Histone deacetylase 1 and 2 are essential for normal T-cell development and genomic stability in mice.

Histone deacetylase 1 and 2 (HDAC1/2) regulate chromatin structure as the catalytic core of the Sin3A, NuRD and CoREST co-repressor complexes. To better understand the key pathways regulated by HDAC1/2 in the adaptive immune system and inform their exploitation as drug targets, we have generated mice with a T-cell specific deletion. Loss of either HDAC1 or HDAC2 alone has little effect, while dual inactivation results in a 5-fold reduction in thymocyte cellularity, accompanied by developmental arrest at the double-negative to double-positive transition. Transcriptome analysis revealed 892 misregulated genes in Hdac1/2 knock-out thymocytes, including down-regulation of LAT, Themis and Itk, key components of the T-cell receptor (TCR) signaling pathway. Down-regulation of these genes suggests a model in which HDAC1/2 deficiency results in defective propagation of TCR signaling, thus blocking development. Furthermore, mice with reduced HDAC1/2 activity (Hdac1 deleted and a single Hdac2 allele) develop a lethal pathology by 3-months of age, caused by neoplastic transformation of immature T cells in the thymus. Tumor cells become aneuploid, express increased levels of c-Myc and show elevated levels of the DNA damage marker, γH2AX. These data demonstrate a crucial role for HDAC1/2 in T-cell development and the maintenance of genomic stability.

Using child age or weight in selecting type of in-vehicle restraint: implications for promotion and design.

A survey of motor vehicle child restraint use found around 28% of children under the age of six using weight-inappropriate restraints. Many parents did not know when a child was likely to outgrow a booster seat nor the weight of their child, but they did know the child's age. Anthropometric data show that, if advice on restraint transition, given solely in terms of age (6 months, 4 years, 8 years) were followed in Australia, incorrect restraint selection would occur in 5% of children under the age of six. Further analysis suggests how rewriting the Standard could reduce this number. We present an argument for placing age-based transitions at the heart of the strategy to improve child restraint compliance. This may be superior to one based on the child's weight or other anthropometric measurement. Our argument may be summarized as follows: 1 Age-based rules for selecting child restraints are simple, require less information to be retained, and might be more natural criteria for parents. They might have a greater chance of being adopted as norms, and of encouraging good peer cues. Anthropometric rules, on the other hand, assume that parents know the current dimensions of their children and have the tools at their disposal to measure these dimensions. 2 The consequences of age-based promotion for the proportion of children in a restraint suitable for their weight can be estimated for alternative regulatory frameworks. We will report such Calculations below and show that this rate can potentially be very high. The rate would be even higher if child restraint design standards were drafted with age-based transitions in mind. Age-based transitions imply restraint specifications (weight and height limits) that can be determined from anthropometric survey data. 3 Such standards would necessarily imply overlapping anthropometric ranges for the different types of restraint. However, we emphasize that these overlaps would exist to facilitate age-based transitions, not to feature in publicity advising on the correct selection of child restraints. Under such a regime, promotion is driven by what information is readily usable by parents, and ceases being consequential to the standards-setting process. In support of this argument we shall report a survey of restraint use among parents of pre-school and school aged children, and an analysis of the weights (or other dimensions) of children that provides a technique for estimating how well age-based transition could work. The remainder of this paper is divided into sections covering the survey and the anthropometric study. These are synthesized in a discussion of their implications for restraint promotions and standards setting.