Maintenance of active chromatin states by HMGN2 is required for stem cell identity in a pluripotent stem cell model.

BACKGROUND: Members of the HMGN protein family modulate chromatin structure and influence epigenetic modifications. HMGN1 and HMGN2 are highly expressed during early development and in the neural stem/progenitor cells of the developing and adult brain. Here, we investigate whether HMGN proteins contribute to the chromatin plasticity and epigenetic regulation that is essential for maintaining pluripotency in stem cells. RESULTS: We show that loss of Hmgn1 or Hmgn2 in pluripotent embryonal carcinoma cells leads to increased levels of spontaneous neuronal differentiation. This is accompanied by the loss of pluripotency markers Nanog and Ssea1, and increased expression of the pro-neural transcription factors Neurog1 and Ascl1. Neural stem cells derived from these Hmgn-knockout lines also show increased spontaneous neuronal differentiation and Neurog1 expression. The loss of HMGN2 leads to a global reduction in H3K9 acetylation, and disrupts the profile of H3K4me3, H3K9ac, H3K27ac and H3K122ac at the Nanog and Oct4 loci. At endodermal/mesodermal genes, Hmgn2-knockout cells show a switch from a bivalent to a repressive chromatin configuration. However, at neuronal lineage genes whose expression is increased, no epigenetic changes are observed and their bivalent states are retained following the loss of HMGN2. CONCLUSIONS: We conclude that HMGN1 and HMGN2 maintain the identity of pluripotent embryonal carcinoma cells by optimising the pluripotency transcription factor network and protecting the cells from precocious differentiation. Our evidence suggests that HMGN2 regulates active and bivalent genes by promoting an epigenetic landscape of active histone modifications at promoters and enhancers.

A quality audit of the service delivered by the NSW Neonatal and Paediatric Transport Service.

AIM: To discover areas of NSW Neonatal and Paediatric Transport Service's (NETS) work with which the parents, referring and receiving doctors are dissatisfied and respond to them. METHODS: An anonymous survey of referring doctors, parents of patients transported by NETS and receiving hospital doctors between July and December 2005. RESULTS: Referring doctors: Fifty-seven per cent of the 288 (30% response rate) doctors who responded were paediatricians and 43% worked in rural settings. Over 90% responded positively about communication with the NETS team at referral and retrieval. Useful feedback included the need to be more time efficient in phone communication and during stabilisation of the child and to improve feedback about management and patient outcomes. Parents: Forty-seven per cent of 152 responses (15% response rate) came from rural families. The majority (>98%) of parents felt that the NETS team were helpful and supportive of them. Parents reported being able to travel with their child 60% of the time and of those who could not, 95% could explain why. Receiving doctors: Ninety-three per cent of 218 responses (42% response rate) thought that the referral was appropriate, that the NETS teams carried out their advice correctly (98%) and that the child's needs were reported accurately by the team (90%). In a minority of retrievals important concerns were raised about ventilation, sedation, patient assessment and management. CONCLUSION: Most retrievals happen in a way that referring consultants, parents and receiving consultants find appropriate. Important suggestions for improvement in service delivery and some areas of risk to patient safety have been identified. Processes for overcoming these situations are being developed and implemented.

Transporting newborn infants with suspected duct dependent congenital heart disease on low-dose prostaglandin E1 without routine mechanical ventilation.

AIM: To evaluate the safety of transporting newborn infants with suspected duct dependent congenital heart disease (CHD) treated with prostaglandin E1 (PGE1) without routine mechanical ventilation. METHODS: A retrospective population-based audit of newborn infants with suspected CHD transported on PGE1 by the New South Wales newborn and paediatric Transport Service from 1995 through 2005. RESULTS: Mechanical ventilation was not used prior to treatment with PGE1 in 94 (31%) of the 300 infants. The indications for mechanical ventilation in the remaining 206 infants (69%) included elective mechanical ventilation because of the intention to use PGE1 (n = 125) and severe hypoxaemia, acidosis or cardiorespiratory failure prior to commencing PGE1 (n = 81). 16 (17%) of the 94 infants who were not ventilated initially required mechanical ventilation before transport because of apnoea, which developed within one hour of commencing PGE1. 2 (2.6%) of the 78 infants transported without mechanical ventilation developed apnoea in transit and both were receiving >or=15 ng/kg/min of PGE1. Apnoea was more likely to occur in non-ventilated infants when the PGE1 infusion rate was >or=15 ng/kg/min compared with <15 ng/kg/min (14/33 vs 4/61, chi(2) = 15.55, p<.001). CONCLUSIONS: Newborn infants with suspected duct dependent CHD treated with low dose PGE1 (<15 ng/kg/min) may not require mechanical ventilation for safe transport.