Kinetics of prion accumulation in splenic cell types of the lymphoreticular system

Prions accumulate in the lymphoreticular system (LRS) at early stages of prion disease, long before they are detected in the brain. A considerable body of evidence showed that both haematopoietic and stromal cells play a role in prion pathogenesis. However, the contribution of different cell types to the accumulation and the spread of prions in the LRS are not well understood. Taking advantage of a quantitative in-vitro infectivity assay, the Scrapie Cell Assay (SCA) and high density magnetic-activated cell sorting (MACS), we studied the kinetics of prion accumulation in various splenic cell types at early stages of prion disease. The determination of statistically robust infectious titres was achieved by statistical modelling using generalised linear model (GLM) regression. With this novel procedure time-dependent changes of prion titres were monitored in seven distinct splenic cells and identified two cell types that have previously not been associated to prion pathogenesis, plasmacytoid dendritic (pDC) and natural killer (NK) cells. Notably, in Prnp-/- mice, e.g. in absence of prion replication, infectivity was detected in macrophages and dendritic cells (DC) after 3 dpi, but not in lymphocytes, underscoring the importance of prion sequestration by antigen-presenting cells which are among the first cells of the immune system to encounter pathogens. Reports of the secretion of endosome-derived membrane particles, so called exosomes by immune-competent cells and prion-infected cell lines raised the question whether prion secretion could be a potential route for the spread of prions. We here present the first evidence that MACS-isolated lymphocytes and DCs from scrapie-infected mice secrete prions which are associated to the release of exosome-like membrane particles into the cell culture supernatant ex vivo

Percepção de enfermeiras sobre o manejo da dor em crianças em um Serviço Hospitalar de de Oncologia no Chile

Inadequate pain management in children continues to be a problem. Pain is a frequent symptom in hospitalized children, being an excellent challenge for nursing, understanding that childhood pain in cancer is multifactorial, which makes its management difficult. The objective is to know the perception of nursing professionals regarding pain management in pediatric oncology people hospitalized during the second half of 2017. Methodology: This research is part of the constructivist paradigm focusing on grounded theory, descriptive with qualitative design. A study carried out at the Hemato-Oncology Service of the Roberto del Río Hospital proposed. Six nurses participate in a semi-structured interview for subsequent content analysis. Results: They are female subjects, mainly young adults and for the majority this constitutes their first work experience. The qualitative analysis allowed structuring the perception of pain management in four categories with subcategories: Definition of Pain: Concept of Pain, Pain in the service, Relevance of Pain. Pain assessment: Subjectivity in assessment, Application of rating scales, Personal experience, Family role in pain assessment. Care planning: Role of the family in pain management, Individualization of care, Teamwork. Pain management: Pharmacological treatment, Non-pharmacological treatment. Conclusions: It is possible to know the nurses' perception of pain, understanding boys and girls as a multifactorial being, which requires an adequate assessment, integrating pharmacological and non-pharmacological treatment for remission.El manejo inadecuado del dolor en niños continúa siendo un problema. El dolor es un síntoma frecuente en los niños hospitalizados, siendo un gran desafío para enfermería, entendiendo que el dolor infantil en cáncer es multifactorial lo que dificulta su manejo. El objetivo fue conocer la percepción de los profesionales de enfermería frente al manejo del dolor en personas oncológicas pediátricas hospitalizadas durante el segundo semestre del año 2017. Metodología: Esta investigación se enmarca en el paradigma constructivista con enfoque en la teoría fundada. El estudio se realizó en el Servicio de Hemato-Oncología del Hospital Roberto del Río. Participaron seis enfermeras en una entrevista semiestructurada para un posterior análisis de contenido.  Resultados: Fueron participantes de sexo femenino, adultos jóvenes y para la mayoría, esta constituye su primera experiencia laboral. El análisis cualitativo permitió estructurar la percepción del manejo del dolor en cuatro categorías con subcategorías: Definición de dolor: Concepto de dolor, Dolor en el servicio, Relevancia del dolor. Valoración del dolor: Subjetividad en la valoración, Aplicación de escalas de valoración, Experiencia personal, Rol familiar en valoración del dolor. Planificación de los cuidados: Rol de la familia en el manejo del dolor, Individualización de los cuidados, Trabajo en Equipo. Tratamiento del dolor: Tratamiento farmacológico, Tratamiento no farmacológico. Conclusiones: Se logró conocer la percepción de las enfermeras sobre el manejo del dolor, comprendiendo los niños y niñas como un ser multifactorial, que requiere una valoración adecuada, integrando el tratamiento farmacológico y no farmacológico para su remisión.  O tratamento inadequado da dor em crianças continua a ser um problema. A dor é um sintoma frequente em crianças hospitalizadas, sendo um grande desafio para a enfermagem, por compreender que a dor na infância no câncer é multifatorial, o que dificulta seu manejo. O objetivo é conhecer a percepção dos profissionais de enfermagem sobre o manejo da dor em oncológicos pediátricos internados no segundo semestre de 2017. Metodologia: Esta pesquisa está enquadrada no paradigma construtivista com foco na teoria fundamentada, descritiva com desenho qualitativo. O estudo foi realizado no Serviço de Hemato-Oncologia do Hospital Roberto del Río. Seis enfermeiros participam de uma entrevista semiestruturada para posterior análise de conteúdo. Resultados: São sujeitos do sexo feminino, principalmente jovens adultos e, para a maioria, constituem sua primeira experiência de trabalho. A análise qualitativa permitiu estruturar a percepção do manejo da dor em quatro categorias com subcategorias: Definição de dor: Conceito de dor, Dor no serviço, Relevância da dor. Avaliação da dor: subjetividade na avaliação, aplicação de escalas de avaliação, experiência pessoal, papel da família na avaliação da dor. Planejamento do cuidado: Papel da família no manejo da dor, Individualização do cuidado, Trabalho em equipe. Tratamento da dor: tratamento farmacológico, tratamento não farmacológico. Conclusões: É possível conhecer a percepção dos enfermeiros sobre o manejo da dor, compreendendo meninos e meninas como um ser multifatorial, o que requer uma avaliação adequada, integrando o tratamento farmacológico e não farmacológico para remissão

Evolução da linha de praia do Peró, Cabo Frio / RJ nos últimos 7.000 anos

The present work aims to evaluate the coastal dynamics along the Peró beach over the last 7,000 years, using shell-midden dating, sediment granulometric analysis, aerial photography from different ages, and field investigation to aid result interpretation and provide for clues on the adaptation of the methodology employed. Paleobeach reconstruction has been made possible by a combination of 14C age-dating and the interpretation of beach ridge disposition. Aerial photography from the years of 1959, 1976, and 2003 allow the evaluation of the present short-term coastline behavior, thus establishing the position of the paleobeach in relation to the current high-tide zone. Results indicate that the paleobeach situated in the present-day coastal plain dates from 3.373 - 3.000 cal A.P. Coastline variation in the 1959 - 1976 period consists of approximately 30m of accretion on its most significant point, while in the it eroded about 30m at the central beach sector during 1976 - 2003 period. In this context, results are considered satisfactory for the understanding of sedimentation dynamics at the Peró beach, in the city of Cabo Frio, Rio de Janeiro, Brazil.O presente trabalho tem como objetivo estudar a dinâmica costeira da praia do Peró nos últimos 7.000 anos, usando como parâmetro datações no depósito de conchas, análise granulométrica, interpretação de fotografias aéreas de diferentes datas de vôo e investigações de campo que facilitassem as interpretações dos resultados encontrados e adequações na metodologia a ser empregada. Através do método de datação por 14C foi possível estabelecer a idade da paleopraia e pela disposição das cristas praias fazer a sua reconstituição. As fotografias aéreas correspondentes aos anos de 1959, 1976 e 2003 permitiram uma avaliação de curto prazo sobre o comportamento da atual linha de costa, estabelecendo assim, a relação do antigo posicionamento da paleopraia em relação à faixa de preamar atual. Os resultados indicaram que a paleopraia situada no interior da planície costeira apresenta idade 3.373 - 3.000 cal A.P. A variação da linha de costa correspondente ao período de 1959 - 1976 foi de aproximadamente 30 m de acresção e entre 1976 - 2003, a retrogradação foi de 30 m. Neste contexto os resultados alcançados mostraram-se satisfatório para compreensão da dinâmica sedimentar da praia do Peró, município de Cabo Frio - Rio de Janeiro

Political Protest in Times of Crisis. Construction of New Frames of Diagnosis and Emotional Climate

In times of crisis, political mobilizations increase. Many of them compete to impose a determined diagnosis of the situation. This work analyses this issue, taking into consideration two of the movements that have had a greater incidence during the crisis in Spain: The Catalonian National Assembly and the Marches for dignity. The objective is to know how the categories of aggrieved ingroup and outgroup responsible were identified and how both these movements defined the emotional climate at that moment. This work includes two studies. In the first one, an analysis of the categories identified in the manifestos published by these two movements was carried out. The results show that the Marches for dignity constructed a more inclusive ingroup identity and show a more negative emotional climate than the Catalonian National Assembly. The second study includes a sample of 919 participants and non-participants in 2 demonstrations called by those organizations. In this case MANOVAs of 2 (Type of demonstration: Catalonian National Assembly, Marches for dignity) × 2 (Type of participants: participants, non-participants) were performed. Results show that participants in both demonstrations have a higher level of injustice than non-demonstrators. Furthermore, demonstrators in Marches for dignity have a more negative perception of emotional climate than non-demonstrators. However, and contrary to the hypothesis, demonstrators of the Catalonian National Assembly have a more positive perception of emotional climate than non-demonstrators. The work explains these results in the socio-political context in which each of these movements acts and highlights the relevance of comparative investigation designs to further the knowledge of political mobilization dynamicsThis work was supported by Consellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia (2016-PG055) and Ministerio de Economía y Competitividad (AP2010-5126)S

Measured Copper Toxicity to Cnesterodon decemmaculatus (Pisces: Poeciliidae) and Predicted by Biotic Ligand Model in Pilcomayo River Water: A Step for a Cross-Fish-Species Extrapolation

In order to determine copper toxicity (LC50) to a local species (Cnesterodon decemmaculatus) in the South American Pilcomayo River water and evaluate a cross-fish-species extrapolation of Biotic Ligand Model, a 96 h acute copper toxicity test was performed. The dissolved copper concentrations tested were 0.05, 0.19, 0.39, 0.61, 0.73, 1.01, and 1.42 mg Cu L−1. The 96 h Cu LC50 calculated was 0.655 mg L−1 (0.823 − 0.488). 96-h Cu LC50 predicted by BLM for Pimephales promelas was 0.722 mg L−1. Analysis of the inter-seasonal variation of the main water quality parameters indicates that a higher protective effect of calcium, magnesium, sodium, sulphate, and chloride is expected during the dry season. The very high load of total suspended solids in this river might be a key factor in determining copper distribution between solid and solution phases. A cross-fish-species extrapolation of copper BLM is valid within the water quality parameters and experimental conditions of this toxicity test

Inflammation-induced IgE promotes epithelial hyperplasia and tumour growth

IgE is the least abundant circulating antibody class but is constitutively present in healthy tissues bound to resident cells via its high-affinity receptor, FcεRI. The physiological role of endogenous IgE antibodies is unclear but it has been suggested that they provide host protection against a variety of noxious environmental substances and parasitic infections at epithelial barrier surfaces. Here we show, in mice, that skin inflammation enhances levels of IgE antibodies that have natural specificities and a repertoire, VDJ rearrangements and CDRH3 characteristics similar to those of IgE antibodies in healthy tissue. IgE-bearing basophils are recruited to inflamed skin via CXCL12 and thymic stromal lymphopoietin (TSLP)/IL-3-dependent upregulation of CXCR4. In the inflamed skin, IgE/FcεRI-signalling in basophils promotes epithelial cell growth and differentiation, partly through histamine engagement of H1R and H4R. Furthermore, this IgE response strongly drives tumour outgrowth of epithelial cells harbouring oncogenic mutation. These findings indicate that natural IgE antibodies support skin barrier defences, but that during chronic tissue inflammation this role may be subverted to promote tumour growth

C3 Drives Inflammatory Skin Carcinogenesis Independently of C5

Nonmelanoma skin cancer such as cutaneous squamous cell carcinoma (cSCC) is the most common form of cancer and can occur as a consequence of DNA damage to the epithelium by UVR or chemical carcinogens. There is growing evidence that the complement system is involved in cancer immune surveillance; however, its role in cSCC remains unclear. Here, we show that complement genes are expressed in tissue from patients with cSCC, and C3 activation fragments are present in cSCC biopsies, indicating complement activation. Using a range of complement-deficient mice in a two-stage mouse model of chemically-induced cSCC, where a subclinical dose of 7,12-dimethylbenz[a]anthracene causes oncogenic mutations in epithelial cells and 12-O-tetradecanoylphorbol-13-acetate promotes the outgrowth of these cells, we found that C3-deficient mice displayed a significantly reduced tumor burden, whereas an opposite phenotype was observed in mice lacking C5aR1, C5aR2, and C3a receptor. In addition, in mice unable to form the membrane attack complex, the tumor progression was unaltered. C3 deficiency did not affect the cancer response to 7,12-dimethylbenz[a]anthracene treatment alone but reduced the epidermal hyperplasia during 12-O-tetradecanoylphorbol-13-acetate-induced inflammation. Collectively, these data indicate that C3 drives tumorigenesis during chronic skin inflammation, independently of the downstream generation of C5a or membrane attack complex

PARP1 Deficiency Reduces Tumour Growth by Decreasing E2F1 Hyperactivation: A Novel Mechanism in the Treatment of Cancer

In recent years, poly (ADP-ribose) polymerase (PARP) inhibitors have been evaluated for treating homologous recombination-deficient tumours, taking advantage of synthetic lethality. However, increasing evidence indicates that PARP1 exert several cellular functions unrelated with their role on DNA repair, including function as a co-activator of transcription through protein-protein interaction with E2F1. Since the RB/E2F1 pathway is among the most frequently mutated in many tumour types, we investigated whether the absence of PARP activity could counteract the consequences of E2F1 hyperactivation. Our results demonstrate that genetic ablation of Parp1 extends the survival of Rb-null embryos, while genetic inactivation of Parp1 results in reduced development of pRb-dependent tumours. Our results demonstrate that PARP1 plays a key role as a transcriptional co-activator of the transcription factor E2F1, an important component of the cell cycle regulation. Considering that most oncogenic processes are associated with cell cycle deregulation, the disruption of this PARP1-E2F1 interaction could provide a new therapeutic target of great interest and a wide spectrum of indicationsThis work received financial support from the Ministerio de Ciencia e Innovación (SAF2008-00543 and SAF2009-08629; J.A.C.) and ISCIII, Ministerio de Economía y Competitividad (PI15/01129), the Consellería de Cultura, Educación e Ordenación Universitaria (GPC2014/030, INCITE08PXIB208091PR and PXIB208091PR; J.A.C.), PRE/2011/131 (I.G.C.), the Centro Singular de Investigación de Galicia accreditation 2016–2019, ED431G/05), and the European Regional Development Fund (ERDF)S

Predicting pharmaceutical inkjet printing outcomes using machine learning

Inkjet printing has been extensively explored in recent years to produce personalised medicines due to its low cost and versatility. Pharmaceutical applications have ranged from orodispersible films to complex polydrug implants. However, the multi-factorial nature of the inkjet printing process makes formulation (e.g., composition, surface tension, and viscosity) and printing parameter optimization (e.g., nozzle diameter, peak voltage, and drop spacing) an empirical and time-consuming endeavour. Instead, given the wealth of publicly available data on pharmaceutical inkjet printing, there is potential for a predictive model for inkjet printing outcomes to be developed. In this study, machine learning (ML) models (random forest, multilayer perceptron, and support vector machine) to predict printability and drug dose were developed using a dataset of 687 formulations, consolidated from in-house and literature-mined data on inkjet-printed formulations. The optimized ML models predicted the printability of formulations with an accuracy of 97.22%, and predicted the quality of the prints with an accuracy of 97.14%. This study demonstrates that ML models can feasibly provide predictive insights to inkjet printing outcomes prior to formulation preparation, affording resource- and time-savings