Upregulation of the cell-cycle regulator RGC-32 in Epstein-Barr virus-immortalized cells

Epstein-Barr virus (EBV) is implicated in the pathogenesis of multiple human tumours of lymphoid and epithelial origin. The virus infects and immortalizes B cells establishing a persistent latent infection characterized by varying patterns of EBV latent gene expression (latency 0, I, II and III). The CDK1 activator, Response Gene to Complement-32 (RGC-32, C13ORF15), is overexpressed in colon, breast and ovarian cancer tissues and we have detected selective high-level RGC-32 protein expression in EBV-immortalized latency III cells. Significantly, we show that overexpression of RGC-32 in B cells is sufficient to disrupt G2 cell-cycle arrest consistent with activation of CDK1, implicating RGC-32 in the EBV transformation process. Surprisingly, RGC-32 mRNA is expressed at high levels in latency I Burkitt's lymphoma (BL) cells and in some EBV-negative BL cell-lines, although RGC-32 protein expression is not detectable. We show that RGC-32 mRNA expression is elevated in latency I cells due to transcriptional activation by high levels of the differentially expressed RUNX1c transcription factor. We found that proteosomal degradation or blocked cytoplasmic export of the RGC-32 message were not responsible for the lack of RGC-32 protein expression in latency I cells. Significantly, analysis of the ribosomal association of the RGC-32 mRNA in latency I and latency III cells revealed that RGC-32 transcripts were associated with multiple ribosomes in both cell-types implicating post-initiation translational repression mechanisms in the block to RGC-32 protein production in latency I cells. In summary, our results are the first to demonstrate RGC-32 protein upregulation in cells transformed by a human tumour virus and to identify post-initiation translational mechanisms as an expression control point for this key cell-cycle regulator

Treatment of displaced intra-articular calcaneal fractures by ligamentotaxis: current concepts’ review

Introduction: A large variety of therapeutic modalities for calcaneal fractures have been described in the literature. No single treatment modality for displaced intra-articular calcaneal fractures has proven superior over the other. This review describes and compares the different percutaneous distractional approaches for intra-articular calcaneal fractures. The history, technique, anatomical and fracture considerations, limitations and the results of different distractional approaches reported in the literature are reviewed. Method: Literature review on different percutaneous distractional approaches for displaced intra-articular calcaneal fractures. Results: Eight studies in which application of a distraction technique was used for the treatment of calcaneal fractures were identified. Because of the use of different classification, techniques, and outcome scoring systems, a meta-analysis was not possible. A literature review reveals overall fair to poor result in 10-29% of patients. Ten up to 26% of patients are unable to return to work after percutaneous treatment of their fracture. A secondary arthrodesis has to be performed in 2-15% of the cases. Infectious complications occur in 2-15%. Some loss of reduction is reported in 4-67%. Conclusion: Percutaneous distractional reduction and fixation appears to be a safe technique with overall good results and an acceptable complication rate, compared with other treatment modalities for displaced intra-articular calcaneal fractures. A meta-analysis, based on Cochrane Library criteria is not possible, because of a lack of level 1 and 2 trials on this subject

Insights into udder health and intramammary antibiotic usage on Irish dairy farms during 2003-2010

By international standards, Ireland is a relatively small dairy producer. However, the industry plays a critical role to the national economy, accounting for approximately 3% of national gross domestic product. This paper presents insights into udder health and intramammary antibiotic usage on Irish dairy farms during 2003-2010, based on data from several sources. Three data sources were used, including data on milk recording data, intramammary antibiotic sales and animal health assessment. The milk recording data included a single unadjusted herd-level somatic cell count (SCC) value for each herd at each milk recording, being the arithmetic mean of cow-level SCC of each cow at that recording, weighted by cow-level yield. These data were used to calculate the percentage of herds each month where the unadjusted herd SCC exceeded 200,000 and 400,000 cells/mL. Two logistic generalised estimating-equations (GEE) models were developed, the outcome variable being either the probability that the monthly SCC of a herd was greater than 400,000 cells/mL or less than or equal to 200,000 cells/mL. Spring herds had a lower probability of a high SCC (> 400,000 cells/mL) during February to October compared to non-Spring herds but a higher probability between November to January. The odds of a high SCC were greater in 2005, 2006, 2009 and 2010 but less in 2007 and 2008 compared to 2004. Smaller herds had higher odds of having a high SCC compared to larger herds. We present the number of intramammary tubes and the quantity of active substance (kg) sold annually in Ireland during 2003-2010. We infer an incidence of clinical mastitis of 54.0 cases per 100 cow-years at risk, assuming 4 tubes per treatment regime, one affected quarter per cow, tubes restricted to clinical cases only and 100% of treated cases considered new cases, based on data collected on sales of in-lactation intra-mammary antibiotics. With differing assumptions, this estimate varied between 25.8 and 77.0 cases per 100 cow-years at risk. Using data on sales of dry cow therapy intra-mammary antibiotics, we also infer that most Irish dairy farmers use blanket dry cow therapy. It is important that Ireland has an objective understanding of current levels of udder health, to facilitate benchmarking and improvement into the future. Udder health is a concern on a number of Irish dairy farms. High SCC results were present throughout the year, but more marked towards the start and end of each milking season. Animal Health Ireland recently commenced a major national programme, CellCheck, in collaboration with a broad range of stakeholders, to support national SCC improvement. In this paper, relevant European and national legislation is also reviewed

To retain or remove the syndesmotic screw: a review of literature

Introduction: Syndesmotic positioning screws are frequently placed in unstable ankle fractures. Many facets of adequate placement techniques have been the subject of various studies. Whether or not the syndesmosis screw should be removed prior to weight-bearing is still debated. In this study, the recent literature is reviewed concerning the need for removal of the syndesmotic screw. Materials and methods: A comprehensive literature search was conducted in the electronic databases of the Cochrane Library, Pubmed Medline and EMbase from January 2000 to October 2010. Results: A total of seven studies were identified in the literature. Most studies found no difference in outcome between retained or removed screws. Patients with screws that were broken, or showed loosening, had similar or improved outcome compared to patients with removed screws. Removal of the syndesmotic screws, when deemed necessary, is usually not performed before 8-12 weeks. Conclusion: There is paucity in randomized controlled trials on the absolute need for removal of the syndesmotic screw. However, current literature suggests that it might be reserved for intact screws that cause hardware irritation or reduced range of motion after 4-6 months

Problem Behavior in Children of Chronically Ill Parents: A Meta-Analysis

The aim of this meta-analysis is to examine whether children of chronically ill parents differ from norm groups in problem behavior. We report moderator effects and overall effect sizes for internalizing, externalizing and total problem behavior assessed by children and parents. In fixed effect models, we found a significant overall effect size for internalizing problem behavior (number of studies k = 19, total sample size N = 1,858, Cohen’s d = .23, p < .01) and externalizing problem behavior (k = 13, N = 1,525, d = .09, p < .01) but not for total problem behavior (k = 7; N = 896). Effects for internalizing and externalizing problem behavior were larger in non-cancer studies, in samples including younger children and younger ill parents, in samples defined by low average SES and in studies including parents with longer illness duration. In addition, effects for externalizing problem behavior were larger in studies characterized by a higher percentage of ill mothers and single parents. With exclusive self-report, effect sizes were significant for all problem behaviors. Based on these results, a family-centered approach in health care is recommended

Nonlinear complexity analysis of brain fMRI signals in schizophrenia

Peer reviewedPublisher PD

Coronary heart disease policy models: a systematic review

BACKGROUND: The prevention and treatment of coronary heart disease (CHD) is complex. A variety of models have therefore been developed to try and explain past trends and predict future possibilities. The aim of this systematic review was to evaluate the strengths and limitations of existing CHD policy models. METHODS: A search strategy was developed, piloted and run in MEDLINE and EMBASE electronic databases, supplemented by manually searching reference lists of relevant articles and reviews. Two reviewers independently checked the papers for inclusion and appraisal. All CHD modelling studies were included which addressed a defined population and reported on one or more key outcomes (deaths prevented, life years gained, mortality, incidence, prevalence, disability or cost of treatment). RESULTS: In total, 75 articles describing 42 models were included; 12 (29%) of the 42 models were micro-simulation, 8 (19%) cell-based, and 8 (19%) life table analyses, while 14 (33%) used other modelling methods. Outcomes most commonly reported were cost-effectiveness (36%), numbers of deaths prevented (33%), life-years gained (23%) or CHD incidence (23%). Among the 42 models, 29 (69%) included one or more risk factors for primary prevention, while 8 (19%) just considered CHD treatments. Only 5 (12%) were comprehensive, considering both risk factors and treatments. The six best-developed models are summarised in this paper, all are considered in detail in the appendices. CONCLUSION: Existing CHD policy models vary widely in their depth, breadth, quality, utility and versatility. Few models have been calibrated against observed data, replicated in different settings or adequately validated. Before being accepted as a policy aid, any CHD model should provide an explicit statement of its aims, assumptions, outputs, strengths and limitations

CpG-Methylation Regulates a Class of Epstein-Barr Virus Promoters

DNA methylation is the major modification of eukaryotic genomes and plays an essential role in mammalian gene regulation. In general, cytosine-phosphatidyl-guanosine (CpG)-methylated promoters are transcriptionally repressed and nuclear proteins such as MECP2, MBD1, MBD2, and MBD4 bind CpG-methylated DNA and contribute to epigenetic silencing. Methylation of viral DNA also regulates gene expression of Epstein-Barr virus (EBV), which is a model of herpes virus latency. In latently infected human B cells, the viral DNA is CpG-methylated, the majority of viral genes is repressed and virus synthesis is therefore abrogated. EBV's BZLF1 encodes a transcription factor of the AP-1 family (Zta) and is the master gene to overcome viral gene repression. In a genome-wide screen, we now identify and characterize those viral genes, which Zta regulates. Among them are genes essential for EBV's lytic phase, which paradoxically depend on strictly CpG-methylated promoters for their Zta-induced expression. We identified novel DNA recognition motifs, termed meZRE (methyl-Zta-responsive element), which Zta selectively binds in order to ‘read’ DNA in a methylation- and sequence-dependent manner unlike any other known protein. Zta is a homodimer but its binding characteristics to meZREs suggest a sequential, non-palindromic and bipartite DNA recognition element, which confers superior DNA binding compared to CpG-free ZREs. Our findings indicate that Zta has evolved to transactivate cytosine-methylated, hence repressed, silent promoters as a rule to overcome epigenetic silencing

Sfrp5 Modulates Both Wnt and BMP Signaling and Regulates Gastrointestinal Organogensis in the Zebrafish, Danio rerio

Sfrp5 belongs to the family of secreted frizzled related proteins (Sfrp), secreted inhibitors of Wingless-MMTV Integration Site (Wnt) signaling, which play an important role in cancer and development. We selected sfrp5 because of its compelling expression profile in the developing endoderm in zebrafish, Danio rerio. In this study, overexpression of sfrp5 in embryos results in defects in both convergent extension (CE) by inhibition of non-canonical Wnt signaling and defects in dorsoventral patterning by inhibition of Tolloid-mediated proteolysis of the BMP inhibitor Chordin. From 25 hours post fertilization (hpf) to 3 days post fertilization (dpf), both overexpression and knockdown of Sfrp5 decrease the size of the endoderm, significantly reducing liver cell number. At 3 dpf, insulin-positive endodermal cells fail to coalesce into a single pancreatic islet. We show that Sfrp5 inhibits both canonical and non-canonical Wnt signaling during embryonic and endodermal development, resulting in endodermal abnormalities. © 2013 Stuckenholz et al