78 research outputs found

    The Critical Role of Notch Ligand Delta-like 1 in the Pathogenesis of Influenza A Virus (H1N1) Infection

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    Influenza A viral infections have been identified as the etiologic agents for historic pandemics, and contribute to the annual mortality associated with acute viral pneumonia. While both innate and acquired immunity are important in combating influenza virus infection, the mechanism connecting these arms of the immune system remains unknown. Recent data have indicated that the Notch system is an important bridge between antigen-presenting cells (APCs) and T cell communication circuits and plays a central role in driving the immune system to overcome disease. In the present study, we examine the role of Notch signaling during influenza H1N1 virus infection, focusing on APCs. We demonstrate here that macrophages, but not dendritic cells (DCs), increased Notch ligand Delta-like 1 (Dll1) expression following influenza virus challenge. Dll1 expression on macrophages was dependent on retinoic acid-inducible gene-I (RIG-I) induced type-I IFN pathway, and not on the TLR3-TRIF pathway. We also found that IFNα-Receptor knockout mice failed to induce Dll1 expression on lung macrophages and had enhanced mortality during influenza virus infection. Our results further showed that specific neutralization of Dll1 during influenza virus challenge induced higher mortality, impaired viral clearance, and decreased levels of IFN-γ. In addition, we blocked Notch signaling by using γ-secretase inhibitor (GSI), a Notch signaling inhibitor. Intranasal administration of GSI during influenza infection also led to higher mortality, and higher virus load with excessive inflammation and an impaired production of IFN-γ in lungs. Moreover, Dll1 expression on macrophages specifically regulates IFN-γ levels from CD4+and CD8+T cells, which are important for anti-viral immunity. Together, the results of this study show that Dll1 positively influences the development of anti-viral immunity, and may provide mechanistic approaches for modifying and controlling the immune response against influenza H1N1 virus infection

    The histopathology of gastrointestinal motility disorders in children

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    Gastrointestinal motility disorders and chronic constipation are common pediatric problems. Symptoms of abdominal discomfort are frequently encountered in the daily practice of pediatricians and pediatric surgeons. Normal peristalsis depends on the interaction between muscles, nerve cells, and tendinous connective tissue of muscularis propria. Malfunction of any of these components results in a motility disorder. Aganglionosis, typically of the left distal colon, is the cause of Hirschsprung disease. Hypoganglionosis constitutes another gastrointestinal motility disorder. In hypoplastic hypoganglionosis, the number of nerve cells and the size of ganglia of the enteric nervous system are reduced, resulting in symptoms similar to aganglionosis. In intestinal neuronal dysplasia type B, submucous plexus development is disturbed. Immaturity of the enteric nervous system, but also ganglioneuromatosis, can be the underlying cause of chronic constipation. Chronic constipation may be caused by a myopathy. Aplasia or atrophy of the tendinous connective tissue of muscularis propria may cause desmosis, which may result in an aperistaltic syndrome. In severe chronic constipation, a histopathological diagnosis of the underlying cause is useful. In the diagnostic approach for most of these causes of chronic constipation, enzyme histochemistry is an efficient tool to complement conventional immunohistochemical and selected molecular technologies. An interdisciplinary approach of a gastrointestinal working group is beneficial in the management of these difficult patients

    Textbook of Clinical Pediatrics

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    LXXIV, 4159 p. 990 illus. eReference.online resou

    Synthesis of Amino-acids - Alkylation of Aldimine and Ketimine Derivatives of Glycine Ethyl-ester Under Various Phase-transfer Conditions

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    The Sciff base derived from glycine ethyl ester and p-chlorobenzaldehyde can be alkylated by the ion-pair extraction method as well as under catalytic liquid-liquid or solid-liquid phase-transfer conditions. This imine is compared with the corresponding benzophenone Schiff base

    A strategy for human factors/ergonomics: developing the discipline and profession

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    Human factors/ergonomics (HFE) has great potential to contribute to the design of all kinds of systems with people (work systems, product/service systems), but faces challenges in the readiness of its market and in the supply of high-quality applications. HFE has a unique combination of three fundamental characteristics: (1) it takes a systems approach (2) it is design driven and (3) it focuses on two closely related outcomes: performance and well-being. In order to contribute to future system design, HFE must demonstrate its value more successfully to the main stakeholders of system design. HFE already has a strong value proposition (mainly well-being) and interactivity with the stakeholder group of 'system actors' (employees and product/service users). However, the value proposition (mainly performance) and relationships with the stakeholder groups of 'system experts' (experts from technical and social sciences involved in system design), and 'system decision makers' (managers and other decision makers involved in system design, purchase, implementation and use), who have a strong power to influence system design, need to be developed. Therefore, the first main strategic direction is to strengthen the demand for high-quality HFE by increasing awareness among powerful stakeholders of the value of high-quality HFE by communicating with stakeholders, by building partnerships and by educating stakeholders. The second main strategic direction is to strengthen the application of high-quality HFE by promoting the education of HFE specialists, by ensuring high-quality standards of HFE applications and HFE specialists, and by promoting HFE research excellence at universities and other organisations. This strategy requires cooperation between the HFE community at large, consisting of the International Ergonomics Association (IEA), local (national and regional) HFE societies, and HFE specialists. We propose a joint world-wide HFE development plan, in which the IEA takes a leadership role. Practitioner Summary: Human factors/ergonomics (HFE) has much to offer by addressing major business and societal challenges regarding work and product/ service systems. HFE potential, however, is underexploited. This paper presents a strategy for the HFE community to strengthen demand and application of *Corresponding author. Email: [email protected] high-quality HFE, emphasising its key elements: systems approach, design driven, and performance and well-being goals

    Gastrointestinal neuromuscular pathology: guidelines for histological techniques and reporting on behalf of the Gastro 2009 International Working Group

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    The term gastrointestinal neuromuscular disease describes a clinically heterogeneous group of disorders of children and adults in which symptoms are presumed or proven to arise as a result of neuromuscular, including interstitial cell of Cajal, dysfunction. Such disorders commonly have impaired motor activity, i.e. slowed or obstructed transit with radiological evidence of transient or persistent visceral dilatation. Whilst sensorimotor abnormalities have been demonstrated by a variety of methods in these conditions, standards for histopathological reporting remain relatively neglected. Significant differences in methodologies and expertise continue to confound the reliable delineation of normality and specificity of particular pathological changes for disease. Such issues require urgent clarification to standardize acquisition and handling of tissue specimens, interpretation of findings and make informed decisions on risk-benefit of full-thickness tissue biopsy of bowel or other diagnostic procedures. Such information will also allow increased certainty of diagnosis, facilitating factual discussion between patients and caregivers, as well as giving prognostic and therapeutic information. The following report, produced by an international working group, using established consensus methodology, presents proposed guidelines on histological techniques and reporting for adult and paediatric gastrointestinal neuromuscular pathology. The report addresses the main areas of histopathological practice as confronted by the pathologist, including suction rectal biopsy and full-thickness tissue obtained with diagnostic or therapeutic intent. For each, indications, safe acquisition of tissue, histological techniques, reporting and referral recommendations are presented
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