Histones mediate dynamic packaging of nuclear DNA in chromatin, a process that is precisely controlled to guarantee efficient compaction of the genome and proper chromosomal segregation during cell division and to accomplish DNA replication, transcription, and repair. Due to the important structural and regulatory roles played by histones, it is not surprising that histone functional dysregulation or aberrant levels of histones can have severe consequences for multiple cellular processes and ultimately might affect development or contribute to cell transformation. Recently, germline frameshift mutations involving the C-terminal tail of HIST1H1E, which is a widely expressed member of the linker histone family and facilitates higher-order chromatin folding, have been causally linked to an as-yet poorly defined syndrome that includes intellectual disability. We report that these mutations result in stable proteins that reside in the nucleus, bind to chromatin, disrupt proper compaction of DNA, and are associated with a specific methylation pattern. Cells expressing these mutant proteins have a dramatically reduced proliferation rate and competence, hardly enter into the S phase, and undergo accelerated senescence. Remarkably, clinical assessment of a relatively large cohort of subjects sharing these mutations revealed a premature aging phenotype as a previously unrecognized feature of the disorder. Our findings identify a direct link between aberrant chromatin remodeling, cellular senescence, and accelerated aging.
These results indicate that systematic screening for child abuse in emergency departments is effective in increasing the detection of suspected child abuse. Both a legal requirement and staff training are recommended to significantly increase the extent of screening.
Although screening for child abuse at emergency departments (EDs) increases the detection rate of potential child abuse, an accurate instrument is lacking. This study was designed to measure the accuracy of a screening instrument for detection of potential child abuse used in EDs. In a prospective cohort study at three Dutch EDs, a 6-item screening instrument for child abuse, Escape, was completed for each child visiting the ED. The data from the completed Escape instrument was used to calculate sensitivity, specificity, and the positive/negative predictive value per item. The clinical notes and conclusions of the screen instruments of all potentially abused children reported to the hospitals' Child Abuse Teams were collected and reviewed by an expert panel. A logistic regression model was used to evaluate the predictors of potential abuse. Completed Escape instruments were available for 18,275 ED visits. Forty-four of the 420 children with a positive screening result, and 11 of the 17,855 children with a negative result were identified as potentially abused. Sensitivity of the Escape instrument was 0.80 and specificity was 0.98. Univariate logistic regression showed that potentially abused children were significantly more likely to have had an aberrant answer to at least one of the items, OR=189.8, 95% CI [97.3, 370.4]. Most of the children at high risk for child abuse were detected through screening. The Escape instrument is a useful tool for ED staff to support the identification of those at high risk for child abuse.
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