Ethical aspects of hemophilia gene therapy:a qualitative interview study with stakeholders

Background: There are great expectations for the potential role of gene therapy in the treatment of hemophilia. At the same time, developments in the field of hemophilia gene therapy have always raised ethical issues. It remains unknown how these ethical issues are perceived by stakeholders, particularly regarding the most recent developments in the field. Objectives: To obtain insight into stakeholders’ morally reasoned opinions on gene therapy for hemophilia. Methods: We conducted qualitative research with Dutch people with hemophilia (n = 13), parents of children with hemophilia (n = 5), physicians (n = 4), nurses (n = 3), a regulator (n = 1), and a representative from a pharmaceutical company (n = 1). We conducted semistructured interviews based on a topic list and reported the results according to the Consolidated Criteria for Reporting Qualitative Research guidelines. Results: We identified 3 main themes. The theme freedom and independence describes the hope people with hemophilia have of increasing their freedom through gene therapy, as well as concerns that gene therapy increases their dependence on their treatment center. The theme trust and altruism describes how people with hemophilia have a high level of trust in their physician and treatment center as well as in scientific research. As a result of this trust, they are willing to participate in research to help other people with hemophilia. The theme incremental benefits describes doubts respondents have about the added value of gene therapy compared to standard treatment. Conclusion: Stakeholders embrace the theoretical potential of gene therapy, while several people with hemophilia question the added value of the current gene transfer products for themselves.</p

PIKES Analysis Reveals Response to Degraders and Key Regulatory Mechanisms of the CRL4 Network

Co-opting Cullin4 RING ubiquitin ligases (CRL4s) to inducibly degrade pathogenic proteins is emerging as a promising therapeutic strategy. Despite intense efforts to rationally design degrader molecules that co-opt CRL4s, much about the organization and regulation of these ligases remains elusive. Here, we establish protein interaction kinetics and estimation of stoichiometries (PIKES) analysis, a systematic proteomic profiling platform that integrates cellular engineering, affinity purification, chemical stabilization, and quantitative mass spectrometry to investigate the dynamics of interchangeable multiprotein complexes. Using PIKES, we show that ligase assemblies of Cullin4 with individual substrate receptors differ in abundance by up to 200-fold and that Cand1/2 act as substrate receptor exchange factors. Furthermore, degrader molecules can induce the assembly of their cognate CRL4, and higher expression of the associated substrate receptor enhances degrader potency. Beyond the CRL4 network, we show how PIKES can reveal systems level biochemistry for cellular protein networks important to drug development

Overexpression of hepatic prothymosin alpha, a novel marker for human hepatocellular carcinoma.

Identification of gene products exclusively or abundantly expressed in cancer may yield novel tumour markers. We recently isolated a number of cDNA clones, including alpha-prothymosin, from rat hepatocellular carcinoma (HCC) using a subtraction-enhanced display technique. Alpha-Prothymosin is involved in cell proliferation and is regulated by the oncogene c-myc in vitro. In the present study, we analysed alpha-prothymosin gene expression and its correlation with c-myc in patients with HCC, cirrhosis and adenoma and in normal controls. Hepatic alpha-prothymosin messenger RNA (mRNA) levels were two- to 9.2-fold higher in tumoral tissues than in adjacent non-tumoral tissues in 14 of 17 patients with HCC, regardless of coexisting cirrhosis and viral hepatitis. No marked difference in alpha-prothymosin mRNA levels was present in patients with adenoma and hepatic cirrhosis and in healthy controls. The c-myc mRNA amounts were two- to fivefold increased in 11 of 17 patients with HCC and correlated significantly with those of alpha-prothymosin (P < 0.001). In situ hybridization revealed that increased alpha-prothymosin mRNA was localized in the tumour nodules of the patients with HCC. These data suggest that overexpression of alpha-prothymosin in HCC patients, correlated with c-myc, is possibly involved in the tumorigenic process and may be a novel molecular marker for human HCC

Orbital and spin physics in LiNiO2 and NaNiO2

We derive a spin-orbital Hamiltonian for a triangular lattice of e_g orbital degenerate (Ni^{3+}) transition metal ions interacting via 90 degree superexchange involving (O^{2-}) anions, taking into account the on-site Coulomb interactions on both the anions and the transition metal ions. The derived interactions in the spin-orbital model are strongly frustrated, with the strongest orbital interactions selecting different orbitals for pairs of Ni ions along the three different lattice directions. In the orbital ordered phase, favoured in mean field theory, the spin-orbital interaction can play an important role by breaking the U(1) symmetry generated by the much stronger orbital interaction and restoring the threefold symmetry of the lattice. As a result the effective magnetic exchange is non-uniform and includes both ferromagnetic and antiferromagnetic spin interactions. Since ferromagnetic interactions still dominate, this offers yet insufficient explanation for the absence of magnetic order and the low-temperature behaviour of the magnetic susceptibility of stoichiometric LiNiO_2. The scenario proposed to explain the observed difference in the physical properties of LiNiO_2 and NaNiO_2 includes small covalency of Ni-O-Li-O-Ni bonds inducing weaker interplane superexchange in LiNiO_2, insufficient to stabilize orbital long-range order in the presence of stronger intraplane competition between superexchange and Jahn-Teller coupling.Comment: 33 pages, 12 postscript figures, uses iopams.sty . This article features in New Journal of Physics as part of a Focus Issue on Orbital Physics - all contributions may be freely accessed at (http://stacks.iop.org/1367-2630/6/i=1/a=E05). The published version of this article may be found at http://stacks.iop.org/1367-2630/7/12

Evaluation of POSSUM for Patients Undergoing Pancreatoduodenectomy

Comparison of operative morbidity rates after pancreatoduodenectomy between units may be misleading because it does not take into account the physiological variable of the condition of the patients. The aim of the present study was to evaluate the Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity (POSSUM) for pancreatoduodenectomy patients and to look for risk factors associated with morbidity in a high-volume center. Between January 1993 and April 2006, 652 patients underwent a pancreatoduodenectomy, 502 of them for malignant disease. POSSUM performance was evaluated by assessing the "goodness-of-fit" with the linear analysis method. Overall, 332 of the 652 patients (50.9%) had one or more complication after pancreatoduodenectomy, and 9 patients (1.4%) died. POSSUM had a significant lack of fit using goodness-of-fit analysis. In multivariate analysis, one statistically significant factor associated with morbidity and not incorporated in POSSUM (P < 0.05) was identified: ampulla of Vater adenocarcinoma (OR = 1.73, 95% CI: 1.07-2.80). Overall, there is a lack of calibration of POSSUM among patients who undergo pancreatoduodenectom

Reference materials (RMs) for analysis of the human factor II (prothrombin) gene G20210A mutation

The Scientific Committee of Molecular Biology Techniques (C-MbT) in Clinical Chemistry of the IFCC has initiated a joint project in co-operation with the European Commission, Joint Research Centre, Institute of Reference Materials and Measurements to develop and produce plasmid-type reference materials (RMs), for the analysis of the human prothrombin gene G20210A mutation. Although DNA tests have a high impact on clinical decision-making and the number of tests performed in diagnostic laboratories is high, issues of quality and quality assurance exist, and currently only a few RMs for clinical genetic testing are available. A gene fragment chosen was produced that spans all primer annealing sites published to date. Both the wild-type and mutant alleles of this gene fragment were cloned into a pUC18 plasmid and two plasmid RMs were produced. In addition, a mixture of both plasmids was produced to mimic the heterozygous genotype. The present study describes the performance of these reference materials in a commutability study, in which they were tested by nine different methods in 13 expert laboratories.. This series of plasmid RMs are, to the best of our knowledge, the first plasmid-type clinical genetic RMs introduced worldwide

Endoscopic tri-modal imaging for surveillance in ulcerative colitis: randomised comparison of high-resolution endoscopy and autofluorescence imaging for neoplasia detection; and evaluation of narrow-band imaging for classification of lesions

Background: Endoscopic tri-modal imaging (ETMI) incorporates white light endoscopy (WLE), autofluorescence imaging (AFI) and narrow-band imaging (NBI). Aims: To assess the value of ETMI for the detection and classification of neoplasia in patients with longstanding ulcerative colitis. Design: Randomised comparative trial of tandem colonoscopies. Setting: Academic Medical Centre Amsterdam, Netherlands. Patients and methods: Fifty patients with ulcerative colitis underwent surveillance colonoscopy with ETMI. Each colonic segment was inspected twice, once with AFI and once with WLE, in random order. All detected lesions were inspected by NBI for Kudo pit pattern analysis and additional random biopsies were taken. Main outcome measures: Neoplasia miss-rates of AFI and WLE, and accuracy of the Kudo classification by NBI. Results: Among patients assigned to inspection with AFI first (n = 25), 10 neoplastic lesions were primarily detected. Subsequent WLE detected no additional neoplasia. Among patients examined with WLE first (n = 25), three neoplastic lesions were detected; subsequent inspection with AFI added three neoplastic lesions. Neoplasia miss-rates for AFI and WLE were 0% and 50% (p = 0.036). The Kudo classification by NBI had a sensitivity and specificity of 75% and 81%; however, all neoplasia was coloured purple on AFI (sensitivity 100%). No additional patients with neoplasia were detected by random biopsies. Conclusion: Autofluorescence imaging improves the detection of neoplasia in patients with ulcerative colitis and decreases the yield of random biopsies. Pit pattern analysis by NBI has a moderate accuracy for the prediction of histology, whereas AFI colour appears valuable in excluding the presence of neoplasia. Trial registration number: ISRCTN0527274

Attitudes towards the use and acceptance of eHealth technologies : a case study of older adults living with chronic pain and implications for rural healthcare

Acknowledgements The research described here is supported by the award made by the RCUK Digital Economy programme to the dot.rural Digital Economy Hub; award reference: EP/G066051/1. MC’s time writing the paper is funded by the Scottish Government’s Rural and Environmental Science and Analytical Services Division (RESAS) under Theme 8 ‘Vibrant Rural Communities’ of the Food, Land and People Programme (2011–2016). MC is also an Honorary Research Fellow at the Division of Applied Health Sciences, University of Aberdeen. The input of other members of the TOPS research team, Alastair Mort, Fiona Williams, Sophie Corbett, Phil Wilson and Paul MacNamee who contributed to be wider study and discussed preliminary findings reported here with the authors of the paper is acknowledged. We acknowledge the feedback on earlier versions of this paper provided by members of the Trans-Atlantic Rural Research Network, especially Stefanie Doebler and Carmen Hubbard. We also thank Deb Roberts for her comments.Peer reviewedPublisher PD

Developing serious games for cultural heritage: a state-of-the-art review

Although the widespread use of gaming for leisure purposes has been well documented, the use of games to support cultural heritage purposes, such as historical teaching and learning, or for enhancing museum visits, has been less well considered. The state-of-the-art in serious game technology is identical to that of the state-of-the-art in entertainment games technology. As a result, the field of serious heritage games concerns itself with recent advances in computer games, real-time computer graphics, virtual and augmented reality and artificial intelligence. On the other hand, the main strengths of serious gaming applications may be generalised as being in the areas of communication, visual expression of information, collaboration mechanisms, interactivity and entertainment. In this report, we will focus on the state-of-the-art with respect to the theories, methods and technologies used in serious heritage games. We provide an overview of existing literature of relevance to the domain, discuss the strengths and weaknesses of the described methods and point out unsolved problems and challenges. In addition, several case studies illustrating the application of methods and technologies used in cultural heritage are presented