Noted as being a rare neurodegenerative disorder, Creutzfeldt-Jakob disease (CJD) is a human spongiform encephalopathy that effects one out of 1,000,000 people (Ricketts & Cashman, 1997). Once contracted, the course of deterioration becomes rapid due to neuronal loss and astrocytosis (Whitehouse, Lerner, & Hedera, 1993). Victims of CJD have been observed as suffering from pre-senile dementia, myoclonus, and progressive motor dysfunction (Ricketts & Cashman, 1997). Current science has accepted the theory that these symptoms, in relation to CJD, are caused by proteinaceous infectious particles (prions), mutated protein cells that appear to be unassailable to traditional viral-based treatment (Whitehouse, et. al., 1993).

Although this type of neurological disorder has been observed in the animal kingdom for some time, it has only been noted in the human population since the 1960's (Ricketts & Cashman, 1997). CJD shares many of the biological and behavioral symptoms of sheep Scrapie and Bovine Spongiform Encephalopathy which are considered to be either directly linked to or at least extremely similar to the human version of the disease (Brown, 1997).

This novel disorder has received much attention by scientists that are interested in discovering its nature, risk factors, diagnosis criteria and possible treatment. One distinction should be noted forthright is that there are two reported versions of CJD. The more common form is known as sporadic Creutzfeldt Jakob disease, believed to be the result of spontaneous cell mutation (Collins & Law, 1999). The more recent strain, prevalent since the early 1990's, is termed variant Creutzfeldt-Jakob disease, assumed to be acquired from an external source (Zeidler & Stewart, 1997). Both forms are equally debilitating and run the same course leading to eventual death (Henderson, 2000).

Researchers are interested in the development of the disease and have formed specialized research groups and methods for collecting new case data. In England, where variant CJD has been spread to humans through contaminated beef products, a special group has been formed to track new and existing cases (Verity, Nicoll, Will, Devereux, & Stellinato, 2000). One of the purposes of this group has been to document "progressive intellectual and neurological deterioration (PIND)". Verity, et. al., (2000), report that there is an increased number of children and adults with variant CJD within recent years. In order to collect this data, the investigators mailed post cards to physicians asking for a report of any PIND activity. This method resulted in an incredibly high response of 90%. The information on the returned card allowed for the prediction of variant CJD infection. In those cases, the researchers requested clinical documentation for the patient, provided with written consent. Names were not concealed from the researchers due to the chance of the patient seeing several physicians. From this data, it was found that variant CJD victims, confirmed upon autopsy, were likely to suffer from psychiatric, cognitive, and neurological symptoms. Specific reports of anxiety, depression, memory loss, low performance, ataxia, paraesthesiae, myoctonic jerks, and impaired vertical eye movements were noted. Prior to this study that found a 12-year-old CJD victim, there were no cases reported below 16 years.

Overall, Verity, et. al., (2000) provided an overview of the continued effect this prion disorder has on the human population. In the introduction, the authors mention the necessity of this research to provide information regarding an incubation period. Although the methods locate the victims, they do not provide such information or mention it further in the article. In general, the article serves as a good reference for the symptoms seen during the progression of the illness. It does note the weakness of a 10% failure of response, which is quite low, compared to normative response rates. It also points out the human error factor of not reporting the symptoms due to not recognizing it or misdiagnosis.

The issue of proper diagnosis may be more complex with the introduction of another strain of CJD noted as new variant CJD. Zeidler and Stewart (2000) examined the presence of this new form and reported that it takes on a distinct phenotype from sporadic and variant CJD. This conclusion was reached through prion gene analysis taken from the cerebrospinal fluid of ten living and four deceased subjects. In these cases, early symptoms took the form of sensory and psychological disturbances. Sensory problems were evident through reports of pain from limbs that were observed as being unharmed and healthy. Psychologically, the patients either reported or were observed as being depressed, apathetic, and withdrawn. This was accompanied by weight loss and mild insomnia.

The deterioration of the patients investigated by Zeidler and Stewart (1997) progressed slowly for a few months until overt neurological dysfunction in the form of ataxia occurred. From this point forward, the patients displayed severe omnipresent cognitive dysfunction, motor disorientation, mutism, and general unresponsiveness. The primary neurological signs of CJD deterioration were cerebellar limb or gate ataxia. Unlike sporadic or variant CJD, the new variant CJD patients were noted as developing an upgaze paresis.

Zeidler and Stewart (1997) did not find gene mutation during gene analysis. In the cases with new variant CJD, it was found that the cause might be from infection with bovine spongiform encephalopathy (BSE). This would be from direct oral ingestion of infected beef products. Although the subject population in this case seems to reliably point to this cause for the new stain, it is probable that there are other causes. The participants in this study were mostly female, young, and limited. The article also fails to use any controls for comparison. Such control groups may have been made up of healthy subjects or those who suffered from illnesses that have similar symptoms to CJD. Although the research provides a description of CJD deterioration, it does not speak of major differences from other neurological disorders. The most severe delinquency in practice is the failure to examine this new variant CJD in comparison to animal forms of BSE, the proposed cause of the new stain. One strength of the methods used in this examination is the inclusion of tissue samples obtained from both living and deceased subjects. This provides a stronger validity when attempting to generalize to other new variant CJD sufferers.

With the rise of documented cases of CJD, such as those noted by Verity, et. al. (2000), it is wise that research investigates the risks and situations that may contribute to its contraction. Collins and Law (1999) attempted to find any problematic contributors to CJD infection through a comparison of the medical histories of confirmed and probable cases to non-infected control patients. The control group consisted of volunteers that responded to phone solicitation. Although the methods of the research clearly stated the age and sex distribution of the CJD population, it did not define the sex or age distribution of the controls. The methodology also describes the procedure for the initial phone interview, which may be an ethical issue. The first problem evident, is the lack of detail on who administered the phone call. The second is the issue of consent. There was no written consent form. When the randomly picked subject answered the phone, they were simply instructed to get permission from the oldest male or female in the house to participate in the research. There were no standardized tests used or appendices that display the questionnaire put into practice. There was also no mention of further explanation or debriefing. Despite the flakiness of this practice, the investigators were able to obtain phone interviews with 784 out of 12,387 people called. This response rate falls way short of that reported through the mailing conducted by Verity, et. al. (2000).

Another flaw in the report done by Collins and Law (1999) is contained within its results. It explains that case and control studies were balanced and well matched for age, sex, and environment. It directly mentions that no data is available on this statement. Surprisingly, the authors continue their report and site several trends in the research. Their findings state that a risk factor for sporadic CJD may be the performance of surgery of any nature. It was further reported that it is less of a risk if the surgery is for transplanted tissue. This was explained for the careful screening of the donor. So, with that information, although not said in the article, it must be an assumption that CJD is being transmitted through infected hospital instruments and perhaps blood transfusions. This implication would mean a very real threat to people of all ages receiving even mild non-life threatening treatment. In essence, putting anyone whom visits a hospital for minor surgery at risk.

This transmission of CJD from one organism to another is the basis of the new variant CJD. In a study that investigated the transmission, susceptibility, and expression of CJD, infected hospital instruments were the least of concern. In order to discover the actions of CJD in human DNA, the researchers had to examine the blot clots taken from individuals that suffered and died from Kuru, contracted during cannibalistic rituals (Cervan, Goldfarb, Garruto, Lee, Gajdusek, and Brown, 1998). Frozen since 1958, the blood clots were put in a centrifuge, dyed, and denatured. Although all the samples were from people who contracted Kuru, noted as the "prototype human transmissible spongiform encephalopathy" (TSE), it was shown that certain genetic factors influenced the progression of the disease. It was also discovered that the same antigens would be expressed differently according to the individual. Apparently, there are certain genetic codes that are susceptible to plaque formation. These genetic trends were similar to samples taken from victims of new variant CJD. The major similarity between TSE and new variant CJD is the oral ingestion of the infected material. The major difference, according to descriptive statistics is the age of onset, reported as being much younger and with less of an incubation period for those who have new variant CJD.

This study presents an interesting trend across time and disorder. It may indicate that basic spongiform encephalopathy is a product of Darwin's evolution, changing to ensure survival. Research has suggested that TSE, BSE, and the three mentioned forms of CJD are quite similar in course but different in contraction. All are forms of spongiform encephalopathy and effect different ages through different means. If the research posed by this article were reliable, then implications may be interpreted to be a unique adaptation that would need to deal with different genes in different ways to get the same results. This would support the success of the prion theory that entails specialized mutation of an individual's own protein.

This finding was supported by research that investigated risk factors of CJD in Europe (Van Duijn & Delasnerie-Laupretre, 1998). This design instituted the use of already diagnosed patients with CJD and a healthy control group. Data collected regarding medical history was analyzed in the terms of odds. Significant trends were then reanalyzed with an unconditional logistic-regression model, balanced for sex, age, and environment. This was performed on a large sized population (n=405). One flaw in the methodology is the failure to include information on the test administrator. This may be crucial on the basis that data was collected in an interview. Depending on the test administrator, some subjects may have been reluctant to divulge personal information and past behaviors. This possible lack of information would not allow for a complete analysis of risk factors.

Van Duijn and Delasnerie-Laupretre (1998) did expand on the transmission theory of Cervan, et. al. (1998). In this case, it was not a question of oral ingestion of the infected material, but working with infected material. Of course, this leads to the possibility that individuals that don't employ clean hygiene practices may accidentally ingest contaminants. Risk factors found among the CJD patients and not the control group were increased exposure to leather products and fertilizer containing hoofs and horns. Confirming the theory of the transmission of spongiform encephalopathy via oral ingestion, it was found that increased eating of raw animal meat and brains increased likelihood of contracting CJD.

In order to test whether or not ingestion of contaminated meat leads to CJD or other TSE, scientists must perform animal studies. Sacrificing the lives of animals in order to save the lives of people has been common practice in the fields of physiology and psychology. It would certainly be unethical to have human subjects consume infected materials for the purpose of study. For this reason, a study was composed that examined the possible transmission of bovine spongiform encephalopathy (BSE) across species (Scott, Safar, Telling, Nguyen, Groth, Torchia, Koehler, Tremblay, Walther, Cohen, DeArmond, and Prusiner, 1997). The animals chosen to give their life to science were mice. The complex methodology involved infecting mice with BSE and sacrificing them upon first impression of neurological impairment. The mouse brains were analyzed and compared to infected bovine brains. Once it was established that transmission to mice was successful via injection directly to the brain, infected mice brains were fed in a dilution to other mice. This resulted in a transmission to the second group of mice. Criteria for determining proper progression of spongiform encephalopathy required observation of "truncal ataxia, increased tone of the tail, and lack of forelimb extensor response when lifted by the tail" (Scott, et. al., 1997).

Upon sacrifice, the brain tissue was treated with paraffin and dyes for microscopic examination of plaques and any other physiological changes. It was found that resistance to BSE in mice depended on the type of dominant protein expression. As stated in the research of Cervan, et. al. (1998), certain individuals may be more or less likely to display neurological dysfunction upon infection. Although all cases in both studies eventually became evidently affected with CJD-like symptoms and subsequently perished, some displayed a longer incubation period than others. Both articles mention that ingestion of contaminants decreases the incubation period.

The contribution the work of Scott, et. al. (1997) offers, is the direct link of a transmission of BSE to other species. With this possibility observed, generalization to humans should spur a careful analysis of the meat products on the market. The article states that prion presence differs in quantity for muscle, pancreas, liver and intestine structures. Although quantity consumed was not tested as a variable in this study, it is assumed to be a factor, as stated by the author. It could also be speculated that the increase of prion in certain foods would increase the likelihood of infection. This rationale makes sense since it employs logical statistical odds of increased exposure. Unfortunately, as other research has mentioned, it seems that any dose of TSE, BSE, or CJD will prove to be eventually fatal.

In order to elaborate and generalize this finding between BSE and mice, researchers must look to any transmissions that can be accredited to human consumption of BSE. Again, this matter is an ethical issue, so research has been forced to find another way. Using similar methods to Scott, et. al. (1997), scientists used CJD confirmed brain tissue from deceased humans and fed or injected it to mice (Scott, Will, Ironside, Nguyen, Tremblay, DeArmond and Prusiner, 1999). While past studies have examined trends based on idiographic research or manipulation using BSE, this research focused on the disease expressed in man.

The results of this study indicate a successful transmission of CJD from human subjects to mice. This transmission was noted as having a short incubation period of 250-270 days. As with the research of Scott, et. al., 1997, observations of neurological dysfunction expressed behaviorally were used to determine proper transmission and sacrifice for examination. Although this method was successful in identifying the expression of the disease, it may have been beneficial to systematically sacrifice the animals over certain time periods, in order to document the progression of the disease as it deteriorated the brain. Perhaps, the researchers felt that such a practice would be unethical with more pain than necessary to inflict on mice. If not an ethical issue, it would have been wise to instill such a method that could examine neurodegeneration from the time first noticeable until death. Perhaps it would be beneficial to extend the sacrifice from day one of infection. This would provide a detail of progression. It could also provide data to investigate the theory that some subjects are more likely to be affected early from TSE.

Since scientists have yet to find a method of investigation that can use living human participants, it has been necessary to look at the tissue of the deceased. Hill and Butterworth (1999) examined the tonsils of CJD victims and found prion activity located at this site. This finding is significant because the experiment used the tissue taken from CJD victims as well as those subject to other prion disease or no disease. Upon tonsil biopsy, CJD prion was evident, unlike the tonsils of other prion disease patients or no disease, in which case no prion activity was found. This may implicate the omnipresence of the CJD prion. It may also allow for explanation of the vast range of symptoms associated with CJD. This finding also coincides with the research that mentions the varying degree of BSE found in all parts of contaminated consumer meat products, as stated by Scott, et. al. (1997). Hill and Butterworth (1999) confirmed this varying quantity of prion presence by including biopsy of the spleen and lymph nodes. Although present in all organs, the highest concentration of prion was in the tonsils. Perhaps there is a link between BSE and CJD, as observed in this comparison of studies.

Although certain diagnosis of CJD can be found through the use of an autopsy, it has been necessary to study suspected CJD infection with less evasive measures. A tool that has been used to look into the mind of a living CJD victim is Magnetic Resonance Imaging (MRI). Using such equipment allows researchers to pinpoint effected areas and trends in neurodegeneration as observed through plaque growth (Zeidler, Sellar, Collie, Knight, Stewart, MacLeod, Ironside, Cousens, Colchester, Hadley, and Will, 2000).

Through the use of MRI, the researchers were able to develop another form of diagnosis for CJD. The films taken with MRI were sent out to "blind" neurologists for examination. The same films were presented twice for reliability measures. The methods required this administration using suspected CJD brain MRI as well as healthy brain MRI. The task involved diagnosis predictions based on the MRI films provided. Ninety-three participants were matched for sex and age. There was no mention of consent or method of participant collection.

Zeidler, et. al. (2000) reported that the most important finding of using MRI to diagnose CJD was the bilateral thalamic high signal. This was observed in a "hockey-stick" appearance upon imaging, compared to other areas of the brain that were hemispherically symmetrical. This helped neurologists come to significant diagnosis of CJD with only 9 out of 124 physicians reporting in error. This study provided another way to come to diagnosis of CJD without having to wait for a patient's death and subsequent autopsy. There were a high number of participants and examiners used that implicate high replication and reliability. The research seems to display high internal validity due to the methods used as well as generalizability to the human CJD population. The use of living human CJD victims enhanced the study of this topic and allowed for relevant, practical findings. Going beyond a positive logical approach, Zeidler, et. al. (2000) expanded the research for the advancement of human disease control and prediction. Of course, more work on this subject using MRI measures would benefit the field.

So far, criteria for diagnosis, possible transmission theories, as well as diagnosis procedures have been discussed. Most articles mention that there is no current cure for CJD or related illness. In order to ameliorate that major problem, a study was constructed to try to revert prions back to natural healthy proteins (Soto, Kascsak, Saborio, Aucouturier, Wisniewski, Prelli, Kascsak, Mendez, Harris, Ironside, Tagliavine, Carp, and Fragione, 2000). Since it is possible in nature for proteins to change into killer prions, it was hypothesized that there is a way to manipulate a reversal.

Attempting to change a prion proved difficult. The researchers used a BETA-sheet breaker peptide to reverse the mutated protein. Some success was shown as prion modification was observed. Unfortunately, the researchers were unsuccessful in forcing inactivity from prion presence. The major changes in course came from a resulting longer incubation period and slower evolution of neurodegenerative behaviors. Such a positive advancement may be considered the first step in successful treatment. This would be a logical approach, considering the advancements in treatments that remit other fatal diseases such as cancer. Perhaps elimination is not necessary or possible, but may become manageable through synthetic means. Overall, the study presented was complex and seemingly well thought out. The researchers were able to present a good argument for CJD stabilization and allowed the reader to understand the positive heuristic value of the examination. Research of this nature provides motivation for other researchers to perform similar experiments with the anticipation of finding the cure of a currently incurable disease, truly a noble task.

Overall, the research on Creutzfeldt-Jakob disease presents a grim tale of fatal consequence for those who are unfortunate enough to contract it. Due to the nature of the disease, experimental manipulation has been difficult. The extreme contagious characteristics of the disease may also make it unattractive to study. This may be easily dismissed by some by the low rate of infection. Despite this, there are researchers devoted to finding the cure or at least treatment. The current methods, as stated in specific examples in this paper, institute the use of retrospective data, animal studies, as well as human autopsies. Thus far, with the exception of the newly released article by Zeidler, et. al. (2000), there haven't been too many successful methods for determining positive CJD diagnosis in living subjects.

Despite the research posed that provides symptomatic criteria that includes neurological and motor deficits as well as a few risk factors, the strongest being BSE transmission, science is baffled by this phenomena. Efforts to destroy the disease have been in vain. Treatment has yet to beat the ultimate outcome of death. Risk factors have also been variant across cultures. Overall, displaying the preliminary findings thus far and implicating a plethora of yet to be found information on the disease.

Careful consideration of future research should include retrospective, physiological (both past and present), as well as observation of living CJD victims. Perhaps science has looked at this problem too specifically. Since this is a less researched disorder, a global perspective should be taken, like when an artist stands back from his or her painting. The situation may benefit from taking in all factors during future study in order to present a clear picture. This may be an overwhelming task, but necessary for full understanding.

References

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