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W N Drohan - One of the best experts on this subject based on the ideXlab platform.
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further studies of blood Infectivity in an experimental model of transmissible spongiform encephalopathy with an explanation of why blood components do not transmit creutzfeldt jakob disease in humans
Transfusion, 1999Co-Authors: Paul Brown, Larisa Cervenakova, Lisa M Mcshane, P Barber, R Rubenstein, W N DrohanAbstract:BACKGROUND: Solid evidence from experimentally infected animals and fragmentary evidence from naturally infected humans indicate that blood may contain low levels of the infectious agent of Creutzfeldt-Jakob disease (CJD), yet blood components have never been identified as a cause of CJD in humans. STUDY DESIGN AND METHODS: Blood components and plasma fractions were prepared from the pooled blood of mice that had earlier been infected with a mouse-adapted strain of human transmissible spongiform encephalopathy (TSE). Infectivity bioassays were conducted in healthy mice, and the brains of all assay animals dying during the course of the experiments were examined for the presence of proteinase-resistant protein. RESULTS: Infectivity in the blood during the preclinical phase of disease occurred in the buffy coat at infectious unit (IU) levels between 6 and 12 per mL and was either absent or present in only trace amounts in plasma and plasma fractions. Infectivity rose sharply at the onset of clinical signs to levels of approximately 100 IU per mL of buffy coat, 20 IU per mL of plasma, 2 IU per mL of cryoprecipitate, and less than 1 IU per mL of fractions IV and V. Plasma Infectivity was not eliminated by either white cell-reduction filtration or high-speed centrifugation. Approximately seven times more plasma and five times more buffy coat were needed to transmit disease by the intravenous route than by the intracerebral route. CONCLUSION: Epidemiologic evidence of the absence in humans of disease transmission from plasma components can probably be explained by 1) the absence of significant plasma Infectivity until the onset of symptomatic disease, and comparatively low levels of Infectivity during the symptomatic stage of disease; 2) the reduction of Infectivity during plasma processing; and 3) the need for at least five to seven times more infectious agent to transmit disease by the intravenous than intracerebral route. These and other factors probably also account for the absence of transmission after the administration of whole blood or blood components.
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the distribution of Infectivity in blood components and plasma derivatives in experimental models of transmissible spongiform encephalopathy
Transfusion, 1998Co-Authors: Paul Brown, R G Rohwer, B C Dunstan, C Macauley, D C Gajdusek, W N DrohanAbstract:BACKGROUND: The administration of blood components from donors who subsequently develop Creutzfeldt-Jakob disease has raised the issue of blood as a possible vehicle for iatrogenic disease. STUDY DESIGN AND METHODS: We examined Infectivity in blood components and Cohn plasma fractions in normal human blood that had been “spiked” with trypsinized cells from a scrapie-infected hamster brain, and in blood of clinically ill mice that had been inoculated with a mouse-adapted strain of human transmissible spongiform encephalopathy. Infectivity was assayed by intracerebral inoculation of the blood specimens into healthy animals. RESULTS: Most of the Infectivity in spiked human blood was associated with cellular blood components; the smaller amount present in plasma, when fractionated, was found mainly in cryoprecipitate (the source of factor VIII) and fraction I+II+III (the source of fibrinogen and immunoglobulin); almost none was recovered in fraction IV (the source of vitamin-K-dependent proteins) and fraction V (the source of albumin). Mice infected with the human strain of spongiform encephalopathy had very low levels of endogenous Infectivity in buffy coat, plasma, cryoprecipitate, and fraction I+II+III, and no detectable Infectivity in fractions IV or V. CONCLUSION: Convergent results from exogenous spiking and endogenous Infectivity experiments, in which decreasing levels of Infectivity occurred in cellular blood components, plasma, and plasma fractions, suggest a potential but minimal risk of acquiring Creutzfeldt-Jakob disease from the administration of human plasma protein concentrates.
James W. Ironside - One of the best experts on this subject based on the ideXlab platform.
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detection of variant creutzfeldt jakob disease Infectivity in extraneural tissues
The Lancet, 2001Co-Authors: Moira E Bruce, I Mcconnell, R G Will, James W. IronsideAbstract:Summary Abnormal accumulations of prion protein (PrP) can be detected in the spleen, lymph nodes, and tonsils of patients with variant Creutzfeldt-Jakob disease (vCJD). Therefore, it has been assumed, but not shown, that these tissues harbour Infectivity, which in turn presents the potential for iatrogenic spread through surgery. Here, we show and measure levels of Infectivity in spleen and tonsil from two patients with vCJD, by bioassay in intracerebrally inoculated RIII mice. Similar bioassays failed to detect Infectivity in buffy coat and plasma.
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Oral infection by the bovine spongiform encephalopathy prion
Proceedings of the National Academy of Sciences of the United States of America, 1999Co-Authors: Robert G. Will, James W. IronsideAbstract:There is, however, variation in pathogenesis that is determined by factors including the interaction between host genome and agent strain. Some breeds of sheep affected by natural scrapie, for example, Montadales, have no detectable Infectivity in peripheral tissues, and the distribution of Infectivity in the brain may vary according to the breed of sheep (5). In bovine spongiform encephalopathy (BSE) Infectivity has not been detected in peripheral tissues in natural disease, except for dorsal root ganglia and possibly bone marrow, although Infectivity has been found in terminal ileum after experimental oral challenge with BSE brain (6). An important implication of this data is that, accepting the limits of the sensitivity of bioassay …
Paul Brown - One of the best experts on this subject based on the ideXlab platform.
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removal of exogenous spiked and endogenous prion Infectivity from red cells with a new prototype of leukoreduction filter
Transfusion, 2005Co-Authors: Samuel O Sowemimocoker, Regina Kascsak, Fabiola Andrade, Susan Pesci, Clifford Meeker, Richard I Carp, Paul BrownAbstract:BACKGROUND: Two recent probable cases of transmission of a variant of human Creutzfeldt-Jakob disease (vCJD) through blood transfusion suggest that the disease can be transmitted through transfusion of blood components from presymptomatic blood donors. In the absence of a preclinical screening test, removal of the infectious agent by processing is the only means by which risk to recipients of blood from donors with inapparent vCJD infections can be eliminated. STUDY DESIGN AND METHODS: In the endogenous Infectivity study, a pool of 500 mL of whole blood was collected into CP2D anticoagulant from 263K-strain scrapie-infected hamsters, processed into 300 mL of red cells (RBCs), and then passed through a prion removal filter. Pre- and postfiltration samples were tested for PrPsc by Western blot and for Infectivity by inoculation of healthy hamsters. In the exogenous (spiking) Infectivity study, 30 mL of 10 percent (wt/vol) scrapie-infected brain homogenates was added to 270 mL of human RBCs and then filtered. Levels of PrPsc and Infectivity were determined by Western blot and bioassay. RESULTS: In the endogenous Infectivity study, the prefiltered RBCs transmitted disease to 6 of 43 animals, whereas the postfiltered RBCs did not transmit disease to any of 35 animals, and a barely visible prefiltration PrPsc Western blot signal was reduced below the level of detection in the postfiltration sample. In the exogenous (spike) study, Infectivity was reduced by 3.7 log LD50 per mL, from 9.2 to 5.5 log LD50 per mL. CONCLUSION: The new filter was effective in removing both Infectivity and PrPsc from RBCs. The use of this type of filter should reduce the risk of vCJD transmission through blood transfusion.
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further studies of blood Infectivity in an experimental model of transmissible spongiform encephalopathy with an explanation of why blood components do not transmit creutzfeldt jakob disease in humans
Transfusion, 1999Co-Authors: Paul Brown, Larisa Cervenakova, Lisa M Mcshane, P Barber, R Rubenstein, W N DrohanAbstract:BACKGROUND: Solid evidence from experimentally infected animals and fragmentary evidence from naturally infected humans indicate that blood may contain low levels of the infectious agent of Creutzfeldt-Jakob disease (CJD), yet blood components have never been identified as a cause of CJD in humans. STUDY DESIGN AND METHODS: Blood components and plasma fractions were prepared from the pooled blood of mice that had earlier been infected with a mouse-adapted strain of human transmissible spongiform encephalopathy (TSE). Infectivity bioassays were conducted in healthy mice, and the brains of all assay animals dying during the course of the experiments were examined for the presence of proteinase-resistant protein. RESULTS: Infectivity in the blood during the preclinical phase of disease occurred in the buffy coat at infectious unit (IU) levels between 6 and 12 per mL and was either absent or present in only trace amounts in plasma and plasma fractions. Infectivity rose sharply at the onset of clinical signs to levels of approximately 100 IU per mL of buffy coat, 20 IU per mL of plasma, 2 IU per mL of cryoprecipitate, and less than 1 IU per mL of fractions IV and V. Plasma Infectivity was not eliminated by either white cell-reduction filtration or high-speed centrifugation. Approximately seven times more plasma and five times more buffy coat were needed to transmit disease by the intravenous route than by the intracerebral route. CONCLUSION: Epidemiologic evidence of the absence in humans of disease transmission from plasma components can probably be explained by 1) the absence of significant plasma Infectivity until the onset of symptomatic disease, and comparatively low levels of Infectivity during the symptomatic stage of disease; 2) the reduction of Infectivity during plasma processing; and 3) the need for at least five to seven times more infectious agent to transmit disease by the intravenous than intracerebral route. These and other factors probably also account for the absence of transmission after the administration of whole blood or blood components.
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the distribution of Infectivity in blood components and plasma derivatives in experimental models of transmissible spongiform encephalopathy
Transfusion, 1998Co-Authors: Paul Brown, R G Rohwer, B C Dunstan, C Macauley, D C Gajdusek, W N DrohanAbstract:BACKGROUND: The administration of blood components from donors who subsequently develop Creutzfeldt-Jakob disease has raised the issue of blood as a possible vehicle for iatrogenic disease. STUDY DESIGN AND METHODS: We examined Infectivity in blood components and Cohn plasma fractions in normal human blood that had been “spiked” with trypsinized cells from a scrapie-infected hamster brain, and in blood of clinically ill mice that had been inoculated with a mouse-adapted strain of human transmissible spongiform encephalopathy. Infectivity was assayed by intracerebral inoculation of the blood specimens into healthy animals. RESULTS: Most of the Infectivity in spiked human blood was associated with cellular blood components; the smaller amount present in plasma, when fractionated, was found mainly in cryoprecipitate (the source of factor VIII) and fraction I+II+III (the source of fibrinogen and immunoglobulin); almost none was recovered in fraction IV (the source of vitamin-K-dependent proteins) and fraction V (the source of albumin). Mice infected with the human strain of spongiform encephalopathy had very low levels of endogenous Infectivity in buffy coat, plasma, cryoprecipitate, and fraction I+II+III, and no detectable Infectivity in fractions IV or V. CONCLUSION: Convergent results from exogenous spiking and endogenous Infectivity experiments, in which decreasing levels of Infectivity occurred in cellular blood components, plasma, and plasma fractions, suggest a potential but minimal risk of acquiring Creutzfeldt-Jakob disease from the administration of human plasma protein concentrates.
Robert G Rohwer - One of the best experts on this subject based on the ideXlab platform.
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reduction in Infectivity of endogenous transmissible spongiform encephalopathies present in blood by adsorption to selective affinity resins
The Lancet, 2006Co-Authors: Luisa Gregori, Patrick V Gurgel, Julia Tait Lathrop, Peter A D Edwardson, Brian C Lambert, Ruben G Carbonell, Steven J Burton, David J Hammond, Robert G RohwerAbstract:Summary Background Transmissible spongiform encephalopathies (TSE) can be contracted through blood transfusion. Selective adsorption of the causative agent from donated blood might be one of the best ways of managing this risk. In our study, affinity resin L13, which reduces brain-derived Infectivity spiked into human red blood cell concentrate by around 4 log 10 ID 50 , and its equivalent, L13A, produced on a manufacturing scale, were assessed for their ability to remove TSE Infectivity endogenously present in blood. Methods 500 mL of scrapie-infected hamster whole blood was leucoreduced at full scale before passage through the affinity resins. Infectivity of whole blood, leucoreduced whole blood (challenge), and the recovered blood from each flow-through was measured by limiting dilution titration. Findings Leucoreduction removed 72% of input Infectivity. 15 of 99 animals were infected by the challenge, whereas none of the 96 or 100 animals inoculated with the final flow-throughs from either resin developed the disease after 540 days. The limit of detection of the bioassay was 0·2 infectious doses per mL. The overall reduction of the challenge Infectivity was more than 1·22 log 10 ID. The results showed removal of endogenous TSE Infectivity from leucoreduced whole blood by affinity ligands. The same resins adsorb normal and abnormal prion protein from human infections with variant, sporadic, and familial Creutzfeldt-Jakob disease, in the presence of blood components. Interpretation TSE affinity ligands, when incorporated into appropriate devices, can be used to mitigate the risks from TSE-infected blood, blood products, and other materials exposed to TSE Infectivity.
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effectiveness of leucoreduction for removal of Infectivity of transmissible spongiform encephalopathies from blood
The Lancet, 2004Co-Authors: Luisa Gregori, Nancy Mccombie, D S Palmer, Paul Birch, Samuel O Sowemimocoker, Antonio Giulivi, Robert G RohwerAbstract:In 1999, the UK implemented universal leucoreduction as a precaution against transmission of variant Creutzfeldt-Jakob disease by transfusion of domestic blood or red blood cells. We aimed to assess how effectively leucoreduction reduced Infectivity of transmissible spongiform encephalopathies (TSEs) in blood. 450 mL of whole blood collected and pooled from scrapie-infected hamsters was leucoreduced with a commercial filter. Blood cell concentrations were quantified, and Infectivity titres measured. Blood cell recovery and white blood cell removal complied with American Association of Blood Banks standards. Leucofiltration removed 42% (SD 12) of the total TSE Infectivity in endogenously infected blood. Leucoreduction is necessary for the removal of white-cell-associated TSE Infectivity from blood; however, it is not, by itself, sufficient to remove all blood-borne TSE Infectivity.
Moira E Bruce - One of the best experts on this subject based on the ideXlab platform.
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detection of variant creutzfeldt jakob disease Infectivity in extraneural tissues
The Lancet, 2001Co-Authors: Moira E Bruce, I Mcconnell, R G Will, James W. IronsideAbstract:Summary Abnormal accumulations of prion protein (PrP) can be detected in the spleen, lymph nodes, and tonsils of patients with variant Creutzfeldt-Jakob disease (vCJD). Therefore, it has been assumed, but not shown, that these tissues harbour Infectivity, which in turn presents the potential for iatrogenic spread through surgery. Here, we show and measure levels of Infectivity in spleen and tonsil from two patients with vCJD, by bioassay in intracerebrally inoculated RIII mice. Similar bioassays failed to detect Infectivity in buffy coat and plasma.