Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Chemokine receptor CXCR3 agonist prevents human T-cell migration in a humanized model of arthritic inflammation

The recruitment of T lymphocytes during diseases such as rheumatoid arthritis is regulated by stimulation of the chemokine receptors expressed by these cells. This study was designed to assess the potential of a CXCR3-specific small-molecule agonist to inhibit the migration of activated human T cells toward multiple chemokines. Further experiments defined the molecular mechanism for this anti-inflammatory activity. Analysis in vitro demonstrated agonist induced internalization of both CXCR3 and other chemokine receptors coexpressed by CXCR3+ T cells. Unlike chemokine receptor-specific antagonists, the CXCR3 agonist inhibited migration of activated T cells toward the chemokine mixture in synovial fluid from patients with active rheumatoid arthritis. A humanized mouse air-pouch model showed that intravenous treatment with the CXCR3 agonist prevented inflammatory migration of activated human T cells toward this synovial fluid. A potential mechanism for this action was defined by demonstration that the CXCR3 agonist induces receptor cross-phosphorylation within CXCR3-CCR5 heterodimers on the surface of activated T cells. This study shows that generalized chemokine receptor desensitization can be induced by specific stimulation of a single chemokine receptor on the surface of activated human T cells. A humanized mouse model was used to demonstrate that this receptor desensitization inhibits the inflammatory response that is normally produced by the chemokines present in synovial fluid from patients with active rheumatoid arthritis

NOD2 mutations predict the risk for surgery in pediatric-onset Crohn's disease.

BACKGROUND/PURPOSE: Three common mutations of the NOD2/CARD15 gene have been associated with Crohn disease (CD), ileal disease location, and fibrostenotic behavior. The aim of this study was to investigate the effect of these mutations on disease manifestation and the risk of surgery in a cohort of German childhood-onset CD patients. METHODS: Genotyping for the NOD2 mutations p.Arg702Trp, p.Gly908Arg, and p.1007fs was performed in 171 CD children (onset of disease <17 years; mean 11.8 years) and in 253 controls. NOD2 mutation status was correlated with the need for surgery during childhood. RESULTS: Seventy-eight children (45.6%) were carriers of at least 1 NOD2 mutation versus 36 (14.2%) in the control group (P < .0001). NOD2 mutations were highly associated with CD and stricturing behavior (P < .0001), with the p.1007fs mutation also conferring a risk for isolated ileal disease (P = .003). Thirty-two children (18.7%) needed an intestinal resection with a significant association between the need of surgery and NOD2 carrier status. Surgery occurred at an earlier stage of disease in children with p.1007fs mutations. CONCLUSIONS: In children with pediatric-onset CD, the need for surgical therapy younger than 17 years is associated with the NOD2 genotype. Genetic testing therefore may identify children with CD who are at risk

Solaroptimiertes Bauen. Teilkonzept 1: Integration eines luftdurchstroemten Solar-Absorbers in eine Gebaeudehuelle Abschlussbericht

The research project was successful in the development of high-efficiency air-filled solar absorbers integrated in the building shell. Several different designs were implemented successfully with regard to absorber integration in the building shell and space HVAC systems. The newly developed solar-air technology provides interesting options for innovative building design in the sense of the EnEV (Energy Conservation Ordinance). The new technology may help to reduce carbon dioxide emissions and help achieve the German government's explicit goal of a reduction of global warming. (orig.)Zu Beginn des Forschungsprojektes gehoerten Luftkollektoren mit durchstroemten und spektral-selektiv beschichteten Absorbern, welche hoechste Wirkungsgrade bei geringem Luftvolumenstrom aufweisen, nicht zum Stand der Technik. Ziel des Forschungsprojektes war die industrielle Herstellung verschiedener, in Gebaeudehuellen integrierbarer Solar-Luft-Systeme, welche auf der Basis luftdurchstroemter Solarabsorber mit dem Prinzip der Grenzschichtabsaugung zu konstruieren waren. Diese sollten bei Volumenstroemen pro m"2-Kollektorflaeche von kleiner 20 m"3/h einen Wirkungsgrad von mehr als 0,60 erzielen koennen. Anhand von Simulationen wurden Entwuerfe mit entsprechender Leistungsfaehigkeit konstruiert. Ergebnis des Forschungsprojektes ist die erfolgreiche Entwicklung von in Gebaeudehuellen integrierten, luftdurchstroemten Solar-Absorbern mit, gegenueber hinterstroemten Absorbern, entsprechend der Zielsetzung verbessertem Wirkungsgrad. Mehrere Konstruktionsentwuerfe konnten hinsichtlich Gebaeudeintegration und Systemeinbindung erfolgreich umgesetzt werden. Die neu entwickelte Solar-Luft-Technik bietet interessante Moeglichkeiten fuer innovative Ausfuehrungen der Gebaeudehuelle ganz im Sinne der Zielsetzung der Energieeinsparverordnung (EnEV): Minimierung des Primaerenergiebedarfes. Entsprechende Verbreitung der Ergebnisse vorausgesetzt, kann der flaechendeckende Einsatz des neu entwickelten Absorbersystems zu einer massiven CO_2-Einsparung fuehren und unterstuetzt damit die Bemuehungen die von der Bundesregierung formulierten Klimaschutzziele zu erreichen. (orig.)SIGLEAvailable from TIB Hannover: QN1(115,60) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekForschungszentrum Juelich GmbH (Germany). Projekttraeger Biologie, Energie, Umwelt (BEO); Forschungszentrum Juelich GmbH (Germany). Programmgruppe TechnologiefolgenforschungDEGerman

Tissue-specific regulation of CXCL9/10/11 chemokines in keratinocytes: Implications for oral inflammatory disease - Fig 3

<p><b>18S (a), CXCL9 (b), CXCL10 (c) and CXCL11 (d) mRNA expression.</b> mRNA expression in 3 different normal human oral keratinocytes (NHOK), either IFN-γ treated for 48 hours (ifn) or control cells that were left untreated for 48hrs (con).</p