The role of DNA methylation in human pancreatic neuroendocrine tumours

Pancreatic neuroendocrine tumours (PNETs) are the second most common pancreatic tumour. However, relatively little is known about their tumourigenic drivers, other than mutations involving the multiple endocrine neoplasia 1 (MEN1), ATRX chromatin remodeler, and death domain-associated protein genes, which are found in ~40% of sporadic PNETs. PNETs have a low mutational burden, thereby suggesting that other factors likely contribute to their development, including epigenetic regulators. One such epigenetic process, DNA methylation, silences gene transcription via 5’methylcytosine (5mC), and this is usually facilitated by DNA methyltransferase enzymes at CpG-rich areas around gene promoters. However, 5’hydroxymethylcytosine, which is the first epigenetic mark during cytosine demethylation, and opposes the function of 5mC, is associated with gene transcription, although the significance of this remains unknown, as it is indistinguishable from 5mC when conventional bisulfite conversion techniques are solely used. Advances in array-based technologies have facilitated the investigation of PNET methylomes and enabled PNETs to be clustered by methylome signatures, which has assisted in prognosis and discovery of new aberrantly regulated genes contributing to tumourigenesis. This review will discuss the biology of DNA methylation, its role in PNET development, and impact on prognostication and discovery of epigenome-targeted therapies

Transfer of congenital heart patients from paediatric to adult services in England

OBJECTIVE: This study assessed the transfer of patients from paediatric cardiac to adult congenital heart disease (ACHD) services in England and the factors impacting on this process. METHODS: This retrospective cohort study used a population-based linked data set (LAUNCHES QI data set: 'Linking Audit and National datasets in Congenital Heart Services for Quality Improvement') including all patients born between 1987 and 2000, recorded as having a congenital heart disease (CHD) procedure in childhood. Hospital Episode Statistics data identified transfer from paediatric to ACHD services between the ages of 16 and 22 years. RESULTS: Overall, 63.8% of a cohort of 10 298 patients transferred by their 22nd birthday. The estimated probability of transfer by age 22 was 96.5% (95% CI 95.3 to 97.7), 86.7% (95% CI 85.6 to 87.9) and 41.0% (95% CI 39.4 to 42.6) for severe, moderate and mild CHD, respectively. 166 patients (1.6%) died between 16 and 22 years; 42 of these (0.4%) died after age 16 but prior to transfer. Multivariable ORs in the moderate and severe CHD groups up to age 20 showed significantly lower likelihood of transfer among female patients (0.87, 95% CI 0.78 to 0.97), those with missing ethnicity data (0.31, 95% CI 0.18 to 0.52), those from deprived areas (0.84, 95% CI 0.72 to 0.98) and those with moderate (compared with severe) CHD (0.30, 95% CI 0.26 to 0.35). The odds of transfer were lower for the horizontal compared with the vertical care model (0.44, 95% CI 0.27 to 0.72). Patients who did not transfer had a lower probability of a further National Congenital Heart Disease Audit procedure between ages 20 and 30 compared with those who did transfer: 12.3% (95% CI 5.1 to 19.6) vs 32.5% (95% CI 28.7 to 36.3). CONCLUSIONS: Majority of patients with moderate or severe CHD in England transfer to adult services. Patients who do not transfer undergo fewer elective CHD procedures over the following decade

Staff experiences of Providing Maternity Services in Rural Southern Tanzania -- A Focus on Equipment, Drug and Supply Issues.

The poor maintenance of equipment and inadequate supplies of drugs and other items contribute to the low quality of maternity services often found in rural settings in low- and middle-income countries, and raise the risk of adverse maternal outcomes through delaying care provision. We aim to describe staff experiences of providing maternal care in rural health facilities in Southern Tanzania, focusing on issues related to equipment, drugs and supplies. Focus group discussions and in-depth interviews were conducted with different staff cadres from all facility levels in order to explore experiences and views of providing maternity care in the context of poorly maintained equipment, and insufficient drugs and other supplies. A facility survey quantified the availability of relevant items. The facility survey, which found many missing or broken items and frequent stock outs, corroborated staff reports of providing care in the context of missing or broken care items. Staff reported increased workloads, reduced morale, difficulties in providing optimal maternity care, and carrying out procedures that carried potential health risks to themselves as a result. Inadequately stocked and equipped facilities compromise the health system's ability to reduce maternal and neonatal mortality and morbidity by affecting staff personally and professionally, which hinders the provision of timely and appropriate interventions. Improving stock control and maintaining equipment could benefit mothers and babies, not only through removing restrictions to the availability of care, but also through improving staff working conditions

The writing on the wall: the concealed communities of the East Yorkshire horselads

This paper examines the graffiti found within late nineteenth and early-twentieth century farm buildings in the Wolds of East Yorkshire. It suggests that the graffiti were created by a group of young men at the bottom of the social hierarchy - the horselads – and was one of the ways in which they constructed a distinctive sense of communal identity, at a particular stage in their lives. Whilst it tells us much about changing agricultural regimes and social structures, it also informs us about experiences and attitudes often hidden from official histories and biographies. In this way, the graffiti are argued to inform our understanding, not only of a concealed community, but also about their hidden histor

Pulmonary Cowpox in Cats: Five Cases

Case series summary: This case series documents five cases of pneumonia (with pleural effusion in three cases) caused by cowpox virus (CPxV) in domestic cats. Predisposition to pneumonia may have resulted from mixed infections in two cases (feline herpesvirus and Bordetella bronchiseptica in one cat, and Mycoplasma species in the other). Relevance and novel information: As well as diagnostic confirmation by previously described methods of virus isolation from skin lesions, and demonstration of pox virions in skin samples using electron microscopy and inclusion bodies in histological preparations, this is the first report of diagnosis by virus isolation from bronchoalveolar lavage fluid or pleural fluid, and demonstration of inclusion bodies in cytological preparations. This is also the first series to report treatment with interferon omega (IFN-ω). Two cats survived, both of which had been treated with IFN-ω. As CPxV represents a serious zoonotic risk it is an important differential diagnosis of pneumonia in cats

The Continuing Use of Problematic Sexual Stereotypes in Judicial Decision-Making

This article examines the continuing use of problematic sexual stereotypes at appellate level in the English and Welsh legal system. Using five cases as illustrations, it argues that, notwithstanding professional training and guidance on sexual equality matters, certain senior judges in this jurisdiction still at least sometimes openly employ crude and problematic sexual stereotypes in their judgments or fail to deal appropriately with the use of these stereotypes by trial judges. The central point is that there is still a significant problem with the open use of crude sexual stereotypes in legal reasoning at a senior level in this jurisdiction, despite the pressure on all members of the legal system to appear to be ‘politically correct’