The connection of prion diseases to the dramatically termed "Mad Cow Disease" and to human cannibalistic practices has inevitably led to numerous human interest articles on the topic. One such recent article that discusses the history and recent new findings on prion diseases is "Mad Cow, Cannibalism, and The Shaking Death" by Mo Costandi--a 2013 article published in the British online newspaper The Guardian (link provided below).
In addition to providing a history of Pruisiner's prion hypothesis and the discovery of the Kuru tribe in New Guinea who spread the disease through their cannibalistic practices of ritual brain eating, Costandi includes video footage of a Kuru tribe member suffering from the disease, which provides a unique insight into the reality of the symptoms and progression of the disease. He also discusses a recent occurrence in New Hampshire where a man died of Creutzfeldt-Jakob Disease after having brain surgery using infected instruments that were not properly sanitized (primary article cited links to this article about the incident: http://www.nbcnews.com/health/fatal-rare-brain-disease-confirmed-n-h-patient-15-possibly-4B11220962).
Costandi uses this example to delve into a discussion about how, while only 156 people in the UK, and a smaller number in other countries, have died of CJD, there is cause for concern (Costandi article). He points out that prion diseases may have a latency period of up to 50 years, which has led some epidemiologists to suspect that an epidemic is not impossible in the near future (Id.). He also points out that "almost every person in the UK was exposed to the agent that causes variant CJD." (he quotes to this linked article: http://www.theguardian.com/uk/2008/aug/03/bse.medicalresearch).
I agree that the threat of variant and sporadic CJD is a more important one that people may realize. Because of the continued issues that arise with transmission through medical devices, and because of the very long latency period for disease to arise, researchers should continue to do more to investigate possible causes of transmission and prevention tactics to face the possible future epidemic.
Costandi does not much address the debate surrounding the different theories of prion transmission, but rather conveys Pruisiner's hypothesis. This could have been expounded upon, at least with some indication that differing theories exist; however, that may be a topic for a future article.
Article:
http://www.theguardian.com/science/neurophilosophy/2013/sep/26/mad-cows-cannibalism-kuru
Friday, January 22, 2016
Review of Miyazawa's "Continuous Production of Prions after Infectious Particles Are Eliminated: Implications for Alzheimer's Disease"
The curious nature of Pruisner's Prion Hypothesis as one that challenged the Central Dogma of molecular biology and seems to contravene a number of Koch's postulates, as described in earlier posts, has led a number of researchers to seek alternative explanations for prion transmission and for the core agent of prion diseases. In one such study, Miyazawa et. al. build on prior work by their co-author Manuelidis that showed an absence of detectable prions in material that was demonstrably infectious when injected into healthy brain tissue (Manuelidis 2007).
Miyazawa built on this anomaly to hypothesize that the formation of misfolded PrP proteins in a host may be, rather than progression and transmission of a disease agent itself (misfolded proteins), part of a pathological host response to a different infection (Miyazawa 2012). Compellingly, the research team measured infectious titers from mice suffering from prion diseases at at different stages of progression and provide compelling evidence that prions are present in tissue that is no longer infectious (Id.). Moreover, misfolded PrP proteins formed in brain tissue that had been exposed to "infected" misfolded PrP cells even after all misfolded PrP proteins had been removed (Id.). These two points directly challenge the broadly accepted model of prion transmission that misfolded PrP proteins "teach" normal PrP proteins to misfold.
To summarize Miyazawa's work, the team exposed rate brain cells to infected PrP titers at both proliferating and arresting conditions and over different periods of time in order to compare infectivity of the disease agents at various stages (Miyazawa 2012). As described above, this led them to the interesting results that infective titers that did not contain actual prion proteins led to transmission of prion formation in the healthy tissue and, conversely, titers with high levels of prion proteins that had been treated in arresting conditions after significant time led to, in some cases, no infection (Id.). Compellingly, issue was shown to be infectious in early stages of prion disease and even before the onset of prion disease symptoms (Miyazawa, 2012). However, brain titers of very late-stage mice suffering from TSEs—and where large amounts of PRPsc were present, did not transmit disease to mice injected with that brain material (Miyazawa, 2012).
The results indicate that the prion agent may well not be the infectious agent itself and, as Miyazawa theorizes, a third party agency, such as a virus, is the likely cause for the host response to fight that third party agent, which results in the misfolded PrP protein (Miyazwa 2012). This is profoundly important from an epidemiological standpoint of how prion disease are transmitted. Indeed, if transmission is not the result of misfolded proteins teaching native proteins to fold incorrectly, but rather of a virus causing a host immune reaction, the lure of treatment possibilities arise.
As a result, these authors could consider a study in which infected hosts or rats are treated with antivirals to see if those have any effect on the formation of the prions. This could indicate that, if the virus was kept at bay, the immune system may not form prions as part of a bodily response. In addition, the authors could consider a study in which immunosuppressant drugs may be provided to the host in order to see if disease progression could be halted on that front. These types of future studies could lead to the development of prevention techniques or treatment options better suited to the true agent of prion diseases.
This figure taken from Miyazawa 2012. It shows total PrP (light grey bars) and percent misfolded PrP (dark grey bars) at progressive times in each of three experiments. Notably, titers with high levels of misfolded proteins later in the studies were less infectious than anticipated.
Article Reviewed:
Miyazawa, Kohtaro, T. Kipkorir, S. Tittman, L. Manuelidis, 2012. Continuous production of prions after infectious particles are eliminated: Implications for Alzheimer’s disease. PLoS One. 7(4): 1-8.
Other Works Cited
Miyazawa built on this anomaly to hypothesize that the formation of misfolded PrP proteins in a host may be, rather than progression and transmission of a disease agent itself (misfolded proteins), part of a pathological host response to a different infection (Miyazawa 2012). Compellingly, the research team measured infectious titers from mice suffering from prion diseases at at different stages of progression and provide compelling evidence that prions are present in tissue that is no longer infectious (Id.). Moreover, misfolded PrP proteins formed in brain tissue that had been exposed to "infected" misfolded PrP cells even after all misfolded PrP proteins had been removed (Id.). These two points directly challenge the broadly accepted model of prion transmission that misfolded PrP proteins "teach" normal PrP proteins to misfold.
To summarize Miyazawa's work, the team exposed rate brain cells to infected PrP titers at both proliferating and arresting conditions and over different periods of time in order to compare infectivity of the disease agents at various stages (Miyazawa 2012). As described above, this led them to the interesting results that infective titers that did not contain actual prion proteins led to transmission of prion formation in the healthy tissue and, conversely, titers with high levels of prion proteins that had been treated in arresting conditions after significant time led to, in some cases, no infection (Id.). Compellingly, issue was shown to be infectious in early stages of prion disease and even before the onset of prion disease symptoms (Miyazawa, 2012). However, brain titers of very late-stage mice suffering from TSEs—and where large amounts of PRPsc were present, did not transmit disease to mice injected with that brain material (Miyazawa, 2012).
The results indicate that the prion agent may well not be the infectious agent itself and, as Miyazawa theorizes, a third party agency, such as a virus, is the likely cause for the host response to fight that third party agent, which results in the misfolded PrP protein (Miyazwa 2012). This is profoundly important from an epidemiological standpoint of how prion disease are transmitted. Indeed, if transmission is not the result of misfolded proteins teaching native proteins to fold incorrectly, but rather of a virus causing a host immune reaction, the lure of treatment possibilities arise.
As a result, these authors could consider a study in which infected hosts or rats are treated with antivirals to see if those have any effect on the formation of the prions. This could indicate that, if the virus was kept at bay, the immune system may not form prions as part of a bodily response. In addition, the authors could consider a study in which immunosuppressant drugs may be provided to the host in order to see if disease progression could be halted on that front. These types of future studies could lead to the development of prevention techniques or treatment options better suited to the true agent of prion diseases.
Article Reviewed:
Miyazawa, Kohtaro, T. Kipkorir, S. Tittman, L. Manuelidis, 2012. Continuous production of prions after infectious particles are eliminated: Implications for Alzheimer’s disease. PLoS One. 7(4): 1-8.
Other Works Cited
Manuelidis,
Laura, Z. Yu, N. Barquero, and B. Mullins, 2007. Cells infected with Scrapie and
Creutzfeldt-Jakob disease agents produce intracellular 25-nm virus-like
particles. 104(14): 1965-1970.
Thursday, January 14, 2016
Prion Tansmission - The Ongoing Debate
Since the discovery of misfolded proteins associated with TSEs, Pruisiner’s Prion Hypothesis has been the subject of great debate (Soto, 2011). At its core, the notion that a protein, with no nucleic acid, can itself reproduce as an infectious agent is contrary to Crick’s Central Dogma of Molecular Biology. The hitherto absolute rule that there is no biological informational transfer from protein to nucleic acid, or from protein to protein, is a high obstacle for the concept that prion infectivity is entirely protein-mediated. Moreover, the Prion Hypothesis violates the second of Koch’s postulates to establish causal relationship between infectious agents and disease (Manuelidis, 2007). The ongoing debate has yielded recent
experimental research indicating that prions may well be the result of some
external agent of disease, such as a virus (Manuelidis, 2007).
As with many pathogens, the discovery of “Prion Diseases” preceded the discovery of prions themselves and, thus, led to the search for the causal agent responsible for this transmissible spongiform encephalopathy family of diseases. Between 1957 and 1976, Dr. Carleton Gajdusek studied a transmissible, always fatal, neurodegenerative disease called Kuru in the Fore tribe of Papua New Guinea (Gajdusek, et al., 1967). By successfully transmitting this disease to chimpanzees through cerebral injection of diseased brain tissue, Gajdusek elucidated that the disease was transmissible and had been spread through the Fore population as a result of their endocannibalistic funeral rituals during which diseased brain tissue was consumed (Gajdusek, et al., 1967). Kuru was later linked to other known diseases in animals and human populations due to their similar pathology, specifically Creutzfeldt-Jakob Disease in humans and Scrapie in sheep (Belay, 1999).
It was not until 1997 that, Stanley Pruisiner posited the discovery of the infectious agent cause of TSEs (Pruisiner, 1998). It was then that he laid out the Prion Hypothesis that a misfolded, protease-resistant, form of the Protein PrP was the agent that caused TSEs, and that that misfolded protein could be transmitted to other organisms and cause infectious misfolding (Pruisiner, 1998). Though both forms are encoded by the same PrP gene sequence and, therefore, contain the same polypeptide sequence, normal cellular PrP (PrPc) is converted into its misfolded form (PrPsc) post-translationally (Pruisiner, 1998).
Transmissibility
As with many pathogens, the discovery of “Prion Diseases” preceded the discovery of prions themselves and, thus, led to the search for the causal agent responsible for this transmissible spongiform encephalopathy family of diseases. Between 1957 and 1976, Dr. Carleton Gajdusek studied a transmissible, always fatal, neurodegenerative disease called Kuru in the Fore tribe of Papua New Guinea (Gajdusek, et al., 1967). By successfully transmitting this disease to chimpanzees through cerebral injection of diseased brain tissue, Gajdusek elucidated that the disease was transmissible and had been spread through the Fore population as a result of their endocannibalistic funeral rituals during which diseased brain tissue was consumed (Gajdusek, et al., 1967). Kuru was later linked to other known diseases in animals and human populations due to their similar pathology, specifically Creutzfeldt-Jakob Disease in humans and Scrapie in sheep (Belay, 1999).
It was not until 1997 that, Stanley Pruisiner posited the discovery of the infectious agent cause of TSEs (Pruisiner, 1998). It was then that he laid out the Prion Hypothesis that a misfolded, protease-resistant, form of the Protein PrP was the agent that caused TSEs, and that that misfolded protein could be transmitted to other organisms and cause infectious misfolding (Pruisiner, 1998). Though both forms are encoded by the same PrP gene sequence and, therefore, contain the same polypeptide sequence, normal cellular PrP (PrPc) is converted into its misfolded form (PrPsc) post-translationally (Pruisiner, 1998).
Transmissibility
A significant
attribute of prions is their ability to spread in spite of modern tools and
methods ordinarily thought to prevent diseases transmission. The 1980s-1990s outbreak of Mad Cow Disease
in the UK was later shown to be the result of agricultural feeding methods
whereby tissue of infected animals was reconstituted into the feed of other
livestock (Belay, 1999). In addition,
numerous cases of transmission of CJD have been reported, ranging
from corneal graft transplants, injection of pituitary-derived human growth
hormone, and receipt of infected dura mater grafts (Belay, et al., 2005). Relatedly, prion proteins have been recently
detected in urine-derived human fertility products, suggesting a need for additional
purification processes in their production (Van Dorsselaer et al., 2011). There have also been cases of transmission
through sanitized neurosurgical equipment, which has led to heightened
standards of sanitization (Belay, et al., 2005). Perhaps most chillingly, one lab recently
reported that transgenic mice bred to overexpress PrPc have
developed PrPsc and prion disease upon exposure to aerosolized
prions, which may warrant additional safety precautions surrounding prions
(Haybaeck et al., 2011).
Misfolded PrPsc
are able to bind to normal PrPc and convert them to PrPsc (Pruisiner,
1998). Recent research indicates that the conversion of PrPc to PrPsc
may take place on lipid rafts (Agostini et al., 2013). In a manner that has been likened to
crystallization, misfolded PrP act as seeds whereby their misfolded b-sheet monomers form
intermolecular hydrogen-bonds with PrP monomers, thereby forming aggregates of
ubiquitinated proteins that cause lesions in the brain (Chaudhuri, et al.,
2006). This model involves the formation
of b-linkages with pleated
sheet strands from PrPsc being inserted into pleated sheets of
nearby PrPc, leading to the hydrogen bond formation (Chaudhuri, et
al., 2006). An alternative model
suggests environmental stressors such as genetic mutations, oxidative stress,
alkalosis, acidosis, pH shift, or osmotic shock as external stimuli that alters
the native confirmation of PrPc (Chaudhuri, et al., 2006). Notably, this alternative hypothesis does not
account for the slow progression of PrPc into PrPsc. A final model—and one that may also serve a
model for future treatment—suggests the presence of chemical chaperone
intermediaries that interact with the PrP conformation (Chaudhuri, et al.,
2006).
Current Treatment and Preventive Measures
Whether genetic, sporadic, or acquired, prion diseases in humans are always fatal and currently untreatable (Prion Alliance). Because they are unlike other infectious agents that have been studied and for which treatments have been developed--they do not have DNA and are in fact differently folded host proteins--the optimal strategy for treatment is yet unclear (Prion Alliance). Scientists are, however, investigating different treatment methods. Researchers have developed small molecule drugs that work on some mouse pron strains (Prion Alliance). In addition, there may be promising research around development of antibodies to the misfolded proteins, but the complication remains that the prions are simply differently-folded forms of native proteins, which may cause complications in the administration of drugs (Prion Alliance).
Because no treatments have been yet developed to cure prion diseases in humans, the focus must remain on prevention. In light of the methods of disease spread discussed earlier, such prevention efforts have focused around properly sterilizing medical equipment, particularly such equipment that is used on human brains (http://www.hopkinsmedicine.org/healthlibrary/conditions/nervous_system_disorders/prion_diseases_134,56/). In addition, proper screening methods for those who may already have prion diseases are needed to prevent those individuals from donating organs (Id.). Finally, because of the zoonotic transfer of the disease from cows to humans, proper handling and screening of livestock is critical (Id.).
Because no treatments have been yet developed to cure prion diseases in humans, the focus must remain on prevention. In light of the methods of disease spread discussed earlier, such prevention efforts have focused around properly sterilizing medical equipment, particularly such equipment that is used on human brains (http://www.hopkinsmedicine.org/healthlibrary/conditions/nervous_system_disorders/prion_diseases_134,56/). In addition, proper screening methods for those who may already have prion diseases are needed to prevent those individuals from donating organs (Id.). Finally, because of the zoonotic transfer of the disease from cows to humans, proper handling and screening of livestock is critical (Id.).
Recommendations: Can These Treatments and Measures Be Effective?
The tragedy remains that there is no effective cure or treatment for prion diseases. As a result, the focus on screening and prevention of disease spread through infected tissue appears to be the most pragmatic approach to prevention measures at this time. In particular, maintenance of proper agricultural and livestock practices to prevent zoonotic transfer from diseased meat will remain a critical component. The USDA assures the public that US livestock practices are safe from bovine spongiform encephalitis (BSE), citing the existence of many systematic safeguards and removal of "specified risk materials" from the human food chain, which could include non-ambulatory cattle or cattle displaying neurological symptoms (http://www.usda.gov/wps/portal/usda/usdahome?contentid=BSE_FAQs.xml). In addition, because of the mad cow outbreaks in other counries like the UK, the U.S. restricts any imports of ruminants and ruminant products from at-risk countries (Id.). Such preventative measures, on the exposure end, seem advisable and effective.
Notably, these measures have not been fool-proof. Indeed, in 2012, a confirmed case of BSE was reported in California (Id.). Prior to that, the USDA confirmed three additional cases 9 years prior (Id.). Unfortunately, the nature of the disease is such that presence in one cow may indicate presence in other cows, which is worrisome and presents the need for more effective and rapid screening practices of livestock and livestock products.
As to the development of actual treatments, however, I believe more research into the actual disease-causing agent of prion diseases themselves is greatly needed. Certainly, the development of a test for prion disease is needed. Beyond that, however, agreement as to the true source of the TSEs must occur.
Indeed, Pruisiner's theory of the infectious protein both contravenes the "central dogma" of molecular biology that the transfer and reproduction of biological information requires programmed information in the form of nucleic acids. Moreover, his model also fails to meet the Koch Postulates typically necessary to establish a causal relationship between an agent and a disease (Manuelidis 2007). An absence of detectable prions in material that is demonstrably infectious when injected into healthy organism brain tissue is a notable exception to the first criterion (Manuelidis 2007).
In sum, the current approach to treatment and prevention is really only the latter. Continued betterment of such prevention techniques, including careful vigilance over U.S. agricultural feeding practices and imported meat products/cattle is essential, as are the sterilization procedures in medical environments. However, for those prion diseases not caused by infected consumption, such as familial CJD, future treatments will rely on a better understanding of how prions truly spread.
Notably, these measures have not been fool-proof. Indeed, in 2012, a confirmed case of BSE was reported in California (Id.). Prior to that, the USDA confirmed three additional cases 9 years prior (Id.). Unfortunately, the nature of the disease is such that presence in one cow may indicate presence in other cows, which is worrisome and presents the need for more effective and rapid screening practices of livestock and livestock products.
As to the development of actual treatments, however, I believe more research into the actual disease-causing agent of prion diseases themselves is greatly needed. Certainly, the development of a test for prion disease is needed. Beyond that, however, agreement as to the true source of the TSEs must occur.
Indeed, Pruisiner's theory of the infectious protein both contravenes the "central dogma" of molecular biology that the transfer and reproduction of biological information requires programmed information in the form of nucleic acids. Moreover, his model also fails to meet the Koch Postulates typically necessary to establish a causal relationship between an agent and a disease (Manuelidis 2007). An absence of detectable prions in material that is demonstrably infectious when injected into healthy organism brain tissue is a notable exception to the first criterion (Manuelidis 2007).
In sum, the current approach to treatment and prevention is really only the latter. Continued betterment of such prevention techniques, including careful vigilance over U.S. agricultural feeding practices and imported meat products/cattle is essential, as are the sterilization procedures in medical environments. However, for those prion diseases not caused by infected consumption, such as familial CJD, future treatments will rely on a better understanding of how prions truly spread.
Soto,
Claudio, 2011. Prion hypothesis: The end
of the controversy? Trends Biochem Sci. 36(3): 151-158.
Manuelidis,
Laura, Z. Yu, N. Barquero, and B. Mullins, 2007. Cells infected with Scrapie and
Creutzfeldt-Jakob disease agents produce intracellular 25-nm virus-like
particles. 104(14): 1965-1970.
Gajdusek,
Carleton, C. Gibbs, Jr., and M. Alpers, 1967.
Transmission and passage of experimental “Kuru” to chimpanzees. Science.
155: 212-214.
Belay,
Ermias, 1999. Transmissible Spongiform
Encephalopathies in Humans. Annu. Rev.
Microbiol. 53: 283-314.
Belay,
Ermias, 1999. Transmissible Spongiform
Encephalopathies in Humans. Annu. Rev.
Microbiol. 53: 283-314.
Belay,
Ermias, and L. Schonberger, 2005. The
public health impact of prion diseases.
Annu. Rev. Public Health. 26:
191-212.
Van
Dorsselaer, Alain, C. Carapito, F. Delalande, C. Schaeffer-Reiss, D. Thierse,
H. Diemer, D. McNair, D. Kewski, N. Cashman, 2011. Detection of prion protein in urine-derived
injectable fertility products by a targeted proteomic approach. Plos One.
6(3): 1-9.
Haybaeck,
Johannes, M. Heikenwalder, B. Klevenz, et al., 2011. Aerosols transmit prions to immunocompetent
and immunodeficient mice. PLos
Pathogens. 7(1): 1-19.
Chaudhuri,
Tapan K., and S. Paul, 2006.
Protein-misfolding diseases and chaperone-based therapeutic
approaches. FEBS Journal. 273: 1331-1349.
Prion Alliance: http://www.prionalliance.org/2014/02/04/what-are-the-potential-treatments-for-prion-disease/
Prion Alliance: http://www.prionalliance.org/2014/02/04/what-are-the-potential-treatments-for-prion-disease/
A Brief History of Prions and the TSEs
The term “prion”
was first introduced in 1998 by Dr. Stanley Pruisiner in his Nobel
Prize-winning paper of the same title (Pruisiner, 1998). Coining a shortened hybrid of the term
“proteinaceous infectious particle,” Pruisiner posited that prions were
transmissible misfolded forms of proteins that cause a set of
neurodegenerative, fatal “prion diseases” known as Transmissible Spongiform Encephalopathies
(“TSEs”) (Pruisiner, 1998). Bovine Spongiform Encephalopathy (commonly known as
Mad Cow Disease), sheep Scrapie, and human Creutzfeldt-Jakob Disease (“CJD”)
are the most notable such TSEs and are marked by a slow onset of degenerative
neurological symptoms including tremors, ataxia, dementia, loss of muscle
control, and behavioral changes ultimately deteriorating to severe myoclonus
and death (Belay, 1999).
Public
discourse involving TSEs has largely revolved around fear of the zoonotic transfer
of Mad Cow Disease through the human agricultural industry (Belay, et al,
2005). Since its first recorded case of
widespread outbreak in the United Kingdom in 1986, it is estimated that more
than 750,000 infected cows were slaughtered and subsequently consumed by
millions of UK residents (Belay, et al, 2005).
Moreover, cases of BSE have been discovered in 22 additional countries
since 1986, including cases in North America (Belay, et al, 2005). Such numbers are particularly alarming given
the strong evidence indicating cross-species transmission of this infectious
agent to humans thereby causing a variant form of CJD (“vCJD”) and a number of
reported cases of human death from vCJD in the UK (Belay, et al, 2005).
According to the CDC, the rate of CJD occurrence in the U.S. is approximately 1-1.5 cases per 1 million per year, though risk increases with age and the annual rate jumps to 3.4 cases per million in persons over 50 (CDC). Moreover, there were approximately 478 deaths due to CJD in the U.S in 2013, a significant increase from the preceding year of 380 (CDC). While the slow onset of symptoms have been discussed, I will close by discussing certain detection methods in humans for prion diseases.
Clinical Presentation and Detection
This entire class of prion diseases came to be known as Transmissible Spongiform Encephalopathies (“TSEs”), so called due to the characteristic sponge-like appearance of infected neuronal tissue due to holes in the brain cortex (Belay, 1999). The four characteristic features of all prion disease include (1) spongiform tissue change, (2) neuronal loss, (3) astrocytosis, and (3) formation of amyloid plaques (Belay, 1999).
Prion diseases such as CJD can be diagnosed using neuropathological techniques (Global Surveillance). One problem with diagnosis is that a diagnosis with 100% certainty can only be made upon death by laboratory testing of brain matter (using techniques such as immunocytochemical tests, western blotting, or confirmation of presence of scrapie-associated fibrils) (Global Surveillance). Probable diagnoses can be made using clinical symptoms, including rapid and progressive dimentia and myoclonus coupled with either MRI abnormalities or a posirive 14-3-3 CSF test (Global Surveillance).
This photo, taken with electron microscopy with silver
intensified ultrasmall immunogold labeling of PrP, shows amalgamated lesions in
a human brain with the lined pattern of an amyloid fiber formation in
characteristic criss-crossing bundles (Manuelidis 2007).
Pruisner,
Stanley B., 1998. Prions. Proceedings
of the National Academy of Sciences of the United States of America. 95(23): 13363-13383.
Belay,
Ermias, 1999. Transmissible Spongiform
Encephalopathies in Humans. Annu. Rev.
Microbiol. 53: 283-314.
Belay,
Ermias, and L. Schonberger, 2005. The
public health impact of prion diseases.
Annu. Rev. Public Health. 26:
191-212.
CDC: http://www.cdc.gov/prions/cjd/occurance-transmisison.html
Global Surveillance, diagnosis, and Therapy of Human Transmissible spongiform Encephalopathies: Report of WHO consultation, February 9-11, 1998, Geneva, Switzerland
Manuelidis,
Laura, and Z. Yu, 2003. Virus-like
interference in the latency and prevention of Creutzfeldt-Jakob disease. Proceedings of the National Academy of
Sciences of the United States of America.
100(9): 5360-5365.
Manuelidis,
Laura, Z. Yu, N. Barquero, and B. Mullins, 2007. Cells infected with Scrapie and
Creutzfeldt-Jakob disease agents produce intracellular 25-nm virus-like
particles. 104(14): 1965-1970.
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