Access of non-residents to transplantation of deceased donor organs: practices and strategies in the European setting.

The access of non-resident patients to the deceased donor waiting list (DDWL) poses different challenges. The European Committee on Organ Transplantation of the Council of Europe (CD-P-TO) has studied this phenomenon in the European setting. A questionnaire was circulated among the Council of Europe member states to inquire about the criteria applied for non-residents to access their DDWL. Information was compiled from 28 countries. Less than 1% of recipients of deceased donor organs were non-residents. Two countries never allow non-residents to access the DDWL, four allow access without restrictions and 22 only under specific conditions. Of those, most give access to non-resident patients already in their jurisdictions who are in a situation of vulnerability (urgent life-threatening conditions). In addition, patients may be given access: (i) after assessment by a specific committee (four countries); (ii) within the framework of official cooperation agreements (15 countries); and (iii) after patients have officially lived in the country for a minimum length of time (eight countries). The ethical and legal implications of these policies are discussed. Countries should collect accurate information about residency status of waitlisted patients. Transparent criteria for the access of non-residents to DDWL should be clearly defined at national level.

Decontamination of prions in a plasma product manufacturing environment.

BACKGROUND: The high resistance of prions to inactivating treatments requires the proper management of decontaminating procedures of equipment in contact with materials of human or animal origin destined for medical purposes. Sodium hydroxide (NaOH) is widely used today for this purpose as it inactivates a wide variety of pathogens including prions. STUDY DESIGN AND METHODS: Several NaOH treatments were tested on prions bound to either stainless steel or chromatographic resins in industrial conditions with multiple prion strains. RESULTS: Data show a strong correlation between inactivation results obtained by immunochemical detection of the prion protein and those obtained with infectivity assays and establish effective inactivation treatments for prions bound to stainless steel or chromatographic resins (ion exchange and affinity), including treatments with lower NaOH concentrations. Furthermore, no obvious strain-specific behavior difference was observed between experimental models. CONCLUSION: The results generated by these investigations show that industrial NaOH decontamination regimens (in combination with the NaCl elution in the case of the chromatography process) attain substantial prion inactivation and/or removal between batches, thus providing added assurance to the biologic safety of the final plasma-derived medicinal products.

Manufacture of plasma-derived products in France and measures to prevent the risk of vCJD transmission: precautionary measures and efficacy of manufacturing processes in prion removal.

The emergence of the variant Creutzfeldt-Jakob disease in the mid 1990s soon raised concerns about its possible transmission through the use of blood and plasma-derived medicinal products. A risk analysis approach was initiated by health authorities, based on updated scientific knowledge and precautionary measures were implemented in France and other countries for the management of this new possible risk. Assessment of the vCJD risk is based on epidemiology and estimates of the number of potential cases in the future, on blood infectivity data from models of transmissible spongiform encephalopathies and on data from studies of the capacity of manufacturing processes to remove the agent, should it be present in the plasma of infected donors. The transmission of vCJD by non leukocyte-depleted labile blood components has recently been confirmed. There have been no reports of cases associated with the use of plasma-derived products and the scientific data, and risk analyses for those plasma products, which are of the greatest therapeutic interest, support their safety with respect to this transmission risk. The precautionary measures applied in France and the data contributing to the risk assessment of plasma products are reviewed and updated in the present paper. The uncertainties, which remain, are also addressed and discussed, as well as the ongoing research and developments in this area.

Prion protein prevents human breast carcinoma cell line from tumor necrosis factor alpha-induced cell death.

To define genetic determinants of tumor cell resistance to the cytotoxic action of tumor necrosis factor alpha (TNF), we have applied cDNA microarrays to a human breast carcinoma TNF-sensitive MCF7 cell line and its established TNF-resistant clone. Of a total of 5760 samples of cDNA examined, 3.6% were found to be differentially expressed in TNF-resistant 1001 cells as compared with TNF-sensitive MCF7 cells. On the basis of available literature data, the striking finding is the association of some differentially expressed genes involved in the phosphatidylinositol-3-kinase/Akt signaling pathway. More notably, we found that the PRNP gene coding for the cellular prion protein (PrP(c)), was 17-fold overexpressed in the 1001 cell line as compared with the MCF7 cell line. This differential expression was confirmed at the cell surface by immunostaining that indicated that PrP(c) is overexpressed at both mRNA and protein levels in the TNF-resistant derivative. Using recombinant adenoviruses expressing the human PrP(c,) our data demonstrate that PrP(c) overexpression converted TNF-sensitive MCF7 cells into TNF-resistant cells, at least in part, by a mechanism involving alteration of cytochrome c release from mitochondria and nuclear condensation.