Biomedical subjects
Marc L Turner
Publications and source records attributed to Marc L Turner.
Managing the risk of transmission of variant Creutzfeldt Jakob disease by blood products.
Whereas plasma-derived clotting factor concentrates now have a very good safety record for not being infectious for lipid enveloped viruses, concern has arisen about the possibility that prion diseases might be transmitted by blood products. There is epidemiological evidence that classical sporadic Creutzfeld Jakob disease (CJD) is not transmitted by blood transfusion. There is now good evidence that the abnormal prion associated with variant CJD can be transmitted by transfusion of fresh blood components and infect recipients. To reduce the risk of the pathological prion in the UK infecting recipients of clotting factor concentrates, these are now only manufactured from imported plasma collected from countries where there has not been bovine spongiform encephalopathy (BSE) in cattle and the risk of variant CJD in the population is, therefore, considered negligible. The safety of these concentrates is also enhanced because prion protein is, to an appreciable extent, excluded by the manufacturing process from the final product. To help reduce the chance of prion transmission by fresh blood products, donations are leucodepleted, there is increasing use of imported fresh frozen plasma (especially for treating children) and potential donors, who have been recipients of blood since 1980 (the beginning of the BSE epidemic in cattle) are deferred.
Prospective epidemiologic study of the outcome and cost-effectiveness of antenatal screening to detect neonatal alloimmune thrombocytopenia due to anti-HPA-1a.
BACKGROUND: To assess the value of antenatal screening to detect neonatal alloimmune thrombocytopenia (NAIT) due to anti-HPA-1a, a prospective study was carried out to quantify the potential clinical benefits and determine whether screening would be cost-effective. STUDY DESIGN AND METHODS: An observational prospective controlled study was carried out on 26,506 pregnant women over 2 years. HPA-1a phenotyping was performed in the first trimester and women confirmed HPA-1a-negative were tested for anti-HPA-1a during pregnancy, at delivery, and 10 to 14 days after birth. Babies of HPA-1a-negative women were tested at delivery for thrombocytopenia and examined for signs of bleeding. Economic evaluation was undertaken on the basis of the data collected during the study. RESULTS: Twenty-five of 318 women (7.9%) had anti-HPA-1a detected for the first time. Eight women (43 per 100,000) gave birth to babies with NAIT, and 5 (27 per 100,000) had severe thrombocytopenia. Three babies had mild signs of bleeding, and no cases of intracranial hemorrhage (ICH) or fetal loss were detected. It is estimated that it would cost 60,596 pounds (98,771 US dollars) to detect a case of severe NAIT, where anti-HPA-1a has been identified for the first time, and 1,151,323 pounds (1,876,656 US dollars) to prevent a case of ICH, assuming that detection allowed successful intervention. CONCLUSIONS: Our data suggest that severe HPA-1a NAIT is underdiagnosed in the absence of routine antenatal screening. Serious bleeding complications and ICH, however, occur less frequently in first cases of NAIT than suspected from the literature, and the costs of screening and possible intervention must be balanced against the procedural risks.
Human cord blood-derived cells can differentiate into hepatocytes in the mouse liver with no evidence of cellular fusion.
BACKGROUND & AIMS: Studies have indicated that stem cells have unexpected plasticity and can differentiate down a multitude of nonhematopoietic cell lineages in rodents. Our aim was to identify whether human cord blood cells, which are a rich source of stem cells, would be able to differentiate into hepatocytes when infused into nonobese diabetic-severe combined immunodeficient (NOD-SCID) mice. We also wanted to test whether such differentiated cells were the result of cellular fusion or true stem cell transdifferentiation. METHODS: Unsorted mononuclear cell preparations of human cord blood were infused into sublethally irradiated NOD-SCID mice. After death, immunohistologic analysis of murine livers was performed using human specific hepatocyte, biliary, and endothelial markers. Fluorescent in situ hybridization (FISH) for mouse and human DNA was also performed. RESULTS: We show that human cord blood cells have the ability to engraft into NOD-SCID liver and become mature hepatocytes. We were unable to identify any biliary or endothelial differentiation. Furthermore, we do not detect any evidence of cell fusion in any of the human cells found in the mouse liver, suggesting that human cord blood cells are capable of true transdifferentiation into hepatocytes in vivo. CONCLUSIONS: We conclude that hepatocytes can derive from human cord blood cells when infused into NOD-SCID mice in the absence of fusion. The demonstration that human stem cell differentiation can occur in this murine model permits comprehensive study of human stem cell plasticity in vivo.
vCJD screening and its implications for transfusion--strategies for the future?
It remains unclear whether Creutzfeldt Jakob disease (CJD) can be transmitted by blood products. Peripheral blood infectivity is demonstrable in experimental animal transmissible spongiform encephalopathy models and has been transmitted via blood transfusion. However, in man, epidemiological case control, lookback and surveillance studies have failed to demonstrate any evidence of sporadic CJD transmission by blood transfusion. It cannot be assumed that variant CJD is not transmissible in this way because it is a different strain of disease, which is known to involve peripheral lymphoid tissues. There is no immune response to PrP(Sc) (pathogenic isoform of cellular prion protein PrP(C)) and no nucleic acid associated with infectivity has been identified; standard serological and molecular assays are therefore inapplicable. Surrogate markers for cerebral damage are unlikely to be useful for preclinical screening because they reflect the breakdown of the blood-brain barrier in advanced neurological disease. Alpha-haemoglobin stabilizing factor may provide a surrogate marker during the incubation phase. Most approaches to PrP(Sc) discrimination are based on the physicochemical characteristics of PrP(Sc); some are now approaching the specificity and sensitivity required. However, their validation and potential impact on the donor base remain to be resolved.
Comparative analysis of normal prion protein expression on human, rodent, and ruminant blood cells by using a panel of prion antibodies.
BACKGROUND: It is not known whether variant CJD can be transmitted within the human population by blood transfusion. The expression of normal cellular prion protein (PrPC) by different blood cell types may permit selective uptake and dissemination of infectivity. STUDY DESIGN AND METHODS: The normal distribution of PrPC on the major blood cell types of species known to be susceptible to natural or experimental transmissible spongiform encephalopathies was studied. Blood from healthy humans, mice, hamsters, cattle, and sheep was examined by flow cytometry by using a large panel of antibodies with different prion protein (PrP) epitope specificities to maximize the detection of PrP variants across species and cell type. RESULTS: PrP was detected on all major human blood cells types except eosinophils, but was not detected as ubiquitously or uniformly on major blood cell types of different animal species. CONCLUSION: Different animal species have unique patterns of expression of PrPC on blood cell types, with none equivalent to the human pattern. This needs to be considered when extrapolating from animal models of blood-borne transmissible spongiform encephalopathy infectivity, particularly in regard to the risk assessment of potential variant CJD spread within the human population. The relationship between PrP distribution and infectivity distribution in blood needs further investigation.