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From: TSS ()
PRODUCT ______________________________ ______________________________ ______________________________ ______________________________ ______________________________ ______________________________ ______________________________ ______________________________ ______________________________ ______________________________ END OF ENFORCEMENT REPORT FOR July 12, 2006 ### http://www.fda.gov/bbs/topics/enforce/2006/ENF00960.html PRODUCT ______________________________ PRODUCT ______________________________ ______________________________ _____________________________________ END OF ENFORCEMENT REPORT FOR July 5, 2006 ### http://www.fda.gov/bbs/topics/enforce/2006/ENF00959.html with new atypical TSE in the bovine, in the sheep, goat, and humans, and the fact that the new BASE TSE in cattle being very very similar to sporadic CJD, rather than the nvCJD, the fact that now science showing the TSE agent of the atypical cattle in Japan showing infectivity other than CNS tissue, the fact that the latest Texas mad cow and the recent Alabama mad cow both being of the atypical strain, it would seem prudent to include all human TSE in the blood ban, in my opinion. ... TSS CJD WATCH MESSAGE BOARD Adriano Aguzzi* and Markus Glatzel Prion infections lead to invariably fatal diseases of the CNS, including Creutzfeldt–Jakob disease (CJD) in humans, bovine spongiform encephalopathy (BSE), and scrapie in sheep. There have been hundreds of instances in which prions have been transmitted iatrogenically among humans, usually through neurosurgical procedures or administration of pituitary tissue extracts. Prions have not generally been regarded as bloodborne infectious agents, and case–control studies have failed to identify CJD in transfusion recipients. Previous understanding was, however, questioned by reports of prion infections in three recipients of blood donated by individuals who subsequently developed variant CJD. On reflection, hematogenic prion transmission does not come as a surprise, as involvement of extracerebral compartments such as lymphoid organs and skeletal muscle is common in most prion infections, and prions have been recovered from the blood of rodents and sheep. Novel diagnostic strategies, which might include the use of surrogate markers of prion infection, along with prion removal strategies, might help to control the risk of iatrogenic prion spread through blood transfusions. ... snip... INTRODUCTION Prion diseases, also termed transmissible SPONGIFORM ENCEPHALOPATHIES, constitute a group of neurodegenerative conditions that are transmissible within and between mammalian species. A characteristic of these diseases is the accumulation of a misfolded prion protein, PrPSc, which is a post-translationally modified form of the host-encoded prion protein (PrPC). The processes underlying PrPSc formation remain enigmatic, but there is little doubt that a conformer of PrPC, which might exist in an oligomeric form,1 is identical to the infectious entity.2 Prions damage the brain by transmitting toxic signals to cells expressing PrPC.3 Although genetic evidence has been taken to indicate that human prion diseases have been with us since prehistoric times,4 the first documented cases of Creutzfeldt–Jakob disease (CJD) date back only 85 years.5–7 Since then, it has become obvious that human prion diseases have three distinct etiologies: they can arise in the absence of any documented exposure to infectious prions as sporadic CJD (sCJD), as an autosomal dominantly inherited disease in the case of genetic, or familial, CJD (gCJD/fCJD), or as an acquired condition in the case of IATROGENIC and variant CJD (iCJD, vCJD), or kuru, which resulted from cannibalism.8 Some prion diseases that occur in animals might have been recognized several centuries ago, as suggested by early descriptions of sheep diseases that seem to correspond to scrapie. Most prion diseases affecting animals, however, were discovered relatively recently.6 A transmissible spongiform encephalopathy affecting cattle (bovine spongiform encephalopathy, or BSE) has caused a massive epidemic in European countries, affecting around 2 million animals.9 Epidemiological, biochemical, neuropathological and transmission studies have substantiated the concern that BSE prions might have crossed the species barrier between cattle and humans, resulting in a novel form of human prion disease, vCJD.10–13 During 1996–2001, the incidence of vCJD in the UK rose year upon year, evoking fears of a large upcoming epidemic. Since 2001, however, the incidence of vCJD in the UK appears to have been stabilizing, indicating that the extent of the epidemic might be limited.14 As might be expected for in frequent stochastic events, the numbers of new cases of vCJD fluctuate from year to year. For example, data available on the web page of the National CJD Surveillance Unit15 show that the number of onsets of vCJD was higher in 2004 than it was in 2003, but this is not necessarily indicative of an upward trend. It must be assumed that a number of asymptomatic carriers of vCJD exist in human populations that have been exposed to BSE. The existence of such a chronic carrier state is a logical and unavoidable consequence of the long incubation time of prion diseases, which is typically in the order of several years and— in the case of oral exposure to prions—can reach several decades. Consequently, anybody who has contracted the infection but has not developed clinical signs and symptoms might be consider ed a carrier. Some of these carriers are likely be ‘preclinical’, and will proceed, in due course, to the development of disease. Alternatively, it is conceivable that the carrier state can persist for an indefinite period of time, in which case infected individuals could be regarded as ‘permanent asymptomatic (sub clinical) carriers’. Studies performed in rodents indicate that the permanent subclinical carrier state might be a common phenomenon, such as occurs when immune deficient mice are exposed to prions.16 Unlinked anonymous screens for hallmarks of prion infection in archival tissues have suggested that the prevalence of individuals with sub clinical vCJD might be higher than previously antici pated, and could reach 237 cases per million individuals.17 The recent discovery of transmission of vCJD via blood in three individuals indicates with near certainty that blood-borne prion transmission, in conjunction with an unknown prevalence of vCJD-infected carriers, leads to secondary transmission of host-adapted prions.18 Consequently, the vCJD epidemic might be prolonged, or, in the worst-case scenario, vCJD be rendered endemic and selfsustained. In this article, we review how prions could act as blood-borne infectious agents, and consider strategies aimed at minimizing the risk of secondary trans mission of prion diseases. TRANSMISSION OF PRION DISEASES IN HUMANS The cause of most human prion diseases is unknown. In the case of sCJD, the term ‘sporadic’ is used as a euphemism, meaning that we have no idea about the origin of this form of CJD. By contrast, gCJD always segregates within families with mutations in the gene encoding the prion protein (PRNP), suggesting that these mutations are causally involved in disease pathogenesis. As no families have been described in which gCJD segregates with mutations in genes other than PRNP, it has been difficult to use human genetics to understand the pathogenesis of prion diseases. The discovery of PRNP mutations in gCJD has led to the proposal that at least some cases of sCJD might be due to somatic PRNP mutations analogous to those found in the germline of gCJD patients. It is equally possible, however, that some of the cases of alleged sCJD derive from hitherto unrecognized infectious causes. In apparent agreement with the ‘intrinsic’ origin of sCJD, which accounts for more than 90% of all human prion diseases, epidemiological studies were not able to identify a conclusive link between this form of CJD and external risk factors.19 This fact is reflected in the pathological and biochemical features of these diseases. Although low levels of PrPSc and prion infectivity can be demonstrated in peripheral sites such as lymphoid organs or skeletal muscle,20,21 the highest levels of PrPSc and prion infectivity appear to occur in the CNS. These facts might account, at least in part, for the lack of evidence of sCJD transmission by labile or stable blood products.22 Indeed, several retrospective studies have failed to identify blood transfusion or exposure to plasma products as risk factors for the development of sCJD,19 and prion diseases appear to be exceedingly rare in hemophiliacs, a group of patients that is at particularly high risk of contracting emerging blood-borne infectious diseases. Although these studies cannot exclude the possibility that transmission of sCJD might have occurred through blood transfusions in rare cases, and despite the fact that the etiology of sCJD is unclear, it would appear that transmission of sCJD by trans fusion of blood or blood products does not play a major role in the pathogenesis of this disease entity. In the case of acquired prion diseases, however, the situation is very different. For vCJD, high levels of prion infectivity and of PrPSc have been detected in lymphoid organs such as the appendix and tonsils (Figure 1).23,24 For this reason, it has been speculated for almost a decade that vCJD might be associated with a higher risk of blood-borne transmission than sCJD. It is important to be cautious, however, as the differences in the organ tropism of sCJD and vCJD might be quantitative rather than qualitative, and PrPSc has been detected in the lymphoid organs of both vCJD and sCJD patients.21 Initial studies have failed to detect PrPSc and prion infectivity in the blood of patients with vCJD, but these negative data are likely to be attributable to the lack of sensitivity of the assays available at the time.23 The recent identification of three indiv iduals with probable transmission of vCJD via blood transfusion has provided tragic evidence that vCJD prions can indeed be transmitted through blood (Figure 2). On the basis of the epi demiological and pathogenetic considerations discussed above, it can only be a matter of time before further cases of blood-transfusion-associated cases of vCJD will ensue (Figure 3). In the first of the cases reported, a patient received a single unit of non-leukodepleted erythrocyte concentrate from an individual who went on to develop vCJD 3.5 years later, and was therefore likely to have been subclinically prion-infected at the time of the donation. The recipient developed vCJD 6.5 years following the transfusion.25 In the second case, transmission of prion disease occurred again via a single unit of nonleukodepleted red-blood-cell concentrate. The donor developed vCJD 2 years following blood donation, again raising the possibility of pre clinical infection at the time of the donation. 18 The recipient died of causes unrelated to the prion infection 5 years after the transfusion. Although this individual did not display overt signs of vCJD, PrPSc could be detected in lymphoid organs, enforcing the concept of subclinical prion disease in this individual. Recently, a third case of blood-borne prion transmission has been reported.26 In this case, the incubation time in the recipient was 8 years, whereas the donor showed vCJD symptoms 20 months following his blood donation. Until now, sequencing of the PRNP gene in all individuals who succumbed to vCJD revealed homozygosity for the sequence ‘ATG’, which encodes methionine, at codon 129. In the general population, only 33% of people are homozygous for ATG at this codon of PRNP, so this particular genetic trait, known as the MM genotype, has been regarded as a risk factor for vCJD.8 The second identified recipient of prioninfected blood, however, was heterozygous for methionine/valine at codon 129 (MV genotype). The MV genotype is underrepresented in sporadic and acquired CJD, and has therefore been considered a protective genetic trait. The fact that this individual died of a cause unrelated to prion disease raises the question of whether MV heterozygotes might develop a permanent carrier status, in which the prion replicates within their body but clinical signs are absent for an indeterminate period of time. Of course, it would be imprudent to draw far-reaching conclusions on the basis of three cases of blood-borne prion infection. We deem it justified, however, to highlight a number of surprising details that have become clear on analysis of these cases. First, vCJD prions can indeed propagate using blood as a vector. In the past, this idea has often been regarded as ‘worst-case scenario’, ‘highly specula tive’, and ‘barely a theoretical possibility’. The wishful thinking of many physicians involved in blood transfusion has often conjured up a sense of safety, which, as we regrettably now know, is unwarranted. Second, a single unit of vCJD-prion-infected blood is sufficient to cause transmission of the disease. This fact is particularly unsettling, as it can only be taken to signify that the concentration of ID50 units in blood is relatively high. One ID50 unit is defined as the infectious dose sufficient to establish infection in 50% of recipients; animal experiments indicate that the amount of prion infectivity needed to reach one ID50 unit is much higher when prions are administered intravenously than when they are inoculated intracerebrally. Third, blood from preclinically vCJD-infected patients can be infectious. Although not un expected, this aspect is particularly worrisome, as it suggests that preclinical donors might subjectively not consider themselves at risk. Consequently, the only way to identify such donors would be to subject the donation to a prion screen of satisfactory sensitivity, which is currently unavailable. Last, despite all epidemiological evidence to the contrary, patients who are methionine/valine heterozygous at codon 129 of the PRNP gene are susceptible to infection with vCJD prions, which raises several important questions. Is the virulence of BSE prions enhanced when passaged from human to human, as opposed to the original bovine to human situation? Passaging experiments of scrapie infectivity between mice and hamsters indicate that this scenario is highly plausible.6 Even more importantly, can vCJD infection of heterozygous individuals establish a permanent subclinical carrier state? Although this situation might constitute a best-case scenario for the infected individuals, it could be disastrous from an epidemiological viewpoint, as it might lead to an unrecognized and possibly self-sustaining epidemic. ... snip... full text ; JUNE 2006 VOL 2 NO 6 AGUZZI AND GLATZEL NATURE CLINICAL PRACTICE NEUROLOGY 329 www.nature.com/clinicalpractice/neuro p.s. please note the 47 PENDING CASES to Sept. 2005 p.s. please note the 2005 Prion D. total 120(8) p.s. please note sporadic CJD 2002(1) 1=3 TYPE UNKNOWN??? p.s. please note 2004 prion disease (6) 6=7 TYPE CWD TO HUMANS = sCJD ??? snip... http://www.bseinquiry.gov.uk/files/yb/1991/01/04004001.pdf As of August 31, 2005, there were 115 scrapie infected snip... full text ; http://www.aphis.usda.gov/vs/nahps/scrapie/monthly_report/monthly-report.html Published online before print October 20, 2005 Proc. Natl. Acad. Sci. USA, 10.1073/pnas.0502296102 A newly identified type of scrapie agent can naturally ( sheep prion | transgenic mice ) Annick Le Dur *, Vincent Béringue *, Olivier Scrapie in small ruminants belongs to transmissible A.L.D. and V.B. contributed equally to this work. To whom correspondence should be addressed. Hubert Laude, E-mail: laude@jouy.inra.fr www.pnas.org/cgi/doi/10.1073/pnas.0502296102 03-025IFA From: Terry S. Singeltary Sr. [flounder9@verizon.net] Sent: Thursday, September 08, 2005 6:17 PM To: fsis.regulationscomments@fsis.usda.gov Subject: [Docket No. 03-025IFA] FSIS Prohibition of the for the Disposition of Non-Ambulatory Disabled Cattle Greetings FSIS, I would kindly like to submit the following to [Docket Requirements for the Disposition of Non-Ambulatory THE BSE/TSE SUB CLINICAL Non-Ambulatory Disabled Cattle Broken bones and such may be the first signs of a sub SUB CLINICAL PRION INFECTION MRC-43-00 Issued: Monday, 28 August 2000 NEW EVIDENCE OF SUB-CLINICAL PRION INFECTION: IMPORTANT FINDINGS RELEVANT TO CJD AND BSE Terry S. Singeltary Sr. P.O. Box 42 Bacliff, Texas USA 77518 9/13/2005 http://www.fsis.usda.gov/OPPDE/Comments/03-025IFA/03-025IFA-2.pdf
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