Creutzfeldt–Jakob disease or CJD (pronounced /ˈkrɔɪtsfɛlt ˈjɑkɔp/ ) (sometimes incorrectly referred to as mad cow disease) is a degenerative neurological disorder (brain disease) that is incurable and invariably fatal. It is the most common among the types of transmissible spongiform encephalopathy found in humans.
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 is considered highly likely that at least two of the patients in initial studies were suffering from a different ailment.
Causes
Pathophysiology
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.
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 (Step 1: UNFOLDING of alpha-helices; Step 2: REFOLDING to beta-pleated sheets.). 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.
Types
Types include:
- sporadic (sCJD)
- variant (vCJD) This type is more likely to be acquired. It can be iatrogenic. It was first identified in 1996.
- familial (fCJD)
Incidence and prevalence
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:
- CJD occurs worldwide at a rate of about 1 case per million population per year.
- On the basis of mortality surveillance from 1979 to 1994, the annual incidence of CJD remained stable at approximately 1 case per million persons in the United States.
- In the United States, CJD deaths among persons younger than 30 years of age are extremely rare (fewer than five deaths per billion per year).
- The disease is found most frequently in patients 55–65 years of age, but cases can occur in people older than 90 years and younger than 55 years of age.
- In more than 85% of cases, the duration of CJD is less than 1 year (median: four months) after onset of symptoms.
New concerns on incidence and prevalence
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. 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, the practice was banned, thereby preventing any further possible transmission. 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. There is dispute as to whether the Fore ever practiced cannibalism, due to the fact that nobody ever observed them and that Kuru could 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.
In 1997 a number of Kentuckians contracted the disease. It was discovered that all the victims had a penchant for squirrel brains. See: http://www.guardian.co.uk/uk/2008/aug/03/bse.medicalresearch for recent concerns.
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.
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
- Electroencephalography — often has characteristic triphasic spikes
- Cerebrospinal fluid analysis for 14-3-3 protein
- MRI of the brain — often shows high signal intensity in the caudate nucleus and putamen bilaterally on T2-weighted images.
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. The involvement of the thalamus can be found in sCJD, is even stronger and constant in vCJD.
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)," PrP Sc , 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.
- Clinical and Pathologic Characteristics:
- An abnormal signal in the posterior thalami on T2- and diffusion-weighted images and fluid-attenuated inversion recovery sequences on brain magnetic resonance imaging (MRI); in the appropriate clinical context, this signal is highly specific for vCJD. (Source: CDC)
Treatm
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