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Are mental health problems associated with use of Accident and Emergency and health-related harm?
No full textBackground: Previous findings indicate that mental health problems are common in Emergency departments; however, there are few studies of the extent of health-related problems and emergency service use in mental health populations as a whole. Methods: Record linkage methods were used to map the association between mental health, age, gender, and health-related harm across total health and mental health care populations in one geographical area, over three years. By examining patterns of health-related harm, an accurate profile of mentally ill Emergency patients was generated enabling identification of factors that increased vulnerability to harm. Results: Of the total population of 625 964 individuals, 10.7% contacted Accident and Emergency (A&E) over three years, this proportion rose to 28.6% among the total secondary care mental health population. Young men and older women were more likely to contact A&E, both overall and within mental health populations and were also more likely to be frequent attendees at A&E. Four distinct groups (typologies) of mental health patients attending A&E emerged: young, male frequent attendees with self-inflicted and other traumatic injuries; young females also presenting with self-harm; older patients with multiple medical conditions; and very old patients with cardiac conditions and fractures. Conclusion: The study indicates increased A+E service use and unmet health-related need within a total mental health population. It identifies specific ‘care populations’ particularly vulnerable to accidents and self-harm and highlights the need for targeted services for mentally ill groups who may not access traditional health and social care services effectively
Phosphoproteomics data classify hematological cancer cell lines according to tumor type and sensitivity to kinase inhibitors
No full textThis is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited
Introductions to the Community: Early-Career Researchers in the Time of COVID-19
No full textCOVID-19 has unfortunately halted lab work, conferences, and in-person networking, which is especially detrimental to researchers just starting their labs. Through social media and our reviewer networks, we met some early-career stem cell investigators impacted by the closures. Here, they introduce themselves and their research to our readers
Slug-based epithelial-mesenchymal transition gene signature is associated with prolonged time to recurrence in glioblastoma
No full textBackground
We previously identified a precise stage-associated gene expression signature of coordinately expressed genes, including the transcription factor Slug (SNAI2) and other epithelial mesenchymal transition (EMT) markers, present in samples from publicly available gene expression datasets in multiple cancer types. The expression levels of the co-expressed genes vary in a continuous and coordinate manner across the samples, ranging from absence of expression to strong co-expression of all genes. These data suggest that tumor cells may pass through an EMT like process of mesenchymal transition to varying degrees. 

Findings
Here we show that this signature in glioblastoma multiforme (GBM) is associated with time to recurrence following initial treatment. By analyzing data from The Cancer Genome Atlas (TCGA), we found that GBM patients who responded to therapy and had long time to recurrence had low levels of the signature in their tumor samples (P = 3x10^-7^). We also found that the signature is strongly correlated in gliomas with the putative stem cell marker CD44, and is highly enriched among the differentially expressed genes in glioblastomas vs. lower grade gliomas. 

Conclusions 
Our results suggest that long delay before tumor recurrence is associated with absence of the mesenchymal transition signature, raising the possibility that inhibiting this transition might improve the durability of therapy in glioma patients
Probabilistic methods for seasonal forecasting in a changing climate: Cox-type regression models
No full textFor climate risk management, cumulative distribution functions (CDFs) are an important source of information. They are ideally suited to compare probabilistic forecasts of primary (e.g. rainfall) or secondary data (e.g. crop yields). Summarised as CDFs, such forecasts allow an easy quantitative assessment of possible, alternative actions. Although the degree of uncertainty associated with CDF estimation could influence decisions, such information is rarely provided. Hence, we propose Cox-type regression models (CRMs) as a statistical framework for making inferences on CDFs in climate science. CRMs were designed for modelling probability distributions rather than just mean or median values. This makes the approach appealing for risk assessments where probabilities of extremes are often more informative than central tendency measures. CRMs are semi-parametric approaches originally designed for modelling risks arising from time-to-event data. Here we extend this original concept to other positive variables of interest beyond the time domain. We also provide tools for estimating CDFs and surrounding uncertainty envelopes from empirical data. These statistical techniques intrinsically account for non-stationarities in time series that might be the result of climate change. This feature makes CRMs attractive candidates to investigate the feasibility of developing rigorous global circulation model (GCM)-CRM interfaces for provision of user-relevant forecasts. To demonstrate the applicability of CRMs, we present two examples for El Niño/Southern Oscillation (ENSO)-based forecasts: the onset date of the wet season (Cairns, Australia) and total wet season rainfall (Quixeramobim, Brazil). This study emphasises the methodological aspects of CRMs rather than discussing merits or limitations of the ENSO-based predictor
Hemostatic activation during cardiopulmonary bypass with different aprotinin dosages in pediatric patients having cardiac operations
No full textInducible expression of RANKL in transgenic pigs under the control of the Tet-On system
No full textBecause of the tremendous need for transgenic large animal models for human diseases, the process of SCNT is a crucial step in transgenic pig production. In our study, we evaluated the particular steps during the production for their impact on the efficiency of cloning transgenic pigs. For this purpose, statistical analysis was performed for all SCNT data from the years 2006 until June 2010. The RANKL transgenic osteoporosis model was chosen for an example for the production steps needed to finally achieve a disease model, to elucidate pitfalls and chances of SCNT procedure. In total 151 in vivo SCNT experiments using different transgenic cell lines were carried out, resulting in 243 piglets and fetuses. Statistical analysis revealed that donor cells treated exclusively in our laboratory had a significant better birth rate than donor cell originated of other laboratories. Furthermore, there was a significant relation between number of transferred NT embryos and later pregnancy checks, birth rate and abortion rate. The more NT embryos were transferred, the more pregnancies finished to terms. It was also elucidated that in our studies a different in vitro culture time of 24 or 48 hours had no significant impact on the outcome like pregnancy or birth rate. Seasonal changes during the years had no significant influence on pregnancy rate, birth or abortion. But there was a strong tendency that autumn showed best performance of all seasons, and most pregnancies were lost after embryo transfers during the summer. All these findings will be integrated in future in vivo SCNT experiments and embryo transfers. For the production of a transgenic osteoporosis model 17 in vivo experiments took place so far, with an outcome of 4 fetuses and 25 piglets. For gaining a controllable expression of RANKL, it was necessary to establish double transgenic pigs to sidestep harmful effects of RANKL overexpression during the fetal development. First attempts to integrate both genes, tetracycline controlled transactivator (Tet-On) and RANKL, in a single step of cell transfection and SCNT, had no satisfying result. We obtained 4 fetuses and stillborn recloned piglets carrying both genes, but they showed only expression of Tet-On and it was impossible to induce RANKL overexpression. Therefore the strategy was changed in favor to two rounds of transfection and nuclear transfer. First Tet-On transgenic piglets were established and screened for integration and expression. Piglet 9894 showed the best expression and severed as donor for next cell transfection step. These Tet-On + TARE RANKL cells were in vitro tested for their inducibility. Thereafter SCNT and embryo transfer of the best candidate were performed and they resulted in 4 pregnancies which all finished to term. One double transgenic piglet could be raised and will be kept until adulthood to establish a line of Tet-On +TARE RANKL transgenic pigs. Importantly, this founder animal showed inducible RANKL overexpression. Other constructs might be based on the existing Tet-On cell line in the future, offering an inducible system for a broad variety of different transgenes. Thus a functional Tet-On system in the pig is reported for the first time.Da es einen enormen Bedarf an transgenen Großtieren als Modelltiere für humane Erkrankungen gibt, wie zum Beispiel für Osteoporose, wurde die Generierung von transgenen Schweinen mittels somatischen Kerntransfers genauer untersucht. Dabei war das Ziel herauszufinden, welchen Einfluss die einzelnen Arbeitsschritte auf die Produktionseffizienz haben. Aus diesem Grund wurde eine statistische Analyse aller in vivo Kerntransfers von Anfang 2006 bis zum Juni 2010 durchgeführt. An dem Beispiel eines RANKL transgenen Osteoporose-Models wurden alle nötigen Produktionsschritte dargestellt und die Schwierigkeiten und Vorteile des somatischen Kerntransfers beschrieben. Die insgesamt 151 in vivo Experimente, wobei unterschiedliche transgene Zelllinien genutzt wurden, resultierten in 243 Ferkeln und Feten. Statistische Analysen zeigten, dass Spenderzellen, die ausschließlich in unserem Labor behandelt wurden, nach Kerntransfer zu einer signifikant höheren Geburtsrate der trächtigen Empfänger führten als Spenderzellen aus anderen Laboren. Weiterhin ergab sich ein Zusammenhang zwischen der Anzahl übertragener Kerntransfer-Embryonen und der späteren Trächtigkeitsrate, Geburtsrate und der Abortrate. Je mehr Embryonen übertragen wurden, desto mehr Trächtigkeiten wurden erfolgreich beendet. Es wurde auch sichtbar, dass in unseren Versuchen eine unterschiedliche in vitro-Kulturdauer der Kerntransfer-Embryonen von 24 bzw. 48 Stunden keinen signifikanten Unterschied in der Trächtigkeits- oder Geburtsrate verursachte. Auch für die verschiedenen Jahreszeiten konnte kein signifikanter Einfluss auf Trächtigkeit oder Geburt nachgewiesen werden. Es zeigte sich aber die Tendenz, dass im Herbst die besten Bedingungen für einen positiven Verlauf der Trächtigkeit herrschen und nach Embryotransfers im Sommer die höchste Abortrate auftritt. All diese Untersuchungsergebnisse werden zukünftig in unseren Arbeitsalltag integriert und der Kerntransfer und Embryotransferablauf optimiert. Zur Erstellung eines transgenen Osteoporosemodells wurden 17 Embryotransfers durchgeführt, die in 4 gewonnenen Feten und 25 geborenen Ferkeln resultierten. Um eine regulierbare RANKL Expression zu erhalten war es notwendig, doppelt transgene Schweine zu erstellen, so dass negative Nebeneffekte der RANKL Überexpression während der Fetalentwicklung vermieden wurden. Die ersten Versuche, Tetrazyklin Transaktivator (Tet-On) und RANKL in einem einzigen Schritt der Zelltransfektion und des in vivo Kerntransfers zu integrieren, führte zu wenig befriedigenden Ergebnissen. Es wurden 4 doppelt transgene Feten und 2 totgeborene Ferkel gewonnen, doch es konnte nur die Expression von Tet-On nachgewiesen werden, da die RANKL Expression nicht induzierbar war. Deswegen wurde die Strategie zu Gunsten von zwei Einzelschritten der Zelltransfektion und in vivo Kerntransfers gewechselt. Zuerst wurden Tet-On transgene Ferkel erstellt und auf Integration und Expression hin untersucht. Das Ferkel 8994 zeigte die beste Expression und seine Zellen wurden für den nächsten Zelltransfektionsschritt verwendet. Die daraus resultierenden Tet-On + TARE RANKL-Zellen wurden in vitro auf ihre Induzierbarkeit getestet. Als Spenderzellen für weitere in vivo Kerntransfers diente der beste Kandidat aus diesen Tests. Alle 4 Embryotransfers resultierten in Trächtigkeiten, die alle auch ausgetragen wurden. Ein doppelt transgenes Ferkel konnte aufgezogen werden, das zum einen nach Erreichen der Geschlechtsreife als Gründer einer transgenen Schweinelinie dienen wird, und im in vivo-Test eine induzierbare Expression von RANKL zeigte. Die regulierbaren Tet-On Zelllinien können auch für weitere zukünftige Konstrukte Verwendung finden, was die Möglichkeit mannigfaltiger genetischer Manipulation durch ein induzierbares System eröffnet. Hiermit wird das erste Mal von einem funktionalen und kontrollierbaren Tet-On System im Schwein berichtet
Carcinoembryonic Antigen Gene Family
No full textThe carcinoembryonic antigen (CEA) gene family belongs to the immunoglobulin supergene family and can be divided into two main subgroups based on sequence comparisons. In humans it is clustered on the long arm of chromosome 19 and consists of approximately 20 genes. The CEA subgroup genes code for CEA and its classical crossreacting antigens, which are mainly membrane-bound, whereas the other subgroup genes encode the pregnancy-specific glycoproteins (PSG), which are secreted. Splice variants of individual genes and differential post-translational modifications of the resulting proteins, e.g., by glycosylation, indicate a high complexity in the number of putative CEA-related molecules. So far, only a limited number of CEA-related antigens in humans have been unequivocally assigned to a specific gene. Rodent CEA-related genes reveal a high sequence divergence and, in part, a completely different domain organization than the human CEA gene family, making it difficult to determine individual gene counterparts. However, rodent CEA-related genes can be assigned to human subgroups based on similarity of expression patterns, which is characteristic for the subgroups. Various functions have been determined for members of the CEA subgroup in vitro, including cell adhesion, bacterial binding, an accessory role for collagen binding or ecto-ATPases activity. Based on all that is known so far on its biology, the clinical outlook for the CEA family has been reassessed
A life course approach to cardiovascular aging.
No full textA life course approach in epidemiology investigates the biological, behavioral and social pathways that link physical and social exposures and experiences during gestation, childhood, adolescence and adult life, and across generations, to later-life health and disease risk. We illustrate how a life course approach has been applied to cardiovascular disease, highlighting the evidence in support of the early origins of disease risk. We summarize how trajectories of cardiometabolic risk factors change over the life course and suggest that understanding underlying 'normal' or 'healthy' trajectories and the characteristics that drive deviations from such trajectories offer the potential for early prevention and for identifying means of preventing future disease
The sHsp expression signature in the brain and modulation in models of chronic neurodegeneration
No full textIntrinsic protein folding pathways are modulated by molecular chaperones, such as the diversegroup of heat shock proteins (Hsps). Among these is the small heat shock protein (sHsp)family which in the mammalian genome consists of 10 low molecular weight (15-30kDa)members. The sHsps have classical chaperone functions but additionally contribute topathways that protect against cellular stresses, maintain the cytoskeleton, prevent proteinaggregation and regulate apoptosis. They contain a characteristic C-terminal ?-crystallindomain, which is exclusive to the sHsp family. In addition to their constitutive expressionunder physiological (non-disease) conditions, they are also induced under conditions ofstress/heat shock which is thought to play a role in response to protein misfolding thatunderpins disease. There are a wide range of diseases in which the sHsps function or aredysfunctional by mutations, such as neurodegenerative disorders, cataract, and desmin relatedmyopathy.Each of the 10 sHsps is believed to have a unique expression profile. Seven of the sHsps areexpressed in heart and muscle, but little is known about their precise expression and/orphysiological role in the CNS. In the present study the expression of the mammalian sHsps invarious mouse tissues including the brain was investigated. This provided evidence for theconstitutive expression of 4 sHsps in the brain. In situ hybridization using naïve adult micerevealed a distinct white matter (oligodendrocyte) specific expression pattern for HspB5 (?Bcrystallin).HspB1 (Hsp25) and HspB8 (Hsp22) demonstrated overlapping expression in thelateral and dorsal ventricles of the brain, as well as expression in a distinct set of motorneurons in the ventral horn of the spinal cord. Further, cellular immunostaining and subfractionationof brain tissue supports a distinct cellular and subcellular protein expression ofHspB1, HspB5, HspB6 (Hsp20) and HspB8 in the brain. Both HspB5 and HspB6 wereenriched in the myelin fraction. In view of the potential for induction of these sHsps by stressand modulation in chronic brain diseases we systematically investigated the sHsp signature intwo distinct models of intracellular (R6/2) and extracellular (ME7) proteinopathies. Thesemodels recapitulate key features of Huntington’s and prion disease, respectively.Analysis of the sHsps in the R6/2 Huntington’s disease (HD) mouse model showed a specificdown-regulation of HspB5 in the white matter at all time points analyzed. All other sHspsinvestigated did not change in this model of HD. Analysis of the sHsps in ME7 prion diseaseshowed up-regulation of HspB1, HspB5 and HspB8 in the hippocampus. For HspB1, this wasselective to an anatomically defined sub-population of astrocytes distributed in the stratumradiatum. In contrast, all GFAP positive astrocytes throughout the hippocampus exhibitedinduced expression of HspB5 and HspB8. Based on QT-PCR data, the changes in expressionof the sHsps in either model was not under transcriptional control, suggesting translation/posttranslationalregulation. The differing results in the two models suggest that the presence ofintracellular (R6/2) or extracellular (ME7) aggregates may dictate the sHsp responseassociated with non-neuronal cells. In view of the emerging significance of non-neuronal cellsin chronic diseases the data supports adaptive and differential responses that might contributeto and/or provide a route to therapy of distinct aspects of neurodegeneration
