Creutzfeldt–Jakob disease

Creutzfeldt–Jakob disease
Classification and external resources

Tonsil biopsy in variant CJD. Prion Protein immunostaining.
ICD-10 A81.0, F02.1
ICD-9 046.1
OMIM 123400
DiseasesDB 3166
eMedicine neuro/725
MeSH D007562

Creutzfeldt–Jakob disease or CJD (pronounced /ˈkrɔɪtsfɛlt ˈjɑːkoʊb/;[1] is a degenerative neurological disorder (brain disease) that is incurable and invariably fatal.[2] It is the most common among the types of transmissible spongiform encephalopathy found in humans.[3]

Contents

Classification

Types include:

Signs and symptoms

The first symptom of CJD is rapidly progressive dementia, leading to memory loss, personality changes and hallucinations. This is accompanied by physical problems such as speech impairment, jerky movements (myoclonus), balance and coordination dysfunction (ataxia), changes in gait, rigid posture, and seizures. The duration of the disease varies greatly, but sporadic (non-inherited) CJD can be fatal within months or even weeks (Johnson, 1998). In some people, the symptoms can continue for years. In most patients, these symptoms are followed by involuntary movements and the appearance of an atypical diagnostic electroencephalogram tracing.

The symptoms of CJD are caused by the progressive death of the brain's nerve cells, which is associated with the build-up of abnormal prion proteins. When brain tissue from a CJD patient is examined under a microscope, many tiny holes can be seen where whole areas of nerve cells have died. The word "spongiform" in "transmissible spongiform encephalopathies" refers to the "spongy" appearance of the brain tissue.

Cause

Transmissible spongiform encephalopathy diseases are caused by prions. The diseases are thus sometimes called prion diseases. Other prion diseases include Gerstmann–Sträussler–Scheinker syndrome (GSS), fatal familial insomnia (FFI) and kuru in humans, as well as bovine spongiform encephalopathy (BSE, commonly known as mad cow disease) in cattle, chronic wasting disease (CWD) in elk and deer, and scrapie in sheep. Alpers' syndrome in infants is also thought to be a transmissible spongiform encephalopathy caused by a prion.[9][10]

The prion that is believed to cause Creutzfeldt–Jakob exhibits at least two stable conformations. One, the native state, is water-soluble and present in healthy cells. As of 2007, its biological function is presumably in transmembrane transport or signaling. The other conformational state is very poorly water-soluble and readily forms protein aggregates.

People can also acquire CJD genetically through a mutation of the gene that codes for the prion protein (PRNP). This only occurs in 5–10% of all CJD cases.

The CJD prion is dangerous because it promotes refolding of native proteins into the diseased state. The number of misfolded protein molecules will increase exponentially, and the process leads to a large quantity of insoluble prions in affected cells. This mass of misfolded proteins disrupts cell function and causes cell death. Mutations in the gene for the prion protein can cause a misfolding of the dominantly alpha helical regions into beta pleated sheets. This change in conformation disables the ability of the protein to undergo digestion. Once the prion is transmitted, the defective proteins invade the brain and are produced in a self-sustaining feedback loop, causing exponential spread of the prion, leading to death within a few months, although a few patients have lived as long as two years.

Stanley B. Prusiner of University of California, San Francisco (UCSF) was awarded the Nobel Prize in physiology or medicine in 1997 for his discovery of prions. For more than a decade, Yale University neuropathologist Laura Manuelidis has been challenging this explanation for the disease. In January 2007 she and her colleagues published an article in the Proceedings of the National Academy of Science and reported that they have found a virus-like particle (but without finding nucleic acids so far) in less than 10% of the cells a scrapie-infected cell line and in a mouse cell line infected by a human CJD agent.[11]

Transmission

The defective protein can be transmitted by contaminated harvested human growth hormone (hGH) products, Immunoglobulins (IVIG), corneal grafts, dural grafts or electrode implants (acquired or iatrogenic form: iCJD); it can be inherited (hereditary or familial form: fCJD); or it may appear for the first time in the patient (sporadic form: sCJD). In the hereditary form, a mutation occurs in the gene for PrP, PRNP. Ten to fifteen percent of CJD cases are inherited. (CDC)

The disease has also been shown to result from usage of HGH drawn from the pituitary glands of cadavers who died from Creutzfeldt–Jakob Disease,[12] though the known incidence of this cause is (as of April 2004) quite small. The risk of infection through cadaveric HGH usage in the US only ceased when the medication was withdrawn in 1985.

It is thought that humans can contract the disease by consuming material from animals infected with the bovine form of the disease. The only suspected cases to arise thus far have been vCJD, although there are fears — based on animal studies — that consuming beef or beef products containing prion particles can also cause the development of classic CJD. When BSE material infects humans the resulting disease is known as (new) variant CJD Disease (nvCJD).[10]

Cannibalism has also been implicated as a transmission mechanism for abnormal prions, causing the disease known as kuru, found primarily among women and children of the Fore tribe in Papua New Guinea. While the men of the tribe ate the body of the deceased and rarely contracted the disease, the women and children, who ate the less desirable body parts, were 8 times more likely to contract the disease from infected tissue.

Prions, the infectious agent of CJD, may not be inactivated by means of routine surgical instrument sterilization procedures. The World Health Organization and the US Centers for Disease Control and Prevention recommend that instrumentation used in such cases be immediately destroyed after use; secondary to destruction, it is recommended that heat and chemical decontamination be used in combination to process instruments that come in contact with high-infectivity tissues. No cases of iatrogenic transmission of CJD have been reported subsequent to the adoption of current sterilization procedures, or since 1976.[13][14][15] Copper–hydrogen peroxide has been suggested as an alternative to the current recommendation of sodium hydroxide or sodium hypochlorite.[16] Thermal depolymerization also destroys prions in infected organic and inorganic matter, since the process dissolves protein at the molecular level.

Blood donor restrictions

In 2004 a new report published in the Lancet medical journal showed that vCJD can be transmitted by blood transfusions.[17] The finding alarmed healthcare officials because a large epidemic of the disease might arise in the near future. There is no test to determine if a blood donor is infected while in the latent phase of vCJD. In reaction to this report, the UK government banned anyone who had received a blood transfusion since January 1980 from donating blood.[18] From 1999 there has been a ban in the UK for using UK blood to manufacture fractional products such as albumin.[19]

On May 28, 2002, the United States Food and Drug Administration instituted a policy that excludes from donation anyone who spent at least six months in certain European countries, (or three months in the United Kingdom), from 1980 to 1996. Given the large number of U.S. military personnel and their dependents residing in Europe, it was expected that over 7% of donors would be deferred due to the policy. Later changes to this policy have relaxed the restriction to a cumulative total of five years or more of civilian travel in European countries (six months or more if military). The three-month restriction on travel to the UK, however, has not been changed.[20]

The American Red Cross's policy is as follows: During the period January 1, 1980 to December 31, 1996, spending a total time of three months or more in the Channel Islands, England, the Falkland Islands, the Isle of Man, Gibraltar, Northern Ireland, Scotland, and Wales precludes individuals from donating. Since January 1, 1980 to present, spending a total time of five years or more in the above countries and countries in Europe. People with a biologic relative who has been diagnosed with CJD or vCJD are unable to donate. Biologic relative in this setting means mother, father, sibling, grandparent, aunt, uncle or children. (For complete listing, please go to Redcross.org)

A similar policy applies to potential donors to the Australian Red Cross' Blood Service, precluding people who have spent a cumulative time of six months or more in the United Kingdom between 1980 and 1996.

The Singapore Red Cross precludes potential donors who have spent a cumulative time of three months or more in the United Kingdom between 1980 and 1996.

In New Zealand anyone who has lived in the UK, France or the Republic of Ireland for a total of six months or more between 1980 and 1996 is prohibited from donating blood.

Similar regulations are in place in Germany, where anyone who has spent six months or more living in the UK between January 1980 and December 1996 is permanently barred from donating blood.[21]

As of 1999, Health Canada announced a policy to defer individuals from donating blood if they have lived within the United Kingdom for one month or more from January 1, 1980 to December 31, 1996. In 2000, the same policy was applied to people who have resided in France, for at least three months from January 1980 to December 1996. Canada will not accept blood from a person who has spent more than six months in a Western European country since January 1, 1980.[22]

The Association of Blood Donors of Denmark precludes potential donors who have spent a cumulative time of at least twelve months in the United Kingdom between 1 January 1980 and 31 December 1996.

The Swiss Blutspendedienst SRK precludes potential donors who have spent a cumulative time of at least six months in the United Kingdom between 1 January 1980 and 31 December 1996.

In Poland, anyone who cumulatively spent 6 months or longer between 1 January 1980 and 31 December 1996 in Great Britain, Ireland or France is permanently barred from donating.[23]

In the Czech Republic, anyone who spent more than six months in the UK or France between the years 1980 and 1996 or received transfusion in the UK after the year 1980 is not allowed to donate blood.[24]

Sperm donor restrictions

In the U.S., the FDA has banned import of any donor sperm, motivated by a risk of Creutzfeldt–Jakob disease, inhibiting the once popular[25] import of, for example, Scandinavian sperm. The risk, however, is not known, since artificial insemination has not been studied as a route of transmission.[26] It is also not known whether prions cross the blood-testis barrier.[26]

Diagnosis

The diagnosis of CJD is suspected when there are typical clinical symptoms and signs such as rapidly progressing dementia with myoclonus. Further investigation can then be performed to support the diagnosis including

Diffusion Weighted Imaging (DWI) images are the most sensitive. In about 24% of cases DWI shows only cortical hyperintensity; in 68%, cortical and subcortical abnormalities; and in 5%, only subcortical anomalies.[27] The involvement of the thalamus can be found in sCJD, is even stronger and constant in vCJD.[28]

Clinical testing for CJD has always been an issue. Diagnosis has mostly been based on clinical and physical examination of symptoms. In recent years, studies have shown that the tumour marker Neuron-specific enolase (NSE) is often elevated in CJD cases .

In one third of patients with sporadic CJD, deposits of "prion protein (scrapie)," PrPSc, can be found in the skeletal muscle and/or the spleen. Diagnosis of vCJD can be supported by biopsy of the tonsils, which harbour significant amounts of PrPSc; however, biopsy of brain tissue is the definitive diagnostic test. Due to its invasiveness, biopsy will not be done if clinical suspicion is sufficiently high or low. A negative biopsy does not rule out CJD since it may predominate in a specific part of the brain [29]

Spongiform change in CJD

The classic histologic appearance is spongiform change in the gray matter: the presence of many round vacuoles from one to 50 microns in the neuropil, in all six cortical layers in the cerebral cortex or with diffuse involvement of the cerebellar molecular layer. These vacuoles appear glassy or eosinophilic and may coalesce. Neuronal loss and gliosis are also seen. [30] Plaques of amyloid-like material can be seen in the neocortex in new-variant CJD.

Unfortunately, vacuolization can be seen in other disease states. Diffuse cortical vacuolization occurs in Alzheimer's, and superficial cortical vacuolization occurs in ischemia and frontotemporal dementia. These vacuoles appear clear and punched-out. Larger vacuoles encircling neurons, vessels, and glia are a possible processing artifact.[31]

Characteristic Classic CJD Variant CJD
Median age at death 68 years 28 years
Median duration of illness 4–5 months 13–14 months
Clinical signs and symptoms Dementia; early neurologic signs Prominent psychiatric/behavioral symptoms; painful dysesthesias;

delayed neurologic signs
Periodic sharp waves on electroencephalogram Often present Often absent
Signal hyperintensity in the caudate nucleus and putamen on diffusion-weighted and FLAIR MRI Often present Often absent
"Pulvinar sign" on MRI Not reported Present in >75% of cases
Immunohistochemical analysis of brain tissue Variable accumulation. Marked accumulation of protease-resistant prion protein
Presence of agent in lymphoid tissue Not readily detected Readily detected
Increased glycoform ratio on immunoblot analysis of

protease-resistant prion protein

 Not reported Marked accumulation of protease-resistant prion protein
Presence of amyloid plaques in brain tissue May be present May be present

Treatment

As of 2010 no generally accepted treatment for CJD exists; the disease is invariably fatal and research continues. An experimental treatment was given to a Northern Irish teenager, Jonathan Simms, beginning in January 2003.[33] The medication, called pentosan polysulphate (PPS) and used to treat interstitial cystitis, is infused into the patient's lateral ventricle within the brain. PPS does not seem to stop the disease from progressing, and both brain function and tissue continue to be lost. However, the treatment is alleged to slow the progression of the otherwise untreatable disease, and may have contributed to the longer than expected survival of the seven patients who were studied.[34] The CJD Therapy Advisory Group to the UK Health Departments advises that data are not sufficient to support claims that pentosan polysulphate is an effective treatment and suggests that further research in animal models is appropriate.[35] A 2007 review of the treatment of 26 patients with PPS finds no proof of efficacy because of the lack of accepted objective criteria.[36]

Scientists have investigated using RNA interference to slow the progression of scrapie in mice. The RNA blocks production of the protein that the CJD process transforms into prions. This research is unlikely to lead to a human therapy for many years.[37]

Both amphotericin B and doxorubicin have been investigated as potentially effective against CJD, but as yet there is no strong evidence that either drug is effective. Further study has been taken with other medical drugs, but none are effective.

Dr. Michael Geschwind, Dr. Bruce Miller and Dr. Stanley Prusiner from University of California, San Francisco are currently running a treatment trial for sporadic CJD using quinacrine, a medicine originally created for malaria. Pilot studies showed quinacrine permanently cleared abnormal prion proteins from cell cultures, but results have not yet been published on the clinical study.

Epidemiology

Although CJD is the most common human prion disease, it is still rare, occurring in about one out of every one million people every year. It usually affects people aged 45–75, most commonly appearing in people between the ages of 60–65. The exception to this is the more recently-recognised 'variant' CJD (vCJD), which occurs in younger people.

CDC monitors the occurrence of CJD in the United States through periodic reviews of national mortality data. According to the CDC:

New concerns

In The Lancet (June 2006), a University College London team suggested that it may take more than 50 years for vCJD to develop, from their studies of kuru, a similar disease in Papua New Guinea.[39] The reasoning behind the claim is that kuru was possibly transmitted through cannibalism in Papua New Guinea when family members would eat the body of a dead relative as a sign of mourning. In the 1950s, cannibalism was banned. In the late 20th century, however, kuru reached epidemic proportions in certain Papua New Guinean communities, therefore suggesting that vCJD may also have a similar incubation period of 30 to 50 years. A critique to this theory is that while mortuary cannibalism was banned in Papua New Guinea in the 1950s, that does not necessarily mean that the practice ended. Fifteen years later Jared Diamond was informed by Papuans that the practice continued.[40] There is dispute as to whether the Fore ever practiced cannibalism, because nobody ever observed the ritual. Kuru may have passed to the Fore through the preparing of the dead body for burial.

These researchers noticed a genetic variation in some kuru patients that has been known to promote long incubation periods. They have also proposed that individuals who contracted CJD in the early 1990s represent a distinct genetic subpopulation, with unusually short incubation periods for BSE. This means that there may be many more vCJD patients who have longer incubation periods, which may surface many years later.[39]

In 1997 a number of Kentuckians contracted the disease. It was discovered that all the victims had consumed squirrel brains.[41] See: http://www.guardian.co.uk/uk/2008/aug/03/bse.medicalresearch for recent concerns.

History

The disease was first described by German neurologist Hans Gerhard Creutzfeldt in 1920 and shortly afterwards by Alfons Maria Jakob, giving it the name Creutzfeldt–Jakob. Some of the clinical findings described in their first papers do not match current criteria for Creutzfeldt–Jakob disease, and it has been speculated that at least two of the patients in initial studies were suffering from a different ailment.

Popular culture

The disease was featured in an episode of The X-Files, "Our Town", in which a group of cannibals eat the entire body (including the brain) of their fellow humans in order to stay young forever. They contract the disease from one of their victims, and it passes through a part of the town, killing 28.

Going Bovine, a novel by Libba Bray, is about a teenage boy fighting Creutzfeld-Jakob disease.

In Law & Order: Criminal Intent: "Dramma Giocoso" in season 5 episode 16 (original air date 9 April 2006), a young violinist is pushed to her death at the opera house. Detectives Logan and Barek focus on the arrogant conductor until they receive jarring medical news that violinist's mother, a famous opera star in love with the conductor, has Creutzfeldt–Jakob disease CJD, which changes everything about the case and catapults her to the position of prime suspect in the murder.

During the fourth season of the TV series House, in episode four "Guardian Angels", House's job applicants suspect the patient of having contracted CJD after doing cosmetic work at a funeral parlor on a cadaver with similar symptoms. To test the diagnosis, the team digs up the grave and carry out a brain biopsy, which is negative. In the end she is revealed to have ergotism.

In season seven of 24 (TV series) CTU agent Jack Bauer is infected with a fictional weaponised form of Creutzfeld-Jakob disease, developed by a private defence company Starkwood, which is fast acting and causes death within days.

In the episode Last Dance (Flashpoint episode) of the TV series Flashpoint (TV series), the SRU team face a couple, the woman dying of CJD, who commit a string of burglaries before taking hostages at a wedding ceremony so that they may have one last dance before the woman kills herself.

References

  1. ↑ Merriam-Webster's Collegiate Dictionary
  2. ↑ 2.0 2.1 "CJD (Creutzfeldt-Jakob Disease, Classic)". Centers for Disease Control and Prevention. 2008-02-26. http://www.cdc.gov/ncidod/dvrd/cjd/index.htm. Retrieved 2009-06-20. 
  3. ↑ "UW Hospital warns 53 patients about possible exposure to fatal disease". Wisconsin State Journal. 2009-07-24. http://www.madison.com/wsj/topstories/459435. Retrieved 2009-07-24. 
  4. ↑ Niimi Y, Iwasaki Y, Umemura T (December 2008). "MM2-cortical-type sporadic Creutzfeldt–Jakob disease with early stage cerebral cortical pathology presenting with a rapidly progressive clinical course". Neuropathology 28 (6): 645–51. doi:10.1111/j.1440-1789.2008.00904.x. PMID 18410280. http://www3.interscience.wiley.com/resolve/openurl?genre=article&sid=nlm:pubmed&issn=0919-6544&date=2008&volume=28&issue=6&spage=645. 
  5. ↑ Jones M, Peden AH, Prowse CV (September 2007). "In vitro amplification and detection of variant Creutzfeldt–Jakob disease PrPSc". J. Pathol. 213 (1): 21–6. doi:10.1002/path.2204. PMID 17614097. 
  6. ↑ Frosh A, Joyce R, ATTN: DO NOT GET AROUND ANYTHING CONTAINING THIS DISEASE BECAUSE IT'S LETHAL!Johnson A (June 2001). "Iatrogenic vCJD from surgical instruments". BMJ 322 (7302): 1558–9. doi:10.1136/bmj.322.7302.1558. PMID 11431283. 
  7. ↑ Will RG, Ironside JW, Zeidler M (April 1996). "A new variant of Creutzfeldt–Jakob disease in the UK". Lancet 347 (9006): 921–5. doi:10.1016/S0140-6736(96)91412-9. PMID 8598754. 
  8. ↑ Wang XF, Dong CF, Zhang J (March 2008). "Human tau protein forms complex with PrP and some GSS- and fCJD-related PrP mutants possess stronger binding activities with tau in vitro". Mol. Cell. Biochem. 310 (1–2): 49–55. doi:10.1007/s11010-007-9664-6. PMID 18038270. 
  9. ↑ Chakraborty C, Nandi S, Jana S (April 2005). "Prion disease: a deadly disease for protein misfolding". Current Pharmaceutical Biotechnology 6 (2): 167–77. doi:10.2174/1389201053642321. PMID 15853695. 
  10. ↑ 10.0 10.1 Obi RK, Nwanebu FC (2008). "Prions And Prion Diseases". African Journal of Clinical and Experimental Microbiology 9 (1): 38–52. ISSN 1595-689X. http://ajol.info/index.php/ajcem/article/view/7481. Retrieved 2009-06-20. 
  11. ↑ Manuelidis L, Yu ZX, Barquero N, Banquero N, Mullins B (February 2007). "Cells infected with scrapie and Creutzfeldt-Jakob disease agents produce intracellular 25-nm virus-like particles". Proceedings of the National Academy of Sciences of the United States of America 104 (6): 1965–70. doi:10.1073/pnas.0610999104. PMID 17267596. 
  12. ↑ Mills JL, Schonberger LB, Wysowski DK (April 2004). "Long-term mortality in the United States cohort of pituitary-derived growth hormone recipients". The Journal of Pediatrics 144 (4): 430–6. doi:10.1016/j.jpeds.2003.12.036. PMID 15069388. Lay summary – Wired (2004-04-09). 
  13. ↑ "Questions and Answers: Creutzfeldt–Jakob Disease Infection-Control Practices". Infection Control Practices/CJD (Creutzfeldt–Jakob Disease, Classic). Centers for Disease Control and Prevention. January 4, 2007. http://www.cdc.gov/ncidod/dvrd/cjd/qa_cjd_infection_control.htm#sterilization. Retrieved 2007-06-09. 
  14. ↑ "WHO Infection Control Guidelines for Transmissible Spongiform Encephalopathies". World Health Organization: Communicable Disease Surveillance and Control. 26 March 1999. http://www.who.int/csr/resources/publications/bse/WHO_CDS_CSR_APH_2000_3/en/. Retrieved 2007-06-09. 
  15. ↑ McDonnell G, Burke P (May 2003). "The challenge of prion decontamination". Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America 36 (9): 1152–4. doi:10.1086/374668. PMID 12715310. 
  16. ↑ Solassol J, Pastore M, Crozet C (2006). "A novel copper–hydrogen peroxide formulation for prion decontamination". J Infect Dis 194 (6): 865–869. doi:10.1086/506947. PMID 16941355. 
  17. ↑ Peden AH, Head MW, Ritchie DL, Bell JE, Ironside JW (2004). "Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient". Lancet 364 (9433): 527–9. doi:10.1016/S0140-6736(04)16811-6. PMID 15302196. 
  18. ↑ "Variant CJD and blood donation" (PDF). National Blood Service. August 2004. http://www.blood.co.uk/pdfdocs/vcjd.pdf. Retrieved 2009-06-20. 
  19. ↑ Regan F, Taylor C (July 2002). "Blood transfusion medicine". BMJ (Clinical Research Ed.) 325 (7356): 143–7. doi:10.1136/bmj.325.7356.143. PMID 12130612. 
  20. ↑ "In-Depth Discussion of Variant Creutzfeld-Jacob Disease and Blood Donation". American Red Cross. Archived from the original on 2007-12-30. http://web.archive.org/web/20071230205118/http://www.redcross.org/services/biomed/blood/supply/cjdv.html. Retrieved 2009-06-20. 
  21. ↑ "Permanent exclusion criteria" (in German). Blutspendedienst Hamburg. http://www.blutspendehamburg.de/blutspender-gesucht/ausschluss. Retrieved 2009-06-20. 
  22. ↑ "Donor Qualification". Héma-Québec. 2009-03-26. http://www.hema-quebec.qc.ca/anglais/dondesang/qualifidonneurs.htm. Retrieved 2009-06-20. 
  23. ↑ "Permanent exclusion criteria / Dyskwalifikacja stała" (in Polish). RCKiK Warszawa. http://www.rckik-warszawa.com.pl/dlakrwio_ds.html. Retrieved 2010-03-03. 
  24. ↑ "Blood donor guidance / Poučení dárce krve" (in Czech). Fakultní nemocnice Královské Vinohrady. http://www.fnkv.cz/soubory/pouceni-darce-krve-2007.doc. Retrieved 2010-03-20. 
  25. ↑ Stein, Rob (August 13, 2008). "Mad Cow Rules Hit Sperm Banks' Patrons". washingtonpost.com (The Washington Post Company). http://www.washingtonpost.com/wp-dyn/content/article/2008/08/12/AR2008081203131.html. Retrieved 2008-10-04. 
  26. ↑ 26.0 26.1 Kotler, Steven (2007-09-27). "The God of Sperm". LA Weekly. http://www.laweekly.com/2007-09-27/news/the-god-of-sperm/. Retrieved 2009-06-20. 
  27. ↑ Young, Geoffrey S.; G; F; M; H; L; L; W et al. (June–July 2005). "Diffusion-Weighted and Fluid-Attenuated Inversion Recovery Imaging in Creutzfeldt–Jakob Disease: High Sensitivity and Specificity for Diagnosis". American Journal of Neuroradiology (American Society of Neuroradiology) 26 (6): 1551–1562. PMID 15956529. http://www.ajnr.org/cgi/content/full/26/6/1551. Retrieved 2007-10-30. 
  28. ↑ Tschampa, Henriette J.; M; F; P; S; U (1 May 2003). "Thalamic Involvement in Sporadic Creutzfeldt–Jakob Disease: A Diffusion-Weighted MR Imaging Study". American Journal of Neuroradiology (American Society of Neuroradiology) 24 (5): 908–915. PMID 12748093. http://www.ajnr.org/cgi/content/full/24/5/908. Retrieved 2007-10-30. 
  29. ↑ Sternberg's Diagnostic Surgical Pathology, 5th edition.
  30. ↑ http://library.med.utah.edu/WebPath/TUTORIAL/CNS/CNSDG.html
  31. ↑ Sternberg's Diagnostic Surgical Pathology, 5th edition.
  32. ↑ Belay ED, Schonberger LB (2002). "Variant Creutzfeldt–Jakob disease and bovine spongiform encephalopathy". Clin. Lab. Med. 22 (4): 849–62, v–vi. doi:10.1016/S0272-2712(02)00024-0. PMID 12489284. 
  33. ↑ "Teenager with vCJD 'stable". London: BBC News. 13 December 2004. http://news.bbc.co.uk/2/hi/uk_news/northern_ireland/4092363.stm. Retrieved 2007-01-01. 
  34. ↑ Bone, Ian (12 July 2006). "Intraventricular Pentosan Polysulphate in Human Prion Diseases: A study of Experience in the United Kingdom". Medical Research Council. http://www.mrc.ac.uk/NewsViewsAndEvents/News/MRC001707. Retrieved 2007-01-01. 
  35. ↑ "Use of Pentosan Polysulphate in the treatment of, or prevention of, vCJD". Department of Health:CJD Therapy Advisory Group. http://www.dh.gov.uk/en/Policyandguidance/Healthandsocialcaretopics/CJD/CJDgeneralinformation/DH_4031039. Retrieved 2007-10-30. 
  36. ↑ Rainov NG, Tsuboi Y, Krolak-Salmon P, Vighetto A, Doh-Ura K (2007). "Experimental treatments for human transmissible spongiform encephalopathies: is there a role for pentosan polysulfate?". Expert opinion on biological therapy 7 (5): 713–26. doi:10.1517/14712598.7.5.713. PMID 17477808. 
  37. ↑ Pfeifer A, Eigenbrod S, Al-Khadra S (December 2006). "Lentivector-mediated RNAi efficiently suppresses prion protein and prolongs survival of scrapie-infected mice". The Journal of Clinical Investigation 116 (12): 3204–10. doi:10.1172/JCI29236. PMID 17143329. Lay summary – BBC News (2006-12-04). 
  38. ↑ "vCJD (Variant Creutzfeldt-Jakob Disease)". Centers for Disease Control and Prevention. 2007-01-04. http://www.cdc.gov/ncidod/dvrd/vcjd/factsheet_nvcjd.htm. Retrieved 2009-06-20. 
  39. ↑ 39.0 39.1 Collinge J, Whitfield J, McKintosh E (June 2006). "Kuru in the 21st century--an acquired human prion disease with very long incubation periods". Lancet 367 (9528): 2068–74. doi:10.1016/S0140-6736(06)68930-7. PMID 16798390. 
  40. ↑ Diamond, JM (7 September 2000). "Archaeology: Talk of cannibalism". Nature 407 (25-26): 25. doi:10.1038/35024175. 
  41. ↑ Berger JR, Waisman E, Weisman B (August 1997). "Creutzfeldt-Jakob disease and eating squirrel brains". Lancet 350 (9078): 642. doi:10.1016/S0140-6736(05)63333-8. PMID 9288058. 

http://www.guardian.co.uk/uk/2001/sep/05/bse.highereducation http://www.dailymail.co.uk/news/article-66015/Briton-cured-CJD-drug-trial.html

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Acesulfame potassium · Aspartame · Cyclamate · High fructose corn syrup · Saccharin · Sorbitol · Sucralose
Food scares

2005 Indonesia food scare · 2006 North American E. coli outbreak · 2007 Vietnam food scare · 2008 Canadian listeriosis outbreak · 2008 Chinese milk scandal · 2008 Irish pork crisis · 2008 United States salmonellosis outbreak · Food safety incidents in the People's Republic of China · Bradford sweets poisoning · Chilean grape scare · ICA meat repackaging controversy · Minamata disease · Toxic oil syndrome · List of foodborne illness outbreaks · List of food contamination incidents
Regulatory/Watchdog

Acceptable daily intake · E number · Early history of food regulation in the United States · European Food Safety Authority · Food and Drug Administration · Food labeling regulations · Food law · Food Safety Act 1990 · Food Standards Agency · International Food Safety Network · Pure Food and Drug Act · Quality Assurance International · List of food safety organisations
Food Processing

4-Hydroxynonenal · Acrylamide · Creutzfeldt–Jakob disease · Food irradiation · Heterocyclic amines · Hydrolyzed vegetable protein · Modified starch · Nitrosamines · Polycyclic aromatic hydrocarbon · Shortening · Trans fat
Misc

Curing (food preservation) · Foodborne illness · Food marketing · Food politics · Food preservation · Food quality · Food safety in the People's Republic of China · Food safety (science) · Genetically modified food