From theory to praxis

International audienceThis article is a description and discussion of a design research project in which we introduced a research idea about the influence of language on number concepts development into praxis on a school in grades K-3. Danish children have difficulties remembering the Danish number names because the Danish language resembles a primitive number concept in mathematical thinking. In the project, we renamed the numbers between 11-99 after the base-10 system. Our hypothesis was that this system would help Danish students to get a more secure concept about the base-10 system. The project lasted for three years ending in spring 2016. Our results were so convincing that the school decided to continue using the mathematical number names, and other schools that heard about the project seem to be interested in using the system as well. In other words, the project goes from being a top-down project to a bottom-up project

Co-administration of iloprost and eptifibatide in septic shock (CO-ILEPSS):A randomised, controlled, double-blind investigator-initiated trial investigating safety and efficacyA randomised, controlled, double-blind investigator-initiated trial investigating safety and efficacy

Publisher's version (útgefin grein). The CO-ILEPSS trial was approved by the ethics committee in The Capital Region of Denmark with protocol number: H-3-2014-087.Background: Part of the pathophysiology in septic shock is a progressive activation of the endothelium and platelets leading to widespread microvascular injury with capillary leakage, microthrombi and consumption coagulopathy. Modulating the inflammatory response of endothelium and thrombocytes might attenuate this vicious cycle and improve outcome. Method: The CO-ILEPSS trial was a randomised, placebo-controlled, double-blind, pilot trial. Patients admitted to the intensive care unit with septic shock were randomised and allocated in a 2:1 ratio to active treatment with dual therapy of iloprost 1 ng/kg/min and eptifibatide 0.5 μg/kg/min for 48 h or placebo. The primary outcomes were changes in biomarkers reflecting endothelial activation and disruption, platelet consumption and fibrinolysis. We compared groups with mixed models, post hoc Wilcoxon signed-rank test and Mann-Whitney U test. Results: We included 24 patients of which 18 (12 active, 6 placebo) completed the full 7-day trial period and were included in the per-protocol analyses of the primary outcomes. Direct comparison between groups showed no differences in the primary outcomes. Analyses of within-group delta values revealed that biomarkers of endothelial activation and disruption changed differently between groups with increasing levels of thrombomodulin (p = 0.03) and nucleosomes (p = 0.02) in the placebo group and decreasing levels of sE-Selectin (p = 0.007) and sVEGFR1 (p = 0.005) in the active treatment group. Platelet count decreased the first 48 h in the placebo group (p = 0.049) and increased from baseline to day 7 in the active treatment group (p = 0.023). Levels of fibrin monomers declined in the active treatment group within the first 48 h (p = 0.048) and onwards (p = 0.03). Furthermore, there was a significant reduction in SOFA score from 48 h (p = 0.024) and onwards in the active treatment group. Intention-to-treat analyses of all included patients showed no differences in serious adverse events including bleeding, use of blood products or mortality. Conclusion: Our results could indicate benefit from the experimental treatment with reduced endothelial injury, reduced platelet consumption and ensuing reduction in fibrinolytic biomarkers along with improved SOFA score. The results of the CO-ILEPSS trial are exploratory and hypothesis generating and warrant further investigation in a large-scale trial. Trial registration: Clinicaltrials.com, NCT02204852 (July 30, 2014); EudraCT no. 2014-002440-41Funding was provided by Professor Per I. Johansson, Senior Physician, DMSC, MPA, The Capital Region Blood Bank, and Rigshospitalet. We would like to acknowledge all the nurses and doctors at the intensive care unit and the nurses at the post-operative care unit at NOH for the work associated with the trial treatment including randomisation, preparation of trial medication and blood sampling.Peer Reviewe

Gut bacteria and necrotizing enterocolitis: cause or effect?

Development of necrotising enterocolitis (NEC) is considered to be dependent on the bacterial colonisation of the gut. With little concordance between published data and a recent study failing to detect a common strain in infants with NEC, more questions than answers are arising about our understanding of this complex disease

Biochemical, clinical and genetic characteristics in adults with persistent hypophosphatasaemia; Data from an endocrinological outpatient clinic in Denmark

BACKGROUND: Hypophosphatasia (HPP) is an inborn disease caused by pathogenic variants in ALPL. Low levels of alkaline phosphatase (ALP) are a biochemical hallmark of the disease. Scarce knowledge about the prevalence of HPP in Scandinavia exists, and the variable clinical presentations make diagnostics challenging. The aim of this study was to investigate the prevalence of ALPL variants as well as the clinical and biochemical features among adults with endocrinological diagnoses and persistent hypophosphatasaemia. METHODS: A biochemical database containing ALP measurements of 26,121 individuals was reviewed to identify adults above 18 years of age with persistently low levels of ALP beneath range (≤ 35 ± 2.7 U/L). ALPL genetic testing, biochemical evaluations and assessment of clinical features by a systematic questionnaire among included patients, were performed. RESULTS: Among 24 participants, thirteen subjects (54.2%) revealed a disease-causing variant in ALPL and reported mild clinical features of HPP, of which musculoskeletal pain was the most frequently reported (n = 9). The variant c. 571G > A; p.(Glu191Lys) was identified in six subjects, and an unreported missense variant (c.1019A > C; p.(His340Pro)) as well as a deletion of exon 2 were detected by genetic screening. Biochemical analyses showed no significant differences in ALP (p = 0.059), the bone specific alkaline phosphatase (BALP) (p = 0.056) and pyridoxal-5′-phosphate (PLP) (p = 0.085) between patients with an ALPL variant and negative genetic screening. Patients with a variant in ALPL had significantly higher PLP levels than healthy controls (p = 0.002). We observed normal ALP activity in some patients classified as mild HPP, and slightly increased levels of PLP in two subjects with normal genetic screening and four healthy controls. Among 51 patients with persistent hypophosphatasaemia, fifteen subjects (29.4%) received antiresorptive treatment. Two patients with unrecognized HPP were treated with bisphosphonates and did not show complications due to the treatment. CONCLUSIONS: Pathogenic variants in ALPL are common among patients with endocrinological diagnoses and low ALP. Regarding diagnostics, genetic testing is necessary to identify mild HPP due to fluctuating biochemical findings. Antiresorptive treatment is a frequent reason for hypophosphatasaemia and effects of these agents in adults with a variant in ALPL and osteoporosis remain unclear and require further studies

Quantitative genetics of taura syndrome resistance in pacific white shrimp (penaeus vannamei): a cure model approach

<p>Abstract</p> <p>Background</p> <p>In aquaculture breeding, resistance against infectious diseases is commonly assessed as time until death under exposure to a pathogen. For some diseases, a fraction of the individuals may appear as "cured" (non-susceptible), and the resulting survival time may thus be a result of two confounded underlying traits, i.e., endurance (individual hazard) and susceptibility (whether at risk or not), which may be accounted for by fitting a cure survival model. We applied a cure model to survival data of Pacific white shrimp (<it>Penaeus vannamei</it>) challenged with the Taura syndrome virus, which is one of the major pathogens of Panaeid shrimp species.</p> <p>Methods</p> <p>In total, 15,261 individuals of 513 full-sib families from three generations were challenge-tested in 21 separate tests (tanks). All challenge-tests were run until mortality naturally ceased. Time-until-event data were analyzed with a mixed cure survival model using Gibbs sampling, treating susceptibility and endurance as separate genetic traits.</p> <p>Results</p> <p>Overall mortality at the end of test was 28%, while 38% of the population was considered susceptible to the disease. The estimated underlying heritability was high for susceptibility (0.41 ± 0.07), but low for endurance (0.07 ± 0.03). Furthermore, endurance and susceptibility were distinct genetic traits (r_g= 0.22 ± 0.25). Estimated breeding values for endurance and susceptibility were only moderately correlated (0.50), while estimated breeding values from classical models for analysis of challenge-test survival (ignoring the cured fraction) were closely correlated with estimated breeding values for susceptibility, but less correlated with estimated breeding values for endurance.</p> <p>Conclusions</p> <p>For Taura syndrome resistance, endurance and susceptibility are apparently distinct genetic traits. However, genetic evaluation of susceptibility based on the cure model showed clear associations with standard genetic evaluations that ignore the cure fraction for these data. Using the current testing design, genetic variation in observed survival time and absolute survival at the end of test were most likely dominated by genetic variation in susceptibility. If the aim is to reduce susceptibility, earlier termination of the challenge-test or back-truncation of the follow-up period should be avoided, as this may shift focus of selection towards endurance rather than susceptibility.</p

APIM-peptide targeting PCNA improves the efficacy of docetaxel treatment in the TRAMP mouse model of prostate cancer

publishedVersio

Mind the gut:Genomic insights to population divergence and gut microbial composition of two marine keystone species

BACKGROUND: Deciphering the mechanisms governing population genetic divergence and local adaptation across heterogeneous environments is a central theme in marine ecology and conservation. While population divergence and ecological adaptive potential are classically viewed at the genetic level, it has recently been argued that their microbiomes may also contribute to population genetic divergence. We explored whether this might be plausible along the well-described environmental gradient of the Baltic Sea in two species of sand lance (Ammodytes tobianus and Hyperoplus lanceolatus). Specifically, we assessed both their population genetic and gut microbial composition variation and investigated not only which environmental parameters correlate with the observed variation, but whether host genome also correlates with microbiome variation. RESULTS: We found a clear genetic structure separating the high-salinity North Sea from the low-salinity Baltic Sea sand lances. The observed genetic divergence was not simply a function of isolation by distance, but correlated with environmental parameters, such as salinity, sea surface temperature, and, in the case of A. tobianus, possibly water microbiota. Furthermore, we detected two distinct genetic groups in Baltic A. tobianus that might represent sympatric spawning types. Investigation of possible drivers of gut microbiome composition variation revealed that host species identity was significantly correlated with the microbial community composition of the gut. A potential influence of host genetic factors on gut microbiome composition was further confirmed by the results of a constrained analysis of principal coordinates. The host genetic component was among the parameters that best explain observed variation in gut microbiome composition. CONCLUSIONS: Our findings have relevance for the population structure of two commercial species but also provide insights into potentially relevant genomic and microbial factors with regards to sand lance adaptation across the North Sea-Baltic Sea environmental gradient. Furthermore, our findings support the hypothesis that host genetics may play a role in regulating the gut microbiome at both the interspecific and intraspecific levels. As sequencing costs continue to drop, we anticipate that future studies that include full genome and microbiome sequencing will be able to explore the full relationship and its potential adaptive implications for these species

A manually curated ChIP-seq benchmark demonstrates room for improvement in current peak-finder programs

Chromatin immunoprecipitation (ChIP) followed by high throughput sequencing (ChIP-seq) is rapidly becoming the method of choice for discovering cell-specific transcription factor binding locations genome wide. By aligning sequenced tags to the genome, binding locations appear as peaks in the tag profile. Several programs have been designed to identify such peaks, but program evaluation has been difficult due to the lack of benchmark data sets. We have created benchmark data sets for three transcription factors by manually evaluating a selection of potential binding regions that cover typical variation in peak size and appearance. Performance of five programs on this benchmark showed, first, that external control or background data was essential to limit the number of false positive peaks from the programs. However, >80% of these peaks could be manually filtered out by visual inspection alone, without using additional background data, showing that peak shape information is not fully exploited in the evaluated programs. Second, none of the programs returned peak-regions that corresponded to the actual resolution in ChIP-seq data. Our results showed that ChIP-seq peaks should be narrowed down to 100–400 bp, which is sufficient to identify unique peaks and binding sites. Based on these results, we propose a meta-approach that gives improved peak definitions