Mouse epiblast stem cells (EpiSCs) can be derived from a wide range of developmental stages. To characterize and compare EpiSCs with different origins, we derived a series of EpiSC lines from pregastrula stage to late-bud-stage mouse embryos. We found that the transcriptomes of these cells are hierarchically distinct from those of the embryonic stem cells, induced pluripotent stem cells (iPSCs), and epiblast/ectoderm. The EpiSCs display globally similar gene expression profiles irrespective of the original developmental stage of the source tissue. They are developmentally similar to the ectoderm of the late-gastrula-stage embryo and behave like anterior primitive streak cells when differentiated in vitro and in vivo. The EpiSC lines that we derived can also be categorized based on a correlation between gene expression signature and predisposition to differentiate into particular germ-layer derivatives. Our findings therefore highlight distinct identifying characteristics of EpiSCs and provide a foundation for further examination of EpiSC properties and potential.

Traditionally wet-to-dry gauze has been used to dress wounds. Dressings that create and maintain a moist environment, however, are now considered to provide the optimal conditions for wound healing. Moisture under occlusive dressings not only increases the rate of epithelialisation but also promotes healing through moisture itself and the presence initially of a low oxygen tension (promoting the inflammatory phase). Gauze does not exhibit these properties; it may be disruptive to the healing wound as it dries and cause tissue damage when it is removed. It is not now widely used in the United Kingdom. Occlusive dressings are thought to increase cell proliferation and activity by retaining an optimum level of wound exudate, which contains vital proteins and cytokines produced in response to injury. These facilitate autolytic debridement of the wound and promote healing. Concerns of increased risk of infection under occlusive dressings have not been substantiated in clinical trials. This article describes wound dressings currently available in the UK. Low adherent dressings Low adherent dressings are cheap and widely available. Their major function is to allow exudate to pass through into a secondary dressing while maintaining a moist wound bed. Most are manufactured in the form of tulles, which are open weave cloth soaked in soft paraffin or chlorhexidine; textiles; or multilayered or perforated plastic films. They are designed to reduce adherence at the wound bed and are particularly useful for patients with sensitive or fragile skin.

Brief cognitive behaviour therapy is of limited efficacy in reducing self-harm repetition, but the findings taken in conjunctin with the economic evaluation (Byford et al. 2003) indicate superiority of MACT over TAU in terms of cost and effectiveness combined.

Using a Cre-mediated conditional deletion approach, we have dissected the function of Twist1 in the morphogenesis of the craniofacial skeleton. Loss of Twist1 in neural crest cells and their derivatives impairs skeletogenic differentiation and leads to the loss of bones of the snout, upper face and skull vault. While no anatomically recognizable maxilla is formed, a malformed mandible is present. Since Twist1 is expressed in the tissues of the maxillary eminence and the mandibular arch, this finding suggests that the requirement for Twist1 is not the same in all neural crest derivatives. The effect of the loss of Twist1 function is not restricted to neural crest-derived bones, since the predominantly mesoderm-derived parietal and interparietal bones are also affected, presumably as a consequence of lost interactions with neural crest-derived tissues. In contrast, the formation of other mesodermal skeletal derivatives such as the occipital bones and most of the chondrocranium are not affected by the loss of Twist1 in the neural crest cells.

Cytidine (C) to Uridine (U) RNA editing is a post-transcriptional modification that is accomplished by the deaminase APOBEC1 and its partnership with the RNA-binding protein A1CF. We identify and characterise here a novel RNA-binding protein, RBM47, that interacts with APOBEC1 and A1CF and is expressed in tissues where C to U RNA editing occurs. RBM47 can substitute for A1CF and is necessary and sufficient for APOBEC1-mediated editing in vitro. Editing is further impaired in Rbm47-deficient mutant mice. These findings suggest that RBM47 and APOBEC1 constitute the basic machinery for C to U RNA editing.

The basic helix-loop-helix transcription factor Twist1 is a key regulator of craniofacial development. Twist1-null mouse embryos exhibit failure of cephalic neural tube closure and abnormal head development and die at E11.0. To dissect the function of Twist1 in the cranial mesoderm beyond mid-gestation, we used Mesp1-Cre to delete Twist1 in the anterior mesoderm, which includes the progenitors of the cranial mesoderm. Deletion of Twist1 in mesoderm cells resulted in loss and malformations of the cranial mesoderm-derived skeleton. Loss of Twist1 in the mesoderm also resulted in a failure to fully segregate the mesoderm and the neural crest cells, and the malformation of some cranial neural crest-derived tissues. The development of extraocular muscles was compromised whereas the differentiation of branchial arch muscles was not affected, indicating a differential requirement for Twist1 in these two types of craniofacial muscle. A striking effect of the loss of Twist1 was the inability of the mesodermal cells to maintain their mesenchymal characteristics, and the acquisition of an epithelial-like morphology. Our findings point to a role of Twist1 in maintaining the mesenchyme architecture and the progenitor state of the mesoderm, as well as mediating mesoderm-neural crest interactions in craniofacial development.

A total of 480 patients were treated in a large, multicenter randomized trial of a brief form of cognitive therapy, manual-assisted cognitive behavior therapy (MACT) versus treatment as usual (TAU) for recurrent deliberate self-harm. Each patient was randomized after a self-harm episode assessed at an accident and emergency center and followed up over 1 year. The main hypothesis tested was that those allocated to MACT would have a lower proportion of self-harm episodes in the succeeding year. A total of 60% of those allocated to MACT had face-to-face treatment and 430 (90%) of all patients had self-harm data recorded after 1 year. Although the results showed no significant difference between those repeating self-harm in the MACT group (39%) compared with the TAU group (46%) (P = 0.20), the treatment was cost effective (10% cheaper than TAU) and the frequency of self-harm episodes was fewer (50%) in the MACT group. A total of nine of 10 patients had some personality disturbance (42% of these with disorder), and for those where information on parasuicide events was collected, the proportion having a repeat episode ranged from 33% to 63% for different personality disorders. Those with BPD were most likely to repeat episodes quickly (mean 89 days for 25% to repeat) with dissocial personality disorder (equivalent mean 384 days) the slowest to repeat. Total costs were significantly greater in those with personality disorder and were reduced in those allocated to MACT; this saving was reversed in those with borderline disorder. On average, MACT appeared to increase the cost of those patients with BPD (BPD) and reduce the cost of those with other personality disorders. It is concluded that MACT has value in preventing self-harm cost effectively but this appears to be confined mainly to those who do not have BPD.

SUMMARYIn mouse embryos, loss of Dickkopf-1 (DKK1) activity is associated with an ectopic activation of WNT signalling responses in the precursors of the craniofacial structures and leads to a complete truncation of the head at early organogenesis. Here, we show that ENU-induced mutations of genes coding for two WNT canonical pathway factors, the co-receptor LRP6 and the transcriptional co-activator -catenin, also elicit an ectopic signalling response and result in loss of the rostral tissues of the forebrain. Compound mutant embryos harbouring combinations of mutant alleles of Lrp6, Ctnnb1 and Dkk1 recapitulate the partial to complete head truncation phenotype of individual homozygous mutants. The demonstration of a synergistic interaction of Dkk1, Lrp6 and Ctnnb1 provides compelling evidence supporting the concepts that (1) stringent regulation of the level of canonical WNT signalling is necessary for head formation, (2) activity of the canonical pathway is sufficient to account for the phenotypic effects of mutations in three different components of the signal cascade and (3) rostral parts of the brain and the head are differentially more sensitive to canonical WNT signalling and their development is contingent on negative modulation of WNT signalling activity.