The genetic basis of medulloblastoma

Medulloblastoma accounts for 25% of all paediatric brain tumours. Most of these tumours respond poorly to therapy and whilst advances in chemotherapy and radiotherapy have improved long term survival, many patients suffer late relapses that are usually fatal. Long term survival is only about 30%. Loss of chromosome 17p is the most common cytogenetic abnormality, observed in 25-50% of cases. Loss of heterozygosity (LOH) analysis has defined the minimum region of deletion distal to p53 suggesting that another gene on 17p contributes to the pathogenesis of medulloblastoma. The aim of the present study was to define regions of allelic loss on chromosome 17p, to identify other genetic changes by comparative genomic hybridisation (CGH) and to correlate the findings with clinical parameters. LOH analysis was used to identify allele loss at which putative tumour suppressor genes may be located on chromosome 17p in a series of medulloblastoma. LOH was determined using polymorphic microsatellite markers to amplify the DNA from specific regions of chromosome 17p between 17p13.1 and 17p13.3. The frequency of LOH was higher than seen in previous studies and was found in all tumours with the most consistent region of loss at 17p13.1, distal to p53. CGH was used to screen the entire genome and a number of non-random regions of genomic imbalance were observed including gain at 2q, 4q, 5q, 6q, 9p and 13q and loss at 1p, 9q, 10, 12q, 16, 17, 19 and 22. The most consistent regions of loss detected by CGH, at 9q, 10q, 12q, 16q and 22q were then studied using LOH analysis. It was found that those children ≤ age 3 years had a significantly better prognosis than those > than 3 years of age. Loss of 16q in the CGH studies and LOH 16q in the microsatellite analysis was significantly associated with longer survival. In conclusion, this study has demonstrated that medulloblastomas are an extremely heterogeneous tumour type. It has provided new evidence of the involvement of several chromosomes in their development, which shows that their pathogenesis is far more complicated than has previously been thought

Reducing Delirium and Functional Decline in Hospitalized Older Adults: Pre-Implementation of CoCare HELP

Background: Delirium is a change in consciousness characterized by rapid onset and fluctuating attention, causing impairment in the ability to process and recall information, occurring in 30% of hospitalized older adults. Delirium can increase falls, length-of-stay, mortality, and cost. The CoCare Hospital Elder Life Program® (HELP) is an evidence-based bundle of interventions targeting cognitive impairment, sleep deprivation, immobility, visual/hearing impairment, and dehydration, embedding geriatric principles in care to prevent delirium. Objectives: To further analyze the pre-implementation of the HELP in order to optimize success of program administration. Methods: Mixed methods were used to collect retrospective/prospective data (interviews (N=25], surveys [N=25], chart audits [N=500]) for an organization assessment from CoCare experts, the hospital, clinicians, and patients. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guided a systematic review on implementation strategies. Results: A high rate of falls (0.89/1000-days), length-of-stay (6.1 days), readmission rate (12.6%), restraint use (19197 hours), BEERs drugs prescribed (15.4%) and delirium (30.2%) were found. The review identified 10 strategies to guide implementation of HELP: engaging stakeholders/champions, educating staff/patients, clinical team creation/use, facilitation, auditing and feedback, examining satisfaction, and public relations. Products completed included: A University undergraduate course, Registered Nurse education, an Implementation Toolkit, clinician competency checklists, system budgeting plan, system sustainability plan, project analysis plan, recruitment fliers and Epic documentation format. Conclusions: Use of HELP can prevent delirium. The identification of a high rate of delirium was confirmed in the hospital. The products developed will enable the hospital to implement HELP over the next year. Implications: Delirium is prevalent among the population of interest and is associated with significant risks; however, pre-implementation of the HELP will promote a successful program launch to reduce delirium in the elderly

Epidemiology of population mortality related to falls in california 2000–2016: an increasing challenge for EMS

Background: Falls mortality increases with age and the U.S. population is aging steadily. This study examined the epidemiology of mortality in California this century due to unintentional falls. Method: Deaths caused by falls were extracted from California Department of Public Health data. Yearly Californian population estimates from the California Department of Finance were used to calculate the incidence of falls mortality. Results: There were 32 276 deaths attributed to falls, out of 618,589,117 person-years. Deaths at age ≥60 years accounted for 26 669 (83%). There were 15% more deaths during winter months, compared with summer. From age 70 mortality approximately doubled every five additional years of age. The age-adjusted falls mortality rate per 1 00 000 person-years (against the 2000 U.S. Standard Population) increased over 2000–2016 from 3.0 to 4.5 in females and from 8.9 to 9.8 in males. The number of falls deaths increased by a mean 77 per year, (95% CI 72, 83, R2=0.98, p<0.0001), doubling from 1251 in 2000 to 2582 in 2016. Conclusion: It may be prudent for EMS in California to anticipate continued increases in falls mortality. If the annual number of falls-related deaths continues to climb by an average of 77 deaths per year, then California will experience more than 3000 falls deaths per year sometime between 2025 and 2030. Recent increases were partly driven by a combination of increasing population and changes in the age distribution, however, age-adjusted mortality rates also increased, especially in females and older age groups. Conflict of interest None. Funding None

A Human Cytomegalovirus-Encoded microRNA Regulates Expression of Multiple Viral Genes Involved in Replication

Although multiple studies have documented the expression of over 70 novel virus-encoded microRNAs (miRNAs), the targets and functions of most of these regulatory RNA species are unknown. In this study a comparative bioinformatics approach was employed to identify potential human cytomegalovirus (HCMV) mRNA targets of the virus-encoded miRNA miR-UL112-1. Bioinformatics analysis of the known HCMV mRNA 3′ untranslated regions (UTRs) revealed 14 potential viral transcripts that were predicted to contain functional target sites for miR-UL112-1. The potential target sites were screened using luciferase reporters that contain the HCMV 3′UTRs in co-transfection assays with miR-UL112-1. Three of the 14 HCMV miRNA targets were validated, including the major immediate early gene encoding IE72 (UL123, IE1), UL112/113, and UL120/121. Further analysis of IE72 regulation by miR-UL112-1 with clones encoding the complete major immediate early region revealed that the IE72 3′UTR target site is necessary and sufficient to direct miR-UL112-1-specific inhibition of expression in transfected cells. In addition, miR-UL112-1 regulation is mediated through translational inhibition rather than RNA degradation. Premature expression of miR-UL112-1 during HCMV infection resulted in a significant decrease in genomic viral DNA levels, suggesting a functional role for miR-UL112-1 in regulating the expression of genes involved in viral replication. This study demonstrates the ability of a viral miRNA to regulate multiple viral genes

Damage, Destruction, Distress: Shared Ownership Debacles

Shared ownership models of land use are part and parcel of our modern environment. In order to build high density, vibrant cities it is important to appreciate the types of problems that can occur where there is shared ownership on a single title of land. This article explores some of these problems, beginning with cross leases. After outlining the history, principles and essential characteristics of cross leases the article suggests that many of these problems could have been avoided if proposals made by the Law Commission in 1999 had been adopted. The article then analyses the Unit Titles Act 2010, aspects of which are working well, despite public concern about its effectiveness. However, there are a number of situations, especially in relation to insurance entitlements, where the Act does not apply, such as liability in negligence where damage has occurred to commercial or multiple use buildings and the role of contributory negligence. In situations of mixed commercial and residential use, problems arise as a result of definitional issues across a range of legislation, such as the Earthquake Commission Act 1993 and the Weathertight Homes Resolution Services Act 2006. Without careful consideration, the unintended consequences of these issues may well create impediments to building more vibrant cities. Finally, the article notes that central to any vibrant city will be the well-being of its residents. Both the cross lease and unit title models pose challenges in this sphere and careful thought should be given to balancing both the affordability and environmental benefits of higher density living with the need for all ages and types of people to be able to live together with easy access to services and open space

Repairs, Renovation, Restoration, Demolition or Replacement or Multi-Dwelling Units on a Single Title

Our research team (the authors of this paper and Professor Jacinta Ruru) based at the School of Law, University of Canterbury and the Faculty of Law, University of Otago has been granted funding from the Building Research Levy through the New Zealand Building Research Association New Zealand (BRANZ) and the New Zealand Law Foundation to investigate the problems that have occurred with repairs, renovation, restoration, demolition or replacement of multi-dwelling units on a single title (for example, unit titles, cross leases, retirement villages and papakainga housing, or units or buildings where mixed commercial or industrial use is combined with residential use). Although the most obvious examples of events that trigger a need for such repair or restoration have been natural disasters (for example, the Christchurch earthquakes) and buildings that have been affected by New Zealand’s “leaky home” syndrome, problems may also be encountered on a much smaller scale with fires or other triggering events. This paper explains our methodology and reveals some of our early findings

High Density Bacterial Nasal Carriage in Children is Transient and Associated With Respiratory Viral Infections - Implications for Transmission Dynamics

To access publisher's full text version of this article click on the hyperlink belowBACKGROUND: This longitudinal study describes the associations between respiratory viral infections, rhinitis and the prevalence and density of the common nasopharyngeal bacterial colonizers, Streptococcus pneumoniae (Sp), Moraxella catarrhalis (Mc), Haemophilus influenzae (Hi) and Staphylococcus aureus. METHODS: In an observational cohort study, 161 children attending day care centers in Bristol, United Kingdom, were recruited. Monthly nasopharyngeal swabs were taken and stored frozen in Skim-milk, tryptone, glucose and glycerin broth (STGG) broth. Quantitative polymerase chain reaction was used for detection of respiratory viruses and 4 bacterial species. t tests and logistic regression models were used for analysis. RESULTS: The frequent colonisers, Sp, Mc and Hi were more frequently found at high density in contrast to Staphylococcus aureus although temporally, high-density carriage was short lived. Respiratory viral infections and symptoms of rhinitis were both independently and consistently associated with higher bacterial density with an observed 2-fold increase in density for Sp, Mc and Hi (P = 0.004-0.017). CONCLUSIONS: For Sp and Hi, the association between young age and higher bacterial DNA density was explained by more frequent viral infection and increased nasal discharge, while the associations between some viral specie's and some bacterial species' density appear to be stronger than others. Increased colonization density and rhinitis may promote transmission of these commonly carried organisms

Vitamin D attenuates sphingosine-1-phosphate (S1P)-mediated inhibition of extravillous trophoblast migration.

Failure of trophoblast invasion and remodelling of maternal blood vessels leads to the pregnancy complication pre-eclampsia (PE). In other systems, the sphingolipid, sphingosine-1-phosphate (S1P), controls cell migration therefore this study determined its effect on extravillous trophoblast (EVT) function.A transwell migration system was used to assess the behaviour of three trophoblast cell lines, Swan-71, SGHPL-4, and JEG3, and primary human trophoblasts in the presence or absence of S1P, S1P pathway inhibitors and 1,25(OH)2D3. QPCR and immunolocalisation were used to demonstrate EVT S1P receptor expression.EVTs express S1P receptors 1, 2 and 3. S1P inhibited EVT migration. This effect was abolished in the presence of the specific S1PR2 inhibitor, JTE-013 (p < 0.05 versus S1P alone) whereas treatment with the S1R1/3 inhibitor, FTY720, had no effect. In other cell types S1PR2 is regulated by vitamin D; here we found that treatment with 1,25(OH)2D3 for 48 or 72 h reduces S1PR2 (4-fold; <0.05), but not R1 and R3, expression. Moreover, S1P did not inhibit the migration of cells exposed to 1,25(OH)2D3 (p < 0.05).This study demonstrates that although EVT express three S1P receptor isoforms, S1P predominantly signals through S1PR2/Gα12/13 to activate Rho and thereby acts as potent inhibitor of EVT migration. Importantly, expression of S1PR2, and therefore S1P function, can be down-regulated by vitamin D. Our data suggest that vitamin D deficiency, which is known to be associated with PE, may contribute to the impaired trophoblast migration that underlies this condition

Passivation of the CuInSe2 surface via cadmium pre-electrolyte treatment

Effective defect passivation of semiconductor surfaces and interfaces is indispensable for the development of high efficiency solar cells. In this study we systematically investigated the surface and grain boundary properties of CuInSe2 (CISe) with scanning tunneling microscopy (STM) and spectroscopy (STS) after different surface treatments such as potassium cyanide (KCN) etching, pre-electrolyte treatment with cadmium ions, and annealing in ultrahigh vacuum (UHV). We show that air exposed samples with a subsequent KCN etching step exhibits a highly defective surface. However, a Cd pre-electrolyte treatment passivates most of these defects, which manifests itself by a reduction of the high conductance in the STS measurements at positive sample biases. The origin of the improvement can be traced back to an increase in surface band bending, which leads to a type inversion, induced by a change in the concentration of Cu vacancies. We observe a defect passivation at the CISe surface and at the grain boundaries. Our results give a direct explanation of why the CdS buffer layer in CISe thin film solar cells is of utmost importance for high efficiency devices

Heterogeneity and Intrinsic Variation in Spatial Genome Organization [preprint]

The genome is hierarchically organized in 3D space and its architecture is altered in differentiation, development and disease. Some of the general principles that determine global 3D genome organization have been established. However, the extent and nature of cell-to-cell and cell-intrinsic variability in genome architecture are poorly characterized. Here, we systematically probe the heterogeneity in genome organization in human fibroblasts by combining high-resolution Hi-C datasets and high-throughput genome imaging. Optical mapping of several hundred genome interaction pairs at the single cell level demonstrates low steady-state frequencies of colocalization in the population and independent behavior of individual alleles in single nuclei. Association frequencies are determined by genomic distance, higher-order chromatin architecture and chromatin environment. These observations reveal extensive variability and heterogeneity in genome organization at the level of single cells and alleles and they demonstrate the coexistence of a broad spectrum of chromatin and genome conformations in a cell population