PRODUCT Source Plasma. Recall # B-1751-10 CODE Units: 4940074276, 4940073715, 4940071471, 4940069659, 4940069033, 4940067949, 4940067284, 4940066697, 4940066186, 4940065501, 4940065059, 4940064400, 4940063689, 4940063201, 4940062301, 4940061045, 4940060118, 4940059432, 4940058612, 4940058035, 4940057327, 4940056944, 4940056102, 4940055531, 4940054916, 4940054377, 4940053585, 4940053352, 4940052476, 4940052053, 4940049911, 4940049641, 4940049033, 4940048708, 4940048167, 4940047623, 4940047193, 4940046601, 4940042440, 4940041959, 4940041499, 4940041081, 4940040644, 4940040281, 4940039741, 4940039321, 4940038905, 4940038496, 4940038086, 4940037701, 4940037068, 4940036329, 4940035745, 4940035507, 4940034949, 4940034585, 4940034066, 4940033784, 4940033321, 4940032928, 4940032509, 4940031829, 4940031581, 4940031046, 4940030789, 4940030315, 4940030001, 4940029514, 4940029296, 4940028529, 4940021502, 4940021131, 4940020946, 4940020482, 4940020217, 4940019234, 4940016753, 4940016190, 4940014889, 4940014693, 4940014270, 4940013994, 4940013711, 4940013405, 4940013024, 4940012532, 4940012060, 4940011866, 4940011351, 4940011205, 4940010801, 4940010451, 4940010120, 4940009762, 4940009437, 4940009264, 4940008972, 4940008801, 4940008451, 4940008262, 4940007933, 4940007763, 4940007371, 4940007289, 4940006944, 4940006904, 4940006543, 4940004253, 4940003913, 4940003525, 4940003400, 4940003161, 4940003016, 4940002791, 4940002646, 4940002380, 4940002307, 4940001986, 4940001797, 4940001533, 4940000538, 4940000373
RECALLING FIRM/MANUFACTURER Recalling Firm: ZLB Plasma Inc., Boca Raton, FL, by fax on April 22, 2008. Manufacturer: ZLB Plasma Inc., Hamilton, OH. Firm initiated recall is complete.
REASON Blood products, collected from a donor considered to be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE 122 units DISTRIBUTION IL, NC
___________________________________
PRODUCT Red Blood Cells Leukocytes Reduced. Recall # B-1899-10 CODE Unit: W043210006492 RECALLING FIRM/MANUFACTURER Blood Assurance, Inc., Chattanooga, TN, by telephone on March 31, 2010. Firm initiated recall is complete.
REASON Blood product, collected from a donor considered to be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), was distributed.
VOLUME OF PRODUCT IN COMMERCE 1 unit DISTRIBUTION GA
___________________________________
END OF ENFORCEMENT REPORT FOR AUGUST 4, 2010
#
http://www.fda.gov/Safety/Recalls/EnforcementReports/ucm221345.htmPRODUCT Source Plasma, For Manufacturing Use Only. Recall # B-2050-10 CODE Units: FD0352541, FD0353287, FD0353501, FD0354000, FD0354230, FD0354726, FD0354938, FD0356975, FD0357302, FD0360235, FD0362117, FD0362267, FD0362670, FD0362917, FD0363328, FD0363526, FD0363892, FD0364098, FD0364535, FD0364753, FD0365175, FD0378255, FD0378534, FD0379225, FD0379524 RECALLING FIRM/MANUFACTURER DCI Biologicals LLC, Farmington, NM, by fax dated August 10, 2009.
Firm initiated recall is complete.
REASON Blood products, collected from a donor who was at risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE 25 units DISTRIBUTION NC, NY
___________________________________
PRODUCT Fresh Frozen Plasma. Recall # B-1985-10 CODE Unit: W037709092267 RECALLING FIRM/MANUFACTURER Hoxworth Blood Center UC Medical Center, Cincinnati, OH, by telephone on January 26, 2010. Firm initiated recall is complete.
REASON Blood product, collected from a donor who was at risk for variant Creutzfeldt-Jakob Disease (vCJD), was distributed.
VOLUME OF PRODUCT IN COMMERCE 1 unit DISTRIBUTION OH
___________________________________
END OF ENFORCEMENT REPORT FOR AUGUST 11, 2010
#
http://www.fda.gov/Safety/Recalls/EnforcementReports/ucm222069.htmBlood product, collected from a donors possibly at increased risk for vCJD only, was distributed USA JULY 2010
PRODUCT 1) Red Blood Cells Leukocytes Reduced. Recall # B-1432-10; 2) Recovered Plasma. Recall # B-1433-10 CODE 1) and 2) Units: X73159; X48910 RECALLING FIRM/MANUFACTURER Blood Assurance Inc., Chattanooga, TN, by fax on September 15, 2009, September 29, 2009 and September 30, 2009. Firm initiated recall is complete.
REASON Blood products, collected from a donor considered to be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE 4 units DISTRIBUTION TN, GA, Korea
___________________________________
PRODUCT 1) Red Blood Cells Leukocytes Reduced. Recall # B-1720-10; 2) Recovered Plasma. Recall # B-1721-10 CODE 1) and 2) Unit: GP53048 RECALLING FIRM/MANUFACTURER Blood Bank Of San Bernardino and Riverside Counties, San Bernardino, CA, by letter and email on February 19, 2010. Firm initiated recall is complete.
REASON Blood products, collected from a donor considered to be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE 2 units DISTRIBUTION CA, Austria
___________________________________
PRODUCT Recovered Plasma. Recall # B-1769-10 CODE Unit: P87454 RECALLING FIRM/MANUFACTURER Tacoma Pierce County Blood Bank, Tacoma, WA, by electronic notification on April 9, 2010. Firm initiated recall is complete.
REASON Blood product, collected from a donor who was at risk for variant Creutzfeldt-Jakob Disease (vCJD), was distributed.
VOLUME OF PRODUCT IN COMMERCE 1 unit DISTRIBUTION Switzerland
___________________________________
PRODUCT Recovered Plasma. Recall # B-1833-10 CODE Unit: W036509031626 RECALLING FIRM/MANUFACTURER LifeShare Blood Centers, Alexandria, LA, by e-mail on February 18, 2010. Firm initiated recall is complete.
REASON Blood product, collected from a donor considered to be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), was distributed.
VOLUME OF PRODUCT IN COMMERCE 1 unit DISTRIBUTION Switzerland
___________________________________
PRODUCT 1) Plasma Frozen. Recall # B-1838-10; 2) Red Blood Cells. Recall # B-1839-10; 3) Fresh Frozen Plasma. Recall # B-1840-10 CODE 1) Units: W038509801565; W038508331750; 2) Units: W038509801565; W038508331750; 4133133; 3) Unit: 4133133 RECALLING FIRM/MANUFACTURER Walter L. Shepeard Community Blood Center, Inc., Augusta, GA, by fax on October 9, 2009. Firm initiated recall is complete.
REASON Blood products, collected from a donor considered to be at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE 6 units DISTRIBUTION GA, SC
___________________________________
END OF ENFORCEMENT REPORT FOR JULY 28, 2010
http://www.fda.gov/Safety/Recalls/EnforcementReports/ucm220487.htmPRODUCT 1) Recovered Plasma. Recall # B-1772-10; 2) Red Blood Cells Leukocytes Reduced. Recall # B-1773-10; 3) Fresh Frozen Plasma. Recall # B-1774-10 CODE 1) Unit: 6174086; 2) Units: 6205935, 6174086, 6142542; 3) Units: 6205935, 6142542 RECALLING FIRM/MANUFACTURER South Texas Blood and Tissue Center, San Antonio, TX, by facsimile on September 29, 2009, October 6, 2009, November 3, 2009, and November 4, 2009. Firm initiated recall is complete.
REASON Blood products, collected from a donor who was at risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE 6 units DISTRIBUTION Austria, TX
___________________________________
PRODUCT 1) Red Blood Cells Leukocytes Reduced. Recall # B-1826-10; 2) Platelets. Recall # B-1827-10; 3) Plasma Frozen. Recall # B-1828-10 CODE 1), 2) and 3) Unit: P51128 RECALLING FIRM/MANUFACTURER Blood Assurance Inc., Chattanooga, TN, by facsimile on January 27, 2010. Firm initiated recall is complete.
REASON Blood products collected from a donor who may have warranted deferral for residency in an area at risk for Creutzfeldt-Jakob Disease (vCJD) were distributed.
VOLUME OF PRODUCT IN COMMERCE 3 units DISTRIBUTION TN, GA
___________________________________
END OF ENFORCEMENT REPORT FOR JULY 21, 2010
http://www.fda.gov/Safety/Recalls/EnforcementReports/ucm219893.htmPRODUCT 1) Red Blood Cells Leukocytes Reduced. Recall # B-1683-10; 2) Plasma Frozen. Recall # B-1684-10 CODE 1) and 2) Unit: 9352826 RECALLING FIRM/MANUFACTURER Blood Centers of the Pacific - Irwin Center, San Francisco, CA, by telephone on February 22, 2010. Firm initiated recall is complete.
REASON Unit: Blood products, collected from a donor who was at risk for variant Creutzfeldt-Jakob Disease (vCJD), were distributed.
VOLUME OF PRODUCT IN COMMERCE 2 units DISTRIBUTION CA
___________________________________
PRODUCT Red Blood Cells Leukocytes Reduced. Recall # B-1736-10 CODE Unit: W038110023096 RECALLING FIRM/MANUFACTURER Florida's Blood Centers, Inc, Orlando, FL, by telephone on January 21, 2010. Firm initiated recall is complete.
REASON Blood product, collected from a donor possibly at increased risk for variant Creutzfeldt-Jakob Disease (vCJD), was distributed.
VOLUME OF PRODUCT IN COMMERCE 1 unit DISTRIBUTION FL
___________________________________
END OF ENFORCEMENT REPORT FOR JULY 14, 2010
http://www.fda.gov/Safety/Recalls/EnforcementReports/ucm219025.htmFC5.1.1
Transmission Results in Squirrel Monkeys Inoculated with Human sCJD, vCJD, and GSS Blood Specimens: the Baxter Study
Brown, P1; Gibson, S2; Williams, L3; Ironside, J4; Will, R4; Kreil, T5; Abee, C3 1Fondation Alliance BioSecure, France; 2University of South Alabama, USA; 3University of Texas MD Anderson Cancer Center, USA; 4Western General Hospital, UK; 5Baxter BioSience, Austria
Background: Rodent and sheep models of Transmissible Spongiform Encephalopathy (TSE) have documented blood infectivity in both the pre-clinical and clinical phases of disease. Results in a (presumably more appropriate) non-human primate model have not been reported.
Objective: To determine if blood components (red cells, white cells, platelets, and plasma) from various forms of human TSE are infectious. Methods: Blood components were inoculated intra-cerebrally (0.1 ml) and intravenously (0.5 ml) into squirrel monkeys from 2 patients with sporadic Creutzfeldt- Jakob disease (sCJD) and 3 patients with variant Creutzfeldt-Jakob disease (vCJD). Additional monkeys were inoculated with buffy coat or plasma samples from chimpanzees infected with either sCJD or Gerstmann-Sträussler-Scheinker disease (GSS). Animals were monitored for a period of 5 years, and all dying or sacrificed animals had post-mortem neuropathological examinations and Western blots to determine the presence or absence of the misfolded 'prion' protein (PrPTSE).
Results: No transmissions occurred in any of the animals inoculated with blood components from patients with sporadic or variant CJD. All donor chimpanzees (sCJD and GSS) became symptomatic within 6 weeks of their pre-clinical phase plasmapheresis, several months earlier than the expected onset of illness.
One monkey inoculated with purified leukocytes from a pre-clinical GSS chimpanzee developed disease after 36 months.
Conclusion: No infectivity was found in small volumes of blood components from 4 patients with sporadic CJD and 3 patients with variant CJD.
However, a single transmission from a chimpanzee-passaged strain of GSS shows that infectivity may be present in leukocytes, and the 'shock' of general anaesthesia and plasmspheresis appears to have triggered the onset of illness in pre-clinical donor chimpanzees.
FC5.1.2
Interim Transmission Results in Cynomolgus Macaques Inoculated with BSE and vCJD Blood Specimens
Lasmezas, C1; Lescoutra, N2; Comoy, E2; Holznagel, E3; Loewer, J3; Motzkus, D4; Hunsmann, G4; Ingrosso, L5; Bierke, P6; Pocchiari, M5; Ironside, J7; Will, R7; Deslys, JP2 1Scripps Florida, Infectology, USA; 2CEA, France; 3PEI, Germany; 4DPZ, Germany; 5Istituto Superiore di Sanita, Italy; 6SMI, Sweden; 7CJD Surveillance Unit, UK
BSE and vCJD transmitted to cynomolgus macaques reproduce many features of human vCJD, including clinical symptoms, neuropathological hallmarks of vCJD, PrPres electrophoretical pattern and, most importantly, the wide distribution of infectivity in peripheral organs. The latter characteristic distinguishes vCJD from sCJD in both humans and cynomolgus macaques, and prompted us to use this non-human primate model for further investigations of vCJD and its risk for human health. The occurrence of four vCJD infections in humans transfused with blood from patients who later developed vCJD has raised concern about blood transfusion safety in countries with vCJD.
In this collaborative European study, we investigated the infectivity of blood components and whole blood administered by intracerebral (ic) and intravenous (iv) routes. Buffy-coat and whole blood was inoculated by ic and iv route, respectively, from two vCJD patients and from two clinical vCJD-inoculated macaques. Transfusions were also performed from whole blood and blood leucodepleted according to hospital practice standards from two clinical BSE inoculated macaques. Blood infectivity during the preclinical phase is being examined in orally infected macaques. Whole blood was collected and transfused from one such animal two years after oral challenge, whereas buffy-coat and plasma from two animals at 2 and 4.5 years post-challenge, respectively, have been inoculated by the ic route.
This is an ongoing study in which recipient animals continue to be observed at various times post-inoculation. So far, we have had one positive transmission in one animal transfused 65 months earlier with 40 ml of whole blood from a vCJD macaque (the characteristics of the disease in this animal will be shown in a separate poster by E. Comoy). This positive transmission reproduces transfusion transmission of vCJD in humans, with an incubation of 5.5 years compatible with incubation periods observed in humans.
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2007/abstract_book.pdfP03.106
Detection of Chronic Wasting Disease Prions in Saliva, Blood, and Excreta of Deer
Mathiason, C1; Powers, J2; Dahmes, S3; Osborn, D4; Miller, K4; Warren, R4; Mason, G1; Hays, S1; Hayes-Klug, J1; Seelig, D1; Wild, M2; Wolfe, L5; Spraker, T6; Miller, M5; Sigurdson, C1; Telling, G7; Hoover, E1 1Colorado State University, Microbiology, Immunology and Pathology, USA; 2National Park Service, Biological Resource Management Division, USA; 3Wildlife Artist Supply Company (WASCO, Inc.), USA; 4University of Georgia, Athens, Warnell School of Forestry and Natural Resources, USA; 5Colorado Division of Wildlife, Wildlife Research Center, USA; 6Colorado State University, Veterinary Diagnostic Laboratory, CVMBS, USA; 7University of Kentucky, Microbiology, Immunology and Molecular Genetics, USA
Background: The potential presence of prions in body fluids is perhaps most relevant to chronic wasting disease (CWD) of cervids, owing to its facile transmission, geographic expansion, and the relatively large amount of aberrant prion protein in peripheral lymphoid tissues. Nevertheless the exact mode by which the CWD prions are shed and transmitted has remained unknown. Objective: To determine whether infectious CWD prions are present in saliva, blood or urine and feces of CWD-positive deer.
Methods: Two bioassay studies comprising three cohorts for a total of n = 6 naïve deer/cohort were exposed either orally to 50 ml saliva, or 50 ml urine and 50 gram feces, or via intravenous transfusion of 250 ml whole blood from CWD-positive deer. Study controls included positive control cohorts totalling (n = 8) deer exposed to brain from CWD-positive deer and a negative control cohort consisting of (n = 2) deer receiving inocula from CWD-negative deer. The recipient animals were maintained under rigorous indoor isolation conditions to exclude potential adventitious prion exposure and monitored for CWD infection for a minimum of 18 months post infection by serial tonsil biopsy and terminal necropsy.
Results: Infectious prions capable of transmitting CWD were detected in saliva (by the oral route) and in blood (by transfusion). PrPCWD was first detected in tonsils between 3 and 12 months post inoculation. To our surprise, no deer fed urine and feces from CWD-positive donors developed CWD infection, despite multiple exposures.
Conclusion: Infectious prions in saliva may explain the efficient transmission of CWD in nature. Infectious prions in the blood of CWD-positive deer establishes a basis for developing antemortem detection of the disease by blood-based assay methods and emphasizes the widespread distribution of infectivity in CWD-positive deer.
O.9.3
Updated risk assessment of variant Creutzfeldt-Jakob disease (vCJD) risks for recipients of plasma-derived blood clotting products in the U.S.
Hong Yang, Richard Forshee, Mark Walderhaug, Steven Anderson
US Food and Drug Administration, USA
Background: A recent announcement by UK health authorities of a case of vCJD infection in a >70 year old person with hemophilia has prompted the US Food & Drug Administration (FDA) to re-evaluate vCJD risks in the U.S. via plasma-derived Factor VIII (pdFVIII) and to update its 2006 risk assessment. As of May 2009, confirmed vCJD deaths have occurred in persons who are homozygous methionine (MM) at codon 129 of the PRP gene. Several reports in the last few years have indicated signs of vCJD infection in persons of methionine-valine (MV) and homozygous valine (VV) genotypes. FDA updated risk assessment by assuming all genotypes are susceptible to vCJD and modeling the incubation periods for all three genotypes.
Objectives: To evaluate the vCJD risk for pdFVIII recipients with severe hemophilia and vonWillebrand diseases.
Methods: The model assumed equal susceptibility of three genotypes, a median incubation period of 12 years for the MM and 32 years for MV and VV genotypes, and vCJD infectivity was present in the blood of infected donors during the last 50% to 90% of incubation period. Model used statistical distributions for inputs including susceptibility to the disease, donation rates, frequency and duration of travel to the UK, France and other countries in Europe since 1980, the effectiveness of donor deferral policies and infectivity clearance during manufacturing processes.
Results: For severe hemophilia patients at the highest risk (prophylaxis, with inhibitor, with immune tolerance) the model estimated annual mean exposure to be ~7 x 10-8 iv ID50 or ~1 in 270,000 with the lower prevalence (4 per million) assumption, and ~1 x 10-4 iv ID50 or ~1 in 12,000 with the higher prevalence (1 per 4,225) assumption. Donor deferral policies reduce the risk by >92%.
Discussion: Due to limited data and knowledge of vCJD, the model estimates are uncertain. However, it suggests the risk is small, and donor deferral and manufacturing processes greatly reduce the risk.
FC5.3
Assessing the Risk of vCJD Transmission by Dentistry; Distribution of Infectivity in Oral Tissues of VM Mice after Simulated Oral Feeding of BSE-301V
Sutton, JM1; Kirby, E1; Dickinson, J1; Dennis, M1; Cornwall, M1; Vassey, MJ1; Smith, A2; Marsh, PD3; Walker, JT1; Raven, NDH1
1Health Protection Agency, Centre for Emergency Preparedness and Response,, TSE Research group, UK; 2University of Glasgow, Dental School, UK; 3Health Protection Agency, Centre for Emergency Preparedness and Response,, UK
Background: Ongoing concerns about the prevalence of variant Creutzfeldt Jakob Disease (vCJD) in the UK population has heightened concerns about the risks of iatrogenic transmission of the disease. Although there have been no cases to date of transmission by surgery there have been 4 cases involving blood transfusion. This study aims to assess the potential of transmission of the disease by dental procedures. Whilst the risks are undoubtably low the very large numbers of procedures carried out annually have the potential to amplify the risks considerably and there is very little data in this area to form the basis for accurate risk assessments.
Aim(s)/Objective(s): To assess the relative levels of infectivity in oral tissues from a murine model following exposure to BSE-301V through the small intestine. Methods. The study uses a BSE-301V, VM mouse model as a clinically relevant model for assessing iatrogenic vCJD transmission between humans. Infectious mouse brain homogenate was prepared and inoculated into a loop of the duodenum, to prevent direct contamination of the oral tissues. Mice were sacrificed at 3-weekly intervals and at appearance of clinical symptoms. A range of oral tissues, including dental pulp, gingival margin, salivary gland, saliva, lingual tonsil and trigeminal ganglia, together with brain and spleen tissues were removed, processed as homogenates and reinoculated intracranially (ic.) into indicator mice.
Results: The primary challenge proved to be a very efficient route of infection with a 100% attack rate and a mean incubation to clinical disease of 157 ± 17 days (compared to 120 days for the same titre inoculum ic.). Infectivity was observed in all oral and control tissues with varying time-courses and titres estimated from incubation period.
Discussion: The results throw new light on the potential routes of dissemination and spread of infectivity from the small intestine to the oral cavity and its implications for possible iatrogenic transmission of vCJD via dental, endoscopic or other forms of surgery.
Conclusion: The data generated from the study provides support for ongoing risk assessments to look at the potential for vCJD transmission via dental procedures alongside other elements of studies looking at effectiveness of decontamination and re-use of dental instruments.
FC5.5.1
BASE Transmitted to Primates and MV2 sCJD Subtype Share PrP27-30 and PrPSc C-terminal Truncated Fragments
Zanusso, G1; Commoy, E2; Fasoli, E3; Fiorini, M3; Lescoutra, N4; Ruchoux, MM4; Casalone, C5; Caramelli, M5; Ferrari, S3; Lasmezas, C6; Deslys, J-P4; Monaco, S3 1University of Verona, of Neurological and Visual Sciences, Italy; 2CEA, IMETI/SEPIA, France; 3University of Verona, Neurological and Visual Sciences, Italy; 4IMETI/SEPIA, France; 5IZSPLVA, Italy; 6The Scripps Research Insitute, USA
The etiology of sporadic Creutzfeldt-Jakob disease (sCJD), the most frequent human prion disease, remains still unknown. The marked disease phenotype heterogeneity observed in sCJD is thought to be influenced by the type of proteinase K-resistant prion protein, or PrPSc (type 1 or type 2 according to the electrophoretic mobility of the unglycosylated backbone), and by the host polymorphic Methionine/Valine (M/V) codon 129 of the PRNP. By using a two-dimensional gel electrophoresis (2D-PAGE) and imunoblotting we previously showed that in sCJD, in addition to the PrPSc type, distinct PrPSc C-terminal truncated fragments (CTFs) correlated with different sCJD subtypes. Based on the combination of CTFs and PrPSc type, we distinguished three PrPSc patterns: (i) the first was observed in sCJD with PrPSc type 1 of all genotypes,; (ii) the second was found in M/M-2 (cortical form); (iii) the third in amyloidogenic M/V- 2 and V/V-2 subtypes (Zanusso et al., JBC 2004) . Recently, we showed that sCJD subtype M/V-2 shared molecular and pathological features with an atypical form of BSE, named BASE, thus suggesting a potential link between the two conditions. This connection was further confirmed after 2D-PAGE analysis, which showed an identical PrPSc signature, including the biochemical pattern of CTFs. To pursue this issue, we obtained brain homogenates from Cynomolgus macaques intracerebrally inoculated with brain homogenates from BASE. Samples were separated by using a twodimensional electrophoresis (2D-PAGE) followed by immunoblotting.
We here show that the PrPSc pattern obtained in infected primates is identical to BASE and sCJD MV-2 subtype. These data strongly support the link, or at least a common ancestry, between a sCJD subtype and BASE.
This work was supported by Neuroprion (FOOD-CT-2004-506579)
FC5.5.2
Transmission of Italian BSE and BASE Isolates in Cattle Results into a Typical BSE Phenotype and a Muscle Wasting Disease
Zanusso, G1; Lombardi, G2; Casalone, C3; D'Angelo, A4; Gelmetti, D2; Torcoli, G2; Barbieri, I2; Corona, C3; Fasoli, E1; Farinazzo, A1; Fiorini, M1; Gelati, M1; Iulini, B3; Tagliavini, F5; Ferrari, S1; Monaco, S1; Caramelli, M3; Capucci, L2
1University of Verona, Neurological and Visual Sciences, Italy; 2IZSLER, Italy; 3IZSPLVA, Italy; 4University of Turin, Animal Pathology, Italy; 5Isituto Carlo Besta, Italy
The clinical phenotype of bovine spongiform encephalopathy has been extensively reported in early accounts of the disorder. Following the introduction of statutory active surveillance, almost all BSE cases have been diagnosed on a pathological/molecular basis, in a pre-symptomatic clinical stage. In recent years, the active surveillance system has uncovered atypical BSE cases, which are characterized by distinct conformers of the PrPSc, named high-type (BSE-H) and low-type (BSE-L), whose clinicopathological phenotypes remain unknown. We recently reported two Italian atypical cases with a PrPSc type similar to BSE-L, pathologically characterized by PrP amyloid plaques. Experimental transmission to TgBov mice has recently disclosed that BASE is caused by a distinct prion strain which is extremely virulent. A major limitation of transmission studies to mice is the lack of reliable information on clinical phenotype of BASE in its natural host. In the present study, we experimentally infected Fresian/Holstein and Alpine/Brown cattle with Italian BSE and BASE isolates by i.c. route. BASE infected cattle showed survival times significantly shorter than BSE, a finding more readily evident in Fresian/Holstein, and in keeping with previous observations in TgBov mice. Clinically, BSE-infected cattle developed a disease phenotype highly comparable with that described in field BSE cases and in experimentally challenged cattle. On the contrary, BASE-inoculated cattle developed an amyotrophic disorder accompanied by mental dullness.
The molecular and neuropathological profiles, including PrP deposition pattern, closely matched those observed in the original cases. This study further confirms that BASE is caused by a distinct prion isolate and discloses a novel disease phenotype in cattle, closely resembling the phenotype previous reported in scrapie-inoculated cattle and in some subtypes of inherited and sporadic Creutzfeldt-Jakob disease.
http://www.prion2009.com/sites/default/files/Prion2009_Book_of_Abstracts.pdfhttp://www.neuroprion.org/resources/pdf_docs/conferences/prion2007/abstract_book.pdfO.2.2
vCJD infection in an asymptomatic UK haemophilic patient
Alexander Peden1, Graham Fairfoul1, Suzanne Lowrie1, Linda McCardle1, Mark Head1, Seth Love2, Hester Ward1, Simon Cousens3, David Keeling4, Carolyn Millar5, FGH Hill6, James Ironside1 1University of Edinburgh, UK; 2Frenchay Hospital, Bristol, UK; 3London School of Hygiene and Tropical Medicine, UK; 4Churchill Hospital, Oxford, UK; 5Imperial College London, UK; 6Birmingham Children's Hospital, Birmingham, UK
We describe a study of 17 UK patients with haemophilia considered to be at increased risk of vCJD through exposure to UK plasma products.
10 autopsy cases and 7 biopsy cases were analysed for disease- associated, protease-resistant prion protein (PrPres). The tissues available from each case were variable, ranging from a single biopsy sample to a wide range of autopsy tissues. A single specimen from the spleen of one autopsy case gave a strong positive result on repeated testing for PrPres by Western blot analysis. This tissue came from a 73 year-old male with no history of neurological disease, who was heterozygous (methionine/valine) at codon 129 in the prion protein gene. He had received over 9,000 units of Factor VIII concentrate prepared from plasma pools known to include donations from a vCJD-infected donor, and some 400,000 units not known to include donations from vCJD-infected donors. He had also received 14 units of red blood cells and had undergone several surgical and invasive endoscopic procedures. Estimates of the relative risks of exposure though diet, surgery, endoscopy, blood transfusion and receipt of UK plasma products suggest that by far the most likely route of infection was receipt of UK plasma products.
http://www.prion2009.com/sites/default/files/Prion2009_Book_of_Abstracts.pdfP04.36
Enhanced Surveillance of Persons Identified as at Increased Risk of CJD Due to Blood Transfusion or Healthcare Procedures
Brookes, D1; Chow, Y1; Ward, HJT2; Will, RG2; Hewitt, P3; Gill, ON1 1HPA, CJD, UK; 2National CJD Surveillance Unit, UK; 3Colindale, NHS Blood and Tissue, UK
Introduction: Reports of four iatrogenic transmissions of variant-CJD (vCJD) infection in the UK (all due to transfusion of blood from donors who later developed vCJD), evidence from iatrogenic transmissions of sporadic CJD and experimental work on CJD infectivity in tissues and on healthcare instruments have given rise to concern about the risks of iatrogenic transmission of CJD. This risk warrants a) certain public health precautions, and b) follow-up of individuals with identified risks in order to gain evidence about their risks and ensure appropriate management of these risks. Evidence of transmission via iatrogenic routes is important to inform public health measures and so prevent ongoing transmission of CJD.
Methods: The Health Protection Agency and Health Protection Scotland holds details of persons identified as 'at-risk' of vCJD due to blood transfusion and of persons identified as 'at-risk' of CJD (of any type) from other healthcare procedures. The GPs/clinicians of all persons identified as 'at-risk' for public health purposes are provided with: information; risk assessment updates; advice on public health precautions and advice on referral to specialist care. Procedures are being established to obtain enhanced surveillance data on these individuals, including: clinical status updates, date and cause of death, surplus tissue and blood specimens, and postmortem investigations.
Results: Persons 'at-risk' of CJD have experienced a range of exposures. Estimated risks are uncertain and overlapping. Some individuals - recipients of vCJD implicated blood components - are considered to be at a clearly higher risk of infection: active follow-up is currently conducted for these individuals. In time, the enhanced surveillance of persons at increased risk of CJD will provide estimates of transmission risks and of the impact of iatrogenic exposures on mortality.
Conclusion: Knowledge about iatrogenic transmission of CJD is being gained by the follow-up of individuals who have been identified as 'at-risk' of CJD in the UK. This enhanced surveillance may need to be sustained for many years.
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2007/abstract_book.pdfP04.49
Case Report of Variant Creutzfeldt-Jakob Disease in a Macaque after Blood
Transfusion
Lescoutra-Etchegaray, N1; Ruchoux, MM1; Correia, E1; Jolit, A1; Freire, S1; Lasmezas, CI2; Deslys, JP1; Comoy, E1 1CEA/DSV/IMETI/SEPIA, France; 2Scripps Florida, USA
A fourth human case of probable transmission of vCJD through transfusion has now been reported but a number of features affecting transfusion-related infection remain imprecise, including infectious dose, length of incubation period and critical infectious window of blood donors.
We report here the first case of experimental transmission of vCJD in primates by blood transfusion. Experimental infection of Cynomolgus macaque has been demonstrated to be a sensitive model for the investigation of human prion diseases, inducing similar distribution of infectivity in peripheral lymphoid tissues and equivalent brain pathology. In our study, transfusion was performed with 40 ml of whole blood drawn from a vCJD-infected macaque at the terminal stage of the disease. Clinical symptoms of vCJD appeared in the recipient animal after five years of incubation. The total amount of infectivity in the transfused blood was approximately 106 fold lower than in the brain (titration still in progress). In several animals infected intravenously with brain homogenate, the presence of PrPres in serial lymph nodes biopsies and in other organs at autopsy was examined and results will be presented.
P04.51
Atypical Presentation of Variant Creutzfeldt-Jakob Disease in a 73 Year Old Blood Transfusion
Recipient Wroe, S1; Pal, S1; Webb, T1; Alner, K2; Hewitt, P3; Brander, S4; Wadsworth, JD5; Collinge, J1 1National Hospital for Neurology and Neurosurgery, National Prion Clinic, UK; 2National Hospital for Neurology and Neurosurgery, Department of Neuropsychology, UK; 3Health Protection Agency, UK; 4National Hospital for Neurology and Neurosurgery, Department of Neuropathology, UK; 5Institute of Neurology, UCL, UK
We report atypical presentation of variant Creutzfeldt-Jakob Disease (vCJD) identified ante-mortem in a 73 year-old recipient of blood products. This patient was transfused following orthopaedic surgery in December 1997. Tracing of blood products identified a single unit of non-leucodepleted red cells from an individual who developed neuropathologically confirmed vCJD eleven months after donation. Nine years post transfusion, this individual was referred to the National Prion Clinic for specialist investigation. Six years post transfusion the recipient complained of fluctuating fatigue and impaired concentration. At this time neurological examination and MRI brain (T1/T2 weighted/DWI) were normal. Progressive symptoms emerged six months later with imbalance and deteriorating cognition. Examination two months after onset of neurological symptoms demonstrated cognitive deficits, dyspraxia or visuospatial dysfunction and normal motor, sensory and gait examination. Six weeks later cognitive impairment was identified alongside tremulousness, impaired manual dexterity and limb ataxia. Serological investigations were normal. MRI (T1/T2 weighted/FLAIR/DWI) demonstrated prominent signal change throughout the dorsal thalamus, consistent with vCJD. PRNP genotyping revealed no mutations and homozygosity for methionine at codon 129. The prolonged incubation period of vCJD and possibility of asymptomatic carrier states pose major public health concerns. This case highlights the significant risk encountered by recipients of contaminated blood products and the necessity for their specialist monitoring.
P04.73
Whole-body Biodistribution and Tissue Uptake Kinetics of PrPSc in the Initial Phase of the Infection
Urayama, A; Morales, R; Soto, C University of Texas Medical Branch, USA
Although prion diseases have been a public health concern for decades, the lack of knowledge about the pharmacokinetics and biodistribution of prions complicates the risk assessment. In our prior studies, we found that the level of PrPSc in blood was undetectable several weeks after inoculation, then it became detectable during the early pre-symptomatic phase, disappeared from blood right before the symptomatic phase and raised to its highest at the clinical stage of the disease. These data suggest that there are several stages of the movement of PrPSc in the body during the progression of the disease. The aim of the current study was to analyze the biodisribution and tissue uptake kinetics of PrPSc in the initial phase of the infection in mice.
After an intravenous injection of [131I]PrPSc (together with [125I]albumin as a vascular space marker), the levels of [131I]PrPSc in serum decreased biphasically with time, whereas albumin levels did not significantly change during the course of the experiment. Elimination half-lives of [131I]PrPSc and [125I]albumin were 3.44 ± 0.42 and 17.6 ± 8.6 hr, respectively. These results suggest that the level of [131I]PrPSc in serum 24 hr after the injection is less than 1 % of the injected dose (ID). The rate for albumin was consistent with previous reports. The volumes of distribution for [131I]PrPSc (3.34 ± 0.16 ml) suggest that PrPSc was well distributed in the extracellular space in the body, whereas the majority of albumin was in the serum space. [131I]PrPSc showed higher systemic clearance rates than that of [125I]albumin. The uptake of [131I]PrPSc was also investigated in various tissues. The quantity of PrPSc taken up by brain was around 0.2 %ID, indicating that the protein can penetrate across the blood-brain barrier with a medium efficiency compared to other proteins. The higher levels of [131I]PrPSc were found in liver, spleen, kidney, lung, heart, and skeletal muscle when compared to the levels in the brain. Interestingly, TCAprecipitable [131I]PrPSc was clearly detected in urine. These results provide a fundamental pharmacokinetic characterization of PrPSc in animals that may be relevant to estimate tissue risks, mechanisms of prion neuroinvassion and to develop novel therapeutic strategies.
P04.102
Has vCJD been Transmitted by Human Blood Plasma Products? 20 Years and Counting
Foster, P
Scottish National Blood Transfusion Service, Protein Fractionation Centre, UK The diagnosis of vCJD in a patient whose plasma had previously been used in the preparation of blood plasma products by the NHS led to the decision in 1998 that the preparation of plasma derivatives from UK-donor plasma should cease as a precautionary measure. Since then, plasma products have either been manufactured by the NHS, using plasma purchased from the USA and Europe, or purchased directly from commercial companies.
It is now known that donations from 11 individuals, later diagnosed with vCJD, had been included in the preparation of a total of 175 batches of different plasma products that were released for use between June 1987 and September 1998. No cases of vCJD have been associated with these products, although 20 years have elapsed since the first implicated batches were released for use. This contrasts with 3 instances of probable transmission of vCJD by red cells in which symptoms of vCJD developed in recipients 6.5 years, 7.8 years and 8.3 years after transfusion.
There are a number of possible explanations for the apparent absence of transmision by plasma products.
(1) Prion infectivity was not present in the donated plasma.
(2) Prion infectivity was present in the donated plasma but not in the manufactured products, due to dilution or removal of infectivity by the manufacturing process.
(3) Prion infectivity was present in manufactured product(s) but has not resulted in clinical symptoms of vCJD because of either a prolonged incubation period or a lack of suceptibility in recipients.
The methods used for the manufacture of blood plasma products by the Scottish National Blood Transfusion Service have been examined to determine the extent to which removal of prions might have occurred. These experiments indicate a possible overall prion reduction of 2.7 logs for intermediate-purity factor VIII concentrate (Z8), 3.0 logs for intermediate-purity factor IX concentrate (DEFIX), 5.8 logs for thrombin, ³6.2 logs for fibrinogen, ³6.5 logs for immunoglobulin, 7.4 logs for high-purity factor IX concentrate and ³11.5 logs for albumin.
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2007/abstract_book.pdfP04.36
Enhanced Surveillance of Persons Identified as at Increased Risk of CJD Due to Blood Transfusion or Healthcare Procedures
Brookes, D1; Chow, Y1; Ward, HJT2; Will, RG2; Hewitt, P3; Gill, ON1 1HPA, CJD, UK; 2National CJD Surveillance Unit, UK; 3Colindale, NHS Blood and Tissue, UK
Introduction: Reports of four iatrogenic transmissions of variant-CJD (vCJD) infection in the UK (all due to transfusion of blood from donors who later developed vCJD), evidence from iatrogenic transmissions of sporadic CJD and experimental work on CJD infectivity in tissues and on healthcare instruments have given rise to concern about the risks of iatrogenic transmission of CJD. This risk warrants a) certain public health precautions, and b) follow-up of individuals with identified risks in order to gain evidence about their risks and ensure appropriate management of these risks. Evidence of transmission via iatrogenic routes is important to inform public health measures and so prevent ongoing transmission of CJD.
Methods: The Health Protection Agency and Health Protection Scotland holds details of persons identified as 'at-risk' of vCJD due to blood transfusion and of persons identified as 'at-risk' of CJD (of any type) from other healthcare procedures. The GPs/clinicians of all persons identified as 'at-risk' for public health purposes are provided with: information; risk assessment updates; advice on public health precautions and advice on referral to specialist care. Procedures are being established to obtain enhanced surveillance data on these individuals, including: clinical status updates, date and cause of death, surplus tissue and blood specimens, and postmortem investigations.
Results: Persons 'at-risk' of CJD have experienced a range of exposures. Estimated risks are uncertain and overlapping. Some individuals - recipients of vCJD implicated blood components - are considered to be at a clearly higher risk of infection: active follow-up is currently conducted for these individuals. In time, the enhanced surveillance of persons at increased risk of CJD will provide estimates of transmission risks and of the impact of iatrogenic exposures on mortality.
Conclusion: Knowledge about iatrogenic transmission of CJD is being gained by the follow-up of individuals who have been identified as 'at-risk' of CJD in the UK. This enhanced surveillance may need to be sustained for many years.
http://www.neuroprion.org/resources/pdf_docs/conferences/prion2007/abstract_book.pdfSaturday, January 20, 2007
Fourth case of transfusion-associated vCJD infection in the United Kingdom
http://vcjdtransfusion.blogspot.com/2007_01_01_archive.htmlP.4.23
Transmission of atypical BSE in humanized mouse models
Liuting Qing1, Wenquan Zou1, Cristina Casalone2, Martin Groschup3, Miroslaw Polak4, Maria Caramelli2, Pierluigi Gambetti1, Juergen Richt5, Qingzhong Kong1 1Case Western Reserve University, USA; 2Instituto Zooprofilattico Sperimentale, Italy; 3Friedrich-Loeffler-Institut, Germany; 4National Veterinary Research Institute, Poland; 5Kansas State University (Previously at USDA National Animal Disease Center), USA
Background: Classical BSE is a world-wide prion disease in cattle, and the classical BSE strain (BSE-C) has led to over 200 cases of clinical human infection (variant CJD). Atypical BSE cases have been discovered in three continents since 2004; they include the L-type (also named BASE), the H-type, and the first reported case of naturally occurring BSE with mutated bovine PRNP (termed BSE-M). The public health risks posed by atypical BSE were largely undefined.
Objectives: To investigate these atypical BSE types in terms of their transmissibility and phenotypes in humanized mice.
Methods: Transgenic mice expressing human PrP were inoculated with several classical (C-type) and atypical (L-, H-, or Mtype) BSE isolates, and the transmission rate, incubation time, characteristics and distribution of PrPSc, symptoms, and histopathology were or will be examined and compared.
Results: Sixty percent of BASE-inoculated humanized mice became infected with minimal spongiosis and an average incubation time of 20-22 months, whereas only one of the C-type BSE-inoculated mice developed prion disease after more than 2 years. Protease-resistant PrPSc in BASE-infected humanized Tg mouse brains was biochemically different from bovine BASE or sCJD. PrPSc was also detected in the spleen of 22% of BASE-infected humanized mice, but not in those infected with sCJD. Secondary transmission of BASE in the humanized mice led to a small reduction in incubation time.
The atypical BSE-H strain is also transmissible with distinct phenotypes in the humanized mice, but no BSE-M transmission has been observed so far.
Discussion: Our results demonstrate that BASE is more virulent than classical BSE, has a lymphotropic phenotype, and displays a modest transmission barrier in our humanized mice.
BSE-H is also transmissible in our humanized Tg mice. The possibility of more than two atypical BSE strains will be discussed.
Supported by NINDS NS052319, NIA AG14359, and NIH AI 77774.
http://www.prion2009.com/sites/default/files/Prion2009_Book_of_Abstracts.pdfP02.35
Molecular Features of the Protease-resistant Prion Protein (PrPres) in H-type BSE
Biacabe, A-G1; Jacobs, JG2; Gavier-Widén, D3; Vulin, J1; Langeveld, JPM2; Baron, TGM1 1AFSSA, France; 2CIDC-Lelystad, Netherlands; 3SVA, Sweden
Western blot analyses of PrPres accumulating in the brain of BSE-infected cattle have demonstrated 3 different molecular phenotypes regarding to the apparent molecular masses and glycoform ratios of PrPres bands. We initially described isolates (H-type BSE) essentially characterized by higher PrPres molecular mass and decreased levels of the diglycosylated PrPres band, in contrast to the classical type of BSE. This type is also distinct from another BSE phenotype named L-type BSE, or also BASE (for Bovine Amyloid Spongiform Encephalopathy), mainly characterized by a low representation of the diglycosylated PrPres band as well as a lower PrPres molecular mass.
Retrospective molecular studies in France of all available BSE cases older than 8 years old and of part of the other cases identified since the beginning of the exhaustive surveillance of the disease in 20001 allowed to identify 7 H-type BSE cases, among 594 BSE cases that could be classified as classical, L- or H-type BSE.
By Western blot analysis of H-type PrPres, we described a remarkable specific feature with antibodies raised against the C-terminal region of PrP that demonstrated the existence of a more C-terminal cleaved form of PrPres (named PrPres#2 ), in addition to the usual PrPres form (PrPres #1). In the unglycosylated form, PrPres #2 migrates at about 14 kDa, compared to 20 kDa for PrPres #1. The proportion of the PrPres#2 in cattle seems to by higher compared to the PrPres#1. Furthermore another PK-resistant fragment at about 7 kDa was detected by some more N-terminal antibodies and presumed to be the result of cleavages of both N- and C-terminal parts of PrP. These singular features were maintained after transmission of the disease to C57Bl/6 mice.
The identification of these two additional PrPres fragments (PrPres #2 and 7kDa band) reminds features reported respectively in sporadic Creutzfeldt-Jakob disease and in Gerstmann-Sträussler-Scheinker (GSS) syndrome in humans.
O.11.3
Infectivity in skeletal muscle of BASE-infected cattle
Silvia Suardi1, Chiara Vimercati1, Fabio Moda1, Ruggerone Margherita1, Ilaria Campagnani1, Guerino Lombardi2, Daniela Gelmetti2, Martin H. Groschup3, Anne Buschmann3, Cristina Casalone4, Maria Caramelli4, Salvatore Monaco5, Gianluigi Zanusso5, Fabrizio Tagliavini1 1Carlo Besta" Neurological Institute,Italy; 2IZS Brescia, Italy; 33FLI Insel Riems, D, Germany; 4CEA-IZS Torino, Italy; 5University of Verona, Italy
Background: BASE is an atypical form of bovine spongiform encephalopathy caused by a prion strain distinct from that of BSE. Upon experimental transmission to cattle, BASE induces a previously unrecognized disease phenotype marked by mental dullness and progressive atrophy of hind limb musculature. Whether affected muscles contain infectivity is unknown. This is a critical issue since the BASE strain is readily transmissible to a variety of hosts including primates, suggesting that humans may be susceptible.
Objectives: To investigate the distribution of infectivity in peripheral tissues of cattle experimentally infected with BASE. Methods: Groups of Tg mice expressing bovine PrP (Tgbov XV, n= 7-15/group) were inoculated both i.c. and i.p. with 10% homogenates of a variety of tissues including brain, spleen, cervical lymph node, kidney and skeletal muscle (m. longissimus dorsi) from cattle intracerebrally infected with BASE. No PrPres was detectable in the peripheral tissues used for inoculation either by immunohistochemistry or Western blot.
Results: Mice inoculated with BASE-brain homogenates showed clinical signs of disease with incubation and survival times of 175±15 and 207±12 days. Five out of seven mice challenged with skeletal muscle developed a similar neurological disorder, with incubation and survival times of 380±11 and 410±12 days. At present (700 days after inoculation) mice challenged with the other peripheral tissues are still healthy. The neuropathological phenotype and PrPres type of the affected mice inoculated either with brain or muscle were indistinguishable and matched those of Tgbov XV mice infected with natural BASE.
Discussion: Our data indicate that the skeletal muscle of cattle experimentally infected with BASE contains significant amount of infectivity, at variance with BSE-affected cattle, raising the issue of intraspecies transmission and the potential risk for humans. Experiments are in progress to assess the presence of infectivity in skeletal muscles of natural BASE.
http://www.prion2009.com/sites/default/files/Prion2009_Book_of_Abstracts.pdfO.2.4
Detection of prions in blood leucocytes
Linda A. Terry, Laurence Howells, Jeremy Hawthorn, Sally Everest, Sarah Jo Moore, Jane C. Edwards Veterinary Laboratories Agency, UK
Background: Infected human blood has been implicated in the iatrogenic transmission of vCJD in four reported cases. Experimental transmission studies have demonstrated that blood from scrapie and BSE infected sheep also contains infectivity. Rodent models of prion disease implicated both cellular and plasma fractions. However, direct detection of PrPsc from blood in the absence of in vitro amplification or bioassay has proved difficult. Methods for the direct detection of PrPsc in blood would be advantageous for the study of the pathogenesis of TSEs and as a basis for a blood test. Objectives: To develop a method for the direct detection of PrPsc in blood cells from scrapie and BSE infected sheep; to study the temporal distribution of PrPsc in blood and to determine the identity of the cells bearing prions in blood. Methods: Peripheral blood mononuclear cells (PBMC) were isolated from sheep naturally infected with scrapie or experimentally infected with BSE at the clinical stage of disease and from scrapie infected sheep from 3 months of age through to clinical end-point. PBMCs were tested for PrPsc content by a direct immunoassay based on the IDEXX CWD HerdChek kit. Different subsets of PBMCs were isolated by subset specific cell surface markers and magnetic bead separation and analysed for PrPsc content. Results: PrPSc was detected in 54% of sheep with clinical scrapie and 71% of sheep with clinical BSE. A longitudinal study of the temporal distribution of blood PBMC associated PrPsc showed that the detection rate increases during the course of disease and is more likely to be observed during the second half of the incubation period. Additionally detection is more likely in scrapie infected sheep if they carry the PRNP genotype of VRQ/VRQ. Cell separation studies showed that the PrPsc is associated with a specific cell subset implicating a subset of B lymphocytes. Discussion. This is the first report of the direct detection of PrPsc in cells isolated from sheep blood in the absence of in vitro amplification or bioassay. Since PrPsc can be detected from as early as 3 months of age in sheep naturally infected with scrapie, correlating with initial replication in the gut-associated lymphoid tissue, the assay could be the basis of a preclinical test. The identification of the cell subset carrying PrPsc progresses our understanding of the pathogenesis of the disease. However, it remains unclear whether this cell subset is responsible for the dissemination of prions or in clearance of circulating PrPsc. Funded by defra, UK and IDEXX.
O.2.6
Human urine and PrP
Silvio Notari1*, Liuting Qing1*, Ayuna Dagdanova1*, Sergei Ilchenko1, Mark E. Obrenovich1, Wen-Quan Zou1, Maurizio Pocchiari2, Pierluigi Gambetti1, Qingzhong Kong1, Shu G. Chen1 1Case Western Reserve University, USA; 2Istituto Superiore di Sanità, Italy
Background: The presence and the characteristics of prion protein (PrP) in human urine under normal conditions are controversial. Similarly, there are no definite data on the presence of infectivity in urine in the course of naturally occurring human prion diseases. Objectives: 1) To definitely determine the presence and characteristics of PrPC in normal urine. 2) To evaluate the prion infectivity in human urine in sporadic Creutzfeldt-Jakob disease (sCJD), we have carried out a set of bioassays in humanized transgenic mouse with urine samples collected from sCJD subjects. Methods: 1) Advanced mass spectrometry and experimental treatments have been used to demonstrate the presence, primary structure and posttranslational modifications of purified urinary PrPC (uPrP). 2) Bioassays were performed by intracerebral inoculation of 100 times concentrated and dialyzed urine, collected from three sCJD-MM1 cases to humanized transgenic mice and from appropriate controls. Results: We found that human urine contains significant amount of PrP (approximately 10 ng/ml) that is truncated with the major N-terminus at residue 112 as the PrPC fragment identified as C1, and it carries an anchor, which is soluble because likely lacks the phosholipid component. None of the humanized transgenic mice inoculated with sCJD concentrated urine had evidence of prion disease during a period of over 700 days (their normal life expectancy) leading to the conclusion that prion infectivity in sCJD urine, if present, must be less than 6 infectious units/100ml. Discussion: The issues raised in the discussion will include: 1) The origin of the truncated uPrP; 2) How the present data compare with the experimental studies published to date that indicate presence of infectivity; 3) The practical implications of our findings. *
O.4.6
All separated components, prepared from BSE-infected sheep blood, are infectious upon transfusion
Sandra McCutcheon1, Anthony Richard Alejo Blanco1, Christopher de Wolf1, Boon Chin Tan1, Nora Hunter1, Valerie Hornsey2, Christopher Prowse2, Marc Turner2, Martin H Groschup3, Dietmar Becher4, Fiona Houston5, Jean C Manson1 1The Roslin Institute and R (D) SVS, University of Edinburgh, UK; 2Scottish National Blood Transfusion Service, UK; 3FLIFederal Research Institute for Animal Health, Germany; 4Micromun, Germany; 5University of Glasgow, UK
Background: The possibility that vCJD may be transmitted by blood transfusion is serious public health issue, of which 4 probable (3 clinical) cases have been attributed. Recently a case of asymptomatic vCJD infection was identified in a haemophiliac; following treatment with clotting factors from UK plasma pools. Sheep orally infected with BSE provide a suitable model, to assess vCJD infection in humans & risk reduction methods, as the distribution of PrPSc & infectivity in lymphoid tissues resembles that of vCJD patients.
Objectives: To determine qualitative and quantitative data on the changes in infectivity in blood and its clinically relevant components with time, to assess the effect of leucodepletion of such products and the potential for secondary transmission by blood transfusion.
Methods: We orally infected sheep with bovine BSE brain homogenate and collected two full-sized donations of whole blood, before the onset of clinical signs. The following components were transfused into naive recipients: whole blood, buffy coat and leucoreduced and non leucoreduced plasma, platelets and red cells. A sub sample of all components was inoculated into TgShpXI mice for determination of infectivity titers. A unit of whole blood from selected primary recipients was transfused into secondary recipients. We are creating a blood archive throughout this study.
Results: 33% of the infected donors have been confirmed as having BSE. We have 4 transmissions of BSE-infectivity following the transfusion of whole blood, buffy coat and plasma. Short incubation times were recorded in these recipients (468, 513, 567 and 594 days) & were similar to those seen in their respective donors (534, 628, 614 and 614 days). The donor of buffy coat also donated both leucodepleted and non leucodepleted blood components to other recipients.
Discussion: Our study will provide invaluable data on the safety of blood products, in relation to TSE infection, used in human medicine (DoH 007/0162)
O.8.1
Variant CJD and plasma products
Robert G. Will National CJD Surveillance Unit, Edinburgh, UK
Evidence from the Transfusion Medicine Epidemiology Review (TMER) project indicates that variant CJD is transmissible through transfusion of labile blood components. The question as to whether plasma products sourced from vCJD contaminated plasma pools has been addressed by a number of risk assessments, with conflicting conclusions. Recently a case of possible vCJD infection in an individual with haemophilia has been described and analysis has suggested that infection may have been related to prior treatment with vCJD implicated Factor VIII. The details of this case will be described together with an analysis of plasma product exposures in UK clinical cases of vCJD.
O.8.2
Blood safety: from screening tests to prion removal
Marc Turner Scottish National Blood Transfusion Service and Department of Haematology, Royal Infirmary, Edinburgh, UK
Although the number of clinical cases of variant CJD continues to fall, concern remains within UK and Western European Blood Services in relation to the risk of transmission of variant CJD due to the estimated prevalence of sub-clinical infection in the general population and the clinical cases of transmission of variant CJD prions by blood components and plasma products. The UK Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO) has considered a number of further precautionary measures including reducing exposure to blood transfusion, importation of blood components, implementation of prion assays and prion reduction for red cell concentrates. The latter two technologies are currently under independent evaluation and it is expected that contingent on the outcome of these an initial decision on whether or not to recommend implementation of these technologies will be made by SaBTO in Autumn 2009.
O.9.3
Updated risk assessment of variant Creutzfeldt-Jakob disease (vCJD) risks for recipients of plasma-derived blood clotting products in the U.S.
Hong Yang, Richard Forshee, Mark Walderhaug, Steven Anderson US Food and Drug Administration, USA
Background: A recent announcement by UK health authorities of a case of vCJD infection in a >70 year old person with hemophilia has prompted the US Food & Drug Administration (FDA) to re-evaluate vCJD risks in the U.S. via plasma-derived Factor VIII (pdFVIII) and to update its 2006 risk assessment. As of May 2009, confirmed vCJD deaths have occurred in persons who are homozygous methionine (MM) at codon 129 of the PRP gene. Several reports in the last few years have indicated signs of vCJD infection in persons of methionine-valine (MV) and homozygous valine (VV) genotypes. FDA updated risk assessment by assuming all genotypes are susceptible to vCJD and modeling the incubation periods for all three genotypes.
Objectives: To evaluate the vCJD risk for pdFVIII recipients with severe hemophilia and vonWillebrand diseases.
Methods: The model assumed equal susceptibility of three genotypes, a median incubation period of 12 years for the MM and 32 years for MV and VV genotypes, and vCJD infectivity was present in the blood of infected donors during the last 50% to 90% of incubation period. Model used statistical distributions for inputs including susceptibility to the disease, donation rates, frequency and duration of travel to the UK, France and other countries in Europe since 1980, the effectiveness of donor deferral policies and infectivity clearance during manufacturing processes.
Results: For severe hemophilia patients at the highest risk (prophylaxis, with inhibitor, with immune tolerance) the model estimated annual mean exposure to be ~7 x 10-8 iv ID50 or ~1 in 270,000 with the lower prevalence (4 per million) assumption, and ~1 x 10-4 iv ID50 or ~1 in 12,000 with the higher prevalence (1 per 4,225) assumption. Donor deferral policies reduce the risk by >92%.
Discussion: Due to limited data and knowledge of vCJD, the model estimates are uncertain. However, it suggests the risk is small, and donor deferral and manufacturing processes greatly reduce the risk.
P.10.7
Serial passage of sCJD in humanised transgenic mice indicates two major transmission strains associated with PrPSc of either type 1 or 2
Matthew Bishop, Robert Will, Enrico Cancellotti, Jean Manson University of Edinburgh, UK
Background: Questions remain about the aetiology of sporadic CJD and whether phenotypic variation is solely controlled by factors such as codon 129 genotype and biochemistry of PrPC. Variation in infective strain has not been clearly demonstrated in sCJD.
Objectives: By serial passage of sCJD in transgenic mice expressing human prion protein with MM, MV, and VV codon 129 genotypes we aimed to understand strain transmission characteristics for the three most commonly observed phenotypes of sCJD.
Methods: We performed intracerebral inoculation of humanised transgenic mice with brain homogenates derived from similar mice previously inoculated with frontal cortex from sCJD patients of subgroups MM1, MV2, and VV2. These mice were assessed for clinical TSE signs, for TSE vacuolation, and deposition of PrPSc.
Results: sCJD(MM1) passage via all mice showed transmission profiles similar to primary inoculation. sCJD(MV2) passage via HuMM and HuVV mice showed a transmission profile similar to primary inoculation. Passage via a HuMV mouse showed transmission properties similar to not only the primary inoculum but also sCJD(MM1). sCJD(VV2) passage via HuMV and HuVV mice showed transmission profiles similar to the primary inoculation. Passage via a HuMM mouse showed transmission properties similar to not only the sCJD(VV2) primary inoculum but also sCJD(MM1). Cluster analysis of the lesion profile data showed that three clusters seen after primary inoculation were reduced to two following second passage, identified by the biochemical type of PrPSc (1 or 2) found in the host mice.
Discussion: Serial passage of sCJD subgroups MM1, MV2, and VV2 shows that PrPSc type and mouse codon 129 genotype determine the secondary transmission profile, independently of the originating inoculum strain. There are associations between type 1 PrPSc and C129-Met, and type 2 PrPSc and C129-Val. This should allow us to investigate further the relationship between PrPSc, genotype, infection, and pathology.
P.5.1
Detection of cellular prion protein (PrPc) in plasma from healthy cynomolgus monkeys (Macaca fascicularis) and changes observed after BSE infection
Barbara Yutzy, Edgar Holznagel, Johannes Löwer Paul-Ehrlich-Institut, Germany
Background: Orally BSE-dosed cynomolgus monkeys represent a valuable model to examine the kinetic of blood infectivity and to assess the risk of blood-borne transmission of variant Creutzfeldt-Jacob disease (vCJD).
Methods: Blood samples were collected monthly from BSE-infected (n = 18) and non-infected female cynomolgus monkeys (n = 8) over a period of up to 9 years. PrPc concentrations were retrospectively analyzed in plasma samples by a dot blot assay and by a sandwich ELISA using a highly sensitive dissociation- enhanced lanthanide fluoro-immunoassay (DELFIA) for detection. Different blood preparation protocols were evaluated to obtain plasma.
Objective: To detect changes in the levels of soluble plasmaderived PrPc. Results: Different blood preparation protocols had a significant effect on the measured plasma PrPc concentrations. In non-infected macaques, concentrations of soluble, plasmaderived PrPc were at least 10-fold lower compared to plasma concentrations in healthy humans. Levels of plasma PrPc increased 6 - 12 months after experimental BSE infection, remained high during the asymptomatic phase, and dropped towards the clinical phase. Soluble, plasma-derived PrPc molecules were PK-sensitive in BSE-infected macaques.
Discussion: There is a species-specific difference in the PrPc concentrations between human and macaque. At least a part of the plasma-derived PrPc fraction originates from blood cells. Andfinally, BSE infection caused an increase in plasma PrPc levels during the asymptomatic phase of infection. Blood transfusion studies have been initiated to examine whether these PK-sensitive PrP molecules carry infectivity.
http://www.prion2009.com/sites/default/files/Prion2009_Book_of_Abstracts.pdfsadly, with unknown phenotypes of cjd roaming around in North American humans and animals, the risk factors from blood products from these individuals are unknown. IF you look at the L-type BSE, which has been documented in North America, which has exposed humans, what would CJD there from look like ? and since it is much more virulent, is blood much more virulent as well not only from L-type BSE, but from humans that have been exposed to L-type BSE from the bovine as well ? are they more virulent ? something to ponder for sure...TSS
OLDER STUDIES ;
Transmission of Creutzfeldt-Jakob Disease from Blood and Urine Into Mice
The Lancet, November 9, 1985
Sir,--Professor Manuelidis and his colleagues (Oct 19, p896) report transmission to animals of Creutzfeldt-Jakob disease (CJD) from the buffy coat from two patients. We also transmitted the disease from whole blood samples of a patient (and of mice) infected with CJD.1 Brain, Cornea, and urine from this patient were also infectious, and the clinicopathological findings2 are summarised as follows.
A 70-year-old man was noted to have a slowing of speech and writing and some disorientation, all of which progressed rapidly. Decorticate rigidity, forced grasping, positive snout reflex, and myoclonus appeared within 2 months. Electroencephalogram revealed typical periodic synchronous discharge, and he died of pneumonia and upper gastrointestinal haemorrhage, about 3 months after onset of the symptoms. The Brain weighed 1290g and showed severe histological changes diagnostic of CJD, including spongiform change, loss of nerve cells, and diffuse proliferation of astrocytes. There were no inflammatory cells, microglia, neurofibrillary tangles, and amyloid plaques, although virus-like particles were detected by electron microscopy.
Results of inoculation in Mice
Inocula NO* Incubation period (days)+ Brain 7/10 (4) 789 (+ or - 112) Cornea 1/6 (0) 1037 Blood 2/13 (0) 1080 (+ or - 69) Urine 5/10 (1) 880 (+ or - 55) CSF 0/10
* Number of mice with CJD change/number examined histologically. Number with amyloid plaques shown in parentheses.
+ means + or - SD
Samples were taken aseptically at necropsy. 10% crude homogenates of brain and cornea in saline, whole blood (after crushing a clot), and untreated CSF and urine were inoculated intracerebrally into CF1 strain mice (20 ul per animal). Some mice showed emaciation, bradykinesia, rigidity of the body and tail, and sometimes tremor after long incubation periods. Tissues obtained after the animal died (or was killed) were studied histologically (table). Animals infected by various inocula showed common pathological changes, consisting of severe spongiform changes, glial proliferation, and a moderate loss of nerve cells. A few mice inoculated with brain tissue or urine had the same amyloid plaques found in patients and animals with CJD.3
In our long-term experiments, inoculating materials taken from twenty patients with CJD or Gerstmann-Straussler-Scheinker's disease (GSS) into rodents, positive results were obtained in seventeen cases, including this patient. Brain tissue transmitted the disease most frequently within the shortes incubation period, except for one case where the lymph node was the most infectious. Transmission through the cornea has been noted in man4 and in guineapigs.5 Whole blood samples taken from three patients were inoculated and a positive transmission occurred only in the case recorded here. Mouse-to-mouse transmission through blood inoculation was successful after a mean incubation period of 365 days.1 Transmission through urine was positive in this patient only, and negative in one other patient and in many infected animals. Transmission through the CSF from eight patients was negative, yet transmission via the CSF of infected rats was positive.1
As viraemia has been proved in guineapigs,6 mice,1,7 and lately in patients with CJD, blood for transfusion or blood products for medical use must be tested for unconventional pathogens. For this purpose, we inoculated blood products into rodents.8 The CJD pathogen was not found in the products examined. However, this approach takes too long to be of practical value. More efficient methods must be developed to detect pathogens and to eliminate them from blood. One proposal9 is to apply membrane filtration to the purification protocol of human growth hormone suspected of being contaminated with CJD. Similar methods are needed for blood contamination.
Department of Neuropathology, Neurological Institute, Faculty of Medicine, Kyushu University, Fukuoka812, Japan
JUN TATEISHI
1. Tateishi J, Sato Y, Kaga M. Doi H, Ohta M. Experimental transmission of human subacute spongiform encephalopathy to small rodents 1: Clinical and histological observations. Acta Neuropathol (Berl) 1980; 51: 127.
2. Shibayama Y, Sakaguchi Y, Nakata K, et al, Creutzfeldt-Jakob disease with demonstration of virus-like particles. Acta pathol Jpn 1982;32: 695.
3. Tateishi J, Nagara H, Hikita K, Sato Y. Amyloid plaques in the brains of mice with Creutzfeldt-Jakob disease. Ann Neurol 1984; 15: 278.
4. Duffy P, Wolf J, Colings G, DeVoe AG, Streeten B, Cowen D. Possible person-to-person transmission of Creutzfeldt-Jakob disease. N Engl J Med 1974; 290: 692.
5. Manuelidis EE, Angelo JN, Gorgacz EJ, Kim JH, Manuelidis L. Experimental Creutzfeldt-Jakob disease transmitted via the eye with infected cornea. N Engl J Med 1977; 296: 1334.
6. Manuelidis EE, Gorgacz EJ, Manuelidis L. Viremia in experimental Creutzfeldt-Jakob disease. Science 1978: 200: 1069.
7. Kuroda Y, Gibbs CJ Jr, Amyx HL, Gajdusek DC. Creutzfeldt-Jakob disease in mice. Persistent viremiam and preferential replication of virus in low-density lymphocytes. Infect Immun 1983; 41: 154.
8. Tateishi J, Tsuji S. Unconventional pathogens causing spongiform encephalopathis absent in blood products. J Med Virol 1985; 15: 11.
9. Tateishi J, Kitamoto T, Hiratani H. Creutzfeldt-Jakob disease pathogen in growth hormone preparations is eliminatable. Lancet (in press).
========================================================
also, this from the Her Majesty's Government...TSS
Subject: Transmission of TSEs through blood Date: Tue, 28 Mar 2000 14:48:35 +0100 From: Ralph Lucas Reply-To: Bovine Spongiform Encephalopathy To: BSE-L@uni-karlsruhe.de
######### Bovine Spongiform Encephalopathy #########
The Lord Lucas asked Her Majesty's Government:
Whether there is any evidence that any Transmissible Spongiform Encephalopathy in any species can be transmitted through blood; and whether they will place in the Library of the House copies of the principal relevant scientific papers. (HL1545)
The Parliamentary Under-Secretary of State, Department of Health (Lord Hunt of Kings Heath):
Some animal studies have shown that certain transmissible spongiform encephalopathies can be experimentally transmitted from animal to animal through blood components. However, the Spongiform Encephalopathy Advisory Committee at its February meeting reviewed recent research undertaken in this area and did not consider any measures were necessary, in addition to those already in place, to reduce any potential risk to public health from human blood and blood products.
Copies of the following relevant scientific papers are being placed in the Library.
Brown P, 1995, "Can Creutzfeldt-Jakob Disease be transmitted by Transfusion?" Haematology 2: 472 - 477.
Brown et al 1999, 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 Vol. 39, November/December 1169 - 1178.
RE-Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 26 March 2003
I lost my mother to hvCJD (Heidenhain Variant CJD). I would like to comment on the CDC's attempts to monitor the occurrence of emerging forms of CJD. Asante, Collinge et al [1] have reported that BSE transmission to the 129-methionine genotype can lead to an alternate phenotype that is indistinguishable from type 2 PrPSc, the commonest sporadic CJD. However, CJD and all human TSEs are not reportable nationally. CJD and all human TSEs must be made reportable in every state and internationally. I hope that the CDC does not continue to expect us to still believe that the 85%+ of all CJD cases which are sporadic are all spontaneous, without route/source. We have many TSEs in the USA in both animal and man. CWD in deer/elk is spreading rapidly and CWD does transmit to mink, ferret, cattle, and squirrel monkey by intracerebral inoculation. With the known incubation periods in other TSEs, oral transmission studies of CWD may take much longer. Every victim/family of CJD/TSEs should be asked about route and source of this agent. To prolong this will only spread the agent and needlessly expose others. In light of the findings of Asante and Collinge et al, there should be drastic measures to safeguard the medical and surgical arena from sporadic CJDs and all human TSEs. I only ponder how many sporadic CJDs in the USA are type 2 PrPSc?
http://www.neurology.org/cgi/eletters/60/2/176#535re-Human Prion Diseases in the United States
Posted by flounder on 01 Jan 2010 at 18:11 GMT
http://www.plosone.org/annotation/listThread.action?inReplyTo=info%3Adoi%2F10.1371%2Fannotation%2F04ce2b24-613d-46e6-9802-4131e2bfa6fd&root=info%3Adoi%2F10.1371%2Fannotation%2F04ce2b24-613d-46e6-9802-4131e2bfa6fdManuscript Draft Manuscript Number: Title: HUMAN and ANIMAL TSE Classifications i.e. mad cow disease and the UKBSEnvCJD only theory Article Type: Personal View Corresponding Author: Mr. Terry S. Singeltary, Corresponding Author's Institution: na First Author: Terry S Singeltary, none Order of Authors: Terry S Singeltary, none; Terry S. Singeltary Abstract: TSEs have been rampant in the USA for decades in many species, and they all have been rendered and fed back to animals for human/animal consumption. I propose that the current diagnostic criteria for human TSEs only enhances and helps the spreading of human TSE from the continued belief of the UKBSEnvCJD only theory in 2007.
http://www.regulations.gov/fdmspublic/ContentViewer?objectId=090000648027c28e&disposition=attachment&contentType=pdfSaturday, June 13, 2009
Monitoring the occurrence of emerging forms of Creutzfeldt-Jakob disease in the United States 2003 revisited 2009
http://cjdusa.blogspot.com/2009/06/monitoring-occurrence-of-emerging-forms.htmlIF you consider the many different TSE strains in different species in North America, and then think 'friendly fire' there from. For a few years now there seems to be a rise here in the U.S.A. of sporadic CJD strains of 'unknown phenotype', with ;
5 Includes 28 cases in which the diagnosis is pending, and 17 inconclusive cases;
6 Includes 28 (24 from 2010) cases with type determination pending in which the diagnosis of vCJD has been excluded
http://www.cjdsurveillance.com/pdf/case-table.pdfThere is a growing number of human CJD cases, and they were presented last week in San Francisco by Luigi Gambatti(?) from his CJD surveillance collection.
He estimates that it may be up to 14 or 15 persons which display selectively SPRPSC and practically no detected RPRPSC proteins.
http://www.fda.gov/ohrms/dockets/ac/06/transcripts/1006-4240t1.htmhttp://www.fda.gov/ohrms/dockets/ac/06/transcripts/2006-4240t1.pdfATYPICAL BSE MORE VIRULENT TO HUMANS THAN UK STRAIN
18 January 2007 - Draft minutes of the SEAC 95 meeting (426 KB) held on 7 December 2006 are now available.
snip...
64. A member noted that at the recent Neuroprion meeting, a study was presented showing that in transgenic mice BSE passaged in sheep may be more virulent and infectious to a wider range of species than bovine derived BSE.
Other work presented suggested that BSE and bovine amyloidotic spongiform encephalopathy (BASE) MAY BE RELATED. A mutation had been identified in the prion protein gene in an AMERICAN BASE CASE THAT WAS SIMILAR IN NATURE TO A MUTATION FOUND IN CASES OF SPORADIC CJD.
snip...
http://www.seac.gov.uk/minutes/95.pdf2008 - 2010
The statistical incidence of CJD cases in the United States has been revised to reflect that there is one case per 9000 in adults age 55 and older. Eighty-five percent of the cases are sporadic, meaning there is no known cause at present.
http://www.cjdfoundation.org/fact.htmlCJD TEXAS 38 YEAR OLD FEMALE WORKED SLAUGHTERING CATTLE EXPOSED TO BRAIN AND SPINAL CORD MATTER
>>> Up until about 6 years ago, the pt worked at Tyson foods where she worked on the assembly line, slaughtering cattle and preparing them for packaging. She was exposed to brain and spinal cord matter when she would euthanize the cattle. <<<
http://creutzfeldt-jakob-disease.blogspot.com/2010/03/irma-linda-andablo-cjd-victim-she-died.htmlCJD TEXAS 38 YEAR OLD FEMALE WORKED SLAUGHTERING CATTLE EXPOSED TO BRAIN AND SPINAL CORD MATTER
http://cjdtexas.blogspot.com/2010/03/cjd-texas-38-year-old-female-worked.htmlCreutzfeldt-Jakob Disease Surveillance in Texas
http://cjdtexas.blogspot.com/Friday, February 05, 2010
New Variant Creutzfelt Jakob Disease case reports United States 2010 A Review
http://vcjd.blogspot.com/2010/02/new-variant-creutzfelt-jakob-disease.htmlCJD or prion disease 2 CASES McLennan County Texas population 230,213 both cases in their 40s
http://creutzfeldt-jakob-disease.blogspot.com/2010/07/cjd-2-cases-mclennan-county-texas.htmlTuesday, June 1, 2010
USA cases of dpCJD rising with 24 cases so far in 2010
http://cjdtexas.blogspot.com/2010/06/usa-cases-of-dpcjd-rising-with-24-cases.html****************PLEASE READ THE FOLLOWING CAREFULLY************
To date the OIE/WAHO assumes that the human and animal health standards set out in the BSE chapter for classical BSE (C-Type) applies to all forms of BSE which include the H-type and L-type atypical forms. This assumption is scientifically not completely justified and accumulating evidence suggests that this may in fact not be the case. Molecular characterization and the spatial distribution pattern of histopathologic lesions and immunohistochemistry (IHC) signals are used to identify and characterize atypical BSE. Both the L-type and H-type atypical cases display significant differences in the conformation and spatial accumulation of the disease associated prion protein (PrPSc) in brains of afflicted cattle. Transmission studies in bovine transgenic and wild type mouse models support that the atypical BSE types might be unique strains because they have different incubation times and lesion profiles when compared to C-type BSE. When L-type BSE was inoculated into ovine transgenic mice and Syrian hamster the resulting molecular fingerprint had changed, either in the first or a subsequent passage, from L-type into C-type BSE. In addition, non-human primates are specifically susceptible for atypical BSE as demonstrated by an approximately 50% shortened incubation time for L-type BSE as compared to C-type. Considering the current scientific information available, it cannot be assumed that these different BSE types pose the same human health risks as C-type BSE or that these risks are mitigated by the same protective measures.
http://www.prionetcanada.ca/detail.aspx?menu=5&dt=293380&app=93&cat1=387&tp=20&lk=no&cat2Tuesday, August 18, 2009
BSE-The Untold Story - joe gibbs and singeltary 1999 - 2009
http://madcowusda.blogspot.com/2009/08/bse-untold-story-joe-gibbs-and.htmlSaturday, July 17, 2010
Variant Creutzfeldt-Jakob disease Ironside JW., Haemophilia.
2010 Jul;16 Suppl 5:175-80 REVIEW ARTICLE
http://vcjdtransfusion.blogspot.com/2010/07/variant-creutzfeldtjakob-disease.htmlMonday, August 9, 2010
National Prion Disease Pathology Surveillance Center Cases Examined (July 31, 2010)
(please watch this damning video at the bottom of this url...tss)
http://prionunitusaupdate2008.blogspot.com/2010/08/national-prion-disease-pathology.html2010
Original Article
Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein
http://creutzfeldt-jakob-disease.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.htmlMonday, August 9, 2010
Variably protease-sensitive prionopathy: A new sporadic disease of the prion protein or just more Prionbaloney ?
http://prionunitusaupdate2008.blogspot.com/2010/08/variably-protease-sensitive-prionopathy.htmlWednesday, August 11, 2010
Heterozygosity at Polymorphic Codon 219 in Variant Creutzfeldt-Jakob Disease Vol. 67 No. 8, August 2010
http://creutzfeldt-jakob-disease.blogspot.com/2010/08/heterozygosity-at-polymorphic-codon-219.htmlSunday, September 6, 2009 MAD COW USA 1997 [SECRET VIDEO]
http://madcowusda.blogspot.com/2009/09/mad-cow-usa-1997-video.htmlU.S.A. HIDING MAD COW DISEASE VICTIMS AS SPORADIC CJD ? [SEE VIDEO at bottom]
http://creutzfeldt-jakob-disease.blogspot.com/2009/07/usa-hiding-mad-cow-disease-victims-as.htmlDAMNING TESTIMONY FROM STANLEY PRUSINER THE NOBEL PEACE PRIZE WINNER ON PRIONS SPEAKING ABOUT ANN VENEMAN [SEE VIDEO]
http://maddeer.org/video/embedded/prusinerclip.htmlSunday, April 12, 2009 r-calf and the USA mad cow problem, don't look, don't find, and then blame Canada
http://prionunitusaupdate2008.blogspot.com/2009/04/r-calf-and-usa-mad-cow-problem-dont.htmlplease remember this ;
> One monkey inoculated with purified leukocytes from a pre-clinical GSS chimpanzee developed disease after 36 months.
Friday, November 30, 2007
CJD QUESTIONNAIRE USA PRION UNIT CWRU AND CJD FOUNDATION
http://cjdquestionnaire.blogspot.com/TSS
Labels: GSS, Leukocytes reduced, nvCJD, RECALL, red blood cells, USA
