Neoplastic human embryonic stem cells as a model of radiation resistance of human cancer stem cells

Studies have implicated that a small sub-population of cells within a tumour, termed cancer stem cells (CSCs), have an enhanced capacity for tumour formation in multiple cancers and may be responsible for recurrence of the disease after treatment, including radiation. Although comparisons have been made between CSCs and bulk-tumour, the more important comparison with respect to therapy is between tumour-sustaining CSC versus normal stem cells that maintain the healthy tissue. However, the absence of normal known counterparts for many CSCs has made it difficult to compare the radiation responses of CSCs with the normal stem cells required for post-radiotherapy tissue regeneration and the maintenance of tissue homeostasis. Here we demonstrate that transformed human embryonic stem cells (t-hESCs), showing features of neoplastic progression produce tumours resistant to radiation relative to their normal counterpart upon injection into immune compromised mice. We reveal that t-hESCs have a reduced capacity for radiation induced cell death via apoptosis and exhibit altered cell cycle arrest relative to hESCs in vitro. t-hESCs have an increased expression of BclXL in comparison to their normal counterparts and re-sensitization of t-hESCs to radiation upon addition of BH3-only mimetic ABT737, suggesting that overexpression of BclXL underpins t-hESC radiation insensitivity. Using this novel discovery platform to investigate radiation resistance in human CSCs, our study indicates that chemotherapy targeting Bcl2-family members may prove to be an adjuvant to radiotherapy capable of targeting CSCs.     

Peripheral and local anaesthetic techniques for paediatric surgery

Peripheral nerve blocks (PNBs) in paediatric patients are usually used as an adjunct to general anaesthesia, providing intra- and postoperative analgesia. These blocks provide good-quality analgesia preventing morbidity related to pain and reducing adverse effects from systemic analgesics. PNBs aid early patient recovery and discharge, which is essential in day-case surgery. Like all invasive techniques, PNBs are associated with complications and adverse effects. They should therefore be performed only after careful analysis of the risk:benefit ratio for each child. This article discusses a general approach to PNBs in children. It covers a small selection of limb and trunk blocks, and discusses the benefit of ultrasound guidance.     

Familial hypercholesterolaemia: what’s new?

Autosomal Dominant Familial Hypercholesterolaemia (FH) is the commonest inherited disorder of lipoprotein metabolism. Untreated monogenic FH caused by mutations in the LDLR, APOB or PCSK9 genes result in early onset cardiovascular death (below the age of 60 years). In the UK the prevalence of heterozygous FH is 1 in 270 and homozygous FH is 160,000 approximately.The introduction of statins nearly three decades ago has altered the natural history of FH, with a significant reduction of cardiovascular related morbidity and mortality. There is increasing evidence that early childhood interventions such as lifestyle choices, healthy eating and commencing statins by the age of 10 years would potentially prevent early onset cardiovascular disease and mortality in monogenic FH. The medium term safety of statins in children has been demonstrated. The UK paediatric FH register data has shown that children with FH are less obese than the normal population and the register aims to monitor the longer-term safety of statins in children with FH. Child-parent screening would potentially benefit the child and enables identifying a parent with FH, before the onset of a life threatening cardiovascular event. In addition, genetic cascade testing of relatives of an affected individual has been shown to be highly cost effective.We review the current literature with brief updates on genetics, the UK paediatric FH register data, published recommendations for the management of homozygous and heterozygous FH, lipid lowering therapies in children and screening for FH in childhood.     

Structure–function relations of primate lower incisors: a study of the deformation of Macaca mulatta dentition using electronic speckle pattern interferometry (ESPI)

Teeth adopt a variety of different morphologies, each of which is presumably optimized for performing specific functions during feeding. It is generally agreed that the enamel cap is a crucial element in controlling the mechanical behavior of mammalian teeth under load. Incisors are particularly interesting in terms of structure–function relations, as their role in feeding is that of the ‘first bite’. However, little is known how incisor cap morphology is related to tooth deformation. In the present paper we examine the mechanical behavior of mandibular central incisors in the cercopithecine primate Macaca mulatta under loads similar to those encountered during ingestion. We map three‐dimensional displacements on the labial surface of the crown as it is compressed, using electronic speckle pattern interferometry (ESPI), an optical metrology method. In addition, micro‐computed tomography is used to obtain data regarding the morphology of the enamel cap, which in the M. mulatta lower incisors exhibits missing or very little enamel on the lingual face. The results showed that although compressed along a longitudinal axis, deformation in the incisors mostly occurred in the lingual direction and orthogonal to the direction of the applied load. Both isolated, embedded teeth and teeth in the mandible showed considerable lingual deformation. Incisor deformation in the mandible was generally greater, reflecting the additional freedom of movement enabled by the supporting structures. We show that the association with adjacent teeth in the arch is significant for the behavior of the tooth under load. Finally, loading two teeth simultaneously in the mandible showed that they work as one functional unit. We suggest that these results demonstrate the importance of enamel cap morphology in directing deformation behavior; an ability stemming from the stiffness of the enamel cap overlying the more pliable dentin.     

Measuring Recovery Related Outcomes: A Psychometric Investigation of the Recovery Markers Inventory

The concept of recovery can be operationalized from either the point of view of the consumer or from the perspective of the provider of services. The Recovery Markers Inventory (RMI) was created to assess recovery-related factors (i.e., actions/events associated with consumer’s recovery) from the provider’s perspective. Evidence, which established the psychometric properties of the RMI, was obtained through the use of: (a) construct validity (i.e., confirmatory factor analysis and Rasch principal components analysis of residuals); (b) concurrent validity (i.e., the calculation of Pearson correlations between the RMI and other recovery-oriented instruments); and (c) reliability (i.e., Rasch Partial Credit models). Evidence presented in this article shows that the RMI scale is unidimensional, has an adequate level of correlation, and acceptable reliability. The current analysis provides evidence to support the RMI as a valid, reliable measure of recovery-related factors, which can complement consumer based instruments in the assessment of changes in recovery.     

Role of viral RNA and lipid in the adverse events associated with the 2010 Southern Hemisphere trivalent influenza vaccine

In Australia, during the 2010 Southern Hemisphere (SH) influenza season, there was an unexpected increase in post-marketing adverse event reports of febrile seizures (FS) in children under 5 years of age shortly after vaccination with the CSL 2010 SH trivalent influenza vaccine (CSL 2010 SH TIV) compared to previous CSL TIVs and other licensed 2010 SH TIVs. In an accompanying study, we described the contribution to these adverse events of the 2010 SH influenza strains as expressed in the CSL 2010 SH TIV using in vitro cytokine/chemokine secretion from whole blood cells and induction of NF-κB activation in HEK293 reporter cells. The aim of the present study was to identify the root cause components that elicited the elevated cytokine/chemokine and NF-κB signature. Our studies demonstrated that the pyrogenic signal was associated with a heat-labile, viral-derived component(s) in the CSL 2010 SH TIV. Further, it was found that viral lipid-mediated delivery of short, fragmented viral RNA was the key trigger for the increased cytokine/chemokine secretion and NF-κB activation. It is likely that the FS reported in children <5 years were due to a combination of the new influenza strains included in the 2010 SH TIV and the CSL standard method of manufacture preserving strain-specific viral components of the new influenza strains (particularly B/Brisbane/60/2008 and to a lesser extent H1N1 A/California/07/2009). These combined to heighten immune activation of innate immune cells, which in a small proportion of children <5 years of age is associated with the occurrence of FS. The data also demonstrates that CSL TIVs formulated with increased levels of splitting agent (TDOC) for the B/Brisbane/60/2008 strain can attenuate the pro-inflammatory signals in vitro, identifying a potential path forward for generating a CSL TIV indicated for use in children <5 years.