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Since its first identification in Scotland, over 1000 cases of unexplained pediatric hepatitis in children have been reported worldwide, including 278 cases in the UK 1 . Here we report investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator subjects, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in liver, blood, plasma or stool from 27/28 cases. We found low levels of Adenovirus (HAdV) and Human Herpesvirus 6B (HHV-6B), in 23/31 and 16/23 respectively of the cases tested. In contrast, AAV2 was infrequently detected at low titre in blood or liver from control children with HAdV, even when profoundly immunosuppressed.AAV2, HAdV and HHV-6 phylogeny excluded 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 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.

To master the task of reading, children need to acquire a coding system representing speech as a sequence of visual symbols. Recent research suggested that performance in the processing of artificial script that relies on the association of sound and symbol may be associated with reading skill. The current longitudinal study examined the predictive value of a preschool sound-symbol paradigm (SSP) of reading performance 3 years later. The Morse-like SSP, IQ, and letter knowledge (LK) was assessed in young preschool children. Reading outcome measures were examined 3 years later. Word reading, pseudoword reading, and reading comprehension were predicted with age, IQ, LK, and SSP. The results showed that SSP substantially predicted reading fluency and reading comprehension 3 years later. For reading fluency measures, the influence of further predictor variables was not significant and SSP served as a sole predictor. Reading comprehension was best explained by SSP and age. The amount of variance SSP explained in reading 3 years later was remarkably high, with an explained variance between 63 and 82%, depending on the outcome reading variable. SSP turned out to be a substantial predictor of later reading performance in a language with statistically reliable spelling-to-sound relations. As LK is highly dependent on educational support, we assume that children in our socioeconomically diverse sample did not have much opportunity to acquire LK in their home environment. In contrast, the SSP challenges students to acquire new spelling-to-sound relations, simulating a core aspect of natural reading acquisition. Future work will test this paradigm in less transparent languages like English and explore its potential as a future standard assessment in the study of early reading development.

Self/non-self discrimination characterizes immunity and allows responses against pathogens but not self-antigens. Understanding the principles that govern this process is essential for designing autoimmunity treatments. p21 is thought to attenuate autoreactivity by limiting T cell expansion. Here, we provide direct evidence for a p21 role in controlling autoimmune T cell autoreactivity without affecting normal T cell responses. We studied C57BL/6, C57BL/6/lpr and MRL/lpr mice overexpressing p21 in T cells, and showed reduced autoreactivity and lymphadenopathy in C57BL/6/lpr, and reduced mortality in MRL/lpr mice. p21 inhibited effector/memory CD4+ CD8+ and CD4−CD8− lpr T cell accumulation without altering defective lpr apoptosis. This was mediated by a previously non-described p21 function in limiting T cell overactivation and overproduction of IFN-γ, a key lupus cytokine. p21 did not affect normal T cell responses, revealing differential p21 requirements for autoreactive and normal T cell activity regulation. The underlying concept of these findings suggests potential treatments for lupus and autoimmune lymphoproliferative syndrome, without compromising normal immunity.