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

Impairment of Caveolae Formation and T-System Disorganization in Human Muscular Dystrophy with Caveolin-3 Deficiency

Caveolin-3, a muscle specific caveolin-related protein, is the principal structural protein of caveolar membranes. We have recently identified an autosomal dominant form of limb girdle muscular dystrophy (LGMD-1C) that is due to caveolin-3 deficiency and caveolin-3 gene mutations. Here, we studied by electron microscopy, including freeze-fracture and lanthanum staining, the distribution of caveolae and the organization of the T-tubule system in caveolin-3 deficient human muscle fibers. We found a severe impairment of caveolae formation at the muscle cell surface, demonstrating that caveolin-3 is essential for the formation and organization of caveolae in muscle fibers. In addition, we also detected a striking disorganization of the T-system openings at the sub-sarcolemmal level in LGMD-1C muscle fibers. These observations provide new perspectives in our understanding of the role of caveolin-3 in muscle and of the pathogenesis of muscle weakness in caveolin-3 deficient muscle

Phenotypic characterization of hypomyelination and congenital cataract

To define the clinical and laboratory findings in a novel autosomal recessive white matter disorder called hypomyelination and congenital cataract, recently found to be caused by a deficiency of a membrane protein, hyccin, encoded by the DRCTNNB1A gene located on chromosome 7p21.3-p15.3. We performed neurological examination, neurophysiological, neuroimaging, and neuropathological studies on sural nerve biopsy in 10 hypomyelination and congenital cataract patients from 5 unrelated families. The clinical picture was characterized by bilateral congenital cataract, developmental delay, and slowly progressive neurological impairment with spasticity, cerebellar ataxia, and mild-to-moderate mental retardation. Neurophysiological studies showed a slightly to markedly slowed motor nerve conduction velocity in 9 of 10 patients, and multimodal evoked potentials indicated increased central conduction times. Neuroimaging studies demonstrated a diffuse supratentorial hypomyelination, with in some patients, additional areas of more prominent signal change in the frontal region. Sural nerve biopsy showed a slight-to-severe reduction in myelinated fiber density, with several axons surrounded by a thin myelin sheath or devoid of myelin. Hypomyelination and congenital cataract is a novel autosomal recessive white matter disorder characterized by the unique association of congenital cataract and hypomyelination of the central and peripheral nervous syste

Kidney and uro-trauma: WSES-AAST guidelines

Renal and urogenital injuries occur in approximately 10-20% of abdominal trauma in adults and children. Optimal management should take into consideration the anatomic injury, the hemodynamic status, and the associated injuries. The management of urogenital trauma aims to restore homeostasis and normal physiology especially in pediatric patients where non-operative management is considered the gold standard. As with all traumatic conditions, the management of urogenital trauma should be multidisciplinary including urologists, interventional radiologists, and trauma surgeons, as well as emergency and ICU physicians. The aim of this paper is to present the World Society of Emergency Surgery (WSES) and the American Association for the Surgery of Trauma (AAST) kidney and urogenital trauma management guidelines