Stephen Rice | PubMed Health

PubMed2006

Herpes simplex virus type 1 ICP27-dependent activation of NF-kappaB.

The ability of herpes simplex virus type 1 (HSV-1) to activate NF-kappaB has been well documented. Beginning at 3 to 5 h postinfection, HSV-1 induces a robust and persistent nuclear translocation of an NF-kappaB-dependent (p50/p65 heterodimer) DNA binding activity, as measured by electrophoretic mobility shift assay. Activation requires virus binding and entry, as well as de novo infected-cell protein synthesis, and is accompanied by loss of both IkappaBalpha and IkappaBbeta. In this study, we identified loss of IkappaBalpha as a marker of NF-kappaB activation, and infection with mutants with individual immediate-early (IE) regulatory proteins deleted indicated that ICP27 was necessary for IkappaBalpha loss. Analysis of both N-terminal and C-terminal mutants of ICP27 identified the region from amino acids 21 to 63 as being necessary for IkappaBalpha loss. Additional experiments with mutant viruses with combinations of IE genes deleted revealed that the ICP27-dependent mechanism of NF-kappaB activation may be augmented by functional ICP4. We also analyzed two additional markers for NF-kappaB activation, phosphorylation of the p65 subunit on Ser276 and Ser536. Phosphorylation of both serines was induced upon HSV infection and required functional ICP4 and ICP27. Pharmacological inhibitor studies revealed that both IkappaBalpha and Ser276 phosphorylation were dependent on Jun N-terminal protein kinase activity, while Ser536 phosphorylation was not affected during inhibitor treatment. These results demonstrate that there are several layers of regulation of NF-kappaB activation during HSV infection, highlighting the important role that NF-kappaB may play in infection.

Active Transport, Cell Nucleus↗

PubMed2005

Can economic evaluations be made more transferable?

Several commentators have identified the lack of generalisability and transferability of economic evaluation results. The aims of this study were: (a) to develop a checklist to assess the level of generalisability and transferability of economic evaluations; (b) to assess the generalisability and transferability of economic evaluations between the UK and France using the checklist; (c) to identify reasons for any lack of transferability and generalisability; (d) to assess how the transferability and generalisability of economic evaluations can be improved; and (e) to outline ways in which databases of economic evaluations and journals can assist in this area. The checklist was developed using previous work and the templates of the NHS EED and CODECS databases. A sub-checklist of essential items was then derived. Validation of the two checklists was undertaken with Health Economists participating in the EURONHEED project. Economic evaluations involving the UK and France were then located and assessed using the checklist. A summary score for each study was calculated based on the percentage of correctly reported (applicable) points, and the results in the empirical analysis compared to identify differences. The extended checklist includes 42 items, and the sub-checklist 16 items. Twenty-five economic evaluations met the inclusion criteria for the empirical analysis. In the extended checklist the mean score was 66.9+/-13.6%. The results for the sub-checklist were very similar. The analysis revealed that costing, assessments of generalisability by the author(s), assessment of data variability, discounting, study population, and the reporting of effectiveness are areas that need more attention. Differences in cost-effectiveness results are often accounted for by price or organisational differences. The developed checklists are useful in assessing the generalisability and transferability of economic evaluations. In order to improve the generalisability and transferability of economic evaluations authors need to be more explicit and detailed in describing and reporting their studies. If they are to provide added value to their users, international databases of economic evaluations should systematically assess the generalisability and transferability of studies. Further research is in progress on producing a weighted version of the checklist.

Cost-Benefit Analysis↗