X-Irradiation-Induced Disorganization of Cytoskeletal Filaments and Cell Contacts in HT29 Cells

Organization of cytoskeleton and cell contacts were studied by immunochemistry and electron microscopy in confluent HT29 cultured cells following exposure to 0.5 and 1.0 Gy doses of X-ray. Microtubules were resistant to irradiation, whereas, the actin and intermediate filaments disrupted rapidly following the treatment and their components appeared as clumps of actin and cytokeratin aggregates in the cytoplasm as demonstrated by immunochemistry. Loss of cell contacts and decrease in the number of desmosomes was also characteristic of irradiated cells. Electron microscopy revealed intact desmosomes in control cells and abnormal desmosomes in the irradiated samples characterized by the absence of tonofilaments. The perinuclear filament network and cortical filaments were well detectable by electron microscopy. Under the effect of irradiation, the perinuclear filaments almost disappeared and, at the same time, small bundles of filaments were formed irregularly in the cytoplasm associated with amorphous material

Effect of age on discrimination learning, reversal learning, and cognitive bias in family dogs

Several studies on age-related cognitive decline in dogs involve laboratory dogs and prolonged training. We developed two spatial tasks that required a single 1-h session. We tested 107 medium-large sized dogs: \u201cyoung\u201d (N=41, aged 2.5\u20136.5 years) and \u201cold\u201d (N=66, aged 8\u201314.5 years). Our results indicated that, in a discrimination learning task and in a reversal learning task, young dogs learned significantly faster than the old dogs, indicating that these two tasks could successfully be used to investigate differences in spatial learning between young and old dogs. We also provide two novel findings. First, in the reversal learning, the dogs trained based on the location of stimuli learned faster than the dogs trained based on stimulus characteristics. Most old dogs did not learn the task within our cut-off of 50 trials. Training based on an object\u2019s location is therefore more appropriate for reversal learning tasks. Second, the contrast between the response to the positive and negative stimuli was narrower in old dogs, compared to young dogs, during the reversal learning task, as well as the cognitive bias test. This measure favors comparability between tasks and between studies. Following the cognitive bias test, we could not find any indication of differences in the positive and negative expectations between young and old dogs. Taken together, these findings do not support the hypothesis that old dogs have more negative expectations than young dogs and the use of the cognitive bias test in older dogs requires further investigation

Pseudo-Hermitian Hamiltonians, indefinite inner product spaces and their symmetries

We extend the definition of generalized parity $P$, charge-conjugation $C$ and time-reversal $T$ operators to nondiagonalizable pseudo-Hermitian Hamiltonians, and we use these generalized operators to describe the full set of symmetries of a pseudo-Hermitian Hamiltonian according to a fourfold classification. In particular we show that $TP$ and $CTP$ are the generators of the antiunitary symmetries; moreover, a necessary and sufficient condition is provided for a pseudo-Hermitian Hamiltonian $H$ to admit a $P$-reflecting symmetry which generates the $P$-pseudounitary and the $P$-pseudoantiunitary symmetries. Finally, a physical example is considered and some hints on the $P$-unitary evolution of a physical system are also given.Comment: 20 page

Extravascular Lung Water Correlates Multiorgan Dysfunction Syndrome and Mortality in Sepsis

BACKGROUND: This study was designated to investigate whether increased extravascular lung water index (EVLWI) may correlate multiple organ dysfunction syndrome (MODS) and mortality in sepsis. METHODS: We designed a prospective cohort study in an intensive care unit of a tertiary care hospital. Sixty-seven patients with severe sepsis were included. Data were used to determine an association between EVLWI and the development of MODS and mortality. These connections were determined by the multiple logistic regression, plotting the receiver operating characteristic (ROC) curve and by Spearman test. RESULTS: EVLWI levels were higher in MODS patients on day 1 (median (IQR), 18(12.8-23.9) ml/kg, n = 38, p<0.0001) than in those without (median (IQR), 12.4 (7.9-16.3) ml/kg, n = 29) and day 3 (median (IQR), 17.8 (11.2-22.8) ml/kg, n = 29, p = 0.004) than in those without (median (IQR), 12.4 (8.0-16.3) ml/kg, n = 29). EVLWI was used as an independent predictor of the development of MODS (odds ratio, 1.6; p = 0.005; 95% confidence interval, 1.2∼2.2) during ICU stay. The area under the ROC curve showed that EVLWI levels could predict MODS (0.866) and mortality (0.881) during ICU stay. Meanwhile, the higher of SOFA score, the more EVLWI was found on day 1 (r = 0.7041, p<0.0001) and day 3 (r = 0.7732, p<0.0001). CONCLUSIONS: Increased EVLWI levels correlates development of MODS and mortality during the patients' ICU stay. Further more, the potential of novel treatment in severe sepsis with lung injury may develop

Research priorities for European paediatric emergency medicine

Objective Research in European Paediatric Emergency Medicine (REPEM) network is a collaborative group of 69 paediatric emergency medicine (PEM) physicians from 20 countries in Europe, initiated in 2006. To further improve paediatric emergency care in Europe, the aim of this study was to define research priorities for PEM in Europe to guide the development of future research projects. Design and Setting We carried out an online survey in a modified three-stage Delphi study. Eligible participants were members of the REPEM network. In stage 1, the REPEM steering committee prepared a list of research topics. In stage 2, REPEM members rated on a 6-point scale research topics and they could add research topics and comment on the list for further refinement. Stage 3 included further prioritisation using the Hanlon Process of Prioritisation (HPP) to give more emphasis to the feasibility of a research topic. Results Based on 52 respondents (response rates per stage varying from 41% to 57%), we identified the conditions 'fever', 'sepsis' and 'respiratory infections', and the processes/interventions 'biomarkers', 'risk stratification' and 'practice variation' as common themes of research interest. The HPP identified highest priority for 4 of the 5 highest prioritised items by the Delphi process, incorporating prevalence and severity of each condition and feasibility of undertaking such research. Conclusions While the high diversity in emergency department (ED) populations, cultures, healthcare systems and healthcare delivery in European PEM prompts to focus on practice variation of ED conditions, our defined research priority list will help guide further collaborative research efforts within the REPEM network to improve PEM care in Europe.publishersversionPeer reviewe

Presentations of children to emergency departments across Europe and the COVID-19 pandemic: A multinational observational study

BACKGROUND: During the initial phase of the Coronavirus Disease 2019 (COVID-19) pandemic, reduced numbers of acutely ill or injured children presented to emergency departments (EDs). Concerns were raised about the potential for delayed and more severe presentations and an increase in diagnoses such as diabetic ketoacidosis and mental health issues. This multinational observational study aimed to study the number of children presenting to EDs across Europe during the early COVID-19 pandemic and factors influencing this and to investigate changes in severity of illness and diagnoses. METHODS AND FINDINGS: Routine health data were extracted retrospectively from electronic patient records of children aged 18 years and under, presenting to 38 EDs in 16 European countries for the period January 2018 to May 2020, using predefined and standardized data domains. Observed and predicted numbers of ED attendances were calculated for the period February 2020 to May 2020. Poisson models and incidence rate ratios (IRRs), using predicted counts for each site as offset to adjust for case-mix differences, were used to compare age groups, diagnoses, and outcomes. Reductions in pediatric ED attendances, hospital admissions, and high triage urgencies were seen in all participating sites. ED attendances were relatively higher in countries with lower SARS-CoV-2 prevalence (IRR 2.26, 95% CI 1.90 to 2.70, p < 0.001) and in children aged <12 months (12 to <24 months IRR 0.86, 95% CI 0.84 to 0.89; 2 to <5 years IRR 0.80, 95% CI 0.78 to 0.82; 5 to <12 years IRR 0.68, 95% CI 0.67 to 0.70; 12 to 18 years IRR 0.72, 95% CI 0.70 to 0.74; versus age <12 months as reference group, p < 0.001). The lowering of pediatric intensive care admissions was not as great as that of general admissions (IRR 1.30, 95% CI 1.16 to 1.45, p < 0.001). Lower triage urgencies were reduced more than higher triage urgencies (urgent triage IRR 1.10, 95% CI 1.08 to 1.12; emergent and very urgent triage IRR 1.53, 95% CI 1.49 to 1.57; versus nonurgent triage category, p < 0.001). Reductions were highest and sustained throughout the study period for children with communicable infectious diseases. The main limitation was the retrospective nature of the study, using routine clinical data from a wide range of European hospitals and health systems. CONCLUSIONS: Reductions in ED attendances were seen across Europe during the first COVID-19 lockdown period. More severely ill children continued to attend hospital more frequently compared to those with minor injuries and illnesses, although absolute numbers fell. TRIAL REGISTRATION: ISRCTN91495258 https://www.isrctn.com/ISRCTN91495258

Duplication of 7q34 is specific to juvenile pilocytic astrocytomas and a hallmark of cerebellar and optic pathway tumours

BACKGROUND: Juvenile pilocytic astrocytomas (JPA), a subgroup of low-grade astrocytomas (LGA), are common, heterogeneous and poorly understood subset of brain tumours in children. Chromosomal 7q34 duplication leading to fusion genes formed between KIAA1549 and BRAF and subsequent constitutive activation of BRAF was recently identified in a proportion of LGA, and may be involved in their pathogenesis. Our aim was to investigate additional chromosomal unbalances in LGA and whether incidence of 7q34 duplication is associated with tumour type or location. METHODS AND RESULTS: Using Illumina-Human-Hap300-Duo and 610-Quad high-resolution-SNP-based arrays and quantitative PCR on genes of interest, we investigated 84 paediatric LGA. We demonstrate that 7q34 duplication is specific to sporadic JPA (35 of 53-66%) and does not occur in other LGA subtypes (0 of 27) or NFI-associated-JPA (0 of 4). We also establish that it is site specific as it occurs in the majority of cerebellar JPA (24 of 30-80%) followed by brainstem, hypothalamic/optic pathway JPA (10 of 16-62.5%) and is rare in hemispheric JPA (1 of 7-14%). The MAP-kinase pathway, assessed through ERK phosphorylation, was active in all tumours regardless of 7q34 duplication. Gain of function studies performed on hTERT-immortalised astrocytes show that overexpression of wild-type BRAF does not increase cell proliferation or baseline MAPK signalling even if it sensitises cells to EGFR stimulation. CONCLUSIONS AND INTERPRETATION: Our results suggest that variants of JPA might arise from a unique site-restricted progenitor cell where 7q34 duplication, a hallmark of this tumour-type in association to MAPK-kinase pathway activation, potentially plays a site-specific role in their pathogenesis. Importantly, gain of function abnormalities in components of MAP-Kinase signalling are potentially present in all JPA making this tumour amenable to therapeutic targeting of this pathway. British Journal of Cancer (2009) 101, 722-733. doi: 10.1038/sj.bjc.6605179 www.bjcancer.com Published online 14 July 2009 (C) 2009 Cancer Research U