Scrapie Essay, Research Paper

Scrapie is a natrually occurring disease of sheep found in many parts of the

world, btu not everwhere. NowKNown for over 200 years, it possibly started in

Spain and spread to thewhole of western Europe. The export of strictly bred

sheep from Britain in the ninteenth centruy is thought to be involved in the

rapid spread to other couuntries. Work in Iceland has shown that the land on

which infected sheep graze may retain the condition and infect later sheep,

even if all scrapie-infected sheep are removed. Although sheep that were

shipped to Australia and New Zealand could not have been tested for scrapie

before they were sent, the illness does not seem to exist there; eradication

procedures appear to have worked. Sheep that are improted into those countries

are kept separately for some years before being alloweed into contact with

local sheep, and scrapie has appeared in sheep durig this quarantine period.

This makes it extremely unlikely that an infected animal will gain entrance to

these countries. Some countries claim to have low numbers of cases (eg.

Germany) but limited outbreaks occur apparently randomly among unconnected

flocks, despite this. The incidence of scrapie in a flock appears to be related

to the breed of sheep with some being relatively resistant to theillness (e.g.

scottish blackface) and others that are prone to it (herdwick, suffolk)

attempts have been made to eradicate scrapie from certain countries (e.g. US)

by slaughtere of infected flocks. This, however, has been largely unsuccessful,

and theoccurence of scrapie has been claimed to be increasing in the UK. Poor

statistics on the prevalence of scrapie abound, and farmers not recognising the

condition may merely slaughtere the infected animal and fail to report it to an

agricultural officer. In 1936 reserarchers showed that scrapie could be transmitted to a healthy

sheep by the intra-ocular inoculation of a homogenate of scrapie infected

brain. This experiment led to large amounts of resrarch conernig the mode of

transmission of TSE. Sheep inoculated with scrapie infected tissue intracerebrally will have a

short (possibly as low as 2 months) incubation period, but on farms it is older

sheep, usually more than 4 years old that show signs of disease. The sheep

irritablility, excitability, and restlessness at the onset, giving rise to

scratching, biting, rubbing of the skin (hence the name scrapei) patchy loss of

wool, tremour (hence the French name ‘tremblante’), loss of weight, weakness of

the hindquarters, and in some animals, impaired vision. The disease is always

fatal. Only a small number of animals in a herd suffer from the clinical signs

of scrapie, and experts have rarely seen 10 cases in a single herd. The natural

mode of transmission between sheep is unclear. Experiments in which sheep with

scrapie and those without it have been kept together on a farm have given rise

to differing results, but goats have been shown to catch the disease from sheep

in this form of experiment. Lambs of scrapie infected sheep are more likely to

develop the disease later in life, but the reason for this is unclear. The

infective agent is present in the membranes of the embryo but it has been

demonstrated neither in the colostrum and milk of the mother nor in the tissues

of the newborn animal. Many cases of scrapie appeared following the accidental

contamination of a louping-ill vaccine; however, the mode of infection in most

cases of scrapie seen on farms is unknown. Transmissible spongiform encephalopathies of humans TSEs of humans are divided into specific clinical types, which may appear

similar histopathologically but are either spread differently or have different

patterns of distribution and prevalence. Creutzfeldt-Jakob Disease CJD was first described in 1920/21 when it was known as ’spastic pseudosclerosis’

or ’subacute spongiform encephalopathy’. The illness exists throughout the

world and is claimed to have a similar prevalence in each ofthe countries

tested with an annual incidence of approximately 1 case per million of the

population. This is almost certainly an underestimate because histopathologists

dislike carrying out necroscopies on cases that may have died of CJD and many

older people dying of a dementing illness do not have necroscopies performed.

There is an increased incidence among Libyan jews (26 cases per million) and

spacial or temperal clusters in areas of Slovakia, Hungary, England, USA and

Chile. Cases are clustered in urban areas (except in Slovakia) but this can be

accounted for by the increased population density. The average age in typical

CJD is 56yrs, and only 7 cases between 18 and 29 years have been reported.

Between 4 and 15 % of cases have a familial connection with other cases. There

is a slight excess of CJD in women. Clinical prodromal symptoms start with changes in sleeping and eating

patterns and progress over a few weeks to a clearly neurological syndrome. A

rapid onset of neurological symptoms appears in 20% of cases, most commonly

vibrating muscular spasms, dementia, loss of higher brain function and behavioural

abnormalities. The disease progresses with deterioration in cerebral and

cerebellar function to a condition which most neurological activity is

decreased, sensory and visual function decays, and the patient dies, possibly

after a decrease in lowere motor neurological function and seizures. 90% of the

cases end in death within 1 year of onset, and the further 5% die within the

following year. However, for 5% of the cases fatality may take up to 10 years,

and in these cases neurological decay is relatively slow. Diagnosis is by clinical assessment of patients with pre-senile dementia and

by examination of electroencephalogram patterns, which characteristically show

triphasic one cycle per second activity or slow wave bursts with intermittent

suppression (also found in animals with TSE). Enlargement of the lateral

ventricals and an increase in a IgG may be found but these factors are of

limited diagnostic value. Post mortem diagnosis is currently carried out by

histological examination under the light microscope of cerebral tissue,

although this is not always reliably diagnostic. Research techniques have been

used to demonstrate CJD (and other TSEs). These may involve the electron

microscope examination of brain tissue for scrapie associated fibrils (SAF), the

staining of the tissue for prion protein antigens, or the intracerebral

injection of tissue into animals, which will go on to die of the disease. In some patients, the source of CJD has been claimed to be an infection

transferred from other patients with the condition. For example, in one case,

cerebral electrodes that had been sterilised with only alcahol and formalin

vapour after use in a patient with CJD, were both used in the brains of two

young epileptic patients, both of whom contracted CJD after a short incubation.

The transfer of CJD by corneal transplant in one patient, by cadaveric dura

mater graphs in two patients and by concentrated human growth hormone

injections in over 40 more have been reported. Some cases in the literature

seem too improbably for the low incidence in a community. For instance the

report of CJD in a neurosurgeon, a mortury attendant, in two men living 200

metres apart in sharing a general practitioner, in a patient who had visited

the Eastern Highlands of New Guinea (the kuru area) ten months previously, in 3

patients who had been operated on in the same neurosurgical unit within a

period of 8 months, in 2 people living together but not genetically linked and

in an individual marrying into an infected family (although the spouse did not

suffer from CJD). Two husband and wife couples have died of CJD as well as a

life long vegetarian. Four farmers that had cases of BSE on their farms have

died in the UK suffering from CJD since 1993, as have 2 teenagers. The mode of

disease transmission may be by personal contact, but only medical procedures

have been described as to how this takes place. If the disease is transmitted

from animal sources, many routes have been suggested but insubstantial evidence

has been available to prove them. The distribution of CJD in the world does not

seem to be the same as that of scrapie in sheep, and human exposure to sheep is

poorly associated with CJD. None of the animals that suffer from CJD except

cows appear to be present in large numbers in all the countries where CJD is

prevalent. Although their tissues are unliekly to be infective, pigs, which are

generally slaughtered, are not consumed by Muslims and Jews, who also suffer

from CJD. Kuru Kuru is a condition of the Fore tribe of the Okapa district of the Eastern

Highland in Papua New Guinea, in which a practice of ritual cannibalism of

fellow tribesmen took place until around 1956. The disease affected mainly

adult woment and children of both sexes to give an annual disease specific

mortality of approximately 3%. Most deaths of women occured through this

disease and some men who died from this disease were thought to have contracted

it when young. Kuru is caught by eating infected tissue. The brain of the dead tribal

member was eaten by women and children and the muscle tissue by men. The

possibility that has also transmitted the disease to men but with a lower dose

of infective agent and, hence, a longer incubation period has not been ruled

out. The cohort of children born since 1956 has not suffered greatly from kuru.

Clinically the disease is of a progressive cerebellar ataxia leading to

uncoodinated movements, neurological weakness, palsies, and decay in brain

cortical function. Most patients dying of kuru are not demented, and this is a

major clinical difference between kuru and CJD. Patients with a longer

incubation period appear to have a slower progression of symptions, but

generally death from inter current infection or medullary involvement takes

place with an average clinical period of 12 months. Gerstmann-Straussler-Scheinker disease Gerstmann-Straussler-Scheinker disease (GSS) is an autosomally dominant

condition rarely present in families. The disease is similar to CJD except that

it has a more extended onset and duration, a tendency towards cerebellar ataxia

as the initial predominant neurological sign, and a large number of amyloid

plaques present among the spongiform encephaloapthic changes of the brain. It

has been transmitted to monkeys and rodents by intracerebral inoculation and to

hamsters merely by the insertion of the human abnormal PrP gene from chromosome

20 into the hamster genome. Alpers disease Alpers disease represents a group of very rare chronic progressive

degenerative disorders of the central nervous system of infants and children.

Histologically this condition is similar to CJD and can be transmitted, like

CJD, to hamsters easily but not to guinea pigs by intracerebral inoculation.

Unlike CJD, however, there is also a fatty degeneration of the liver. Transmissible mink encephalopathy TME is an uncommon fatal disease that occurs as outbreaks in ranch mink

(mustella vision). The condition was first reported in 1947 in Wisconsin and

has also been reported in Canada and Finland with a similar pattern. Most of

the mink on the farm die rapidly after a short encephalopathic period. The

incubation in experimental situations is considered to be approximately 6

months. Because mink are generally separate from each of the other on farms

(except when less than 3 months old) and because little contact is made between

them and external animals, the disease is thought to be derived from their

food, which is contaminated with a TSE of an other animal. Fighting and

canibalism among young mink is difficult to prevent and this may be reason why

most animals on the ranch become infected. One outbreak in Stetsonville,

Wisconsin, USA, followed the feeding of the mink with the meat and bone meal of

a cow that had died of a disease similar clinically simialr to BSE. No sheep

were included in their diet. The experimental feeding of food that contained

scrapie or BSE infective agent to mink has given rise to the disease but not of

apparently the same clinical type. Chronic wasting disease of deer CWDD is a TSE seen in 1978 in a mule deer herd and in an adjacent herd of

elk at Ford Collins, Colorado, USA. Both herds were captive. The disease shows

typical spongiform change in the cerebral grey matter and can be transmitted to

deer and ferrets by inoculation. Bovine spongiform encephalopathy BSE, a condition seen generally in adult cattle of either sex was first

recognised in 1986 in the UK, where it now infects greater than 55% of milking

herds. The numbers are highest in Southern England where more than 60 cases

have been reported in a single herd but are generally spread throughout the

British Isles, often as less than 3 cases per herd of 100 cattle per annum. It

has been reported now in Oman, Switzerland, France, Germany, Canada, Denmark,

Portugal, and Italy but these cases are probably associated with the export of

either infected animals or infected meat and bone meal for bovine feed from the

UK. It is difficult to explain the cases in Portugal in that many are the

offspring of cattle exported from the UK, whereas their mothers are apparently

not clinically infected. The disease is thought to have been derived either

from the change in the manufacture procedure of meat and bone meal (for bovine

consumption) or from the inclusion of an uncomon bovine case of spontaneous BSE

in bovine food in approximately 1978-1980. Claims have been made that this is

not a new disease; in the past, although not histologically diagnosed, it has

been seen in approximately 1 cow in 20,000 to 30,000. The rapid increase of the

disease (850 cases reported per week in 1994) is probably due to the inclusion

of undiagnosed cases of BSE in the meat and bone meal used for bovine food.

This was stopped in the UK in July 1988, but the meal was simply exported to

other countries by its manufacturers (this has now been stopped). BSE has now

been transmitted to cattle, mice, sheep, and goats both orally and by

inoculation, and to pigs, marmoset monkeys but not hamsters merely by

inoculation. Over 18,000 cases have been developed BSE although they were born

after the ban of oral infectious material being present in their food. It is

still unclear whether the cattle become infected directly from the food that

they eat or from asymptomatic mothers that have done this.The possibility that

an environmental factor other than the BSE infective agent may be involved with

the transmission of BSE has been suggested due to the relatively low incidence

of disease on ‘organic’ farms and organosphorus insecticide use has been

suggested as being involved. The long incubation period (presumed to be more than 2 years and most

commonly 5 years) means that case numbers have appeared to decrease accoreding

to MAFF statistics since 1994. There is argument about the validity of this

data. Clinically, the cow appears alert but agitated, anxious, and apprehensive.

As the disease progresses, however, the animal starts to take a wide base

stance, the abdomen is drawn up and the gait becomes abnormal and exaggerated

and it gives rise to tumbling and skin wounds. Fine muscle contractions are

seen involving small muscle groups over the surface of the neck and body with

occaisional larger muscular jerks. The animal loses weight and is taken to

frenzied movements including aimless headbutting. The possibility that BSE may be infectious to humans was considered to minimal

in the UK until November 1989, when the feeding of bovine tissue, lymphoid

tissue, spleen, thymus or gut (from cattle over the age of 6 months) to humans

was banned. All animals that show signs of BSE in the UK must now be

slaughtered and disposed of by incineration or burial. Beef in the UK would be

expected to carry a lower titre of the infectious agent at the present time,

but the larger amounts eaten by humans and the long human lifespan make its

safety unclear. Feline spongiform encephaloapthy FSE is a condition that was reported in May 1990 in a 5 year old male

siamese cat and has then been reported in many other in the UK. The

epidemiology of FSE is unclear at the present but attempts to find previous

cases among demented or neurologically degenerate cats from the past have been

uncussessful. We must therefore consider it to be a new disease.

Histologically, it is similar to other TSEs. It is now felt to be due to BSE

being present in feline food. The owner of the original cat with FSE denied feeding

it tinned cat food and insisted that it was fed fresh meat. Zoological spongiform encephalopathy Zoological animal TSE has been reported since 1986 in an eland, a nyala, an

Arabian oryx, a greater kudu, a gemsbok, a cheetah, a puma, and an ocelot in British

zoos. Various offspring of the mother kudu have died of the disease and the

possibility that it is passed vertically must be considered. They had not been

given food thought to be infected. The animals became clinically unwell after

the appearance of BSE on British farms, and they were probably infected either

from the same source as the cattle or from BSE contaminated foodstuff. No TSE

in similar animals has been reported before and, hence, these must be

considered new diseases. Four ostriches in the zoos of northern Germany have

developed simialr conditions but no evidence is currently available as to

whether the diseases are transmissible. Transmissible of spongiform encephalopathies Infected nervous tissue from some animals was injected, often intracerebrally,

into others to find the range of infectivity of the agent. From this it was

found that only approximately 70% of animals developed disease. Dose experiments Dose experiments were carried out to understand the nature of the infective

agent. Scrapie infected brain was exposed to various agents (e.g. irradiation)

and then injected in multiply diluted forms into the brain of an uninfected

animal. In this way, the agent could be filtered. Multiple ten-fold dilutions

were made of the infective material, and each of the dilutions was inoculated

in a similar amount into an animal of the same species. The infective dose of

the greatest dilution that caused the animal to die (often after years of

incubation), was defined as infective unit (IU) if the animal receiving the

inoculum was the same species as that of the animal that was donating it. The

brain of an animal dying of TSE commonly contained between one million and ten

thousand million IU per gram. The oral infective dose of scrapie for a mouse was

4 x 10,000 IU, which represents between one hundredth and one hundred

thousandth of a gram of infected brain tissue. In these experiments,

researchers noticed that the incubation period was inversely related to the

dose given to the animal and that the animal may be infected with a small dose

of TSE but die of old age before clinical signs appear. Effect of host passage on the properties of the infectious agent 1. The infectous dose between species is usually higher than between animals

of the same species (possibly a million fold), but it is some times the same

(e.g. between scrapie doses for mink perhaps) 2. When a species has been infected with a TSE of a different species it can

then go on to infect a range of animals that the original species could not,

and with a different dose. 3. When a species has been infected, it can infect additional animals of the

same species with much lower doses of agent. 4. The histopathology of the disease in an animal infected from another

species is not the same as if it had been infected from one of the same

species. 5. The incubation period of an animal infected from another species is much

longer than that of an animal from one of the same species. To demonstrate these factors, brain tissue of a sheep with scrapie would

only need one 1IU to infect another sheep, but if mice were injected a much

larger dose would be needed, the incubation period would be relatively long,

and a low percentage of the mice would be affected. If brain tissue from these

infected mice was inoculated into addicitonal mice, the dose would be one IU (a

very small amount) the incubation period would be much lower, a high percentage

of the mice would become infected, and the histology would be the same as in

further passages of the disease in mice (but different from the histopathology

of the mouse infected from the sheep). The mice would also be able to infect a

distinct range of animals other than sheep. These factors are known as the species barrier (SB) and behave as if the

agent is altered by passage through a species to a form that is more likely to

infect that species. The insertion of the hamster PrP gene (vide infra) in to

the genes of a mouse removes the SB between the animals; i.e. when injected

with scrapie from a hamster, such a mouse would develop scrapie as if it is a

hamster. This has been explained by the possibility that the PrP protein is all

or part of the infective agent and, as it is produced from the genes of the

host animal, it has a different structure in different species. Tissue infectivity of clinical cases of TSEs TSE infectivity is present in most tissues tested (e.g. liver, kidney,

muscle, brain, thymus, spleen, etc), and the distributions vary among species.

The finding of infectivity in the buffy coat of blood has led to fears that CJD

may be transferred by blood transfusions, but there has been no report of this

at time. The finding that the scrapie agent was present in perpheral as well as

central nervous tissue and in lymphoid tissue has given little surprise to the

finding of TSE agent in muscles of goats, hamsters, mink and possibly humans. Tissue infectivity during the incubation period The animal is as asymptomatic for a long period before the disease becomes

clinically apparent. During this time, many of the tissues of the body are

infectious but at a relatively low titre compared to the nervous system during

the symptomatic period. This titre is adequately high, however, to permit

infection of other animals by intracerebral inoculation and possibly by parenteral

or oral routes. The mode of spread of TSEs inside the body Research has shown that the agent will pass along peripheral nerves and

hence will travel in this way form a site of absorbtion to the brain. Other

resarch has shown it to be present in the buffy coat (probably the macrophages

or lymphocytes) of the blood. The exact mode of spread of TSE inside the body

is unclear. Immunity Developed immunity against the infective agent has not been demonstrated.

Apparently no antibodies that react with it are produced, even in chronically

infected animals. The possibility that this may permit multiple inoculations of

sublethal doses of the agent to be effectively additive in their effect has

been considered and is presumed by some researchers but no specific proof of

this has been shown. Rabbits may produced antibodies against PrP derived from

sheep (vide infra). Resistance of the agent to destruction Chemical disinfectants (e.g. domestic bleach), weak acids, DNAase, RNAase,

proteinases (including those found in the animal gut), ultraviolet light,

ionising radiation, heat (cooking tempertures), and chemicals that react with

DNA (psoralins/UV light, hydroxylamine, zinc ions), all have little effect on

the infectivity of the agent. High temperature autoclaving (135 degrees

centegrade for 18 minutes) decreases the infectivity dramatically, as does the

use of 1M NaOH, but neither will fully destroy the agent, as it has been found

to remain infective after 360 degrees C for 1 hour or even after incineration.

Internment of infective tissue in the soil for three years did not destroy the

agent. Some phenols and proteases will decrease the infectivity of the agent

but not to an adequate degree to be of value in disinfection. Prevention of TSEs Nosocomial CJDs should be prevented by prohibiting CJD, GSS, or Alpers

disease patients (or those with obscure neurological conditions) from becoming

blood or tissue donors, by the incineration or high temperature autoclaving of

all materials that came into contact with blood, or post mortem tissue from

such a patient, and by the disposal of all surgical instruments used for brain

surgery on such a patient. The body should not be used for teaching anatomy or

surgery. Correct action to be taken concerning BSE infected herds is currently

under intense discussion. Histopathogical changes Characteristic lesions under the light microscope consist of spongy changes

in the neuropil nerve cells and astrocytes with nerve cell degeneration and

astrocytosis. These changes generally take place in the grey matter of the

cerebrum and cerebellum. The distribution of the histopathology may vary

according to the strain of the disease, as has been shown with inbred strains

of mice. It may also vary with the site of inoculation, for example, if the infection

reaches the brain through the optic nerve, then the spongy degeneration is

clustered around the occipital lobe. Amyloid plaques may be seen between cells

in some TSEs (e.g. kuru, hamster scrapie) and strained with Congo red. These

contain PrP and have been shown to be infective. Electron microscocopy shows

twig-like structures 12 to 16 nanometers in width and 100 to 500 nanometers

long, which are found only in TSE and are now called scrapie associated fibrils

(SAF). Nature of the infective agent for TSEs PrP: A cellular protein found altered in cases of TSEs PrP is a sialoglycoprotein produced from a gene normally found in the genome

of the infected animal. This gene on chromosome 2 in mice (or chromosome 20 in

humans), may be conserved between strains but altered between species. PrP in a

normal brain has glycoside modifications and is held onto the membrain of the

cell by covalent attatchement to phospholipid. In scrapie, however, the PrP is

present much more within the membrane and has a different structural form

(PrPsc). This modification, whatever it may be, renders the protein resistant

to heat and to most proteases and when treated with proteinase K (a very

powerful enzyme) it is split into particles fo 27-30 kDa the structures of

which are uncertain. PrPsc structure has been shown to vary with the strain of

TME and for the altered form of PrP to induce such a change in normal PrP (this

is, however, very inefficient, and the infectivity of the PrPsc that is formed

has not been shown). The PrP of patients with GSS is mutated so that proline is

replaced by leucine at position 102. The PrP of CJD in the Libyan Jew and

Slovak clusters and some cases of familial CJD have a different alteration from

that in GSS and various changes have been reported. Patients with CJD that is

not familial do not generally have PrP mutations. When the gene for PrP in a

patient who suffers from GSS (PrPgss) is inserted into a hamster genome, about

one in twenty animals spontaneously develop a TSE. PrP is therefore greatly

involved in the infectivity and pathogenesis of the disease, but how it could

be the infective agent (vide infra) is not clear. Inbred mouse strains with

long and short incubation periods (known as sinc genes) for scrapie have been

found to have differences in their PrP codons, which are claimed by some to be

the sinc genes themselves. Mice have been developed that do not carry a PrP

gene at all. These mice appear to grow in an asymptomatic way and cannot be

infected with scrapie (nor do they become infected and remain asymptomatic). Structure of the transmissible spongiform infective agent Conjecture is currently complex and hence, there are many hypotheses: Virus: No specific particle (although many have been claimed to have been

seen under the elecron microscrope) has been isolated but the transmissibility

is similar to this form of agent. Prion: A protein infectious agent.Felt to be the PrP altered form (PrPsc),

which is resistant to destruction, would not cause antibody production in the

infected animal, and would vary according to the species infected. Purified

PrPsc has been claimed to transmit scrapie but experimental methods have been

challenged as being fully vaid. How a prion would transmit strains of disease

without an independent genome is currently unclear. The recent transmission of

GSS to hamsters by an artificial PrP GSS gene has made this hypothesis more

likely. Virino: Small fragment of DNA/RNA closely wrapped in protein. The SAF that

are found only in TSEs and that have PrP involved in their structure could be

virinos. They are sugested to contain some genetic material (although none has

been found), which could explain the different strains of disease. However, the

agent is resistant to chemicals and ionising radiation, which would be expected

to destroy the nucleic acid. Tubulofilamentous particles: these are the items seen under the electron

microscope in all cases of TSE. Their association with infection has not been

demonstrated. Crystalloids: These would be the growing crystals of prion protein that

would cause the PrP to change into the PrPsc form with the release of energy.

This would explain the strain types as being the form of crystalloid depending

on other factors apart from the PrP protein structure (possibly depending on

the glycan chains to which are attatched). Spiroplasmas. These are infective agents that can be cultured in vitro and

are well known in microbiology. Althogh no spiroplasma has been found

specifically, the appearance of the structure of the EM particles suggest it. Future prospects The incidence of CJD is apparently unchanged over any years, although poor

statistics to confirm this. The epidemic of BSE in the UK is expected to

continue there for up to 10 years but the incidence to decrease after 1993. It

is, however likely to spread to Europe and other countries that imported

infected British meat and bone meal. The precise risk that this may be followed

after 5-25 yrs by a wave of CJD, FSE and Zoological SE, is unknown but the

possibility should be considered.

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