Xenotransplantation public perceptions: rather cells than organs.

The aim of this study was to describe some of the factors that might play a role in influencing attitude to xenotransplantation: first, the consideration of receiving cells and tissue from xenotransplants in relation to whole xeno-organs; secondly, the fact that there is greater uncertainty regarding the result and risk of infection associated with xenotransplantation than with allotransplantation. We also describe the attitude to research on xenotransplantation, and the relationship between the attitude to receiving a xenotransplant and an allotransplant. Finally, we describe the attitude to xenotransplantation in relation to treatment for renal failure and waiting-time for allotransplantation. A questionnaire was sent to randomly selected members of the public aged 18 to 75 (n=1000) and to all patients in the same age range who were waiting for kidney transplants in Sweden in the spring of 1998 (n=460). The response rate was 60% among the public and 87% among the patients. Both study groups were positive to a greater extent in their attitude to receiving cells and tissue than to receiving a whole organ such as a kidney. The response `rather positive' to receiving organs was generally favored by the public, whereas the most generally favored response to receiving cells and tissue was `very positive'. When there was suggested to be a greater uncertainty regarding the outcome with xenotransplantation compared with allotransplantation, the number of negative and uncertain respondents increased, both among the public and the patients. Eighty percent of the public and about 90% of the patients were in favor of continued research on xenotransplantation. Of those members of the public who responded, the attitude to receiving an organ from a human was positive in 86% of cases, with an emphasis on `very positive'. There was a moderate relation between the attitude to receiving an organ from a human and to receiving a xenotransplant. Among the patients, there was no systematic or strong relation between the attitude to xenotransplantation and the kind of dialysis treatment they were on. Neither was there any systematic or strong relation to the waiting-time. The overall impression is that the attitude to xenotransplantation seems to be most influenced by whether the xenotransplant would involve whole organs or cells and uncertainty regarding the outcome

Site-Selective Orbital Interactions in an Ultrathin Iron-Carbene Photosensitizer Film

We present the first experimental study of the frontier orbitals in an ultrathin film of the novel hexa-carbene photosensitizer [Fe(btz)3]3+, where btz is 3,3′-dimethyl-1,1′-bis(p-tolyl)-4,4′-bis(1,2,3-triazol-5-ylidene). Resonant photoelectron spectroscopy (RPES) was used to probe the electronic structure of films where the molecular and oxidative integrities had been confirmed with optical and X-ray spectroscopies. In combination with density functional theory calculations, RPES measurements provided direct and site-selective information about localization and interactions of occupied and unoccupied molecular orbitals. Fe 2p, N 1s, and C 1s measurements selectively probed the metal, carbene, and side-group contributions revealing strong metal–ligand orbital mixing of the frontier orbitals. This helps explain the remarkable photophysical properties of iron-carbenes in terms of unconventional electronic structure properties and favorable metal–ligand bonding interactions—important for the continued development of these type of complexes toward light-harvesting and light-emitting applications

Diverse Bone Morphogenetic Protein Expression Profiles and Smad Pathway Activation in Different Phenotypes of Experimental Canine Mammary Tumors

BACKGROUND:BMPs are currently receiving attention for their role in tumorigenesis and tumor progression. Currently, most BMP expression studies are performed on carcinomas, and not much is known about the situation in sarcomas. METHODOLOGY/PRINCIPAL FINDINGS:We have investigated the BMP expression profiles and Smad activation in clones from different spontaneous canine mammary tumors. Spindle cell tumor and osteosarcoma clones expressed high levels of BMPs, in particular BMP-2, -4 and -6. Clones from a scirrhous carcinoma expressed much lower BMP levels. The various clones formed different tumor types in nude mice but only clones that expressed high levels of BMP-6 gave bone formation. Phosphorylated Smad-1/5, located in the nucleus, was detected in tumors derived from clones expressing high levels of BMPs, indicating an active BMP signaling pathway and BMP-2 stimulation of mammary tumor cell clones in vitro resulted in activation of the Smad-1/5 pathway. In contrast BMP-2 stimulation did not induce phosphorylation of the non-Smad pathway p38 MAPK. Interestingly, an increased level of the BMP-antagonist chordin-like 1 was detected after BMP stimulation of non-bone forming clones. CONCLUSIONS/SIGNIFICANCE:We conclude that the specific BMP expression repertoire differs substantially between different types of mammary tumors and that BMP-6 expression most probably has a biological role in bone formation of canine mammary tumors

Validation of Plasmodium falciparum dUTPase as the target of 5'-tritylated deoxyuridine analogues with anti-malarial activity

BACKGROUND: Malaria remains as a major global problem, being one of the infectious diseases that engender highest mortality across the world. Due to the appearance of resistance and the lack of an effective vaccine, the search of novel anti-malarials is required. Deoxyuridine 5'-triphosphate nucleotido-hydrolase (dUTPase) is responsible for the hydrolysis of dUTP to dUMP within the parasite and has been proposed as an essential step in pyrimidine metabolism by providing dUMP for thymidylate biosynthesis. In this work, efforts to validate dUTPase as a drug target in Plasmodium falciparum are reported. METHODS: To investigate the role of PfdUTPase in cell survival different strategies to generate knockout mutants were used. For validation of PfdUTPase as the intracellular target of four inhibitors of the enzyme, mutants overexpressing PfdUTPase and HsdUTPase were created and the IC50 for each cell line with each compound was determined. The effect of these compounds on dUTP and dTTP levels from P. falciparum was measured using a DNA polymerase assay. Detailed localization studies by indirect immunofluorescence microscopy and live cell imaging were also performed using a cell line overexpressing a Pfdut-GFP fusion protein. RESULTS:Different attempts of disruption of the dut gene of P. falciparum were unsuccessful while a 3' replacement construct could recombine correctly in the locus suggesting that the enzyme is essential. The four 5'-tritylated deoxyuridine analogues described are potent inhibitors of the P. falciparum dUTPase and exhibit antiplasmodial activity. Overexpression of the Plasmodium and human enzymes conferred resistance against selective compounds, providing chemical validation of the target and confirming that indeed dUTPase inhibition is involved in anti-malarial activity. In addition, incubation with these inhibitors was associated with a depletion of the dTTP pool corroborating the central role of dUTPase in dTTP synthesis. PfdUTPase is mainly localized in the cytosol. CONCLUSION: These results strongly confirm the pivotal and essential role of dUTPase in pyrimidine biosynthesis of P. falciparum intraerythrocytic stages

Forecasting drug utilization and expenditure in a metropolitan health region

<p>Abstract</p> <p>Background</p> <p>New pharmacological therapies are challenging the healthcare systems, and there is an increasing need to assess their therapeutic value in relation to existing alternatives as well as their potential budget impact. Consequently, new models to introduce drugs in healthcare are urgently needed. In the metropolitan health region of Stockholm, Sweden, a model has been developed including early warning (horizon scanning), forecasting of drug utilization and expenditure, critical drug evaluation as well as structured programs for the introduction and follow-up of new drugs. The aim of this paper is to present the forecasting model and the predicted growth in all therapeutic areas in 2010 and 2011.</p> <p>Methods</p> <p>Linear regression analysis was applied to aggregate sales data on hospital sales and dispensed drugs in ambulatory care, including both reimbursed expenditure and patient co-payment. The linear regression was applied on each pharmacological group based on four observations 2006-2009, and the crude predictions estimated for the coming two years 2010-2011. The crude predictions were then adjusted for factors likely to increase or decrease future utilization and expenditure, such as patent expiries, new drugs to be launched or new guidelines from national bodies or the regional Drug and Therapeutics Committee. The assessment included a close collaboration with clinical, clinical pharmacological and pharmaceutical experts from the regional Drug and Therapeutics Committee.</p> <p>Results</p> <p>The annual increase in total expenditure for prescription and hospital drugs was predicted to be 2.0% in 2010 and 4.0% in 2011. Expenditures will increase in most therapeutic areas, but most predominantly for antineoplastic and immune modulating agents as well as drugs for the nervous system, infectious diseases, and blood and blood-forming organs.</p> <p>Conclusions</p> <p>The utilisation and expenditure of drugs is difficult to forecast due to uncertainties about the rate of adoption of new medicines and various ongoing healthcare reforms and activities to improve the quality and efficiency of prescribing. Nevertheless, we believe our model will be valuable as an early warning system to start developing guidance for new drugs including systems to monitor their effectiveness, safety and cost-effectiveness in clinical practice.</p

Kidneys from marginal donors: views of patients on informed consent.

BACKGROUND:Considering the fact that donor age is a major risk factor for graft survival, and taking into account the importance attached to the principle of autonomy in the Swedish Health Care Law, we decided that allocation of kidneys from marginal donors should be restricted to patients who have given their informed consent. Written information was given to the patients on the waiting list for kidney transplantation in the southern part of Sweden. Patients were asked to state whether they would accept either a single kidney or dual transplantation kidneys from marginal donors. The aim of this study was to investigate the views of patients on the information they received about kidneys from marginal donors and their reaction to being asked to make a decision on this issue. METHODS:A questionnaire was posted to 61 patients who had already replied to the question of whether or not they would accept kidneys from a marginal donor for themselves. The median age of the patients was 52 years (range 22-74 years). Answers were given anonymously. RESULTS:Among the 53 respondents, 48 considered the information to be comprehensible. The extent of the information was considered sufficient by 43 patients. No patient thought that the information was too extensive. According to 41 patients, it is totally right to be asked to make a decision on this type of issue. Two patients thought it was totally wrong. Finally, 33 patients thought it was easy to make a decision on this issue. CONCLUSIONS:This study indicates that patients on the waiting list for kidney transplantation accept information on donor-related risk factors and most patients want to be involved in the decision concerning transplantation with a kidney from a marginal donor

Tissue reactions to polyethylene implants with different surface topography

This study investigates the importance of implant surface topography on soft tissue response. The tissue response in the rat abdominal wall to discs of low density polyethylene with smooth to coarse surfaces was evaluated after one, six or 12 weeks. Capsule thickness and immunohistochemical quantification of monocytes-macrophages were used as measures. The macrophage specific antibody ED1 was used for identification of newly recruited macrophages and the ED2 antibody for the mature tissue macrophages. The smoother surfaces gave a thicker capsule than the rougher surfaces, and at one week also larger total numbers of cells and ED1 positive macrophages at interface. The capsule thickness increased over time for the smooth and intermediate surface topographies. In contrast, the cell numbers generally decreased over time. In conclusion, a coarse surface elicited lesser tissue reaction compared with a smooth surface