control individuals, alterations of editing levels of 5-HT2CR mRNA were detected in both cortical areas of depressed suicides. A marked increase in editing on 5-HT2CR was especially observed in the anterior cingulate cortex in suicides, implicating this cortical area in suicide risk. The results suggest that region-specific changes in RNA editing of 5-HT2CR mRNA and deficient receptor function likely contribute to the etiology of major depressive disorder or suicide.

CO2 fluxes for the Netherlands and surroundings are estimated for the year 2008, from concentration measurements at four towers, using an inverse model. The results are compared to direct CO2 flux measurements by aircraft, for 6 flight tracks over the Netherlands, flown multiple times in each season. We applied the Regional Atmospheric Mesoscale Modeling system (RAMS) coupled to a simple carbon flux scheme (including fossil fuel), which was run at 10 km resolution, and inverted with an Ensemble Kalman Filter. The domain had 6 eco-regions, and inversions were performed for the four seasons separately. Inversion methods with pixel-dependent and -independent parameters for each eco-region were compared. The two inversion methods, in general, yield comparable flux averages for each eco-region and season, whereas the difference from the prior flux may be large. Posterior fluxes co-sampled along the aircraft flight tracks are usually much closer to the observations than the priors, with a comparable performance for both inversion methods, and with best performance for summer and autumn. The inversions showed more negative CO2 fluxes than the priors, though the latter are obtained from a biosphere model optimized using the Fluxnet database, containing observations from more than 200 locations worldwide. The two different crop ecotypes showed very different CO2 uptakes, which was unknown from the priors. The annual-average uptake is practically zero for the grassland class and for one of the cropland classes, whereas the other cropland class had a large net uptake, possibly because of the abundance of maize there.

We present results from an intercomparison program of CO2, δ(O2/N2) and δ13CO2 measurements from atmospheric flask samples. Flask samples are collected on a bi-weekly basis at the High Altitude Research Station Jungfraujoch in Switzerland for three European laboratories: the University of Bern, Switzerland, the University of Groningen, the Netherlands and the Max Planck Institute for Biogeochemistry in Jena, Germany. Almost 4 yr of measurements of CO2, δ(O2/N2) and δ13CO2 are compared in this paper to assess the measurement compatibility of the three laboratories. While the average difference for the CO2 measurements between the laboratories in Bern and Jena meets the required compatibility goal as defined by the World Meteorological Organisation, the standard deviation of the average differences between all laboratories is not within the required goal. However, the obtained annual trend and seasonalities are the same within their estimated uncertainties. For δ(O2/N2) significant differences are observed between the three laboratories. The comparison for δ13CO2 yields the least compatible results and the required goals are not met between the three laboratories. Our study shows the importance of regular intercomparison exercises to identify potential biases between laboratories and the need to improve the quality of atmospheric measurements.

Surface emissions of CO2 from fossil fuel combustion (ϕFFCO2) are estimated for the Netherlands for the period of May 2006–June 2009 using ambient atmospheric observations taken at station Lutjewad in the Netherlands (6°21′E, 53°24′N, 1 m. a.s.l.). Measurements of Δ14C on 2-weekly integrations of CO2 and CO mixing ratios are combined to construct a quasi-continuous proxy record (FFCO2*) from which surface fluxes (ϕFFCO2*) are determined using the 222Rn flux method. The trajectories of the air masses are analysed to determine emissions, which are representative for the Netherlands. We compared our observationally based estimates to the national inventories and we evaluated our methodology using the regional atmospheric transport model REMO. Based on 3 yr of observations we find annual mean ϕFFCO2* emissions of (4.7 ± 1.6) kt km-2 a-1 which is in very good agreement with the Dutch inventories of (4.5 ± 0.2) kt km-2 a-1 (average of 2006–2008).DOI: 10.1111/j.1600-0889.2010.00493.x

International audience

We report results from our atmospheric flask sampling network for three European sites: Lutjewad in the Netherlands, Mace Head in Ireland and the North Sea F3 platform. The air samples from these stations are primarily being analyzed for their CO2 and O2 concentrations. In this paper we present the CO2 and O2 data series from these sites between 1998 and 2009, as well as the atmospheric potential oxygen (APO). The seasonal pattern and long term trends agree to a large extent between our three measurement locations. We however find an increasing gradient between Mace Head and Lutjewad, both for CO2 and O2. As Lutjewad is influenced by local fluctuations in the fossil fuel sources, we use an atmospheric transport model in combination with CO2 emission data and information on the fossil fuel mix per region and category in order to correct the tracer APO for a residual fossil fuel component. For Lutjewad this correction differs significantly from the global average. Using the APO trend from Mace Head we obtain an estimate for the global oceanic CO2 uptake of 1.8 ± 0.8 PgC/year.

A new atmospheric measurement station has been established on the North Sea oil and gas production platform F3, 200 km north off the Dutch coast (5°51' N, 4°44' E). Atmospheric concentrations of O2 and CO2 are continuously measured using fuel cell technology and compact infrared absorption instruments, respectively. Furthermore, the station includes an automated air flask sampler for laboratory analysis of the atmospheric concentrations of CO2, CH4, CO and O2 and isotope measurements of δ13C, δ18O and Δ14C from CO2. This station is the first fixed sea based station with on-site continuous O2 and CO2 measurements and therefore yields valuable information about the CO2 uptake in coastal marine regions, specifically the North Sea. This paper presents the measurement station and the used methodologies in detail. In comparison to land-based stations, the data show low day-to-day variability, as they are practically free of nightly inversions as well as human influences, due to the station's remoteness. Therefore, the data set collected at this measurement station serves directly as background data for the coastal northwest European region. Additionally, the first data are presented showing the seasonal cycle as expected during August 2008 through June 2009. Furthermore, some short-term O2 and CO2 signals are presented. The observations at the platform include several large and fast changing negative atmospheric O2 excursions without an accompanying change in the CO2 signal, which most likely indicate marine O2 uptake.

Nuclear receptor coregulators are proteins that modulate the transcriptional activity of steroid receptors and may explain cell-specific effects of glucocorticoid receptor action. Based on the uneven distribution of a number of coregulators in CRH-expressing cells in the hypothalamus of the rat brain, we tested the hypothesis that these proteins are involved as mediators in the glucocorticoid-induced repression of the CRH promoter. Therefore, we assessed the role of coregulator proteins on both induction and repression of CRH in the AtT-20 cell line, a model system for CRH repression by glucocorticoids. The steroid receptor coactivator 1a (SRC1a), SRC-1e, nuclear corepressor (N-CoR), and silencing mediator of the retinoid and thyroid hormone receptor (SMRT) were studied in this system. We show that the concentration of glucocorticoid receptor and the type of ligand, i.e. corticosterone or dexamethasone, determines the repression. Furthermore, overexpression of SRC1a, but not SRC1e, increased both efficacy and potency of the glucocorticoid receptor-mediated repression of the forskolin-induced CRH promoter. Unexpectedly, cotransfection of the corepressors N-CoR and SMRT did not affect the corticosterone-dependent repression but resulted in a marked decrease of the forskolin stimulation of the CRH gene. Altogether, our data demonstrate that 1) the concentration of the receptor, 2) the type of ligand, and 3) the coregulator recruited all determine the expression and the repression of the CRH gene. We conclude that modulation of coregulator activity may play a role in the control of the hypothalamus-pituitary-adrenal axis.

The mechanisms of receptor- and cell-specific effects of the adrenal corticosteroid hormones via mineralo- (MRs) and glucocorticoid receptors (GRs) are still poorly understood. Because the expression levels of two splice variants of the steroid receptor coactivator-1 (SRC-1) 1a and 1e, can differ significantly in certain cell populations, we tested the hypothesis that their relative abundance could determine cell- and receptor-specific effects of corticosteroid receptor-mediated transcription. In transient transfections, we demonstrate three novel types of SRC-1a- and SRC-1e-specific effects for corticosteroid receptors. One is promoter dependence: SRC-1e much more potently coactivated transcription from several multiple response element-containing promoters. Mammalian 1-hydrid studies indicated that this likely does not involve promoter-specific coactivator recruitment. Endogenous phenylethanolamine-N-methyltransferase mRNA induction via GRs was also differentially affected by the splice variants. Another type is receptor specificity: responses mediated by the N-terminal part of the MR, but not the GR, were augmented by SRC-1e at synergizing response elements. SRC fragment SRC(988-1240) by the MR but not the GR N-terminal fragment in a 1-hybrid assay. The last type, for GRs, is ligand dependence. Due to effects on partial agonism of RU486-activated GRs, different ratios of SRC-1a and 1e can lead to large differences in the extent of antagonism of RU486 on GR-mediated transcription. Furthermore, we show that SRC-1e but not SRC-1a mRNA expression was regulated in the pituitary by corticosterone. We conclude that the cellular differences in SRC-1a to SRC-1e ratio demonstrated in vivo might be involved in cell-specific responses to corticosteroids in a promoter- and ligand-dependent way.

The case history of a patient developing tubulointerstitial nephritis (TIN) during carbamazepine therapy is described. After withdrawal of the drug and introduction of prednisone renal function normalised. TIN is a rare side-effect of carbamazepine of which only a few cases have been described. There seems to be a remarkable time interval of 2 months between the onset of therapy with carbamazepine and the development of TIN.

Aman inhis 20spresentedwith a 10-year historyof relapsingpapuleson theantihelixof the left ear. Less frequently, thepapuleswere found on the right ear as well. Sometimes the lesions were painful to applied pressure or when exposed to cold winds. On physical examination, the right external ear showed no abnormalities, and the left antihelix showed 5 yellowish papuleswith surroundingerythemaandscattered telangiectasias, firm in consistency and tender to applied pressure. Each lesion measured 3 to 5 mm in size (Figure, A). There was no history of trauma, infection, insect bites, tuberculosis, or diabetes mellitus. The patient used methylphenidate hydrochloride to treat attention-deficit/ hyperactivity disorder. The lesionswereexcised toestablishadiagnosis.Excisionof the lesionswas performedunder local anesthetic. Both the dermis and underlying cartilage were excised. Histologicexaminationshowedan intact epidermis,withoutulceration. Also the cartilage and perichondrium were not histologically abnormal. In the dermis, lesions were found with central degeneration (necrobiosis) of collagen, surrounded by palisading histiocytes. A few lymphocyteswere present aswell (Figure, B and C). Mucin stains showed the presence of mucin in the necrobiotic foci (arrow) (Figure, D). Periodic acid–Schiff and auraminerhodamine stains remained negative for mycobacteria. What is your diagnosis? A B