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Clinical Implications of Bovine Spongiform Encephalopathy

  1. Chris MacKnight
  1. Division of Geriatric Medicine, Dalhousie University, Halifax, Nova Scotia, Canada
  1. Reprints or correspondence: Dr. Chris MacKnight, Rm. 1308, Camp Hill Veterans' Memorial Building, 5955 Veterans' Memorial Ln., Halifax, NS, B3H 2E1, Canada (domcrm{at}qe2-hsc.ns.ca).
 
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Abstract

Bovine spongiform encephalopathy (BSE) is a new prion disease that was first identified in the United Kingdom in 1987. Its appearance was likely caused by changes in the rendering process used to produce a meat and bone supplement for cattle, changes that allowed this prion to enter the bovine food supply. Despite measures that were made to reduce the risk to humans, a new variant of Creutzfeldt-Jakob disease appeared in the mid-1990s and has been linked to BSE. Although the extent of the disease's impact on humans is not yet known, current estimates predict that there will be 136,000 cases of this fatal disease by the year 2040. The risk to humans of medications produced with bovine materials, gelatin, and blood transfusion is unknown.

Bovine spongiform encephalopathy (BSE), commonly known as “mad cow disease,” is a member of the family of prion diseases, or transmissible spongiform encephalopathies. After the first recognition of BSE in England in 1987 [1], an epidemic of disease occurred among cattle, and BSE has since been implicated in new diseases of humans (variant Creutzfeldt-Jakob Disease [vCJD]) and animals (feline spongiform encephalopathy, encephalopathy of exotic ungulates, and spongiform encephalopathy of captive primates). Prions are unique infectious agents that pose unique challenges for physicians. This discussion will focus on the nature of prions, factors that led to the BSE epidemic, implications for the treatment of patients with suspected CJD, and efforts to limit the spread of the responsible agent.

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Prion Diseases

The prion diseases are summarized in table 1. Scrapie was the first to be described, in Europe in the eighteenth century [2]. Scrapie is a rapidly progressive, fatal neurological disease of sheep and goats that is endemic in many parts of the world, including Europe and North America. Both infectious and inheritable components were recognized early, but an understanding of the transmission and pathophysiology developed only in the twentieth century. Scrapie was experimentally transmitted by inoculation of brain or spinal cord tissue from affected animals into unaffected animals. The incubation period was longer for animals with peripheral inoculation that it was for animals with direct intracerebral inoculation. This led to a number of transmission experiments that demonstrated that the disease could be transmitted to sheep by feeding the sheep contaminated tissue, that unaffected herds that had pastured with affected herds developed the disease, and even that unaffected herds that had grazed in pastures that were previously used by affected herds developed the disease. (This last observation has since been explained by persistence of the infectious agent in hay mites in the pastures [3]). Despite a few suggestive studies, in utero transmission of the scrapie agent has not been demonstrated [4]. Studies of naturally infected sheep demonstrate that the infectious agent first appears in tonsils and gut lymphatic tissue when the sheep are very young, which strongly suggests that natural infection occurs by the oral route [5].

Table 1
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Table 1

Prion diseases in humans and nonhumans and the dates on which they were first reported.

Diseases similar to scrapie were recognized in mink on Wisconsin mink farms (transmissible mink encephalopathy) and were believed to have originated with the consumption of scrapie-infected sheep products in feed, and in elk, black-tailed deer, and mule deer (chronic wasting disease) in western North America. The source of chronic wasting disease is not known, although the most likely explanations are either that it is caused by exposure to scrapie-infected animals or that it is a natural, albeit rare, disease of these animals.

In 1955, a new illness, kuru, was recognized among the Fore people of New Guinea [6]. Kuru was a rapidly progressive neurological disorder characterized by cerebellar and cognitive deterioration, and affected persons usually died within 6 months of onset. Gadjusek linked the disease to the Fore's death ritual, which involved exposure to and ingestion of the brain tissue of deceased relatives. A veterinarian, Hadlow, recognized the similarity between kuru and scrapie. This lead to studies that showed that kuru could be transmitted to primates by means of both inoculation and consumption of contaminated tissue. For this work, Gadjusek and a colleague were awarded the Nobel Prize in 1976.

A similarity was also recognized between kuru and CJD. CJD was first described in 1920, and a related condition, Gerstmann-Sträussler-Scheinker (GSS) syndrome, was identified soon thereafter, in 1928. Both conditions are rapidly progressive encephalopathies; CJD is found in sporadic, familial and iatrogenic forms, whereas GSS syndrome is purely familial. After the relationship to kuru was recognized, both of these diseases were experimentally transmitted to primates. The family of transmissible spongiform encephalopathies was beginning to take shape.

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Prions

Science, however, was stumped. How could a disease be both inherited and infectious? What was known was that the agents of scrapie and CJD did not behave like viruses, because they were resistant to inactivation by heat, radiation, and formalin, and they lacked nucleic acid. Prusiner [7] proposed that the responsible agent was an infectious protein and coined the term “prion.” This lead to the discovery of the prion protein, its gene, and an understanding of its pathophysiology. Prions are normal components of neurons with an unclear function, although they are involved in neuronal development and function and prevention of cell death. Abnormal forms of prion protein (PrPsc) fold into insoluble amyloid, are very resistant to metabolism by proteases, and can induce conformational change in normal prion (PrPc). Therefore, a prion disease can be genetic, if a mutation in the prion gene leads to formation of PrPsc, and it can be infectious, if exposure to PrPsc causes the host's PrPc to undergo conformational change. The presumably sporadic CJD reflects the rare chance—literally, one in a million—that a normal PrPc will assume the abnormal conformation. The absence of nucleic acid and the stable abnormal conformation explain the difficulty in disinfecting contaminated objects. Prusiner was awarded the Nobel Prize for this work in 1997. Not all scientists have accepted the prion hypothesis, and some have expressed contrary views [8, 9].

The spread of prions within the body can also be explained by Prusiner's hypothesis. Gut epithelium expresses both prion protein and appropriate receptors [10, 11]. After crossing the epithelium, the initial infection and replication involve follicular dendritic cells, followed by neuroinvasion via peripheral nerves [12]. Studies with mice that lack the prion gene confirm that the host prion is necessary for infection.

Furthermore, Prusiner's hypothesis also explains the presence of prion strains [7]. Prions that are isolated from different hosts may have different characteristics, chiefly with regard to incubation period and neuropathology. A species barrier exists: prions that infect 1 species are usually not pathogenic for many others. For example, although mice are susceptible to scrapie, hamsters are not; there is no evidence that scrapie infects humans; and not all primates can be infected with CJD. Differences in prion structure and sequence presumably explain the presence of strains and the species barrier.

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Clinical Characteristics

CJD is rare; it has a stable incidence of 1 case per million persons worldwide [13]. Many risk factors have been implicated for sporadic CJD, but other than those for iatrogenic CJD (which is reviewed comprehensively elsewhere [14]) and familial CJD, none is well proven.

CJD is a horrible disease that progresses rapidly. The median duration from onset to death is only 4.5 months. A definitive diagnosis can only be made at autopsy. As outlined in table 2, the diagnosis is predominantly clinical [15]. Electroencephalography, assays of CSF, and MRI can sometimes be helpful. Despite interest in biopsies of tonsillar specimens to identify prion protein, the sensitivity, specificity, and use of biopsy in patients with the various forms of CJD are not yet understood [16]. CJD should be suspected in any case of rapidly progressive neurological disorder and an autopsy should be requested for confirmation of diagnosis.

Table 2
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Table 2

Criteria of the World Health Organization for clinical diagnosis of sporadic Creutzfeldt-Jakob disease (CJD).

There is no treatment for CJD. Promising avenues of research include use of molecules to disrupt the prion molecule or to prevent its spread from the gut to the brain.

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Infection Control

Surfaces that have been contaminated by prions are notoriously difficult to disinfect, and individuals who are exposed to the CNS of CJD victims are theoretically at great risk. Recommendations and exact protocols are available from the World Health Organization [17]. There are some surprising dilemmas; for instance, infectivity of surfaces and instruments is enhanced and stabilized by drying and fixation through exposure to alcohol, formalin, and glutaraldehyde. The safest method of preventing the spread of disease is to destroy all instruments that have been used on an affected individual. If this is impossible, objects should be mechanically cleaned, immersed in 1 M sodium hydroxide, and then autoclaved. Work surfaces should be flooded with 2 M sodium hydroxide and then allowed to soak for 1 h. Personnel must also take special precautions. Extraordinary nursing precautions are not needed, because casual contact poses no transmission risk.

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BSE

In 1986, a new, rapidly progressive encephalopathy of cattle was identified in the United Kingdom [1]. Within a year, its status as a prion disease was established. BSE was made a notifiable disease (i.e., a disease that must be reported to the appropriate government agency), and epidemiological studies were initiated to identify the source. The discoveries that most affected animals were 3–5 years old, that the disease was much more common among dairy cattle than it was among beef cattle, and that BSE had first appeared in widely separated areas all suggested a common point-source for the epidemic of disease [18]. A series of case-control studies implicated a commonly used meat and bone meal supplement [19].

Prior to the late 1970s, rendering plants converted cattle refuse into both tallow and a meat and bone meal supplement. Organic solvents were used to extract the fat to make the tallow. This process was modified, driven by the declining value of tallow, the increasing costs of this high-energy extraction process, and concerns regarding worker safety. The resulting system left the fat intact—fat in which a prion could remain viable. The current hypothesis is that either scrapie-infected sheep tissue entered this process or that a very rare but preexisting BSE was allowed to flourish while tissue from sick animals was recycled through the system. The same substance was implicated in new diseases discovered in cats, ungulates, and primates.

In 1988, the United Kingdom banned ruminant tissue from cattle feed, and a slaughter policy was introduced for all sick cattle. Bovine offal was banned from human food in 1989, from animal feed in 1990, and from fertilizer in 1991. The use of any nervous tissue from cattle in human food was banned in 1995. These policies, coupled with public suspicion and international export bans, effectively destroyed the cattle industry in the United Kingdom. These policies also successfully slowed the epidemic of disease, which reached a peak in 1993 with an incidence of ∼3500 cases per month. As of 1999, ∼175,000 cases had been reported in the United Kingdom and ∼1100 had been reported elsewhere in Europe [20]. Despite this success in controlling the BSE epidemic, ∼750,000 cattle that were infected with the BSE agent would have entered the human food chain in the United Kingdom from 1980 through 1996 [21]. Unfortunately, other countries have not been as vigilant; even in the year 2001, meat from BSE-affected cattle continues to enter the human food chain in some European countries.

Cattle in North America are unlikely to be at risk for acquisition of BSE. No cases have been identified in cattle that are native to continents other than Europe. Extensive surveillance in the United States has not uncovered a hidden epidemic of disease [22], despite early reports that sick American cattle, when fed to mink, caused transmissible mink encephalopathy [23]. The United States has not imported beef from the United Kingdom since the mid-1980s. Another factor that has limited the risk in the United States is that little sheep-derived material enters the feed for American cattle [22].

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VCJD

At the height of public fears surrounding BSE, the unthinkable became true. The National CJD Surveillance Unit in the United Kingdom, which was founded in 1990 in anticipation of just this event, reported that, in early 1994, a new form of CJD (vCJD) had been identified [24]. These cases differed from cases of sporadic CJD in many important ways: the affected patients tended to be young to middle-aged, psychiatric symptoms and ataxia were prominent early in the course of disease, the typical findings on electroencephalography were not present, and the PrP plaques found during neuropathological testing were extensively distributed and surrounded by a unique halo of spongiform change. All of the cases had a particular PrP genotype (i.e., all were homozygous for methionine at codon 129) [25]. Codon 129 is polymorphic; in the United Kingdom, 38% of the population is homozygous for methionine, 12% is homozygous for valine, and 50% have mixed valine-methionine [26]. Individuals who were homozygous for methionine were known to be more susceptible to iatrogenic CJD. Diagnostic criteria for vCJD have been proposed by the World Health Organization (table 3) [15]. The unique neuropathology adds to the convincing reasons to request an autopsy of patients with suspected CJD; if a case of vCJD is discovered in a North American person who has not traveled to Europe, the epidemiology and epidemic potential will need careful reconsideration.

Table 3
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Table 3

World Health Organization diagnostic criteria for new variant Creutzfeldt-Jakob disease.

Although there is no direct evidence that links BSE with vCJD, the epidemiological evidence is strong. In addition, the strain of prion found in BSE and vCJD and in cats in the United Kingdom is identical and distinct from the strain that is found in sporadic or iatrogenic CJD [27].

At the time of writing, 85 cases of vCJD have been reported in the United Kingdom, 3 have been reported in France, and 1 has been reported in Ireland. The rate of incidence in the United Kingdom has steadily increased (figure 1), from 2 per quarter in 1994 to 6.5 per quarter in 2000 [28]. On the assumption that there is no ongoing new infection and that the incubation period will be <60 years, ∼136,000 cases are expected in the United Kingdom by 2040 [29].

Figure 1
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Figure 1

Incidence of variant Creutzfeldt-Jakob disease (vCJD). (Reproduced with permission from [28].)

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Further Risks

It is difficult to know how accurate the prediction by Ghani et al. [29] will prove to be, but several factors could conspire to inflate the number of cases. Hamster species, which had been believed to be resistant to scrapie, carry the agent without becoming ill [30]. Could silent reservoirs of the BSE agent exist in other species that have consumed contaminated meal supplement or with unrecognized prion diseases [20]? For example, 3 recent cases of CJD in North America involved deer hunters, although this was probably a coincidence, because no evidence of chronic wasting disease has been found in deer in these patients' regions [20].

Ghani et al. [29] assumed that only the 38% of the population that is homozygous for methionine at codon 129 would be susceptible. Originally, only homozygotes were believed to be susceptible to iatrogenic CJD from human growth hormone. Further experience, however, has shown that heterozygotes do develop the disease, although the duration of the incubation period is much longer [31].

Maternal transmission may prolong the BSE epidemic. Although vertical infection (as opposed to genetic transmission) has not been definitively proven for other prion diseases, low-level maternal transmission does occur among cattle with BSE [32]. In the summer of 2000, a news report in the British Medical Journal suggested that the infant of a woman dying of vCJD also had the disease. Finally, persistence of the BSE agent in the environment, as occurs with scrapie, may prolong the epidemic [3].

The infectivity of drugs and vaccines produced from cattle, such as bovine insulin and some rabies vaccines, is unknown. To address this concern, the US Food and Drug Administration has banned biological agents of bovine origin produced in countries at risk of BSE [33]. Similarly, the risks from other substances of bovine origin, such as gelatins, is unknown.

The risk of acquiring CJD by means of blood transfusion is also unknown. Although prions are present in blood and can be experimentally transmitted by means of transfusion [34], no known case of transfusion-related CJD has occurred [35]. To minimize any risk, a number of countries, including Canada and the United States, have implemented policies to prevent the use of blood obtained from people who have been exposed to a prion disease; Canada has even prevented the use of blood obtained from people who lived in certain parts of Europe during the BSE epidemic.

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Policy Implications

Many of the policy implications of prion diseases, and particularly the fallout from the BSE/vCJD epidemic, have been touched on above. CJD is a notifiable disease in many countries, many intensive surveillance programs exist, and CJD is a topic of special interest to the World Health Organization (see, for example, their Web site, at http://www.who.int/health-topics/tse.htm). Restrictions have been placed on blood donations, animal husbandry, and trade. Despite severe criticism of the British government for perceived foot dragging [36], there have been outbreaks of BSE in Europe in 2000–2001, which shows that little has been learned. Deregulation of the agricultural industry in the United Kingdom during the Thatcher years has also been blamed [37]. In 1979, a parliamentary committee recommended against changes to the rendering process that might have prevented this epidemic of disease, but no legislation was passed.

The BSE experience is sobering and frightening. The use of a more efficient technology (i.e., the change in the rendering process) has resulted in the possibility that >100,000 people will die of a new disease and the beef industry in the United Kingdom will be destroyed. Any future changes to our food, or the manner in which it is produced, should be carefully considered and long-term studies should be performed before widespread implementation.

  • Received November 27, 2000.
  • Revision received January 25, 2001.
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References

  1. ↵
    1. Wells GAH,
    2. Scott AC,
    3. Johnson CT,
    4. et al
    . A novel progressive spongiform encephalopathy in cattle. Vet Rec 1987;121:419-20.
    CrossRefMedlineWeb of Science
  2. ↵
    1. Brown P,
    2. Bradley R
    . 1755 and all that: a historical primer of transmissible spongiform encephalopathy. BMJ 1998;317:1688-92.
    FREE Full Text
  3. ↵
    1. Wisniewski HM,
    2. Sigurdarson S,
    3. Rubenstein R,
    4. Kascsak RJ,
    5. Carp RI
    . Mites as vectors for scrapie. Lancet 1996;347:1114.
    MedlineWeb of Science
  4. ↵
    1. Ridley RM,
    2. Baker HF
    . The myth of maternal transmission of spongiform encephalopathy. BMJ 1995;311:1071-6.
    FREE Full Text
  5. ↵
    1. Hadlow WJ,
    2. Kennedy RC,
    3. Race RE
    . Natural infection of Suffolk sheep with scrapie virus. J Infect Dis 1982;146:657-64.
    Abstract/FREE Full Text
  6. ↵
    1. Gadjusek DC
    . Unconventional viruses and the origin and disappearance of kuru. Science 1977;197:943-60.
    FREE Full Text
  7. ↵
    1. Prusiner SB
    . Prions. Proc Natl Acad Sci U S A 1998;95:13363-83.
    Abstract/FREE Full Text
  8. ↵
    1. Balter M
    . Prions: a lone killer or a vital accomplice? Science 1999;286:660-2.
    FREE Full Text
  9. ↵
    1. Somerville RA
    . Is there more to TSE diseases than PrP? Trends Microbiol 2000;8:157-8.
    CrossRefMedlineWeb of Science
  10. ↵
    1. Pammer J,
    2. Cross HS,
    3. Frobert Y,
    4. Tschachler E,
    5. Oberhuber G
    . The pattern of prion-related expression in the gastrointestinal tract. Virchows Arch 2000;436:466-72.
    CrossRefMedlineWeb of Science
  11. ↵
    1. Shmakov AN,
    2. Bode J,
    3. Kilshaw PJ,
    4. Ghosh S
    . Diverse patterns of expression of the 67-kD laminin receptor in human small intestinal mucosa: potential binding sites for prion proteins? J Pathol 2000;191:318-22.
    CrossRefMedlineWeb of Science
  12. ↵
    1. Brown KL,
    2. Stewart K,
    3. Ritchie DL,
    4. et al
    . Scrapie replication in lymphoid tissues depends on prion protein-expressing follicular dendritic cells. Nat Med 1999;5:1308-12.
    CrossRefMedlineWeb of Science
  13. ↵
    1. MacKnight C,
    2. Rockwood K
    . Bovine spongiform encephalopathy and Creutzfeldt-Jakob disease: implications for physicians. CMAJ 1996;155:529-36.
    Abstract
  14. ↵
    1. Brown P,
    2. Preece M,
    3. Brandel J-P,
    4. et al
    . Iatrogenic Creutzfeldt-Jakob disease at the millennium. Neurology 2000;55:1075-81.
    Abstract/FREE Full Text
  15. ↵
    World Health Organization. Global surveillance, diagnosis, and therapy of human transmissible spongiform encephalopathies: report of a WHO consultation. World Health Organization Web site, 1998; available at http://www.who.int/health-topics/tse.htm.
  16. ↵
    1. Hill AF,
    2. Butterworth RJ,
    3. Joiner S,
    4. et al
    . Investigation of variant Creutzfeldt-Jakob disease and other human prion diseases with tonsil biopsy samples. Lancet 1999;353:183-9.
    CrossRefMedlineWeb of Science
  17. ↵
    World Health Organization. WHO infection control guidelines for transmissible spongiform encephalopathies. World Health Organization Web site, 2000; available at http://www.who.int/health-topics/tse.htm.
  18. ↵
    1. Nathanson N,
    2. Wilesmith J,
    3. Griot C
    . Bovine spongiform encephalopathy (BSE): causes and consequences of a common source epidemic. Am J Epidemiol 1997;145:959-69.
    Abstract/FREE Full Text
  19. ↵
    1. Wilesmith JW,
    2. Ryan JB,
    3. Atkinson MJ
    . Bovine spongiform encephalopathy: epidemiological studies on the origin. Vet Rec 1991;128:199-203.
    Abstract
  20. ↵
    World Health Organization. WHO consultation on public health and animal transmissible spongiform encephalopathies: epidemiology, risk, and research requirements. World Health Organization Web site, 2000; available at http://www.who.int/health-topics/tse.htm.
  21. ↵
    1. Anderson RM,
    2. Donnelly CA,
    3. Ferguson NM,
    4. et al
    . Transmission dynamics and epidemiology of BSE in British cattle. Nature 1996;382:779-88.
    CrossRefMedline
  22. ↵
    1. Tan L,
    2. Williams MA,
    3. Khan MK,
    4. Champion HC,
    5. Nielsen NH
    ; for the Council on Scientific Affairs, American Medical Association. Risk of transmission of bovine spongiform encephalopathy to humans in the United States: report of the Council on Scientific Affairs. JAMA 1999;281:2330-9.
    Abstract/FREE Full Text
  23. ↵
    1. Marsh RF,
    2. Bessen RA,
    3. Lehmann S,
    4. Hartsough GR
    . Epidemiological and experimental studies on a new incident of transmissible mink encephalopathy. J Gen Virol 1991;72:589-94.
    Abstract/FREE Full Text
  24. ↵
    1. Will RG,
    2. Ironside JW,
    3. Zeidler M,
    4. et al
    . A new variant of Creutzfeldt-Jakob disease in the UK. Lancet 1996;347:921-5.
    CrossRefMedlineWeb of Science
  25. ↵
    1. Zeidler M,
    2. Stewart GE,
    3. Barraclough CR,
    4. et al
    . New variant Creutzfeldt-Jakob disease: neurological features and diagnostic tests. Lancet 1997;350:903-7.
    CrossRefMedlineWeb of Science
  26. ↵
    1. Collinge J,
    2. Palmer MS,
    3. Dryden AJ
    . Genetic predisposition to iatrogenic Creutzfeldt-Jakob disease. Lancet 1991;337:1441-2.
    CrossRefMedlineWeb of Science
  27. ↵
    1. Collinge J,
    2. Sidle KCL,
    3. Meads J,
    4. Ironside J,
    5. Hill AF
    . Molecular analysis of prion strain variation and the aetiology of “new variant” CJD. Nature 1996;383:685-90.
    CrossRefMedline
  28. ↵
    1. Andrews NJ,
    2. Farrington CP,
    3. Cousens SN,
    4. et al
    . Incidence of variant Creutzfeldt-Jakob disease in the UK. Lancet 2000;356:481-2.
    CrossRefMedlineWeb of Science
  29. ↵
    1. Ghani AC,
    2. Ferguson NM,
    3. Donnelly CA,
    4. Anderson RM
    . Predicted vCJD mortality in Great Britain. Nature 2000;406:583-4.
    CrossRefMedline
  30. ↵
    1. Hill AF,
    2. Joiner S,
    3. Linehan J,
    4. Desbruslais M,
    5. Lantos PL,
    6. Collinge J
    . Species-barrier-independent prion replication in apparently resistant species. Proc Natl Acad Sci U S A 2000;97:10248-53.
    Abstract/FREE Full Text
  31. ↵
    1. Deslys J-P,
    2. Jaegly A,
    3. Huillard d'Aignaux J,
    4. et al
    . Genotype at codon 129 and susceptibility to Creutzfeldt-Jakob disease. Lancet 1998;351:1251.
    MedlineWeb of Science
  32. ↵
    1. Donnelly CA,
    2. Ferguson NM,
    3. Ghani AC,
    4. Wilesmith JW,
    5. Anderson RM
    . Analysis of dam-calf pairs of BSE cases: confirmation of a maternal risk enhancement. Proc R Soc Lond B Biol Sci 1997;264:1647-56.
    Abstract/FREE Full Text
  33. ↵
    1. Asher DM
    . Bovine sera used in the manufacture of biologicals: current concerns and policies of the U.S. Food and Drug Administration regarding the transmissible spongiform encephalopathies. Dev Biol Stand 1999;99:41-4.
    Medline
  34. ↵
    1. Houston F,
    2. Foster JD,
    3. Chong A,
    4. Hunter N,
    5. Bostock CJ
    . Transmission of BSE by blood transfusion in sheep. Lancet 2000;356:999-1000.
    CrossRefMedlineWeb of Science
  35. ↵
    1. Wilson K,
    2. Code C,
    3. Ricketts MN
    . Risk of acquiring Creutzfeldt-Jakob disease from blood transfusions: systematic review of case-control studies. BMJ 2000;321:17-9.
    Abstract/FREE Full Text
  36. ↵
    1. O'Brien M
    . Have lessons been learned from the UK bovine spongiform encephalopathy (BSE) epidemic? Int J Epidemiol 2000;29:730-3.
    Abstract/FREE Full Text
  37. ↵
    1. McKee M,
    2. Lang T,
    3. Roberts JA
    . Deregulating health: policy lessons from the BSE affair. J R Soc Med 1996;89:424-6.
    MedlineWeb of Science
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  1. Clin Infect Dis. (2001) 32 (12): 1726-1731. doi: 10.1086/320760
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