Molecular markers for urothelial bladder cancer prognosis: toward implementation in clinical practice

OBJECTIVES To summarize the current status of clinicopathological and molecular markers for the prediction of recurrence or progression or both in non-muscle-invasive and survival in muscle-invasive urothelial bladder cancer, to address the reproducibility of pathology and molecular markers, and to provide directions toward implementation of molecular markers in future clinical decision making. METHODS AND MATERIALS Immunohistochemistry, gene signatures, and FGFR3-based molecular grading were used as molecular examples focussing on prognostics and issues related to robustness of pathological and molecular assays. RESULTS The role of molecular markers to predict recurrence is limited, as clinical variables are currently more important. The prediction of progression and survival using molecular markers holds considerable promise. Despite a plethora of prognostic (clinical and molecular) marker studies, reproducibility of pathology and molecular assays has been understudied, and lack of reproducibility is probably the main reason that individual prediction of disease outcome is currently not reliable. CONCLUSIONS Molecular markers are promising to predict progression and survival, but not recurrence. However, none of these are used in the daily clinical routine because of reproducibility issues. Future studies should focus on reproducibility of marker assessment and consistency of study results by incorporating scoring systems to reduce heterogeneity of reporting. This may ultimately lead to incorporation of molecular markers in clinical practice.

Sportmotorische Leistungsfähigkeit und schulische Leistung – Zum mediierenden Effekt der exekutiven Funktionen

Introduction: Die sportmotorische Leistungsfähigkeit (SMLF) hängt nicht nur positiv mit der körperlichen Gesundheit zusammen, sondern gilt auch als Prädiktor für die schulische Leistung (SL) (van der Niet, Hartmann, Smith, & Visscher, 2014). Um die Frage zu beantworten, wie denn zwei auf den ersten Blick so distale Merkmale zusammenhängen sollen, werden unterschiedliche erklärende Variablen diskutiert, wobei die kognitive Stimulationshypothese die exekutiven Funktionen (EF) als mediierende Variable im Zusammenhang zwischen SMLF und SL postuliert. Die Annahme hierbei ist, dass die mit komplexen motorischen Kontrollprozessen einhergehende kognitive Beanspruchung bei einem wiederholten Ausführen von nicht-automatisierten sportbezogenen Handlungen zu einer Aktivierung und somit Förderung der EF führt (Best, 2010). EF, verstanden als höhere kognitive Prozesse, die ein zielorientiertes und situationsangepasstes Handeln erlauben, sind für den schulischen Erfolg von zentraler Bedeutung und gleichzeitig wichtige Prädiktoren der SL (Diamond, 2013). Obwohl diese Mediation seit einigen Jahren in der Literatur diskutiert wird, wurde sie bis heute noch nicht mit Hilfe längsschnittlicher Daten geprüft. Daher wird im Folgenden der mediierende Effekt der EF im Zusammenhang zwischen SMLF und SL getestet. Methods: Im Rahmen der Studie Sport und Kognition 5.0 wurden insgesamt 237 Primarschulkinder (52.3% ♀; 11.31 ± 0.62 Jahre) zu drei Messzeitpunkten in ihrer SMLF (T1) und ihren EF (T2) getestet. Zusätzlich wurde die SL (T3) mittels objektiver Schulleistungstests (Mathematik und Deutsch) erhoben. Um die Hauptfragestellung zu prüfen, ob die SL vorwiegend mediiert über die EF durch die SMLF vorhergesagt werden kann, wurde eine bootstrapping-basierte Mediationsanalyse in AMOS 22 durchgeführt. Results: Das theoretisch abgeleitete Strukturgleichungsmodell (2 (22, N = 237) = 30.357, p = .110; CFI = .978) weist eine zufriedenstellende Anpassungsgüte auf. Erwartungsgemäss zerfällt der Zusammenhang innerhalb des Mediationsmodells zwischen der SMLF und der SL, alsbald die EF ins Modell aufgenommen werden (β = .16, p = .634). Sowohl der Zusammenhang zwischen der SMLF und den EF (β = .38, p = .039), als auch der Zusammenhang zwischen den EF und der SL fallen signifikant aus (β = .91, p = .001) und ergeben dabei eine volle Mediation über den indirekten (p = .021) und totalen Effekt (p = .001). Discussion/Conclusion: Die erstmals vorliegenden längsschnittlichen Daten bestätigen den Zusammenhang zwischen SMLF und SL bei einer Mediation über die EF und decken sich mit den, aus einem querschnittlichen Design stammenden, Befunden von van der Niet et al. (2014). Zur Steigerung der schulischen Leistung sollten zukünftige Schulsportinterventionen die SMLF von Kindern erhöhen und dabei die EF bei der Auswahl von sportlichen Aufgaben mitberücksichtigen. References: Best, J. R. (2010). Effects of physical activity on children’s executive function: Contributions of experimental research on aerobic exercise. Developmental Review, 30, 331-351. Diamond, A. (2013). Executive functions. Annual Review of Psychology, 64, 135-168. van der Niet, A. G., Hartmann, E., Smith, J. & Visscher, C. (2014). Modeling relationships between physical fitness, executive functioning, and academic achievement in primary school children. Psychology of Sport & Exercise, 15(4), 319-325.

Geschiednis der joden in Nederland

door H. J. Koenen. Uitgeg. door het Provinciaal Utrechtsche Genootschap van kunsten en wetenschappen

The global carbon budget 1959–2011

Accurate assessment of anthropogenic carbon dioxide (CO2) emissions and their redistribution among the atmosphere, ocean, and terrestrial biosphere is important to better understand the global carbon cycle, support the climate policy process, and project future climate change. Present-day analysis requires the combination of a range of data, algorithms, statistics and model estimates and their interpretation by a broad scientific community. Here we describe datasets and a methodology developed by the global carbon cycle science community to quantify all major components of the global carbon budget, including their uncertainties. We discuss changes compared to previous estimates, consistency within and among components, and methodology and data limitations. Based on energy statistics, we estimate that the global emissions of CO2 from fossil fuel combustion and cement production were 9.5 ± 0.5 PgC yr−1 in 2011, 3.0 percent above 2010 levels. We project these emissions will increase by 2.6% (1.9–3.5%) in 2012 based on projections of Gross World Product and recent changes in the carbon intensity of the economy. Global net CO2 emissions from Land-Use Change, including deforestation, are more difficult to update annually because of data availability, but combined evidence from land cover change data, fire activity in regions undergoing deforestation and models suggests those net emissions were 0.9 ± 0.5 PgC yr−1 in 2011. The global atmospheric CO2 concentration is measured directly and reached 391.38 ± 0.13 ppm at the end of year 2011, increasing 1.70 ± 0.09 ppm yr−1 or 3.6 ± 0.2 PgC yr−1 in 2011. Estimates from four ocean models suggest that the ocean CO2 sink was 2.6 ± 0.5 PgC yr−1 in 2011, implying a global residual terrestrial CO2 sink of 4.1 ± 0.9 PgC yr−1. All uncertainties are reported as ±1 sigma (68% confidence assuming Gaussian error distributions that the real value lies within the given interval), reflecting the current capacity to characterise the annual estimates of each component of the global carbon budget. This paper is intended to provide a baseline to keep track of annual carbon budgets in the future.

From Framework to Action: The DESIRE Approach to Combat Desertification

It has become increasingly clear that desertification can only be tackled through a multi-disciplinary approach that not only involves scientists but also stakeholders. In the DESIRE project such an approach was taken. As a first step, a conceptual framework was developed in which the factors and processes that may lead to land degradation and desertification were described. Many of these factors do not work independently, but can reinforce or weaken one another, and to illustrate these relationships sustainable management and policy feedback loops were included. This conceptual framework can be applied globally, but can also be made site-specific to take into account that each study site has a unique combination of bio-physical, socio-economic and political conditions. Once the conceptual framework was defined, a methodological framework was developed in which the methodological steps taken in the DESIRE approach were listed and their logic and sequence were explained. The last step was to develop a concrete working plan to put the project into action, involving stakeholders throughout the process. This series of steps, in full or in part, offers explicit guidance for other organizations or projects that aim to reduce land degradation and desertification.

Pollen-based quantitative reconstructions of Holocene regional vegetation cover (plant-functional types and land-cover types) in Europe suitable for climate modelling

We present quantitative reconstructions of regional vegetation cover in north-western Europe, western Europe north of the Alps, and eastern Europe for five time windows in the Holocene around 6k, 3k, 0.5k, 0.2k, and 0.05k calendar years before present (bp)] at a 1 degrees x1 degrees spatial scale with the objective of producing vegetation descriptions suitable for climate modelling. The REVEALS model was applied on 636 pollen records from lakes and bogs to reconstruct the past cover of 25 plant taxa grouped into 10 plant-functional types and three land-cover types evergreen trees, summer-green (deciduous) trees, and open land]. The model corrects for some of the biases in pollen percentages by using pollen productivity estimates and fall speeds of pollen, and by applying simple but robust models of pollen dispersal and deposition. The emerging patterns of tree migration and deforestation between 6k bp and modern time in the REVEALS estimates agree with our general understanding of the vegetation history of Europe based on pollen percentages. However, the degree of anthropogenic deforestation (i.e. cover of cultivated and grazing land) at 3k, 0.5k, and 0.2k bp is significantly higher than deduced from pollen percentages. This is also the case at 6k in some parts of Europe, in particular Britain and Ireland. Furthermore, the relationship between summer-green and evergreen trees, and between individual tree taxa, differs significantly when expressed as pollen percentages or as REVEALS estimates of tree cover. For instance, when Pinus is dominant over Picea as pollen percentages, Picea is dominant over Pinus as REVEALS estimates. These differences play a major role in the reconstruction of European landscapes and for the study of land cover-climate interactions, biodiversity and human resources.

Support of hepatic regeneration by trophic factors from liver-derived mesenchymal stromal/stem cells

Mesenchymal stromal/stem cells (MSCs) have multilineage differentiation potential and as such are known to promote regeneration in response to tissue injury. However, accumulating evidence indicates that the regenerative capacity of MSCs is not via transdifferentiation but mediated by their production of trophic and other factors that promote endogenous regeneration pathways of the tissue cells. In this chapter, we provide a detailed description on how to obtain trophic factors secreted by cultured MSCs and how they can be used in small animal models. More specific, in vivo models to study the paracrine effects of MSCs on regeneration of the liver after surgical resection and/or ischemia and reperfusion injury are described.

Crystal structures of isotypic poly[bis(benzimidazolium) [tetra-μ-iodido-stannate(II)]] and poly[bis(5,6-difluorobenzimidazolium) [tetra-μ-iodido-stannate(II)]]

The isostructural title compounds, {(C7H7N2)2[SnI4]}n, (1), and {(C7H5F2N2)2[SnI4]}n, (2), show a layered perovskite-type structure composed of anionic {[SnI4]2-}n sheets parallel to (100), which are decorated on both sides with templating benzimidazolium or 5,6-di­fluoro­benzimidazolium cations, respectively. These planar organic heterocycles mainly form N-H...I hydrogen bonds to the terminal I atoms of the corner-sharing [SnI6] octa­hedra (point group symmetry 2) from the inorganic layer, but not to the bridging ones. This is in contrast to most of the reported structures of related compounds where ammonium cations are involved. Here hydrogen bonding to both types of iodine atoms and thereby a distortion of the inorganic layers to various extents is observed. For (1) and (2), all Sn-I-Sn angles are linear and no out-of-plane distortions of the inorganic layers occur, a fact of relevance in view of the material properties. The arrangement of the aromatic cations is mainly determined through the direction of the N-H...I hydrogen bonds. The coherence between organic bilayers along [100] is mainly achieved through van der Waals inter­actions.

Dissecting abdominal aortic aneurysm in Ang II-infused mice: suprarenal branch ruptures and apparent luminal dilatation.

AIMS In this work, we provide novel insight into the morphology of dissecting abdominal aortic aneurysms in angiotensin II-infused mice. We demonstrate why they exhibit a large variation in shape and, unlike their human counterparts, are located suprarenally rather than infrarenally. METHODS AND RESULTS We combined synchrotron-based, ultra-high resolution ex vivo imaging (phase contrast X-Ray tomographic microscopy) with in vivo imaging (high-frequency ultrasound and contrast-enhanced micro-CT) and image-guided histology. In all mice, we observed a tear in the tunica media of the abdominal aorta near the ostium of the celiac artery. Independently we found that, unlike the gradual luminal expansion typical for human aneurysms, the outer diameter increase of angiotensin II-induced dissecting aneurysms in mice was related to one or several intramural haematomas. These were caused by ruptures of the tunica media near the ostium of small suprarenal side branches, which had never been detected by the established small animal imaging techniques. The tear near the celiac artery led to apparent luminal dilatation, while the intramural haematoma led to a dissection of the tunica adventitia on the left suprarenal side of the aorta. The number of ruptured branches was higher in those aneurysms that extended into the thoracic aorta, which explained the observed variability in aneurysm shape. CONCLUSION Our results are the first to describe apparent luminal dilatation, suprarenal branch ruptures, and intramural haematoma formation in dissecting abdominal aortic aneurysms in mice. Moreover, we validate and demonstrate the vast potential of phase contrast X-ray tomographic microscopy in cardiovascular small animal applications.

Effect of thrombocytopenia on treatment tolerability and outcome in patients with chronic HCV infection and advanced hepatic fibrosis.

BACKGROUND & AIMS Pegylated interferon is still the backbone of hepatitis C treatment and may cause thrombocytopenia, leading to dose reductions, early discontinuation, and eventually worse clinical outcome. We assessed associations between interferon-induced thrombocytopenia and bleeding complications, interferon dose reductions, early treatment discontinuation, as well as SVR and long-term clinical outcome. METHODS All consecutive patients with chronic HCV infection and biopsy-proven advanced hepatic fibrosis (Ishak 4-6) who initiated interferon-based therapy between 1990 and 2003 in 5 large hepatology units in Europe and Canada were included. RESULTS Overall, 859 treatments were administered to 546 patients. Baseline platelets (in 10(9)/L) were normal (⩾150) in 394 (46%) treatments; thrombocytopenia was moderate (75-149) in 324 (38%) and severe (<75) in 53 (6%) treatments. Thrombocytopenia-induced interferon dose reductions occurred in 3 (1%); 46 (16%), and 15 (30%) treatments respectively (p<0.001); interferon was discontinued due to thrombocytopenia in 1 (<1%), 8 (3%), and in 8 (16%) treatments respectively (p<0.001). In total, 104 bleeding events were reported during 53 treatments. Only two severe bleeding complications occurred. Multivariate analysis showed that cirrhosis and a platelet count below 50 were associated with on-treatment bleeding. Within thrombocytopenic patients, patients attaining SVR had a lower occurrence of liver failure (p<0.001), hepatocellular carcinoma (p<0.001), liver related death or liver transplantation (p<0.001), and all-cause mortality (p=0.001) compared to patients without SVR. CONCLUSIONS Even in thrombocytopenic patients with chronic HCV infection and advanced hepatic fibrosis, on-treatment bleedings are generally mild. SVR was associated with a marked reduction in cirrhosis-related morbidity and mortality, especially in patients with baseline thrombocytopenia.

Risk of infections during interferon-based treatment in patients with chronic HCV infection and advanced hepatic fibrosis.

BACKGROUND & AIMS Pegylated interferon-based treatment is still the backbone of current hepatitis C therapy and is associated with bone marrow suppression and an increased risk of infections. The aim of this retrospective cohort study was to assess the risk of infections during interferon-based treatment among patients with chronic HCV infection and advanced hepatic fibrosis and its relation to treatment-induced neutropenia. METHODS This cohort study included all consecutive patients with chronic HCV infection and biopsy-proven bridging fibrosis or cirrhosis (Ishak 4-6) who started treatment between 1990 and 2003 in five large hepatology units in Europe and Canada. Neutrophil counts between 500/μL-749/μL and below 500/μL were considered as moderate and severe neutropenia, respectively. RESULTS This study included 723 interferon-based treatments, administered to 490 patients. In total, 113 infections were reported during 88 (12%) treatments, of which 24 (21%) were considered severe. Only one patient was found to have moderate neutropenia and three patients were found to have severe neutropenia at the visit before the infection. Three hundred and twelve (99.7%) visits with moderate neutropenia and 44 (93.6%) visits with severe neutropenia were not followed by an infection. Multivariable analysis showed that cirrhosis (OR 2.85, 95%CI 1.38-5.90, p=0.005) and severe neutropenia at the previous visit (OR 5.42, 95%CI 1.34-22.0, p=0.018) were associated with the occurrence of infection, while moderate neutropenia was not. Among a subgroup of patients treated with PegIFN, severe neutropenia was not significantly associated (OR 1.63, 95%CI 0.19-14.2, p=0.660). CONCLUSIONS In this large cohort of patients with bridging fibrosis and cirrhosis, infections during interferon-based therapy were generally mild. Severe interferon-induced neutropenia rarely occurred, but was associated with on-treatment infection. Moderate neutropenia was not associated with infection, suggesting that current dose reduction guidelines might be too strict.

EPA guidance on the early intervention in clinical high risk states of psychoses

This guidance paper from the European Psychiatric Association (EPA) aims to provide evidence-based recommendations on early intervention in clinical high risk (CHR) states of psychosis, assessed according to the EPA guidance on early detection. The recommendations were derived from a meta-analysis of current empirical evidence on the efficacy of psychological and pharmacological interventions in CHR samples. Eligible studies had to investigate conversion rate and/or functioning as a treatment outcome in CHR patients defined by the ultra-high risk and/or basic symptom criteria. Besides analyses on treatment effects on conversion rate and functional outcome, age and type of intervention were examined as potential moderators. Based on data from 15 studies (n = 1394), early intervention generally produced significantly reduced conversion rates at 6- to 48-month follow-up compared to control conditions. However, early intervention failed to achieve significantly greater functional provements because both early intervention and control conditions produced similar positive effects. With regard to the type of intervention, both psychological and pharmacological interventions produced significant effects on conversion rates, but not on functional outcome relative to the control conditions. Early intervention in youth samples was generally less effective than in predominantly adult samples. Seven evidence-based recommendations for early intervention in CHR samples could have been formulated, although more studies are needed to investigate the specificity of treatment effects and potential age effects in order to tailor interventions to the individual treatment needs and risk Status.

EPA guidance on the early detection of clinical high risk states of psychoses

The aim of this guidance paper of the European Psychiatric Association is to provide evidence-based recommendations on the early detection of a clinical high risk (CHR) for psychosis in patients with mental problems. To this aim, we conducted a meta-analysis of studies reporting on conversion rates to psychosis in non-overlapping samples meeting any at least any one of the main CHR criteria: ultra-high risk (UHR) and/or basic symptoms criteria. Further, effects of potential moderators (different UHR criteria definitions, single UHR criteria and age) on conversion rates were examined. Conversion rates in the identified 42 samples with altogether more than 4000 CHR patients who had mainly been identified by UHR criteria and/or the basic symptom criterion ‘cognitive disturbances’ (COGDIS) showed considerable heterogeneity. While UHR criteria and COGDIS were related to similar conversion rates until 2-year follow-up, conversion rates of COGDIS were significantly higher thereafter. Differences in onset and frequency requirements of symptomatic UHR criteria or in their different consideration of functional decline, substance use and co-morbidity did not seem to impact on conversion rates. The ‘genetic risk and functional decline’ UHR criterion was rarely met and only showed an insignificant pooled sample effect. However, age significantly affected UHR conversion rates with lower rates in children and adolescents. Although more research into potential sources of heterogeneity in conversion rates is needed to facilitate improvement of CHR criteria, six evidence-based recommendations for an early detection of psychosis were developed as a basis for the EPA guidance on early intervention in CHR states.

Vertebral artery stenosis in the Basilar Artery International Cooperation Study (BASICS): prevalence and outcome

We assessed the prevalence of vertebral artery (VA) stenosis or occlusion and its influence on outcome in patients with acute basilar artery occlusion (BAO). We studied 141 patients with acute BAO enrolled in the Basilar Artery International Cooperation Study (BASICS) registry of whom baseline CT angiography (CTA) of the intracranial VAs was available. In 72 patients an additional CTA of the extracranial VAs was available. Adjusted risk ratios (aRRs) for death and poor outcome, defined as a modified Rankin Scale score ≥4, were calculated with Poisson regression in relation to VA occlusion, VA occlusion or stenosis ≥50 %, and bilateral VA occlusion. Sixty-six of 141 (47 %) patients had uni- or bilateral intracranial VA occlusion or stenosis ≥50 %. Of the 72 patients with intra- and extracranial CTA, 46 (64 %) had uni- or bilateral VA occlusion or stenosis ≥50 % and 9 (12 %) had bilateral VA occlusion. Overall, VA occlusion or stenosis ≥50 % was not associated with the risk of poor outcome. Patients with intra- and extracranial CTA and bilateral VA occlusion had a higher risk of poor outcome than patients without bilateral VA occlusion (aRR, 1.23; 95 % CI 1.02-1.50). The risk of death did not depend on the presence of unilateral or bilateral VA occlusion or stenosis ≥50 %. In conclusion, in patients with acute BAO, unilateral VA occlusion or stenosis ≥50 % is frequent, but not associated with an increased risk of poor outcome or death. Patients with BAO and bilateral VA occlusion have a slightly increased risk of poor outcome.

Fast adaptive responses in the oral jaw of Lake Victoria cichlids

Rapid morphological changes in response to fluctuating natural environments are a common phenomenon in species that undergo adaptive radiation. The dramatic ecological changes in Lake Victoria provide a unique opportunity to study environmental effects on cichlid morphology. This study shows how four haplochromine cichlids adapted their premaxilla to a changed diet over the past 30 years. Directly after the diet change toward larger and faster prey in the late 1980s, the premaxilla (upper jaw) changed in a way that is in agreement with a more food manipulating feeding style. During the 2000s, two zooplanktivorous species showed a reversal of morphological changes after returning to their original diet, whereas two other species showed no reversal of diet and morphology. These rapid changes indicate a potential for extremely fast adaptive responses to environmental fluctuations, which are likely inflicted by competition release and increase, and might have a bearing on the ability of haplochromines to cope with environmental changes. These responses could be due to rapid genetic change or phenotypic plasticity, for which there is ample evidence in cichlid fish structures associated with food capture and processing. These versatile adaptive responses are likely to have contributed to the fast adaptive radiation of haplochromines.