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

Changes in Gray Matter Volume and White Matter Microstructure in Adolescents with Obsessive-Compulsive Disorder

BACKGROUND: There is a paucity of neuroimaging data in pediatric-onset obsessive-compulsive disorder (OCD). This multimodal neuroimaging study aimed to identify structural gray (GM) and white matter (WM) microstructure changes in pediatric OCD. METHODS: We obtained structural and diffusion tensor magnetic resonance images from 26 OCD patients and 26 matched healthy adolescents. We carried out a series of image analyses including, volumetric and shape analysis of subcortical gray structures, as well as voxel-based morphometry on GM volume and fractional anisotropy of the WM. RESULTS: Patients had increased GM volume in the caudate bilaterally and right putamen. Shape analyses revealed specific hypertrophy of the dorsal caudate in pediatric OCD. The striatum was larger in healthy boys compared with healthy girls, whereas such a gender effect was not seen in the OCD group. OCD subjects showed higher fractional anisotropy values in left inferior longitudinal fasciculus, bilateral superior longitudinal fasciculus, right inferior fronto-occipital fasciculus, bilateral corticospinal tract, corpus callosum splenium and genu, bilateral forceps major, bilateral forceps minor, left cingulum, and right uncinate fasciculus. OCD symptom severity was positively correlated with GM volume in right insula, posterior orbitofrontal cortex, brainstem, and cerebellum and inversely correlated with widespread reduction in cortical GM volume. Furthermore, symptom severity positively correlated with increased WM fractional anisotropy in various WM tracts, including the anterior limb of the internal capsule. CONCLUSIONS: Adolescents with OCD had a wide range of GM and WM changes compared to healthy control subjects that are broadly consistent with those identified in the adult OCD literature but are more extensive