Multi-parametric flow cytometric and genetic investigation of the peripheral B cell compartment in human type 1 diabetes.

The appearance of circulating islet-specific autoantibodies before disease diagnosis is a hallmark of human type 1 diabetes (T1D), and suggests a role for B cells in the pathogenesis of the disease. Alterations in the peripheral B cell compartment have been reported in T1D patients; however, to date, such studies have produced conflicting results and have been limited by sample size. In this study, we have performed a detailed characterization of the B cell compartment in T1D patients (n = 45) and healthy controls (n = 46), and assessed the secretion of the anti-inflammatory cytokine interleukin (IL)-10 in purified B cells from the same donors. Overall, we found no evidence for a profound alteration of the B cell compartment or in the production of IL-10 in peripheral blood of T1D patients. We also investigated age-related changes in peripheral B cell subsets and confirmed the sharp decrease with age of transitional CD19(+) CD27(-) CD24(hi) CD38(hi) B cells, a subset that has recently been ascribed a putative regulatory function. Genetic analysis of the B cell compartment revealed evidence for association of the IL2-IL21 T1D locus with IL-10 production by both memory B cells (P = 6·4 × 10(-4) ) and islet-specific CD4(+) T cells (P = 2·9 × 10(-3) ). In contrast to previous reports, we found no evidence for an alteration of the B cell compartment in healthy individuals homozygous for the non-synonymous PTPN22 Trp(620) T1D risk allele (rs2476601; Arg(620) Trp). The IL2-IL21 association we have identified, if confirmed, suggests a novel role for B cells in T1D pathogenesis through the production of IL-10, and reinforces the importance of IL-10 production by autoreactive CD4(+) T cells

Evaluation of Intensivist-Nurses’ Knowledge Concerning Medication Administration Through Nasogastric and Enteral Tubes

This study evaluates the knowledge of nurses working in intensive care units concerning recommendations for the proper administration of medication through nasogastric and enteral tubes. This exploratory-descriptive study with a quantitative approach was carried out with 49 nurses in an intensive care unit of a tertiary hospital in Fortaleza, CE, Brazil. A total of 36.7% of nurses reported they disregard the dosage forms provided by the pharmacy at the time of administering the medication through tubes. Metal, wood, or a plastic mortar is the method most frequently reported (42.86%) for crushing prescribed solid forms; 32.65% leave the drugs in 20ml of water until dissolved; 65.3% place the responsibility for choosing the pharmaceutical formulation and its correlation with the tube site, either into the stomach or into the intestine, on the physician. The results indicate there is a gap between specific literature on medication administered through tubes and knowledge of nurses on the subject.El objetivo del estudio fue evaluar los conocimientos del enfermero de la unidad de cuidados intensivos sobre las recomendaciones para la correcta administración de medicamentos por sonda nasogástrica y nasoentérica. Se trata de un estudio exploratorio-descriptivo y cuantitativo con 49 enfermeros en una unidad de cuidados intensivos de un hospital terciario, en la ciudad de Fortaleza, estado de Ceará, Brasil. 36,7% no prestan atención a las formas disponibles en el sector de farmacia en el momento de su utilización por sonda. El pilón de metal, madera o plástico fue el método más citado (42,86%) para triturar las formas sólidas prescritas. 32,65% dejan los fármacos en 20mL de agua hasta que se disuelvan. 65,3% atribuyen al médico la responsabilidad de decidir sobre la formulación y la correlación con la ubicación de la sonda en el tracto gastrointestinal. Los resultados indican que hay una diferencia entre la literatura para los medicamentos administrados por sonda y el conocimiento de los enfermeros sobre el tema.O estudo objetivou avaliar o conhecimento do enfermeiro de unidade de terapia intensiva sobre as recomendações para a correta administração de medicamentos, por sondas nasogástrica e nasoenteral. Estudo exploratório-descritivo, com abordagem quantitativa, realizado com 49 enfermeiros em uma unidade de terapia intensiva de um hospital terciário, localizado na cidade de Fortaleza, no Estado do Ceará, Brasil. Dos enfermeiros, 36,7% relataram não dar atenção às formas farmacêuticas disponibilizadas pelo setor de farmácia na hora da utilização por sonda. O pilão de metal, madeira ou plástico foi o método mais referido (42,86%) para triturar as formas sólidas prescritas. Sendo que 32,65% costuma deixar os fármacos em 20mL de água até dissolver, 65,3% atribuem ao médico a responsabilidade sobre a decisão da formulação farmacêutica e a correlação com a localização da sonda no trato gastrointestinal. Os achados apontam para diferença entre a literatura específica para medicamentos administrados por sonda e o conhecimento de enfermeiros sobre o assunto

Cells with Treg-specific FOXP3 demethylation but low CD25 are prevalent in autoimmunity

Identification of alterations in the cellular composition of the human immune system is key to understanding the autoimmune process. Recently, a subset of FOXP3+ cells with low CD25 expression was found to be increased in peripheral blood from systemic lupus erythematosus (SLE) patients, although its functional significance remains controversial. Here we find in comparisons with healthy donors that the frequency of FOXP3+ cells within CD127lowCD25low CD4+ T cells (here defined as CD25lowFOXP3+ T cells) is increased in patients affected by autoimmune disease of varying severity, from combined immunodeficiency with active autoimmunity, SLE to type 1 diabetes. We show that CD25lowFOXP3+ T cells share phenotypic features resembling conventional CD127lowCD25highFOXP3+ Tregs, including demethylation of the Treg-specific epigenetic control region in FOXP3, HELIOS expression, and lack of IL-2 production. As compared to conventional Tregs, more CD25lowFOXP3+HELIOS+ T cells are in cell cycle (33.0% vs 20.7% Ki-67+; P = 1.3 × 10−9) and express the late-stage inhibitory receptor PD-1 (67.2% vs 35.5%; P = 4.0 × 10−18), while having reduced expression of the early-stage inhibitory receptor CTLA-4, as well as other Treg markers, such as FOXP3 and CD15s. The number of CD25lowFOXP3+ T cells is correlated (P = 3.1 × 10−7) with the proportion of CD25highFOXP3+ T cells in cell cycle (Ki-67+). These findings suggest that CD25lowFOXP3+ T cells represent a subset of Tregs that are derived from CD25highFOXP3+ T cells, and are a peripheral marker of recent Treg expansion in response to an autoimmune reaction in tissues.This work was supported by the JDRF UK Centre for Diabetes - Genes, Autoimmunity and Prevention (D-GAP; 4-2007-1003) in collaboration with M. Peakman and T. Tree at Kings College London, a strategic award to the Diabetes and Inflammation Laboratory from the JDRF (9-2011-253) and the Wellcome Trust (WT; WT061858/091157), and the National Institute for Health Research Cambridge Biomedical Research Centre. RCF is funded by an advanced JDRF post-doctoral fellowship (2-APF-2017-420-A-N). CW is funded by the Wellcome Trust (088998)

Chromosome contacts in activated T cells identify autoimmune disease candidate genes

BACKGROUND: Autoimmune disease-associated variants are preferentially found in regulatory regions in immune cells, particularly CD4+ T cells. Linking such regulatory regions to gene promoters in disease-relevant cell contexts facilitates identification of candidate disease genes. RESULTS: Within four hours, activation of CD4+ T cells invokes changes in histone modifications and enhancer RNA transcription that correspond to altered expression of the interacting genes identified by promoter capture Hi-C (PCHi-C). By integrating PCHi-C data with genetic associations for five autoimmune diseases we prioritised 245 candidate genes with a median distance from peak signal to prioritised gene of 153 kb. Just under half (108/245) prioritised genes related to activation-sensitive interactions. This included IL2RA, where allele-specific expression analyses were consistent with its interaction-mediated regulation, illustrating the utility of the approach. CONCLUSIONS: Our systematic experimental framework offers an alternative approach to candidate causal gene identification for variants with cell state-specific functional effects, with achievable sample sizes.This work was funded by the JDRF (9-2011-253), the Wellcome Trust (089989, 091157, 107881), the UK Medical Research Council (MR/L007150/1, MC_UP_1302/5), the UK Biotechnology and Biological Sciences Research Council (BB/J004480/1) and the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre. The research leading to these results has received funding from the European Union’s 7th Framework Programme (FP7/2007-2013) under grant agreement no. 241447 (NAIMIT). The Cambridge Institute for Medical Research (CIMR) is in receipt of a Wellcome Trust Strategic Award (100140)

Preterm birth and small for gestational age in relation to alcohol consumption during pregnancy: stronger associations among vulnerable women? Results from two large Western-European studies

Pfinder M, Kunst AE, Feldmann R, van Eijsden M, Vrijkotte TGM. Preterm birth and small for gestational age in relation to alcohol consumption during pregnancy: stronger associations among vulnerable women? Results from two large Western-European studies. BMC Pregnancy and Childbirth. 2013;13(1): 49.BACKGROUND: Inconsistent data on the association between prenatal alcohol exposure and a range of pregnancy outcomes, such as preterm birth (PTB) and small for gestational age (SGA) raise new questions. This study aimed to assess whether the association between low-moderate prenatal alcohol exposure and PTB and SGA differs according to maternal education, maternal mental distress or maternal smoking. METHODS: The Amsterdam Born Children and their Development (ABCD) Study (N=5,238) and the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) (N=16,301) are both large studies. Women provide information on alcohol intake in early pregnancy, 3 months postpartum and up to 17 years retrospectively. Multivariate logistic regression analyses and stratified regression analyses were performed to examine the association between prenatal alcohol exposure and PTB and SGA, respectively. RESULTS: No association was found between any level of prenatal alcohol exposure (non-daily, daily, non-abstaining) and SGA. The offspring of daily drinkers and non-abstainers had a lower risk of PTB [ABCD: odds ratio (OR) 0.31, 95% confidence interval (CI) 0.13, 0.77; KiGGS: OR 0.75, 95% CI 0.57, 0.99]. Interactions with maternal education, maternal distress or maternal smoking were not significant. CONCLUSIONS: Although these results should be interpreted with caution, both studies showed no adverse effects of low-moderate prenatal alcohol exposure on PTB and SGA, not even in the offspring of women who were disadvantaged in terms of low education, high levels of distress, or smoking during pregnancy

Guia de cuidados de enfermagem na prevenção da extubação acidental Conductas de enfermería para la prevención de la extubación accidental Guideline for nursing care in the prevention of accidental extubation

Artigo que relata a experiência do emprego de um guia preventivo da extubação acidental que ocorre associada ao cuidado de enfermagem para os quatro momentos de maior incidência e que são: banho no leito, transporte, troca de fixação e mudança de decúbito. O conteúdo do guia está pautado nas recomendações encontradas em levantamento bibliográfico no MedLine e na experiência profissional. O guia vem sendo aplicado desde setembro de 2005. Espera-se que o guia contribua para diminuir cada vez mais a incidência da extubação acidental e por tanto seja uma ferramenta para desenvolver um indicador de qualidade na Unidade de Terapia Intensiva, assim como, seja capaz de oferecer uma assistência que objetive a segurança do paciente.<br>És un artículo que trata del empleo de un guía para orientar los cuidados de enfermería e evitar la extubación que ocurre con más frecuencia en cuatro tiempos: en el baño, la transferencia del enfermo, el cambio de la fixación y los cambios de posición en la cama. Su contenido se apoyo en la experiencia y en levantamiento bibliográfico en el Medline.Se ha venido usando desde septiembre de 2005 y hemos tenido solo dos extubaciones. Creemos que sirva para atender al enfermo con más seguranza así también como un indicador de calidad de enfermería.<br>Article reports the experience of the use of a preventive guideline for the prevention of accidental extubation that occurs associated nursing care for the four moments of bigger incidence that are: bath in the stream bed, transportation, exchange of setting and change of decubitus. The content of the guide is based in the recommendations found in bibliographical survey in the MedLine and in the professional experience. The guideline is being used since September, 2005. This contribution aims at decreasing extubation incidence and to be a tool to develop a quality indicator in Intensive Care Units as well as for offering an assistance that aims patient safety

Cells with Treg-specific FOXP3 demethylation but low CD25 are prevalent in autoimmunity

Identification of alterations in the cellular composition of the human immune system is key to understanding the autoimmune process. Recently, a subset of FOXP3+ cells with low CD25 expression was found to be increased in peripheral blood from systemic lupus erythematosus (SLE) patients, although its functional significance remains controversial. Here we find in comparisons with healthy donors that the frequency of FOXP3+ cells within CD127lowCD25low CD4+ T cells (here defined as CD25lowFOXP3+ T cells) is increased in patients affected by autoimmune disease of varying severity, from combined immunodeficiency with active autoimmunity, SLE to type 1 diabetes. We show that CD25lowFOXP3+ T cells share phenotypic features resembling conventional CD127lowCD25highFOXP3+ Tregs, including demethylation of the Treg-specific epigenetic control region in FOXP3, HELIOS expression, and lack of IL-2 production. As compared to conventional Tregs, more CD25lowFOXP3+ HELIOS+ T cells are in cell cycle (33.0% vs 20.7% Ki-67+ ; P = 1.3 x 10-9 ) and express the late-stage inhibitory receptor PD-1 (67.2% vs 35.5%; P = 4.0 x 10-18 ), while having reduced expression of the early-stage inhibitory receptor CTLA-4, as well as other Treg markers, such as FOXP3 and CD15s. The number of CD25lowFOXP3+ T cells is highly correlated (P = 3.1 x 10−7 ) with the proportion of CD25highFOXP3+ T cells in cell cycle (Ki-67+ ). These findings suggest that CD25lowFOXP3+ T cells represent a subset of Tregs that are derived from CD25highFOXP3+ T cells, and are a peripheral marker of recent Treg expansion in response to an autoimmune reaction in tissues

Neonatal and adult recent thymic emigrants produce IL-8 and express complement receptors CR1 and CR2

The maintenance of peripheral naive T lymphocytes in humans is dependent on their homeostatic division, not continuing emigration from the thymus, which undergoes involution with age. However, postthymic maintenance of naive T cells is still poorly understood. Previously we reported that recent thymic emigrants (RTEs) are contained in CD31+CD25- naive T cells as defined by their levels of signal joint T cell receptor rearrangement excision circles (sjTRECs). Here, by differential gene expression analysis followed by protein expression and functional studies, we define that the naive T cells having divided the least since thymic emigration express complement receptors (CR1 and CR2) known to bind complement C3b- and C3d-decorated microbial products and, following activation, produce IL-8 (CXCL8), a major chemoattractant for neutrophils in bacterial defense. We also observed an IL-8-producing memory T cell subpopulation coexpressing CR1 and CR2 and with a gene expression signature resembling that of RTEs. The functions of CR1 and CR2 on T cells remain to be determined, but we note that CR2 is the receptor for Epstein-Barr virus, which is a cause of T cell lymphomas and a candidate environmental factor in autoimmune disease