EFSA's Panel on Animal Health and Welfare (AHAW) has published five scientific opinions and a scientific report on the overall effects of the most relevant farming systems on the welfare of dairy cows and related diseases. The Panel concluded that long term genetic selection for higher milk yield and the nature of the farming systems used - i.e. housing and equipment, as well as management and handling practices - are major factors affecting the health and welfare of dairy cows. Lameness and mastitis are the most significant indicators of poor dairy cow welfare, as well as reproductive, metabolic and behavioural disorders. The Panel proposed a series of recommendations which could be taken into account by risk managers in view of further improving welfare in the areas of housing, feeding and the genetic selection of dairy cows.
On request of the European Commission, the AHAW Panel considered, in its first opinions in the area of dairy cow welfare whether current farming and husbandry systems meet the welfare needs of dairy cows. The Panel also evaluated the impact of genetic selection aimed at increasing milk yield on dairy cow welfare in the various farming systems used , and highlighted the correlation between genetic selection and the incidence of lameness, mastitis, reproductive and metabolic disorders.
Over the last thirty years genetic selection for higher milk yield has changed the body shape and increased the size of dairy cows, therefore increasing their requirement for space. Scientific experts highlighted the importance of allocating enough space for cattle movement when designing resting, feeding and walking areas. The Panel recommended that the genetic selection of dairy cows should address their resistance to diseases such as lameness and mastitis, as well as improve their fertility, health and longevity.
Scientific experts took into account all available data in defining levels for light, indoor temperature and relative humidity for good welfare. They recommended that the design of resting, walking and feeding areas in the buildings should allow for sufficient movement and exercise. The Panel also said that while the use of tie-stalls continues, cows should have daily exercise that involves walking freely. On this point, six members of the AHAW Panel expressed a minority opinion highlighting evidence of poor welfare in dairy cattle held in tie-stalls and recommended that dairy cattle should not be routinely kept in tie-stalls
The Panel concluded that achieving reduction of mastitis can be obtained not only from treating the disease and preventing its transmission, but also from improving the animals' immune systems. This can be achieved by minimising stress factors and through controlled and nutritionally-balanced feeding (e.g. by providing the most appropriate type of dietary fibre for the digestive system of dairy cows).
The Panel also concluded that farms with a high prevalence of lameness in dairy cows (e.g. above 10%) do not have an adequate prevention programme and should improve housing conditions, genetic selection and management practices. Moreover, farmers who are well trained in recognising signs of disease at an early stage and in knowing when to seek veterinary advice can contribute to reducing the prevalence of lameness.
Source
EFSA
воскресенье, 15 мая 2011 г.
Prion Filter Could Prevent VCJD Spread From Donated Blood
A filter that takes prions (carriers of vCJD) out of infected blood has been successfully tested on hamsters and UK scientists are optimistic of getting similar results with human donated blood.
The results of this research are reported in The Lancet.
Prions are proteins that cause a range of diseases, including Bovine Spongiform Encephalopathy (BSE, mad cow disease), scrapie (like BSE but occurs in sheep) and variant Creutzfeldt-Jakob Disease (vCJD, the human form of mad cow disease). They latch onto brain tissue and create havoc by making the surrounding brain proteins change their shape, thus interfering with vital functions like message transmission from brain cell to brain cell.
Prion-related diseases can take many years to develop and are difficult to diagnose in the early or dormant stages.
The Cambridge-based scientists have found that a molecule called L13 sticks to prion protein (PrP) in blood that is infected with scrapie. Early tests show it could also stick to prions that cause vCJD in humans.
They processed a batch of hamster blood in two stages, and kept some unprocessed blood. The first stage removed the white blood cells (leucoreduction - a procedure performed on donated human blood before it is banked), and the second stage passed it through a filter using L13.
They also had a batch that was filtered with L13A, a version that is made on a manufactured scale.
They injected the leucoreduced blood into 99 hamsters. 15 of them were infected with scrapie 540 days later.
The L13 and L13A filtered blood was injected into 96 (100 for the L13A) hamsters, none of which became infected with scrapie.
The potential benefits of this process, if proven for humans, lie in the fact that you only need very low concentrations of prions (virtually impossible to detect) to cause vCJD in a recipient. The donor may not have any symptoms for years, making detection very difficult. In such a scenario the only safe option is to clean all donated blood.
However, blood transfusion experts are cautious, saying the results need to be repeated on human blood. Quite how this is to be done is not clear, since there are no precedents and they see many problems, for example how much precious blood might be lost, and how might filtering affect the other properties of human blood?
Restrictions on blood donation because of potential infection by prions were triggered in 2004 when a report in The Lancet suggested that vCJD could be passed from human to human (as opposed to ingesting BSE infected products) via blood transfusion. Fearful of an epidemic, the UK authorities banned anyone who had received a blood transfusion since 1980 from giving blood.
And in 2002 in the US, the Food and Drug Administration (FDA), introduced a ban that stops people who stayed in certain European countries for 6 months or more (3 months in the UK) between 1980 and 1996 from giving blood. Australia has a similar policy, as does Canada.
"Reduction in infectivity of endogenous transmissible spongiform encephalopathies present in blood by adsorption to selective affinity resins."
Luisa Gregori PhD, Patrick V Gurgel PhD, Julia T Lathrop PhD, Peter Edwardson PhD, Brian C Lambert, Prof Ruben G Carbonell PhD, Steven J Burton PhD, David J Hammond PhD and Dr Robert G Rohwer PhD.
The Lancet 2006; 368:2226-2230
DOI:10.1016/S0140-6736(06)69897-8
Click here for abstract.
The results of this research are reported in The Lancet.
Prions are proteins that cause a range of diseases, including Bovine Spongiform Encephalopathy (BSE, mad cow disease), scrapie (like BSE but occurs in sheep) and variant Creutzfeldt-Jakob Disease (vCJD, the human form of mad cow disease). They latch onto brain tissue and create havoc by making the surrounding brain proteins change their shape, thus interfering with vital functions like message transmission from brain cell to brain cell.
Prion-related diseases can take many years to develop and are difficult to diagnose in the early or dormant stages.
The Cambridge-based scientists have found that a molecule called L13 sticks to prion protein (PrP) in blood that is infected with scrapie. Early tests show it could also stick to prions that cause vCJD in humans.
They processed a batch of hamster blood in two stages, and kept some unprocessed blood. The first stage removed the white blood cells (leucoreduction - a procedure performed on donated human blood before it is banked), and the second stage passed it through a filter using L13.
They also had a batch that was filtered with L13A, a version that is made on a manufactured scale.
They injected the leucoreduced blood into 99 hamsters. 15 of them were infected with scrapie 540 days later.
The L13 and L13A filtered blood was injected into 96 (100 for the L13A) hamsters, none of which became infected with scrapie.
The potential benefits of this process, if proven for humans, lie in the fact that you only need very low concentrations of prions (virtually impossible to detect) to cause vCJD in a recipient. The donor may not have any symptoms for years, making detection very difficult. In such a scenario the only safe option is to clean all donated blood.
However, blood transfusion experts are cautious, saying the results need to be repeated on human blood. Quite how this is to be done is not clear, since there are no precedents and they see many problems, for example how much precious blood might be lost, and how might filtering affect the other properties of human blood?
Restrictions on blood donation because of potential infection by prions were triggered in 2004 when a report in The Lancet suggested that vCJD could be passed from human to human (as opposed to ingesting BSE infected products) via blood transfusion. Fearful of an epidemic, the UK authorities banned anyone who had received a blood transfusion since 1980 from giving blood.
And in 2002 in the US, the Food and Drug Administration (FDA), introduced a ban that stops people who stayed in certain European countries for 6 months or more (3 months in the UK) between 1980 and 1996 from giving blood. Australia has a similar policy, as does Canada.
"Reduction in infectivity of endogenous transmissible spongiform encephalopathies present in blood by adsorption to selective affinity resins."
Luisa Gregori PhD, Patrick V Gurgel PhD, Julia T Lathrop PhD, Peter Edwardson PhD, Brian C Lambert, Prof Ruben G Carbonell PhD, Steven J Burton PhD, David J Hammond PhD and Dr Robert G Rohwer PhD.
The Lancet 2006; 368:2226-2230
DOI:10.1016/S0140-6736(06)69897-8
Click here for abstract.
USA - some quarantined cows could be killed
At least some cows from two Washington state herds quarantined since discovery of a Holstein with mad cow disease will have to be killed, some who may have been exposed to the infection and others because of public fear.
A decision on the first cows to be euthanized will be made very soon, Dr. Ron DeHaven, the Agriculture Department's chief veterinarian, said Friday.
'It would be safe to assume that ... some or all of those animals will need to be sacrificed,' DeHaven said of the two Washington state herds.
Two of the quarantined herds contain calves of the infected Holstein, and mother-to-calf transmission is considered unlikely but can't be ruled out.
One of the calves lives in the mother's own herd in Mabton, Washington, home also to nine other cows that entered the United States from Canada along with the infected Holstein.
The infected mother was born before August 1997, when cow parts were prohibited from cattle feed, the main way that mad cow disease is thought to spread through livestock -- and thus the chief suspect in how she became infected. The question now is how many other cows in that Mabton herd would have eaten pre-1997 feed, too, and thus need to be sacrificed.
But other cows may ultimately be sacrificed, too, DeHaven said.
'Even though we know with a very good degree of certainty that there's no direct disease spread animal to animal, simply being on the same farm there are some public perception issues related to those animals,' he said.
Mad cow disease is a concern because humans can develop a brain-wasting illness, variant Creutzfeldt-Jakob disease, from consuming contaminated beef products. Although 153 people worldwide have contracted that illness, most in Britain, it has never been diagnosed in an American.
A total of 81 animals were believed shipped across the border with the Holstein from Canada in 2001, and USDA has accounted for 11 of them. One is at a dairy farm in Mattawa, Washington, which recently was quarantined, the third herd to be contained.
A decision on the first cows to be euthanized will be made very soon, Dr. Ron DeHaven, the Agriculture Department's chief veterinarian, said Friday.
'It would be safe to assume that ... some or all of those animals will need to be sacrificed,' DeHaven said of the two Washington state herds.
Two of the quarantined herds contain calves of the infected Holstein, and mother-to-calf transmission is considered unlikely but can't be ruled out.
One of the calves lives in the mother's own herd in Mabton, Washington, home also to nine other cows that entered the United States from Canada along with the infected Holstein.
The infected mother was born before August 1997, when cow parts were prohibited from cattle feed, the main way that mad cow disease is thought to spread through livestock -- and thus the chief suspect in how she became infected. The question now is how many other cows in that Mabton herd would have eaten pre-1997 feed, too, and thus need to be sacrificed.
But other cows may ultimately be sacrificed, too, DeHaven said.
'Even though we know with a very good degree of certainty that there's no direct disease spread animal to animal, simply being on the same farm there are some public perception issues related to those animals,' he said.
Mad cow disease is a concern because humans can develop a brain-wasting illness, variant Creutzfeldt-Jakob disease, from consuming contaminated beef products. Although 153 people worldwide have contracted that illness, most in Britain, it has never been diagnosed in an American.
A total of 81 animals were believed shipped across the border with the Holstein from Canada in 2001, and USDA has accounted for 11 of them. One is at a dairy farm in Mattawa, Washington, which recently was quarantined, the third herd to be contained.
Seeking The Cause Of Mad Cow Disease
The cause of diseases such as BSE in cattle and Creutzfeld-Jakob disease in humans is a prion protein. This protein attaches to cell membranes by way of an anchor made of sugar and lipid components (a glycosylphosphatidylinositol, GPI) anchor. The anchoring of the prions seems to have a strong influence on the transformation of the normal form of the protein into its pathogenic form, which causes scrapie and mad cow disease. A team headed by Christian F. W. Becker at the TU Munich and Peter H. Seeberger at the ETH Zurich has now "recreated" the first GPI-anchored prion in the laboratory. As they report in the journal Angewandte Chemie, they have been able to develop a new general method for the synthesis of anchored proteins.
The isolation of a complete prion protein that includes the anchor has not yet been achieved, nor has it been possible to produce a synthetic GPI-anchored protein. The function of the GPI anchor has thus remained in the dark. A new synthetic technique has now provided an important breakthrough for the German and Swiss team of researchers.
The sugar component of natural prion GPI anchors consists of five sugar building blocks, to which further sugars are attached through branches. Details of the lipid component have not been determined before. As a synthetic target, the researchers thus chose a construct made of the five sugars and one C18-lipid chain and worked out the corresponding synthetic route. First, the anchor was furnished with the sulfur-containing amino acid cysteine. The prion protein was produced with the use of bacteria and was given an additional thioester (a sulfur-containing group). The centerpiece of the new concept is the linkage of the protein and anchor by means of a native chemical ligation, in which the cysteine group reacts with the thioester. This allowed the prion protein to firmly attach to the vesicle membranes by way of the artificial anchor.
This new concept will allow production of sufficient quantities of proteins modified with GPI anchors for in-depth studies. Experiments with the artificial GPI prion protein should help to clarify the influence of membrane association on conversion of the protein into the pathogenic scrapie form. This should finally make it possible to track down the infectious form of the prion.
This release is available in German.
Author: Christian F. W. Becker, Max-Planck-Institut f??r molekulare Physiologie, Dortmund (Germany), ch.tum.de/proteinchemie/
Title: Semisynthesis of a Glycosylphosphatidylinositol-Anchored Prion Protein
Angewandte Chemie International Edition 2008, 47, No. 43, 8215-8219, doi: 10.1002/anie.200802161
The isolation of a complete prion protein that includes the anchor has not yet been achieved, nor has it been possible to produce a synthetic GPI-anchored protein. The function of the GPI anchor has thus remained in the dark. A new synthetic technique has now provided an important breakthrough for the German and Swiss team of researchers.
The sugar component of natural prion GPI anchors consists of five sugar building blocks, to which further sugars are attached through branches. Details of the lipid component have not been determined before. As a synthetic target, the researchers thus chose a construct made of the five sugars and one C18-lipid chain and worked out the corresponding synthetic route. First, the anchor was furnished with the sulfur-containing amino acid cysteine. The prion protein was produced with the use of bacteria and was given an additional thioester (a sulfur-containing group). The centerpiece of the new concept is the linkage of the protein and anchor by means of a native chemical ligation, in which the cysteine group reacts with the thioester. This allowed the prion protein to firmly attach to the vesicle membranes by way of the artificial anchor.
This new concept will allow production of sufficient quantities of proteins modified with GPI anchors for in-depth studies. Experiments with the artificial GPI prion protein should help to clarify the influence of membrane association on conversion of the protein into the pathogenic scrapie form. This should finally make it possible to track down the infectious form of the prion.
This release is available in German.
Author: Christian F. W. Becker, Max-Planck-Institut f??r molekulare Physiologie, Dortmund (Germany), ch.tum.de/proteinchemie/
Title: Semisynthesis of a Glycosylphosphatidylinositol-Anchored Prion Protein
Angewandte Chemie International Edition 2008, 47, No. 43, 8215-8219, doi: 10.1002/anie.200802161
Active vaccine prevents mice from developing prion disease
NYU School of Medicine scientists have created the first active vaccine that can significantly delay and possibly prevent
the onset of a brain disease in mice that is similar to mad cow disease. The new findings, published online this week in the
journal Neuroscience, could provide a platform for the development of a vaccine to prevent a group of fatal brain diseases
caused by unusual infectious particles called prions.
Although no cure for these diseases -- which include scrapie, mad cow disease, and chronic wasting disease -- is on the
horizon, many research groups in both the United States and Europe are working on prion vaccines. But the NYU study is
important because it breaks new ground in demonstrating that active immunization can protect a significant percentage of
animals from developing symptoms of prion disease, explains Thomas Wisniewski, M.D., Professor of Neurology, Pathology, and
Psychiatry, and the lead author of the study.
The vaccines that provide active immunization are made, in part, from proteins found on disease-causing organisms. In
response to these proteins, the animal's immune system produces antibodies that will destroy them any time they appear in the
body. Most vaccines in use today provide such active immunization.
The prion vaccine developed at NYU would most likely first be used to protect livestock, since most prion infections occur in
animals and are thought to be transmitted orally, explains Dr. Wisniewski. The version of prion disease that affects humans
usually occurs spontaneously, and only rarely as a result of eating contaminated meat.
"The potential use for a prion vaccine in humans is still theoretical," says Dr. Wisniewski. "But if, for example, there is
ever a more significant outbreak of chronic wasting disease and if this disease were found to be transmissible to humans,
then we would need a vaccine like this to protect people in hunting areas."
Currently, an outbreak of chronic wasting disease is occurring in some Western states, and the disease's geographic range is
expanding. Two cases in wild deer have recently been reported for the first time in New York State, according to the New York
State Department of Environmental Conservation.
First mucosal prion vaccine
The NYU study is also the first to use a mucosal prion vaccine, given by mouth rather than through the skin, which localizes
the initial immune response to the gut and mainly stimulates an antibody response, says Dr. Wisniewski. "By giving our
vaccine orally, we're stimulating an immune response mainly in the digestive tract," he explains. "Thus, harmful prions in
contaminated food will be destroyed in the gut and will not reach other organs in the body." Because the research was
conducted in normal mice, the NYU researchers say it will be easier to apply in animals in the wild, which are at risk for
developing prion disease.
Prion disease is contracted when an animal eats the body parts of other animals contaminated with prions. What makes these
infectious particles unusual is that they are proteins that have the same amino acid composition as equivalent proteins
occurring naturally in the body. But the prions turn deadly by changing shape. These "misfolded" proteins tend to aggregate
in toxic, cell-killing clumps. As an infection takes hold, prion proteins invade brain tissue and force normal proteins to
adopt their configuration. In time, the diseased animal develops dementia, loses control of its limbs, and eventually dies.
There are no treatments for prion-related diseases, and prions can easily infect the body because they do not elicit any
immune response.
To create a vaccine that could rally the immune system of mice, the NYU researchers designed a vaccine in which scrapie
prions were attached to a genetically modified strain of Salmonella. This bacterium is also used in several animal vaccines
and in human vaccines for cholera and typhoid fever. Among mice vaccinated prior to prion exposure, approximately 30%
remained alive and symptom-free for 500 days, according to the study. By comparison, mice that didn't receive the vaccine
survived only an average of 185 days, and all were dead by 300 days.
The NYU scientists are in the process of redesigning the vaccine for deer and cattle. After choosing the appropriate bacteria
for each vaccine, they must genetically modify it to carry the prion protein. "These technical issues are not major hurdles,"
says Dr. Wisniewski. "Developing a marketable vaccine for livestock is something that is very achievable."
The authors of the new study are: Fernando Go?i, Elin Knudsen, Henrieta Scholtzova, Joanna Pankiewicz, Einar M. Sigurdsson,
and Thomas Wisniewski of the NYU School of Medicine; Fernanda Schreiber and Jose Alejandro Chabalgoity of the University of
Uruguay; Richard Carp and Harry C. Meeker of the New York State Institute for Basic Research in Developmental Disabilities,
New York City; David R. Brown of the University of Bath, United Kingdom; and Man-Sun Sy of Case Western Reserve University
School of Medicine, Cleveland, Ohio.
Contact: Pamela Mcdonnell
pamela.mcdonnellnyumc
212-404-3555
New York University Medical Center and School of Medicine
med.nyu
the onset of a brain disease in mice that is similar to mad cow disease. The new findings, published online this week in the
journal Neuroscience, could provide a platform for the development of a vaccine to prevent a group of fatal brain diseases
caused by unusual infectious particles called prions.
Although no cure for these diseases -- which include scrapie, mad cow disease, and chronic wasting disease -- is on the
horizon, many research groups in both the United States and Europe are working on prion vaccines. But the NYU study is
important because it breaks new ground in demonstrating that active immunization can protect a significant percentage of
animals from developing symptoms of prion disease, explains Thomas Wisniewski, M.D., Professor of Neurology, Pathology, and
Psychiatry, and the lead author of the study.
The vaccines that provide active immunization are made, in part, from proteins found on disease-causing organisms. In
response to these proteins, the animal's immune system produces antibodies that will destroy them any time they appear in the
body. Most vaccines in use today provide such active immunization.
The prion vaccine developed at NYU would most likely first be used to protect livestock, since most prion infections occur in
animals and are thought to be transmitted orally, explains Dr. Wisniewski. The version of prion disease that affects humans
usually occurs spontaneously, and only rarely as a result of eating contaminated meat.
"The potential use for a prion vaccine in humans is still theoretical," says Dr. Wisniewski. "But if, for example, there is
ever a more significant outbreak of chronic wasting disease and if this disease were found to be transmissible to humans,
then we would need a vaccine like this to protect people in hunting areas."
Currently, an outbreak of chronic wasting disease is occurring in some Western states, and the disease's geographic range is
expanding. Two cases in wild deer have recently been reported for the first time in New York State, according to the New York
State Department of Environmental Conservation.
First mucosal prion vaccine
The NYU study is also the first to use a mucosal prion vaccine, given by mouth rather than through the skin, which localizes
the initial immune response to the gut and mainly stimulates an antibody response, says Dr. Wisniewski. "By giving our
vaccine orally, we're stimulating an immune response mainly in the digestive tract," he explains. "Thus, harmful prions in
contaminated food will be destroyed in the gut and will not reach other organs in the body." Because the research was
conducted in normal mice, the NYU researchers say it will be easier to apply in animals in the wild, which are at risk for
developing prion disease.
Prion disease is contracted when an animal eats the body parts of other animals contaminated with prions. What makes these
infectious particles unusual is that they are proteins that have the same amino acid composition as equivalent proteins
occurring naturally in the body. But the prions turn deadly by changing shape. These "misfolded" proteins tend to aggregate
in toxic, cell-killing clumps. As an infection takes hold, prion proteins invade brain tissue and force normal proteins to
adopt their configuration. In time, the diseased animal develops dementia, loses control of its limbs, and eventually dies.
There are no treatments for prion-related diseases, and prions can easily infect the body because they do not elicit any
immune response.
To create a vaccine that could rally the immune system of mice, the NYU researchers designed a vaccine in which scrapie
prions were attached to a genetically modified strain of Salmonella. This bacterium is also used in several animal vaccines
and in human vaccines for cholera and typhoid fever. Among mice vaccinated prior to prion exposure, approximately 30%
remained alive and symptom-free for 500 days, according to the study. By comparison, mice that didn't receive the vaccine
survived only an average of 185 days, and all were dead by 300 days.
The NYU scientists are in the process of redesigning the vaccine for deer and cattle. After choosing the appropriate bacteria
for each vaccine, they must genetically modify it to carry the prion protein. "These technical issues are not major hurdles,"
says Dr. Wisniewski. "Developing a marketable vaccine for livestock is something that is very achievable."
The authors of the new study are: Fernando Go?i, Elin Knudsen, Henrieta Scholtzova, Joanna Pankiewicz, Einar M. Sigurdsson,
and Thomas Wisniewski of the NYU School of Medicine; Fernanda Schreiber and Jose Alejandro Chabalgoity of the University of
Uruguay; Richard Carp and Harry C. Meeker of the New York State Institute for Basic Research in Developmental Disabilities,
New York City; David R. Brown of the University of Bath, United Kingdom; and Man-Sun Sy of Case Western Reserve University
School of Medicine, Cleveland, Ohio.
Contact: Pamela Mcdonnell
pamela.mcdonnellnyumc
212-404-3555
New York University Medical Center and School of Medicine
med.nyu
FDA Proposes Barring Certain Cattle Material From Medical Products As BSE Safeguard
The U.S. Food and Drug Administration is proposing to limit the materials used in some medical products in order to keep them free of the agent thought to cause mad cow disease, also known as bovine spongiform encephalopathy or BSE.
This is the latest in a series of BSE safeguards that would bar material that has been found to harbor the highest concentrations of this fatal agent in infected cattle. These materials would be prohibited from use as ingredients in medical products or elements of product manufacturing.
The proposed rule would cover drugs (prescription, over-the-counter, and homeopathic), biologics (such as vaccines) and medical devices intended for use in humans as well as drugs intended for use in ruminant animals like cattle and sheep. Cattle can get mad cow disease, while sheep can get a similar disease known as scrapie.
"These measures build on a series of barriers FDA and the U.S. Department of Agriculture have erected to further protect humans from exposure to the fatal agent linked to BSE," said Andrew von Eschenbach, M.D., Commissioner Food and Drugs. "This proposed rule adds one more safeguard that will reduce the risk of transmission even further."
The cattle materials prohibited in the proposed rule are those that pose the highest risk of containing infectious material and include:
-- the brain, skull, eyes and spinal cords from cattle 30 months and older;
-- the tonsils and a portion of the small intestines from all cattle regardless of their age or health;
-- any material from "downer" cattle--those that cannot walk;
-- any material from cattle not inspected and passed for human consumption;
-- fetal calf serum if appropriate procedures have not been followed to prevent its contamination with materials prohibited by this proposed rule;
-- tallow that contains more than 0.15 percent insoluble impurities if the tallow is derived from materials prohibited by this proposed rule and;
-- mechanically separated beef.
To ensure that companies comply with these prohibitions, FDA proposes to require that records be kept to demonstrate that any cattle material used as an ingredient in these medical products or as part of their manufacturing process meet the rule's requirements.
Since 1996, strong evidence has accumulated for a causal relationship between ongoing outbreaks of mad cow disease in Europe and a disease in humans called variant Creutzfeldt-Jakob (vCJD) disease. Both disorders, which are thought to be caused by an unconventional transmissible agent, are invariably fatal brain diseases with incubation periods typically measured in years. Transmission of the BSE agent to humans, leading to vCJD, is believed to occur via ingestion of cattle products contaminated with the BSE agent; however the specific products associated with this transmission are unknown.
About 200 cases of vCJD have been identified worldwide, including three cases in the U.S. However, there is no evidence that those three patients contracted the BSE agent in the U.S.
FDA and USDA's efforts to help protect the public from vCJD have included several other significant steps such as the FDA's 1997 ruminant feed regulation, which forbids the use of certain mammalian-origin proteins in ruminant feed. Also, a 2005 interim final rule bans the use of certain high-risk cattle material in food, dietary supplements and cosmetics.
fda
This is the latest in a series of BSE safeguards that would bar material that has been found to harbor the highest concentrations of this fatal agent in infected cattle. These materials would be prohibited from use as ingredients in medical products or elements of product manufacturing.
The proposed rule would cover drugs (prescription, over-the-counter, and homeopathic), biologics (such as vaccines) and medical devices intended for use in humans as well as drugs intended for use in ruminant animals like cattle and sheep. Cattle can get mad cow disease, while sheep can get a similar disease known as scrapie.
"These measures build on a series of barriers FDA and the U.S. Department of Agriculture have erected to further protect humans from exposure to the fatal agent linked to BSE," said Andrew von Eschenbach, M.D., Commissioner Food and Drugs. "This proposed rule adds one more safeguard that will reduce the risk of transmission even further."
The cattle materials prohibited in the proposed rule are those that pose the highest risk of containing infectious material and include:
-- the brain, skull, eyes and spinal cords from cattle 30 months and older;
-- the tonsils and a portion of the small intestines from all cattle regardless of their age or health;
-- any material from "downer" cattle--those that cannot walk;
-- any material from cattle not inspected and passed for human consumption;
-- fetal calf serum if appropriate procedures have not been followed to prevent its contamination with materials prohibited by this proposed rule;
-- tallow that contains more than 0.15 percent insoluble impurities if the tallow is derived from materials prohibited by this proposed rule and;
-- mechanically separated beef.
To ensure that companies comply with these prohibitions, FDA proposes to require that records be kept to demonstrate that any cattle material used as an ingredient in these medical products or as part of their manufacturing process meet the rule's requirements.
Since 1996, strong evidence has accumulated for a causal relationship between ongoing outbreaks of mad cow disease in Europe and a disease in humans called variant Creutzfeldt-Jakob (vCJD) disease. Both disorders, which are thought to be caused by an unconventional transmissible agent, are invariably fatal brain diseases with incubation periods typically measured in years. Transmission of the BSE agent to humans, leading to vCJD, is believed to occur via ingestion of cattle products contaminated with the BSE agent; however the specific products associated with this transmission are unknown.
About 200 cases of vCJD have been identified worldwide, including three cases in the U.S. However, there is no evidence that those three patients contracted the BSE agent in the U.S.
FDA and USDA's efforts to help protect the public from vCJD have included several other significant steps such as the FDA's 1997 ruminant feed regulation, which forbids the use of certain mammalian-origin proteins in ruminant feed. Also, a 2005 interim final rule bans the use of certain high-risk cattle material in food, dietary supplements and cosmetics.
fda
Infectious Prions Can Arise Spontaneously In Normal Brain Tissue
In a startling new study that involved research on both sides of the Atlantic, scientists from The Scripps Research Institute in Florida and the University College London (UCL) Institute of Neurology in England have shown for the first time that abnormal prions, bits of infectious protein devoid of DNA or RNA that can cause fatal neurodegenerative disease, can suddenly erupt from healthy brain tissue.
The catalyst in the study was the metallic surface of simple steel wires. Previous research showed that prions bind readily to these types of surfaces and can initiate infection with remarkable efficiency. Surprisingly, according to the new research, wires coated with uninfected brain homogenate could also initiate prion disease in cell culture, which was transmissible to mice.
The findings are being published the week of July 26, 2010, in an advance, online edition of the journal Proceedings of the National Academy of Sciences (PNAS).
"Prion diseases such as sporadic Creutzfeldt-Jakob disease in humans or atypical bovine spongiform encephalopathy, a form of mad cow disease, occur rarely and at random," said Charles Weissmann, M.D., Ph.D., chair of Scripps Florida's Department of Infectology, who led the study with John Collinge, head of the Department of Neurodegenerative Disease at UCL Institute of Neurology. "It has been proposed that these events reflect rare, spontaneous formation of prions in brain. Our study offers experimental proof that prions can in fact originate spontaneously, and shows that this event is promoted by contact with steel surfaces."
Infectious prions, which are composed solely of protein, are classified by distinct strains, originally characterized by their incubation time and the disease they cause. These toxic prions have the ability to reproduce, despite the fact that they contain no nucleic acid genome.
Mammalian cells normally produce harmless cellular prion protein (PrPC). Following prion infection, the abnormal or misfolded prion protein (PrPSc) converts PrPC into a likeness of itself, by causing it to change its conformation or shape. The end-stage consists of large aggregates of these misfolded proteins, which cause massive tissue and cell damage.
A Highly Sensitive Test
In the new study, the scientists used the Scrapie Cell Assay, a test originally created by Weissmann that is highly sensitive to minute quantities of prions.
Using the Scrapie Cell Assay to measure infectivity of prion-coated wires, the team observed several unexpected instances of infectious prions in control groups where metal wires had been exposed only to uninfected normal mouse brain tissue. In the current study, this phenomenon was investigated in rigorous and exhaustive control experiments specifically designed to exclude prion contamination. Weissmann and his colleagues in London found that when normal prion protein is coated onto steel wires and brought into contact with cultured cells, a small but significant proportion of the coated wires cause prion infection of the cells - and when transferred to mice, they continue to spawn the disease.
Weissmann noted that an alternative interpretation of the results is that infectious prions are naturally present in the brain at levels not detectable by conventional methods, and are normally destroyed at the same rate they are created. If that is the case, he noted, metal surfaces could be acting to concentrate the infectious prions to the extent that they became quantifiable by the team's testing methods.
The first author of the study, "Spontaneous Generation of Mammalian Prions," is Julie Edgeworth of the UCL Institute of Neurology. Other authors of the study include Nathalie Gros, Jack Alden, Susan Joiner, Jonathan D.F. Wadsworth, Jackie Linehan, Sebastian Brandner, and Graham S. Jackson, also of the UCL Institute of Neurology.
The study was supported by the U.K. Medical Research Council.
The catalyst in the study was the metallic surface of simple steel wires. Previous research showed that prions bind readily to these types of surfaces and can initiate infection with remarkable efficiency. Surprisingly, according to the new research, wires coated with uninfected brain homogenate could also initiate prion disease in cell culture, which was transmissible to mice.
The findings are being published the week of July 26, 2010, in an advance, online edition of the journal Proceedings of the National Academy of Sciences (PNAS).
"Prion diseases such as sporadic Creutzfeldt-Jakob disease in humans or atypical bovine spongiform encephalopathy, a form of mad cow disease, occur rarely and at random," said Charles Weissmann, M.D., Ph.D., chair of Scripps Florida's Department of Infectology, who led the study with John Collinge, head of the Department of Neurodegenerative Disease at UCL Institute of Neurology. "It has been proposed that these events reflect rare, spontaneous formation of prions in brain. Our study offers experimental proof that prions can in fact originate spontaneously, and shows that this event is promoted by contact with steel surfaces."
Infectious prions, which are composed solely of protein, are classified by distinct strains, originally characterized by their incubation time and the disease they cause. These toxic prions have the ability to reproduce, despite the fact that they contain no nucleic acid genome.
Mammalian cells normally produce harmless cellular prion protein (PrPC). Following prion infection, the abnormal or misfolded prion protein (PrPSc) converts PrPC into a likeness of itself, by causing it to change its conformation or shape. The end-stage consists of large aggregates of these misfolded proteins, which cause massive tissue and cell damage.
A Highly Sensitive Test
In the new study, the scientists used the Scrapie Cell Assay, a test originally created by Weissmann that is highly sensitive to minute quantities of prions.
Using the Scrapie Cell Assay to measure infectivity of prion-coated wires, the team observed several unexpected instances of infectious prions in control groups where metal wires had been exposed only to uninfected normal mouse brain tissue. In the current study, this phenomenon was investigated in rigorous and exhaustive control experiments specifically designed to exclude prion contamination. Weissmann and his colleagues in London found that when normal prion protein is coated onto steel wires and brought into contact with cultured cells, a small but significant proportion of the coated wires cause prion infection of the cells - and when transferred to mice, they continue to spawn the disease.
Weissmann noted that an alternative interpretation of the results is that infectious prions are naturally present in the brain at levels not detectable by conventional methods, and are normally destroyed at the same rate they are created. If that is the case, he noted, metal surfaces could be acting to concentrate the infectious prions to the extent that they became quantifiable by the team's testing methods.
The first author of the study, "Spontaneous Generation of Mammalian Prions," is Julie Edgeworth of the UCL Institute of Neurology. Other authors of the study include Nathalie Gros, Jack Alden, Susan Joiner, Jonathan D.F. Wadsworth, Jackie Linehan, Sebastian Brandner, and Graham S. Jackson, also of the UCL Institute of Neurology.
The study was supported by the U.K. Medical Research Council.
Prions Block Cell Recycling System To Cause Disease
The rogue prion proteins responsible for diseases like BSE and vCJD can destroy brain cells by blocking the protein recycling process that helps keep cells healthy. An international group of scientists, led by Dr Sarah Tabrizi of University College London's Institute of Neurology, has now discovered which part of the structure of the protein it is that creates this effect and that even a tiny number of rogue prions are toxic enough to stop a cell's protein clearing machinery and cause disease.
Together with colleagues at the Medical Research Council Prion Unit, Dr Tabrizi's team monitored the action of rogue prion proteins on the brain cells of mice genetically designed for the task. The brain cells of these mice produce a protein that glows green when the cell's recycling machinery is failing allowing scientists to assess how the system has been affected. Their results are published in Molecular Cell.
''When we looked closely at the interaction between rogue prions and the protein recycling process in healthy cells, it was clear that just three or four molecules, a really tiny concentration of prions, is enough to disrupt the system and damage the brain cell'' explains Dr Tabrizi.
''This suggests there is a direct relationship between destruction of brain cells and blockage of protein recycling. Exactly how rogue prion proteins destroy brain cells is still a puzzle, but this research is evidence that blocking the cell's protein recycling machinery is one way prion infection can cause disease.''
The protein recycling system is crucial to a healthy cell because it protects it from a potentially toxic build-up of faulty proteins. The process itself is known as the ubiquitin-proteasome system or UPS. The idea to investigate the cell's protein recycling system came from previous research by Dr Tabrizi and her colleagues. They found that if prion infected nerve cells are treated with a drug that causes the UPS to be stressed, abnormally shaped prion proteins build up more quickly and eventually kill the cell. These collections of abnormally shaped proteins are a feature of many prion diseases and can be clearly seen in the brains of prion-infected mice.
Commenting on this research, Professor John Collinge, Director of the MRC Prion Unit said:
''Understanding how rogue prions kill cells is crucial to learning more about the prion diseases that remain a major concern for public and animal health following the BSE epidemic in UK cattle and the emergence of its human counterpart variant CJD. This work forms part of a major research strategy at the MRC Prion Unit to translate basic research findings into potential treatments in the years ahead. The underlying mechanism by which rogue prion proteins disrupt the UPS may be of wider relevance in understanding how misshaped proteins cause other disorders too, like Alzheimer's disease.''
mrc.ac.uk
Together with colleagues at the Medical Research Council Prion Unit, Dr Tabrizi's team monitored the action of rogue prion proteins on the brain cells of mice genetically designed for the task. The brain cells of these mice produce a protein that glows green when the cell's recycling machinery is failing allowing scientists to assess how the system has been affected. Their results are published in Molecular Cell.
''When we looked closely at the interaction between rogue prions and the protein recycling process in healthy cells, it was clear that just three or four molecules, a really tiny concentration of prions, is enough to disrupt the system and damage the brain cell'' explains Dr Tabrizi.
''This suggests there is a direct relationship between destruction of brain cells and blockage of protein recycling. Exactly how rogue prion proteins destroy brain cells is still a puzzle, but this research is evidence that blocking the cell's protein recycling machinery is one way prion infection can cause disease.''
The protein recycling system is crucial to a healthy cell because it protects it from a potentially toxic build-up of faulty proteins. The process itself is known as the ubiquitin-proteasome system or UPS. The idea to investigate the cell's protein recycling system came from previous research by Dr Tabrizi and her colleagues. They found that if prion infected nerve cells are treated with a drug that causes the UPS to be stressed, abnormally shaped prion proteins build up more quickly and eventually kill the cell. These collections of abnormally shaped proteins are a feature of many prion diseases and can be clearly seen in the brains of prion-infected mice.
Commenting on this research, Professor John Collinge, Director of the MRC Prion Unit said:
''Understanding how rogue prions kill cells is crucial to learning more about the prion diseases that remain a major concern for public and animal health following the BSE epidemic in UK cattle and the emergence of its human counterpart variant CJD. This work forms part of a major research strategy at the MRC Prion Unit to translate basic research findings into potential treatments in the years ahead. The underlying mechanism by which rogue prion proteins disrupt the UPS may be of wider relevance in understanding how misshaped proteins cause other disorders too, like Alzheimer's disease.''
mrc.ac.uk
Suspected BSE Sample Sent to England for Further Testing, Statement by US Agriculture Secretary
This is a statement by US Agriculture Secretary:
"We find ourselves in a situation where we have two internationally accepted tests that have produced conflicting results. I
believe in this situation we have an obligation to be thorough. We've consulted with our top scientists at USDA and with
internationally recognized experts to determine our best course in this unique case. We have agreed upon a protocol that
includes additional testing both here at USDA and at an international reference laboratory in Weybridge, England. When we
have all of the final results we will share them very publicly.
"We know there is absolutely no risk to animal or human health related to this case. Our safeguards worked exactly as they
were designed to work. Because they worked, we now have the opportunity to learn more about this sample, knowing it could
advance the science behind our testing efforts."
US Dept of Agriculture
"We find ourselves in a situation where we have two internationally accepted tests that have produced conflicting results. I
believe in this situation we have an obligation to be thorough. We've consulted with our top scientists at USDA and with
internationally recognized experts to determine our best course in this unique case. We have agreed upon a protocol that
includes additional testing both here at USDA and at an international reference laboratory in Weybridge, England. When we
have all of the final results we will share them very publicly.
"We know there is absolutely no risk to animal or human health related to this case. Our safeguards worked exactly as they
were designed to work. Because they worked, we now have the opportunity to learn more about this sample, knowing it could
advance the science behind our testing efforts."
US Dept of Agriculture
Next Stage Of Notification Exercise To Reduce Risk Of Variant CJD Transmission Begins, UK
Precautionary measures to reduce the possible risk of transmitting
vCJD through surgical procedures are to be extended. Around 50 people
who have received blood transfusions will be traced and notified of
their potential exposure to vCJD.
This follows an announcement in July 2005, when around 100 blood
donors were told they may have a greater chance of carrying the vCJD
agent, compared with the general population. Blood from these donors
had been given to three people who later developed vCJD and experts
advised that it was not possible to exclude the donated blood as a
possible source of that infection.
The CJD Incidents Panel has now advised that certain other patients
who received blood from some of these donors should also be
contacted, so that additional precautions can be taken against the
possibility of further transmission.
The UK blood services are contacting hospitals where the donated
blood was issued, requesting their help in identifying patients
involved. This process is likely to take a number of months to
complete. Patients will be informed on a case by case basis and will
be offered advice and support. The notification of patients and their
general practitioners is being co-ordinated by the blood services
together with the health protection agencies
The likelihood of a person who may be infected with vCJD going on to
develop symptoms of the disease is uncertain. It is possible that an
infected person may never develop symptoms, but until a reliable
blood screening test becomes available, it is sensible to proceed on
a precautionary basis to protect public health.
1. There is currently no validated diagnostic test that can be used
before the onset of clinical symptoms to diagnose whether someone has
contracted vCJD. Since 1995, the Department has contributed over ?30
million into CJD research, including research for the development of
an effective test.
2. Individuals identified as 'at risk of vCJD for public health
purposes' are advised not to donate blood, organs or tissues; to tell
health professionals in charge of their care whenever they are going
to have surgery or invasive medical procedures, of their status and
to tell their family in case they require emergency surgery.
3. People who have themselves received a transfusion of whole blood
components since January 1980 have been excluded from donating blood
since 2004. This is one of a number of measures taken to improve the
safety of blood in relation to vCJD.
4. We have also invested ?200 million in improving decontamination
standards for surgical instruments and an extra ?6.6 million into
research of new decontamination technologies that are more effective
against the CJD agent.
5. About 3 million units of blood are transfused to over half a
million patients in the NHS each year. Most patients receive more
than one transfusion.
6. The report of the first possible case of transmission of vCJD by
blood transfusion was in December 2003.
7. For some of the 100 or so donors who were notified in July 2005,
the implied risk of vCJD infection was estimated to be clearly above
1%. 1% is the threshold generally used by the CJD Incidents Panel in
recommending whether individuals should be informed, so that
additional precautions can be taken against further transmission.
The measures being taken today will identify the other recipients of
blood from this subset of donors, on the basis that these recipients
are also liable to have a greater than 1% risk of vCJD infection.
UK DEPT OF HEALTH
vCJD through surgical procedures are to be extended. Around 50 people
who have received blood transfusions will be traced and notified of
their potential exposure to vCJD.
This follows an announcement in July 2005, when around 100 blood
donors were told they may have a greater chance of carrying the vCJD
agent, compared with the general population. Blood from these donors
had been given to three people who later developed vCJD and experts
advised that it was not possible to exclude the donated blood as a
possible source of that infection.
The CJD Incidents Panel has now advised that certain other patients
who received blood from some of these donors should also be
contacted, so that additional precautions can be taken against the
possibility of further transmission.
The UK blood services are contacting hospitals where the donated
blood was issued, requesting their help in identifying patients
involved. This process is likely to take a number of months to
complete. Patients will be informed on a case by case basis and will
be offered advice and support. The notification of patients and their
general practitioners is being co-ordinated by the blood services
together with the health protection agencies
The likelihood of a person who may be infected with vCJD going on to
develop symptoms of the disease is uncertain. It is possible that an
infected person may never develop symptoms, but until a reliable
blood screening test becomes available, it is sensible to proceed on
a precautionary basis to protect public health.
1. There is currently no validated diagnostic test that can be used
before the onset of clinical symptoms to diagnose whether someone has
contracted vCJD. Since 1995, the Department has contributed over ?30
million into CJD research, including research for the development of
an effective test.
2. Individuals identified as 'at risk of vCJD for public health
purposes' are advised not to donate blood, organs or tissues; to tell
health professionals in charge of their care whenever they are going
to have surgery or invasive medical procedures, of their status and
to tell their family in case they require emergency surgery.
3. People who have themselves received a transfusion of whole blood
components since January 1980 have been excluded from donating blood
since 2004. This is one of a number of measures taken to improve the
safety of blood in relation to vCJD.
4. We have also invested ?200 million in improving decontamination
standards for surgical instruments and an extra ?6.6 million into
research of new decontamination technologies that are more effective
against the CJD agent.
5. About 3 million units of blood are transfused to over half a
million patients in the NHS each year. Most patients receive more
than one transfusion.
6. The report of the first possible case of transmission of vCJD by
blood transfusion was in December 2003.
7. For some of the 100 or so donors who were notified in July 2005,
the implied risk of vCJD infection was estimated to be clearly above
1%. 1% is the threshold generally used by the CJD Incidents Panel in
recommending whether individuals should be informed, so that
additional precautions can be taken against further transmission.
The measures being taken today will identify the other recipients of
blood from this subset of donors, on the basis that these recipients
are also liable to have a greater than 1% risk of vCJD infection.
UK DEPT OF HEALTH
Human "Mad Cow Disease" Prion May Lead To Test To Estimate Extent Of Humans Infected
In the July 7, 2006, issue of the journal Science, researchers at the University of Texas Medical Branch at Galveston (UTMB) describe experiments that may soon lead to a test that will enable medical science to estimate how many people are infected with the human form of mad cow disease, which can take as long as 40 years before manifesting itself.
Such a blood test could also help prevent accidental transmission of the malformed proteins that cause variant Creutzfeldt-Jakob disease (vCJD) via blood transfusions and organ transplants, the scientists suggest.
Done in hamsters, the experiments are the first ever to biochemically detect the malformed proteins during the "silent phase" of the disease--just weeks after the animals were infected and months before they showed clinical symptoms.
The scientists say that they detected prions--the infectious proteins responsible for such brain-destroying disorders as bovine spongiform encephalopathy (BSE) in cattle and vCJD in humans--in the blood of the hamsters in as few as 20 days after the animals had been infected. That discovery occurred about three months before the hamsters began showing clinical symptoms of the disease, the Science paper reports.
To detect the very small quantities of prions found in blood samples, UTMB professor Claudio Soto, assistant professor Joaquin Castilla and research assistant Paula Sa?? used a technique known as protein misfolding cyclic amplification (PMCA), invented by Soto's group, which greatly accelerates the process by which prions convert normal proteins to misshapen infectious forms.
"With this method, for the first time we have detected prions in what we call the silent phase of infection, which in humans can last up to 40 years," said Soto, senior author of the Science paper.
"The concern is that if many people are incubating the disease silently, then secondary transmission from human to human by blood transfusion or surgical procedures could become a big problem," he continued. "This result is an important step toward a practical biochemical test that will determine how common variant CJD is, and keep contaminated blood and organs from spreading it further."
Creating such a test is a high priority for Soto, who is also director of UTMB's George and Cynthia Mitchell Center for Alzheimer's Disease. "We're now working with natural samples, both from humans and cattle but mostly from humans," he said. With an eye toward making a human test commercially available, Soto and UTMB recently formed a startup company, dubbed "Amprion."
"All our effort so far has been to prove the scientific concepts, so we're building this company to go into issues of development, scalability and practicality," Soto said. "We are hopeful that development of this technology into a useful blood test will be a pretty straightforward process."
-UTMB-
The University of Texas Medical Branch at Galveston
Public Affairs Office
301 University Boulevard, Suite 3.102
Galveston, Texas
utmb/
Contact: Jim Kelly
University of Texas Medical Branch at Galveston
Such a blood test could also help prevent accidental transmission of the malformed proteins that cause variant Creutzfeldt-Jakob disease (vCJD) via blood transfusions and organ transplants, the scientists suggest.
Done in hamsters, the experiments are the first ever to biochemically detect the malformed proteins during the "silent phase" of the disease--just weeks after the animals were infected and months before they showed clinical symptoms.
The scientists say that they detected prions--the infectious proteins responsible for such brain-destroying disorders as bovine spongiform encephalopathy (BSE) in cattle and vCJD in humans--in the blood of the hamsters in as few as 20 days after the animals had been infected. That discovery occurred about three months before the hamsters began showing clinical symptoms of the disease, the Science paper reports.
To detect the very small quantities of prions found in blood samples, UTMB professor Claudio Soto, assistant professor Joaquin Castilla and research assistant Paula Sa?? used a technique known as protein misfolding cyclic amplification (PMCA), invented by Soto's group, which greatly accelerates the process by which prions convert normal proteins to misshapen infectious forms.
"With this method, for the first time we have detected prions in what we call the silent phase of infection, which in humans can last up to 40 years," said Soto, senior author of the Science paper.
"The concern is that if many people are incubating the disease silently, then secondary transmission from human to human by blood transfusion or surgical procedures could become a big problem," he continued. "This result is an important step toward a practical biochemical test that will determine how common variant CJD is, and keep contaminated blood and organs from spreading it further."
Creating such a test is a high priority for Soto, who is also director of UTMB's George and Cynthia Mitchell Center for Alzheimer's Disease. "We're now working with natural samples, both from humans and cattle but mostly from humans," he said. With an eye toward making a human test commercially available, Soto and UTMB recently formed a startup company, dubbed "Amprion."
"All our effort so far has been to prove the scientific concepts, so we're building this company to go into issues of development, scalability and practicality," Soto said. "We are hopeful that development of this technology into a useful blood test will be a pretty straightforward process."
-UTMB-
The University of Texas Medical Branch at Galveston
Public Affairs Office
301 University Boulevard, Suite 3.102
Galveston, Texas
utmb/
Contact: Jim Kelly
University of Texas Medical Branch at Galveston
Protein involved in 'mad cow' disease
The PrPC is a normal physiological protein, especially present in the central nervous system, including that of the human, with functions that are little known as yet. Altered prionic proteins, pathogens, infectants, i.e. prions, are responsible for spongiform encephalopathies, amongst these being bovine spongiform encephalopathy (BSE or mad cow disease). In order to operate, prions require the presence of the PrPC. Thus, the importance of this investigation for the location of the PrPC in the central nervous system.
Knowing where in the central nervous system the prions operate
Locating the PrPC meant being able to identify which places in the central nervous system the prions operate. The findings enabled the research team to establish that the PrPC is a protein involved in the neuronal metabolism of calcium. Moreover, the existence of neurones without PrPC and surrounded by perineuronal nests breaks with the hypothesis, to date, that the disappearance of such nests - a special form of extracellular matrix - is a primary event in the course of spongiform encephalopathies; rather it is secondary event.
According to the researchers' observations, the loss of these nests and consequent neuronal death are due to the damage produced after the appearance of the prions in the brain, where they act upon such perineuronal nests, amongst other structures.
According to the researchers' comments, extrapolating these results from the rat to the human is valid, given that similar results had been obtained after carrying out the study on human brains. Moreover, this work and others carried out on the brains of the autochthonous Pyrenees breed of cow will help to explain the operating mechanisms of the prions in bovine spongiform encephalopathy.
This study, published in Brain Research, is an addition to the work of the Department of Pathological Histology and Anatomy at the University of Navarra regarding the manner in which prions enter the digestive tube of bovine animals, from which organ they enter the central nervous system, causing the mad cow disease or bovine spongiform encephalopathy.
The authors are Jos? Luis Velayos and Francisco Jos? Moleres, research scientists at the Department of Anatomy at the University of Navarra.
Garazi Andonegi
garazielhuyar
Elhuyar Fundazioa
basqueresearch
Knowing where in the central nervous system the prions operate
Locating the PrPC meant being able to identify which places in the central nervous system the prions operate. The findings enabled the research team to establish that the PrPC is a protein involved in the neuronal metabolism of calcium. Moreover, the existence of neurones without PrPC and surrounded by perineuronal nests breaks with the hypothesis, to date, that the disappearance of such nests - a special form of extracellular matrix - is a primary event in the course of spongiform encephalopathies; rather it is secondary event.
According to the researchers' observations, the loss of these nests and consequent neuronal death are due to the damage produced after the appearance of the prions in the brain, where they act upon such perineuronal nests, amongst other structures.
According to the researchers' comments, extrapolating these results from the rat to the human is valid, given that similar results had been obtained after carrying out the study on human brains. Moreover, this work and others carried out on the brains of the autochthonous Pyrenees breed of cow will help to explain the operating mechanisms of the prions in bovine spongiform encephalopathy.
This study, published in Brain Research, is an addition to the work of the Department of Pathological Histology and Anatomy at the University of Navarra regarding the manner in which prions enter the digestive tube of bovine animals, from which organ they enter the central nervous system, causing the mad cow disease or bovine spongiform encephalopathy.
The authors are Jos? Luis Velayos and Francisco Jos? Moleres, research scientists at the Department of Anatomy at the University of Navarra.
Garazi Andonegi
garazielhuyar
Elhuyar Fundazioa
basqueresearch
Researchers Create Prototype Test To Screen For Creutzfeldt-Jakob Disease (CJD) From Donor Blood
Evidence shows there is a risk of transmitting the neurodegenerative condition variant Creutzfeldt-Jakob disease (vCJD) through transfusion of blood and blood products, and thus also via surgery and dental procedures. Current strategies to reduce this risk in the UK are expensive and their benefit is uncertain. Furthermore, the disease-causing proteins (or prions) responsible for vCJD can lay dormant in humans for decades, meaning there are concerns there could be a time-bomb of vCJD hidden in the general population arising from the time of the mad-cow disease scare in the late1980s (mad cow disease, or bovine spongiform encephalopathy [BSE] is caused by the same prions). Estimates from a previous study, and used currently by the Department of Health, England, suggest that as many as 1 in 4000 people could be infected.
In an Article published Online First and an upcoming Lancet, researchers announce the creation of a new assay test that can detect minute amounts of the tiny CJD-causing particles, known as prions, in human blood. The Article is by Professor John Collinge, of The UK Medical Research Council Prion Unit and University College London, UK, and colleagues. The study was funded by the UK Medical Research Council. The authors hope this test, once fully developed, could ultimately be used to reveal the true prevalence of vCJD in the population.
To establish the sensitivity and specificity of the assay for detection of vCJD, the authors analysed a masked panel of 190 whole blood samples from 21 patients with vCJD, 27 with sporadic* CJD, 42 with other neurological diseases, and 100 normal controls. The researchers found the new method to be more sensitive by many orders of magnitude than the best current standard tests, since they were able to detect levels of CJD-causing prions at a dilution of 100,000-fold greater. 15 samples tested positive in the assay, and all 15 samples were from patients with vCJD, showing an assay sensitivity for vCJD of 71???4% (15 out of 21 cases) and a specificity of 100% (no false positives). Regarding the six vCJD cases that did not test positive, the authors suggest this could be because either their prion levels were too low, or possibly that not everyone infected with vCJD has prions in their blood.
The findings lead the authors to suggest that an assay-style test such as this could be used in the future to screen donated blood before it is accepted. As mentioned above, current methods to protect the population are expensive. These include leucocyte depletion - "this is removal of white blood cells. It was thought when this was recommended that this would remove most of the prions but this may not be the case. Other protection methods include sourcing blood plasma from the USA (where there was minimal exposure of the population to BSE) and importing blood for transfusion to young children from countries with no history of BSE (as discussed above, all countries have sporadic CJD). The UK Department of Health is also considering using prion blood filters through which the transfused blood is passed to try to remove most of the prions. Both the existing and proposed methods are extremely expensive, in the order of hundreds of millions of pounds annually. Thus a cheap, easy to use screening test could mitigate these costs.
However, the authors caution that, prior to large scale roll-out, large numbers (>10 000) of negative controls with low exposure to these prions would be needed to accurately determine the specificity of the test. They add that extended longitudinal study of individuals testing positive will be needed to establish the proportion of patients with positive tests that go on to develop clinical vCJD and how many are chronic carriers that pose a risk to others via blood transfusion or contamination of surgical instruments, but who do not themselves develop the disease.
They conclude: "Our findings demonstrate the ability to detect prion infection in blood and show that a donor blood screening test is technically feasible. The use of this test in differential diagnosis of suspected vCJD will be further investigated in large case series."
Prof Collinge adds*: "Long term co-ordinated research at the Medical Research Council (MRC) Prion Unit and NHS National Prion Clinic has been necessary to achieve this key breakthough. We expect this research will lead to improved and earlier diagnosis for our patients and, with further development and testing, provide the means to screen donated blood for prion infection. Such a screening test would allow estimation of the number of silently infected healthy individuals in the UK and other BSE-exposed populations to more effectively guide public health risk management in future."
In a linked Comment, Dr Luisa Gregori, US Food and Drug Administration, Rockville, MD, USA., asks whether the assay has sufficient sensitivity to detect the presumably lower concentrations of abnormal prion proteins that are expected to be present in blood of asymptomatic donors.
She agrees that large numbers of negative donors will have to be screened to determine the specificity of the test, and concludes: "Communication to the public of the uncertainty around a positive test result will be challenging and could result in fewer donors as well as causing unnecessary anxiety to deferred uninfected donors. These practical issues need to be addressed before this assay or others like it can be considered for clinical use as a donor screening test."
Notes*:
Sporadic (or classical) CJD is present all over the world and has been recognised since the 1920's. It arises seemingly at random in the population without evidence for patients being exposed to prions. It is thought to result from prions forming spontaneously in the brain as an unlucky event although it is possible that some cases will be due to unrecognised environmental exposure to prions either via diet or medical procedures. Variant CJD was first recognised in 1996 in the UK and was a new form of prion disease different from other types described. It predominantly affected young people (in sharp contrast to sporadic CJD which is a disease of late adult life) and had a very different appearance of the brain when examined microscopically. It was suspected this was due to BSE and this was confirmed by strain typing which showed vCJD patients had the same prion strain as that causing BSE. In vCJD prions are present in many tissues of the body (including blood) whereas in sporadic CJD prions are very largely confined to nervous tissue.
**Quote direct from Prof Collinge that does not appear in text of Article
***Dr. Gregori's views are her own and should not be taken to represent any FDA determination or policy.
Link to article
Source
The Lancet
In an Article published Online First and an upcoming Lancet, researchers announce the creation of a new assay test that can detect minute amounts of the tiny CJD-causing particles, known as prions, in human blood. The Article is by Professor John Collinge, of The UK Medical Research Council Prion Unit and University College London, UK, and colleagues. The study was funded by the UK Medical Research Council. The authors hope this test, once fully developed, could ultimately be used to reveal the true prevalence of vCJD in the population.
To establish the sensitivity and specificity of the assay for detection of vCJD, the authors analysed a masked panel of 190 whole blood samples from 21 patients with vCJD, 27 with sporadic* CJD, 42 with other neurological diseases, and 100 normal controls. The researchers found the new method to be more sensitive by many orders of magnitude than the best current standard tests, since they were able to detect levels of CJD-causing prions at a dilution of 100,000-fold greater. 15 samples tested positive in the assay, and all 15 samples were from patients with vCJD, showing an assay sensitivity for vCJD of 71???4% (15 out of 21 cases) and a specificity of 100% (no false positives). Regarding the six vCJD cases that did not test positive, the authors suggest this could be because either their prion levels were too low, or possibly that not everyone infected with vCJD has prions in their blood.
The findings lead the authors to suggest that an assay-style test such as this could be used in the future to screen donated blood before it is accepted. As mentioned above, current methods to protect the population are expensive. These include leucocyte depletion - "this is removal of white blood cells. It was thought when this was recommended that this would remove most of the prions but this may not be the case. Other protection methods include sourcing blood plasma from the USA (where there was minimal exposure of the population to BSE) and importing blood for transfusion to young children from countries with no history of BSE (as discussed above, all countries have sporadic CJD). The UK Department of Health is also considering using prion blood filters through which the transfused blood is passed to try to remove most of the prions. Both the existing and proposed methods are extremely expensive, in the order of hundreds of millions of pounds annually. Thus a cheap, easy to use screening test could mitigate these costs.
However, the authors caution that, prior to large scale roll-out, large numbers (>10 000) of negative controls with low exposure to these prions would be needed to accurately determine the specificity of the test. They add that extended longitudinal study of individuals testing positive will be needed to establish the proportion of patients with positive tests that go on to develop clinical vCJD and how many are chronic carriers that pose a risk to others via blood transfusion or contamination of surgical instruments, but who do not themselves develop the disease.
They conclude: "Our findings demonstrate the ability to detect prion infection in blood and show that a donor blood screening test is technically feasible. The use of this test in differential diagnosis of suspected vCJD will be further investigated in large case series."
Prof Collinge adds*: "Long term co-ordinated research at the Medical Research Council (MRC) Prion Unit and NHS National Prion Clinic has been necessary to achieve this key breakthough. We expect this research will lead to improved and earlier diagnosis for our patients and, with further development and testing, provide the means to screen donated blood for prion infection. Such a screening test would allow estimation of the number of silently infected healthy individuals in the UK and other BSE-exposed populations to more effectively guide public health risk management in future."
In a linked Comment, Dr Luisa Gregori, US Food and Drug Administration, Rockville, MD, USA., asks whether the assay has sufficient sensitivity to detect the presumably lower concentrations of abnormal prion proteins that are expected to be present in blood of asymptomatic donors.
She agrees that large numbers of negative donors will have to be screened to determine the specificity of the test, and concludes: "Communication to the public of the uncertainty around a positive test result will be challenging and could result in fewer donors as well as causing unnecessary anxiety to deferred uninfected donors. These practical issues need to be addressed before this assay or others like it can be considered for clinical use as a donor screening test."
Notes*:
Sporadic (or classical) CJD is present all over the world and has been recognised since the 1920's. It arises seemingly at random in the population without evidence for patients being exposed to prions. It is thought to result from prions forming spontaneously in the brain as an unlucky event although it is possible that some cases will be due to unrecognised environmental exposure to prions either via diet or medical procedures. Variant CJD was first recognised in 1996 in the UK and was a new form of prion disease different from other types described. It predominantly affected young people (in sharp contrast to sporadic CJD which is a disease of late adult life) and had a very different appearance of the brain when examined microscopically. It was suspected this was due to BSE and this was confirmed by strain typing which showed vCJD patients had the same prion strain as that causing BSE. In vCJD prions are present in many tissues of the body (including blood) whereas in sporadic CJD prions are very largely confined to nervous tissue.
**Quote direct from Prof Collinge that does not appear in text of Article
***Dr. Gregori's views are her own and should not be taken to represent any FDA determination or policy.
Link to article
Source
The Lancet
prion-free cows immune to BSE could be a reality soon
A major advance towards producing prion-free cows that would be immune to mad cow disease has been made by researchers at companies in the US and Japan.
Their principal aim is to make genetically modified cattle that produce pharmaceuticals in their milk. But the companies hope that also making the animals resistant to BSE (bovine spongiform encephalopathy) will reassure consumers.
The researchers have now achieved the considerable feat of creating cell lines which have both copies of the cow's PrP gene switched off. The PrP protein can be switched to an infectious state by contact with a mutated prion. This switch causes prion diseases such as BSE in cows and variant Creutzfeldt Jakob Disease (vCJD) in humans.
Making live animals from these cell lines should be relatively straightforward using cloning techniques similar to those that created Dolly the sheep.
The companies say they have no intention of producing prion-free animals destined for human consumption. Instead they want to assuage public fears about pharmaceuticals derived from cow's milk, even though the process used to extract proteins from milk has already been shown to remove prion contamination.
Consumer choice
"Because of public perception, we feel an added benefit would be to knock out the gene and remove the possibility that the animals could be infected," says James Robl, chief scientific officer at US biotech company, which carried out the research jointly with the Kirin Brewery in Tokyo, Japan. "Japanese consumers have a high degree of concern about BSE."
Some experts have suggested creating prion-free cattle to eliminate BSE from the beef herd. But it is not clear that consumers would prefer genetically modified beef over meat that has a very small chance of infection with prions. To date there have only been around 140 cases of vCJD in total worldwide, although the ultimate extent of the human epidemic remains uncertain.
Furthermore, replacing beef herds with prion-free cattle would take decades. "Getting a herd of any size would be quite difficult," says Harry Griffin at the Roslin Institute in Scotland, where Dolly was cloned.
Another question mark hangs over what effect knocking out both copies of PrP will have on cows. Mice lacking both copies appear to be normal, although some disputed research suggests they may have disrupted sleep patterns.
TO CONTINUE READING THIS ARTICLE PLEASE GO TO THIS WEB PAGE IN THE NEW SCIENTIST
Their principal aim is to make genetically modified cattle that produce pharmaceuticals in their milk. But the companies hope that also making the animals resistant to BSE (bovine spongiform encephalopathy) will reassure consumers.
The researchers have now achieved the considerable feat of creating cell lines which have both copies of the cow's PrP gene switched off. The PrP protein can be switched to an infectious state by contact with a mutated prion. This switch causes prion diseases such as BSE in cows and variant Creutzfeldt Jakob Disease (vCJD) in humans.
Making live animals from these cell lines should be relatively straightforward using cloning techniques similar to those that created Dolly the sheep.
The companies say they have no intention of producing prion-free animals destined for human consumption. Instead they want to assuage public fears about pharmaceuticals derived from cow's milk, even though the process used to extract proteins from milk has already been shown to remove prion contamination.
Consumer choice
"Because of public perception, we feel an added benefit would be to knock out the gene and remove the possibility that the animals could be infected," says James Robl, chief scientific officer at US biotech company, which carried out the research jointly with the Kirin Brewery in Tokyo, Japan. "Japanese consumers have a high degree of concern about BSE."
Some experts have suggested creating prion-free cattle to eliminate BSE from the beef herd. But it is not clear that consumers would prefer genetically modified beef over meat that has a very small chance of infection with prions. To date there have only been around 140 cases of vCJD in total worldwide, although the ultimate extent of the human epidemic remains uncertain.
Furthermore, replacing beef herds with prion-free cattle would take decades. "Getting a herd of any size would be quite difficult," says Harry Griffin at the Roslin Institute in Scotland, where Dolly was cloned.
Another question mark hangs over what effect knocking out both copies of PrP will have on cows. Mice lacking both copies appear to be normal, although some disputed research suggests they may have disrupted sleep patterns.
TO CONTINUE READING THIS ARTICLE PLEASE GO TO THIS WEB PAGE IN THE NEW SCIENTIST
FDA Proposes Additional ''Mad Cow'' Safeguards
The U.S. Food and Drug Administration (FDA) today announced new measures to help further protect consumers against the agent thought to cause bovine spongiform encephalopathy (BSE, also known as "mad cow disease"). The Agency is proposing to amend its animal feed regulations to prohibit from use in the food or feed of all animals certain high risk cattle materials that can potentially carry the BSE-infectious agent. All of the proposed prohibitions, except for those related to tallow, have already applied to cattle feed since 1997.
"These additional measures that we proposed today will make an already small risk even smaller by further strengthening the effective measures already in place to protect American consumers from BSE," said Acting FDA Commissioner Dr. Andrew von Eschenbach.
These high risk cattle materials prohibited in the new proposed rule include:
* the brains and spinal cords from cattle 30 months of age and older,
* the brains and spinal cords from cattle of any age not inspected and passed for human consumption,
* the entire carcass of cattle not inspected and passed for human consumption if the brains and spinal cords have not been removed,
* tallow that is derived from the materials prohibited by this proposed rule if the tallow contains more than 0.15 percent insoluble impurities,
* mechanically separated beef that is derived from the materials prohibited by this proposed rule.
Today's proposed regulation builds on a series of firewalls that include FDA's 1997 feed regulation which prohibits the use of certain mammalian-origin proteins in ruminant feed (e.g. for cattle and sheep), but allows these materials to be used in feed for non-ruminant species. The removal of high-risk materials from all animal feed -- including pet food -- will protect against the transmission of the agent of BSE that could occur either through cross-contamination of ruminant feed with non-ruminant feed or feed ingredients during feed manufacture and transport, or intentional or unintentional misfeeding of non-ruminant feed to ruminants on the farm.
In July 2004, FDA and USDA jointly published an Advance Notice of Proposed Rulemaking (ANPRM) in which FDA announced its tentative conclusion that it should propose banning SRMs in all animal feed. In this ANPRM, FDA asked for comment on this measure and also on other feed control measures such as prohibiting the use of all mammalian and poultry protein in ruminant feed.
FDA also asked for comment on the set of measures that the agency had announced in January 2004 including the elimination of the exemptions for blood and blood products and "plate waste" from the 1997 ruminant feed rule, a prohibition on the use of poultry litter in ruminant feed, and a requirement for dedicated equipment and facilities to prevent cross-contamination.
FDA has carefully analyzed the comments it received on the 2004 ANPRM and has concluded that the other feed control measures discussed in the ANPRM are not needed if the high-risk tissues identified in this proposed rule are excluded from all animal feed channels.
Comprehensive information about FDA's work on BSE and links to other related websites are available at fda/oc/opacom/hottopics/bse.html.
FDA
"These additional measures that we proposed today will make an already small risk even smaller by further strengthening the effective measures already in place to protect American consumers from BSE," said Acting FDA Commissioner Dr. Andrew von Eschenbach.
These high risk cattle materials prohibited in the new proposed rule include:
* the brains and spinal cords from cattle 30 months of age and older,
* the brains and spinal cords from cattle of any age not inspected and passed for human consumption,
* the entire carcass of cattle not inspected and passed for human consumption if the brains and spinal cords have not been removed,
* tallow that is derived from the materials prohibited by this proposed rule if the tallow contains more than 0.15 percent insoluble impurities,
* mechanically separated beef that is derived from the materials prohibited by this proposed rule.
Today's proposed regulation builds on a series of firewalls that include FDA's 1997 feed regulation which prohibits the use of certain mammalian-origin proteins in ruminant feed (e.g. for cattle and sheep), but allows these materials to be used in feed for non-ruminant species. The removal of high-risk materials from all animal feed -- including pet food -- will protect against the transmission of the agent of BSE that could occur either through cross-contamination of ruminant feed with non-ruminant feed or feed ingredients during feed manufacture and transport, or intentional or unintentional misfeeding of non-ruminant feed to ruminants on the farm.
In July 2004, FDA and USDA jointly published an Advance Notice of Proposed Rulemaking (ANPRM) in which FDA announced its tentative conclusion that it should propose banning SRMs in all animal feed. In this ANPRM, FDA asked for comment on this measure and also on other feed control measures such as prohibiting the use of all mammalian and poultry protein in ruminant feed.
FDA also asked for comment on the set of measures that the agency had announced in January 2004 including the elimination of the exemptions for blood and blood products and "plate waste" from the 1997 ruminant feed rule, a prohibition on the use of poultry litter in ruminant feed, and a requirement for dedicated equipment and facilities to prevent cross-contamination.
FDA has carefully analyzed the comments it received on the 2004 ANPRM and has concluded that the other feed control measures discussed in the ANPRM are not needed if the high-risk tissues identified in this proposed rule are excluded from all animal feed channels.
Comprehensive information about FDA's work on BSE and links to other related websites are available at fda/oc/opacom/hottopics/bse.html.
FDA
vCJD transmission via blood transfusion second patient dies
The UK Department of Health says a 'A second case of possible transmission of vCJD from person to person via blood transfusion has now been confirmed by the National CJD Surveillance Unit."
As a result restrictions on blood donations have been extended.
The first case is thought to have happened in December 2003 when the blood recipient died several years after receiving blood from a donor who had vCJD.
The second patient who has died received blood in 1999. The donor was also later found to have had vCJD.
Secretary of Health John Reid said "Although people may have concerns about the implications of this announcement, I would emphasise again that the exclusion criteria are being tightened because of a small but unquantifiable risk."
As a result of the first case people who had received blood during the last 24 years were banned from donating blood.
The restriction now also includes people who are not sure whether they have received blood during the last 24 years.
The UK government knows of 15 blood recipients whose donors went on to develop vCJD. They have all been contacted and offered counselling.
FREQUENTLY ASKED QUESTIONS ABOUT VARIANT CREUTZFELDT - JAKOB DISEASE (Variant CJD)
From Health Canada
What is Creutzfeldt-Jakob Disease (CJD)?
Creutzfeldt-Jakob Disease (CJD) is one of a small group of fatal diseases caused by infectious agents called prions. These attack the brain, killing cells and creating gaps in tissue. The disease is always fatal.
There are two types of CJD: classical and variant.
What are prions (in relation to variant CJD)?
The agent that causes variant CJD is believed to be an abnormal form of a protein, known as a prion. Prions are normal cellular proteins that are present in many organs and tissues, including the brain, spinal cord and eyes of healthy humans and animals. The abnormal form of prion causes surrounding proteins to change their shape. The abnormal protein collects in central nervous tissue and by an unknown mechanism causes the nerve cells to die. This results in the characteristic holes in the brain tissue that can be seen under the microscope.
How do people get variant CJD?
Scientific evidence has linked variant CJD to eating contaminated beef products from animals infected with bovine spongiform encephalopathy (BSE) or "mad-cow disease." Processed meat products made from cows infected with BSE carry a high risk for transmitting the disease.
What are the symptoms of variant CJD?
Variant CJD symptoms include early psychiatric symptoms such as anxiety, depression, withdrawal and behavioural changes. Persistent pain or odd sensations in the face or limbs often develop. The disease then progresses to motor difficulties, involuntary movements and mental deterioration, often ending in a persistent vegetative state. The patient may live on average for about one year after the onset of symptoms.
How is variant CJD diagnosed?
Once a suspected case of variant CJD is reported to Health Canada's CJD Surveillance System, the Department coordinates testing and works with case physicians and international experts to confirm the diagnosis. The diagnosis of variant CJD is very difficult, but brain scans, using magnetic resonance imaging (MRI), and tonsil biopsy are two types of tests used to establish a probable diagnosis. However, the final confirmation of variant CJD can only be done by examining brain tissue, generally after the patient has died.
What treatment is available for a person who has variant CJD?
At present, there is no cure or treatment to slow the progression of the disease.
Is there a test to screen for variant CJD?
No screening test is available for persons who may have been exposed to "mad-cow disease," hence there is no known method of detecting variant CJD before symptoms appear.
Can variant CJD be transmitted from person to person by blood?
Scientists haven't yet determined if variant CJD can be transmitted by blood. To date, there has never been a documented case of variant CJD transmitted through blood transfusion. However, evidence from experimental work in animals suggests that transmission of variant CJD by blood is theoretically possible. As a precaution, since 1999, Health Canada has implemented policies to protect Canadians from the theoretical risk of transmission of variant CJD through blood. Because people living in or visiting high risk countries for BSE could have been exposed to meat or meat products from cattle infected with BSE, donor screening questionnaires restrict individuals from giving blood if they have:
-- spent a cumulative total of three months or more in the United Kingdom (UK) between the years 1980 and 1996; or
-- spent a cumulative total of three months or more in France between the years 1980 and 1996; or
-- spent a cumulative total of five years or more in Western Europe (other than UK and France) between the years 1980 and ongoing; or
-- received a blood transfusion in the UK between the years 1980 and ongoing.
As well, people who have been exposed to medical devices used on a person subsequently diagnosed with variant CJD will be advised not to donate blood, tissues or organs.
Can variant CJD be transmitted by casual contact or other means?
Scientists do not believe that variant CJD can be transmitted through casual contact, like touching or kissing, or even intimate (sexual) contact with a person with the disease.
Because variant CJD is a relatively new disease, how it is transmitted is not well understood. If the disease is transmitted in the same way as classical CJD, it may theoretically be possible for it to spread following exposure to medical devices used on a person subsequently diagnosed with variant CJD and through transplants. The tissues that are most infectious include the brain, spinal cord, pituitary gland and some parts of the eye. In variant CJD, other tissues such as the tonsils and appendix have also been found to be infective, in contrast with classical CJD.
Can variant CJD be transmitted from a mother to her unborn child or through breast milk to her baby?
Variant CJD is a relatively new disease, and knowledge about it is limited. However, to date there is no evidence that transmission of variant CJD from a mother to her unborn child or through breast milk has occurred in people with variant CJD.
How many cases of variant CJD are there in Canada every year?
In August, 2002 the first confirmed case of variant CJD was diagnosed in Canada. However, all the evidence indicates that, in this case, the individual was infected in the UK. There have been no subsequent cases of variant CJD in Canada.
With respect to variant CJD what is the Government of Canada doing to protect the health of Canadians?
Health Canada works closely with other federal agencies and experts on CJD around the world to protect the health of Canadians. For example, when a suspected case is reported, the coordinator of Health Canada's CJD Surveillance System works closely with the medical officers of health, case physician and hospital, the patient's family and experts in Canada, the United States and UK.
Variant CJD has been linked to the consumption of meat or meat products from cattle infected with BSE. To this point Canada has been free of BSE in domestic cattle.
To date, there has never been a documented case of variant CJD transmitted through blood transfusion. However, as a precaution, since 1999 Health Canada has implemented policies to protect Canadians from the theoretical risk of transmission of variant CJD through blood.
What advice does Health Canada provide to travelers to the UK and Europe ?
The best available scientific evidence indicates that whole cuts of meat without the bone, such as steaks and roast, provide a lower level of risk of potential BSE contamination than do processed products such as sausages, burgers or pat?s. Higher risk items also include any other food products such as minced meats that might contain brain or spinal cord parts, since these are considered to have the highest concentration of prions in infected cattle and therefore carry the highest potential risk of transmission. It is important to note that BSE is unlike many other food-borne pathogens in that it cannot be killed simply by cooking the infected meat.
As a result restrictions on blood donations have been extended.
The first case is thought to have happened in December 2003 when the blood recipient died several years after receiving blood from a donor who had vCJD.
The second patient who has died received blood in 1999. The donor was also later found to have had vCJD.
Secretary of Health John Reid said "Although people may have concerns about the implications of this announcement, I would emphasise again that the exclusion criteria are being tightened because of a small but unquantifiable risk."
As a result of the first case people who had received blood during the last 24 years were banned from donating blood.
The restriction now also includes people who are not sure whether they have received blood during the last 24 years.
The UK government knows of 15 blood recipients whose donors went on to develop vCJD. They have all been contacted and offered counselling.
FREQUENTLY ASKED QUESTIONS ABOUT VARIANT CREUTZFELDT - JAKOB DISEASE (Variant CJD)
From Health Canada
What is Creutzfeldt-Jakob Disease (CJD)?
Creutzfeldt-Jakob Disease (CJD) is one of a small group of fatal diseases caused by infectious agents called prions. These attack the brain, killing cells and creating gaps in tissue. The disease is always fatal.
There are two types of CJD: classical and variant.
What are prions (in relation to variant CJD)?
The agent that causes variant CJD is believed to be an abnormal form of a protein, known as a prion. Prions are normal cellular proteins that are present in many organs and tissues, including the brain, spinal cord and eyes of healthy humans and animals. The abnormal form of prion causes surrounding proteins to change their shape. The abnormal protein collects in central nervous tissue and by an unknown mechanism causes the nerve cells to die. This results in the characteristic holes in the brain tissue that can be seen under the microscope.
How do people get variant CJD?
Scientific evidence has linked variant CJD to eating contaminated beef products from animals infected with bovine spongiform encephalopathy (BSE) or "mad-cow disease." Processed meat products made from cows infected with BSE carry a high risk for transmitting the disease.
What are the symptoms of variant CJD?
Variant CJD symptoms include early psychiatric symptoms such as anxiety, depression, withdrawal and behavioural changes. Persistent pain or odd sensations in the face or limbs often develop. The disease then progresses to motor difficulties, involuntary movements and mental deterioration, often ending in a persistent vegetative state. The patient may live on average for about one year after the onset of symptoms.
How is variant CJD diagnosed?
Once a suspected case of variant CJD is reported to Health Canada's CJD Surveillance System, the Department coordinates testing and works with case physicians and international experts to confirm the diagnosis. The diagnosis of variant CJD is very difficult, but brain scans, using magnetic resonance imaging (MRI), and tonsil biopsy are two types of tests used to establish a probable diagnosis. However, the final confirmation of variant CJD can only be done by examining brain tissue, generally after the patient has died.
What treatment is available for a person who has variant CJD?
At present, there is no cure or treatment to slow the progression of the disease.
Is there a test to screen for variant CJD?
No screening test is available for persons who may have been exposed to "mad-cow disease," hence there is no known method of detecting variant CJD before symptoms appear.
Can variant CJD be transmitted from person to person by blood?
Scientists haven't yet determined if variant CJD can be transmitted by blood. To date, there has never been a documented case of variant CJD transmitted through blood transfusion. However, evidence from experimental work in animals suggests that transmission of variant CJD by blood is theoretically possible. As a precaution, since 1999, Health Canada has implemented policies to protect Canadians from the theoretical risk of transmission of variant CJD through blood. Because people living in or visiting high risk countries for BSE could have been exposed to meat or meat products from cattle infected with BSE, donor screening questionnaires restrict individuals from giving blood if they have:
-- spent a cumulative total of three months or more in the United Kingdom (UK) between the years 1980 and 1996; or
-- spent a cumulative total of three months or more in France between the years 1980 and 1996; or
-- spent a cumulative total of five years or more in Western Europe (other than UK and France) between the years 1980 and ongoing; or
-- received a blood transfusion in the UK between the years 1980 and ongoing.
As well, people who have been exposed to medical devices used on a person subsequently diagnosed with variant CJD will be advised not to donate blood, tissues or organs.
Can variant CJD be transmitted by casual contact or other means?
Scientists do not believe that variant CJD can be transmitted through casual contact, like touching or kissing, or even intimate (sexual) contact with a person with the disease.
Because variant CJD is a relatively new disease, how it is transmitted is not well understood. If the disease is transmitted in the same way as classical CJD, it may theoretically be possible for it to spread following exposure to medical devices used on a person subsequently diagnosed with variant CJD and through transplants. The tissues that are most infectious include the brain, spinal cord, pituitary gland and some parts of the eye. In variant CJD, other tissues such as the tonsils and appendix have also been found to be infective, in contrast with classical CJD.
Can variant CJD be transmitted from a mother to her unborn child or through breast milk to her baby?
Variant CJD is a relatively new disease, and knowledge about it is limited. However, to date there is no evidence that transmission of variant CJD from a mother to her unborn child or through breast milk has occurred in people with variant CJD.
How many cases of variant CJD are there in Canada every year?
In August, 2002 the first confirmed case of variant CJD was diagnosed in Canada. However, all the evidence indicates that, in this case, the individual was infected in the UK. There have been no subsequent cases of variant CJD in Canada.
With respect to variant CJD what is the Government of Canada doing to protect the health of Canadians?
Health Canada works closely with other federal agencies and experts on CJD around the world to protect the health of Canadians. For example, when a suspected case is reported, the coordinator of Health Canada's CJD Surveillance System works closely with the medical officers of health, case physician and hospital, the patient's family and experts in Canada, the United States and UK.
Variant CJD has been linked to the consumption of meat or meat products from cattle infected with BSE. To this point Canada has been free of BSE in domestic cattle.
To date, there has never been a documented case of variant CJD transmitted through blood transfusion. However, as a precaution, since 1999 Health Canada has implemented policies to protect Canadians from the theoretical risk of transmission of variant CJD through blood.
What advice does Health Canada provide to travelers to the UK and Europe ?
The best available scientific evidence indicates that whole cuts of meat without the bone, such as steaks and roast, provide a lower level of risk of potential BSE contamination than do processed products such as sausages, burgers or pat?s. Higher risk items also include any other food products such as minced meats that might contain brain or spinal cord parts, since these are considered to have the highest concentration of prions in infected cattle and therefore carry the highest potential risk of transmission. It is important to note that BSE is unlike many other food-borne pathogens in that it cannot be killed simply by cooking the infected meat.
Coroners Reluctant To Test For vCJD, UK News
According to BBC News, coroners in England and Wales are reluctant to carry out tests for vCJD because it is outside their scope of their job
and might undermine their neutrality, despite pleas from scientists and the government that this might be the only effective way to determine how many
people might be infected.
Professor John Collinge, a member of the government appointed Spongiform Encepalopathy Advisory Committee (SEAC), told the BBC that he
hoped the coroners would be able to do the tests because he couldn't see "any other way for us to get this information at the moment".
vCJD is short for variant Creutzfeldt-Jakob disease, a brain-wasting disease that humans get from eating beef from cattle infected with Bovine
Spongiform Encephalopathy (BSE). There is also an unknown risk of cross infection from blood transfusions and surgery.
The prion proteins that cause the disease are found mainly in the brain and spinal cord, although lower levels may be found in the spleen, tonsils and
other lymph tissue.
Both vCJD and BSE belong to a family of diseases known as transmissible spongiform encephalopathies (TSEs), that have been recognised for
hundreds of years. However, the first case of vCJD occurred in 1995 and it was not recognized as a new form of CJD until 1996, the same year that
an article in The Lancet first suggested evidence for a link to BSE.
Since then, 164 people have died of vCJD and over that time new regulations have been brought into the UK and other countries to eliminate BSE
from the human food chain, so it is thought that any prevalence in the population at large stems from infections that occurred in the 1980s when
people may still have been eating BSE infected beef and products derived from it.
But, while the numbers of deaths from vCJD may suggest the prevalence is low and thus the risk of person to person transmission is also low (eg via
blood transfusions, surgical operations and dental procedures), we can't rely on this evidence alone to tell us how many people could be carrying the
disease without realizing it.
For example, how can we estimate the number of infected people who will either develop the disease some time in the future (preclinical infections) or
who carry it and have the potential to transmit it to others, but will never develop the clinical disease (subclinical carrier infections)?
A study published in the Journal of Pathology in 2004 that surveyed appendix tissue samples suggested that there could be considerably more
people infected with vCJD than predictions that rely on clinical cases alone would imply.
Another study published in BMJ in May this year that reported the first results from a large tissue survey in Britain also called for more data
through continuing to archive and test tonsils, and other anonymous tissue samples, from people born before 1996.
An editorial review of that study also suggested that precautions to avoid transmission of vCJD between humans and surveillance of disease in the UK
and in the rest of Europe should continue.
However, while appendices, tonsils and other organs removed surgically might be a source of tissue to test for dormant vCJD, they would not produce
a representative sample for testing subclinical infections, said SEAC.
In a position statement dated August 2008 they said:
"As SEAC has previously concluded, the most effective approach to establish the prevalence of subclinical infections is the testing of spleen and, when
possible, brain samples collected from Coroners' autopsies."
One of the concerns on the part of coroners appears to be that taking on such a task would open the floodgates to them being asked to do what
essentially constitutes research, which is not a part of their role.
It is likely that it would also need a change in the law, since asking coroners to produce and possibly store samples for research is outside of their legal
powers. They would also need a lot more money and resources to establish what is essentially a tissue archive.
There are also ethical considerations such as whether the coroner should be asking relatives for permission to use the deceased's tissue samples for
research, as opposed to establishing the cause of death.
Christine Lord, a journalist and campaigner whose son Andy Black died nearly two years ago of vCJD at the age of 24, told the BBC that coroners
could save lives by agreeing to do the tests.
Sources: BBC News, Kent County Council, Department of Health.
, PhD
and might undermine their neutrality, despite pleas from scientists and the government that this might be the only effective way to determine how many
people might be infected.
Professor John Collinge, a member of the government appointed Spongiform Encepalopathy Advisory Committee (SEAC), told the BBC that he
hoped the coroners would be able to do the tests because he couldn't see "any other way for us to get this information at the moment".
vCJD is short for variant Creutzfeldt-Jakob disease, a brain-wasting disease that humans get from eating beef from cattle infected with Bovine
Spongiform Encephalopathy (BSE). There is also an unknown risk of cross infection from blood transfusions and surgery.
The prion proteins that cause the disease are found mainly in the brain and spinal cord, although lower levels may be found in the spleen, tonsils and
other lymph tissue.
Both vCJD and BSE belong to a family of diseases known as transmissible spongiform encephalopathies (TSEs), that have been recognised for
hundreds of years. However, the first case of vCJD occurred in 1995 and it was not recognized as a new form of CJD until 1996, the same year that
an article in The Lancet first suggested evidence for a link to BSE.
Since then, 164 people have died of vCJD and over that time new regulations have been brought into the UK and other countries to eliminate BSE
from the human food chain, so it is thought that any prevalence in the population at large stems from infections that occurred in the 1980s when
people may still have been eating BSE infected beef and products derived from it.
But, while the numbers of deaths from vCJD may suggest the prevalence is low and thus the risk of person to person transmission is also low (eg via
blood transfusions, surgical operations and dental procedures), we can't rely on this evidence alone to tell us how many people could be carrying the
disease without realizing it.
For example, how can we estimate the number of infected people who will either develop the disease some time in the future (preclinical infections) or
who carry it and have the potential to transmit it to others, but will never develop the clinical disease (subclinical carrier infections)?
A study published in the Journal of Pathology in 2004 that surveyed appendix tissue samples suggested that there could be considerably more
people infected with vCJD than predictions that rely on clinical cases alone would imply.
Another study published in BMJ in May this year that reported the first results from a large tissue survey in Britain also called for more data
through continuing to archive and test tonsils, and other anonymous tissue samples, from people born before 1996.
An editorial review of that study also suggested that precautions to avoid transmission of vCJD between humans and surveillance of disease in the UK
and in the rest of Europe should continue.
However, while appendices, tonsils and other organs removed surgically might be a source of tissue to test for dormant vCJD, they would not produce
a representative sample for testing subclinical infections, said SEAC.
In a position statement dated August 2008 they said:
"As SEAC has previously concluded, the most effective approach to establish the prevalence of subclinical infections is the testing of spleen and, when
possible, brain samples collected from Coroners' autopsies."
One of the concerns on the part of coroners appears to be that taking on such a task would open the floodgates to them being asked to do what
essentially constitutes research, which is not a part of their role.
It is likely that it would also need a change in the law, since asking coroners to produce and possibly store samples for research is outside of their legal
powers. They would also need a lot more money and resources to establish what is essentially a tissue archive.
There are also ethical considerations such as whether the coroner should be asking relatives for permission to use the deceased's tissue samples for
research, as opposed to establishing the cause of death.
Christine Lord, a journalist and campaigner whose son Andy Black died nearly two years ago of vCJD at the age of 24, told the BBC that coroners
could save lives by agreeing to do the tests.
Sources: BBC News, Kent County Council, Department of Health.
, PhD
vCJD Monthly creutzfeldt jakob disease statistics UK
The UK Department of Health is today issuing the latest information about the numbers of known cases of Creutzfeldt Jakob disease. This includes cases of variant Creutzfeldt Jakob disease (vCJD) - the form of the disease thought to be linked to BSE. The latest results which are correct as at *5 April 2004 can be seen by clicking on the link below.
Summary of vCJD cases
Deaths
Deaths from definite vCJD (confirmed): 104
Deaths from probable vCJD (without neuropathological confirmation): 36
Deaths from probable vCJD (neuropathological confirmation pending): 0
--------------------------------------------------------------------------------------------------------
Number of deaths from definite or probable vCJD (as above): 140
---------------------------------------------------------------------------------------------------------
Alive
Number of definite/probable vCJD cases still alive: 6
Total number of definite or probable vCJD (dead and alive): 146
The next table will be published on Tuesday 4th May 2004
Referrals: a simple count of all the cases which have been referred to the National CJD Surveillance Unit for further investigation in the year in question. CJD may be no more than suspected; about half the cases referred in the past have turned out not to be CJD. Cases are notified to the Unit from a variety of sources including neurologists, neuropathologists, neurophysiologists, general physicians, psychiatrists, electroencephalogram (EEG) departments etc. As a safety net, death certificates coded under the specific rubrics 046.1 and 331.9 in the 9th ICD Revisions are obtained from the Office for National Statistics in England and Wales, the General Register Office for Scotland and the General Register Office for Northern Ireland.
Deaths: All columns show the number of deaths that have occurred in definite and probable cases of all types of CJD and GSS in the year shown. The figures include both cases referred to the Unit for investigation while the patient was still alive and those where CJD was only discovered post mortem (including a few cases picked up by the Unit from death certificates). There is therefore no read across from these columns to the referrals column. The figures will be subject to retrospective adjustment as diagnoses are confirmed.
Definite cases: this refers to the diagnostic status of cases. In definite cases the diagnosis will have been pathologically confirmed, in most cases by post mortem examination of brain tissue (rarely it may be possible to establish a definite diagnosis by brain biopsy while the patient is still alive).
Probable vCJD cases: are those who fulfil the 'probable' criteria set out in the Annex and are either still alive, or have died and await post mortem pathological confirmation. Those still alive will always be shown within the current year's figures.
Sporadic: Classic CJD cases with typical EEG and brain pathology. Sporadic cases appear to occur spontaneously with no identifiable cause and account for 85% of all cases.
Probable sporadic: Cases with a history of rapidly progressive dementia, typical EEG and at least two of the following clinical features; myoclonus, visual or cerebellar signs, pyramidal/extrapyramidalsigns or akinetic mutism.
Iatrogenic: where infection with classic CJD has occurred accidentally as the result of a medical procedure. All UK cases have resulted from treatment with human derived pituitary growth hormones or from grafts using dura mater (a membrane lining the skull).
Familial: cases occurring in families associated with mutations in the PrP gene (10 - 15% of cases).
GSS: Gerstmann-Straussler-Scheinker syndrome - an exceedingly rare inherited autosomal dominant disease, typified by chronic progressive ataxia and terminal dementia. The clinical duration is from 2 to 10 years, much longer than for CJD.
vCJD: Variant CJD, the hitherto unrecognised variant of CJD discovered by the National CJD Surveillance Unit and reported in The Lancet on 6 April 1996. This is characterised clinically by a progressive neuropsychiatric disorder leading to ataxia, dementia and myoclonus (or chorea) without the typical EEG appearance of CJD. Neuropathology shows marked spongiform change and extensive florid plaques throughout the brain.
Definite vCJD cases still alive: These will be cases where the diagnosis has been pathologically confirmed (by brain biopsy).
ANNEX
DIAGNOSTIC CRITERIA FOR VARIANT CJD
I A) PROGRESSIVE NEUROPSYCHIATRIC DISORDER
B) DURATION OF ILLNESS > 6 MONTHS
C) ROUTINE INVESTIGATIONS DO NOT SUGGEST AN ALTERNATIVE
DIAGNOSIS
D) NO HISTORY OF POTENTIAL IATROGENIC EXPOSURE
II A) EARLY PSYCHIATRIC SYMPTOMS *
B) PERSISTENT PAINFUL SENSORY SYMPTOMS **
C) ATAXIA
D) MYOCLONUS OR CHOREA OR DYSTONIA
E) DEMENTIA
III A) EEG DOES NOT SHOW THE TYPICAL APPEARANCE OF SPORADIC
CJD *** (OR NO EEG PERFORMED)
B) BILATERAL PULVINAR HIGH SIGNAL ON MRI SCAN
IV A) POSITIVE TONSIL BIOPSY
DEFINITE: IA (PROGRESSIVE NEUROPSYCHIATRIC DISORDER) and
NEUROPATHOLOGICAL CONFIRMATION OF vCJD ****
PROBABLE: I and 4/5 OF II and III A and III B
or I and IV A
* depression, anxiety, apathy, withdrawal, delusions.
** this includes both frank pain and/ or unpleasant dysaesthesia
*** generalised triphasic periodic complexes at approximately one per second
****spongiform change and extensive PrP deposition with florid plaques, throughout
the cerebrum and cerebellum.
Notes to editor
For further information contact the Department of Health Media Centre
Contact
Media Centre
Phone
Press Officers
020 7210 4860/5287
From the UK Department of Health:
dh.uk/PublicationsAndStatistics/PressReleases/fs/en?OpenView
Summary of vCJD cases
Deaths
Deaths from definite vCJD (confirmed): 104
Deaths from probable vCJD (without neuropathological confirmation): 36
Deaths from probable vCJD (neuropathological confirmation pending): 0
--------------------------------------------------------------------------------------------------------
Number of deaths from definite or probable vCJD (as above): 140
---------------------------------------------------------------------------------------------------------
Alive
Number of definite/probable vCJD cases still alive: 6
Total number of definite or probable vCJD (dead and alive): 146
The next table will be published on Tuesday 4th May 2004
Referrals: a simple count of all the cases which have been referred to the National CJD Surveillance Unit for further investigation in the year in question. CJD may be no more than suspected; about half the cases referred in the past have turned out not to be CJD. Cases are notified to the Unit from a variety of sources including neurologists, neuropathologists, neurophysiologists, general physicians, psychiatrists, electroencephalogram (EEG) departments etc. As a safety net, death certificates coded under the specific rubrics 046.1 and 331.9 in the 9th ICD Revisions are obtained from the Office for National Statistics in England and Wales, the General Register Office for Scotland and the General Register Office for Northern Ireland.
Deaths: All columns show the number of deaths that have occurred in definite and probable cases of all types of CJD and GSS in the year shown. The figures include both cases referred to the Unit for investigation while the patient was still alive and those where CJD was only discovered post mortem (including a few cases picked up by the Unit from death certificates). There is therefore no read across from these columns to the referrals column. The figures will be subject to retrospective adjustment as diagnoses are confirmed.
Definite cases: this refers to the diagnostic status of cases. In definite cases the diagnosis will have been pathologically confirmed, in most cases by post mortem examination of brain tissue (rarely it may be possible to establish a definite diagnosis by brain biopsy while the patient is still alive).
Probable vCJD cases: are those who fulfil the 'probable' criteria set out in the Annex and are either still alive, or have died and await post mortem pathological confirmation. Those still alive will always be shown within the current year's figures.
Sporadic: Classic CJD cases with typical EEG and brain pathology. Sporadic cases appear to occur spontaneously with no identifiable cause and account for 85% of all cases.
Probable sporadic: Cases with a history of rapidly progressive dementia, typical EEG and at least two of the following clinical features; myoclonus, visual or cerebellar signs, pyramidal/extrapyramidalsigns or akinetic mutism.
Iatrogenic: where infection with classic CJD has occurred accidentally as the result of a medical procedure. All UK cases have resulted from treatment with human derived pituitary growth hormones or from grafts using dura mater (a membrane lining the skull).
Familial: cases occurring in families associated with mutations in the PrP gene (10 - 15% of cases).
GSS: Gerstmann-Straussler-Scheinker syndrome - an exceedingly rare inherited autosomal dominant disease, typified by chronic progressive ataxia and terminal dementia. The clinical duration is from 2 to 10 years, much longer than for CJD.
vCJD: Variant CJD, the hitherto unrecognised variant of CJD discovered by the National CJD Surveillance Unit and reported in The Lancet on 6 April 1996. This is characterised clinically by a progressive neuropsychiatric disorder leading to ataxia, dementia and myoclonus (or chorea) without the typical EEG appearance of CJD. Neuropathology shows marked spongiform change and extensive florid plaques throughout the brain.
Definite vCJD cases still alive: These will be cases where the diagnosis has been pathologically confirmed (by brain biopsy).
ANNEX
DIAGNOSTIC CRITERIA FOR VARIANT CJD
I A) PROGRESSIVE NEUROPSYCHIATRIC DISORDER
B) DURATION OF ILLNESS > 6 MONTHS
C) ROUTINE INVESTIGATIONS DO NOT SUGGEST AN ALTERNATIVE
DIAGNOSIS
D) NO HISTORY OF POTENTIAL IATROGENIC EXPOSURE
II A) EARLY PSYCHIATRIC SYMPTOMS *
B) PERSISTENT PAINFUL SENSORY SYMPTOMS **
C) ATAXIA
D) MYOCLONUS OR CHOREA OR DYSTONIA
E) DEMENTIA
III A) EEG DOES NOT SHOW THE TYPICAL APPEARANCE OF SPORADIC
CJD *** (OR NO EEG PERFORMED)
B) BILATERAL PULVINAR HIGH SIGNAL ON MRI SCAN
IV A) POSITIVE TONSIL BIOPSY
DEFINITE: IA (PROGRESSIVE NEUROPSYCHIATRIC DISORDER) and
NEUROPATHOLOGICAL CONFIRMATION OF vCJD ****
PROBABLE: I and 4/5 OF II and III A and III B
or I and IV A
* depression, anxiety, apathy, withdrawal, delusions.
** this includes both frank pain and/ or unpleasant dysaesthesia
*** generalised triphasic periodic complexes at approximately one per second
****spongiform change and extensive PrP deposition with florid plaques, throughout
the cerebrum and cerebellum.
Notes to editor
For further information contact the Department of Health Media Centre
Contact
Media Centre
Phone
Press Officers
020 7210 4860/5287
From the UK Department of Health:
dh.uk/PublicationsAndStatistics/PressReleases/fs/en?OpenView
Leeds Research Finds New Piece Of BSE Puzzle
New research funded mainly through the Wellcome Trust with additional support from the Medical Research Council shows that a new treatment route for bovine spongiform encephalopathy (BSE) and its human form Creutzfeldt Jakob disease (CJD) could be a step closer. The research carried out by scientists at the University of Leeds was published today (November 20) in PLoS Pathogens.
The team have found that a protein called Glypican-1 plays a key role in the development of BSE - otherwise known as Mad Cow Disease.
BSE is known to be caused by an infectious and abnormal form of the prion protein which is present on cells within the nervous system. But scientists have been unclear as to what causes the prions to become abnormal.
The new research from Leeds' Faculty of Biological Sciences provides part of the answer. The researchers have shown that the presence of Glypican-1 causes the numbers of abnormal prion proteins to rise. In experiments, when levels of Glypican-1 were reduced in infected cells, the levels of the abnormal prion reduced as well.
The discovery was a mixture of scientific detective work and luck, according to Professor of Biochemistry, Nigel Hooper.
"We were looking at how the normal prion protein functions in cells and spotted that it was interacting with something," he said. "Some lateral thinking and deduction led us to Glypican-1 and when we carried out the experiment, we found we were right."
The team believe that Glypican-1 acts as a scaffold bringing the two forms of the prion protein together and that this contact causes normal prions to mutate into the infectious form. They are seeking further funding to investigate their hypothesis.
The findings have implications for the treatment of both BSE and the human form of the disease, CJD, according to Professor Hooper.
"Now that we know the identity of one of the key molecules in the disease process, we may in the future be able to design drugs that target this."
Although the scientists mainly conducted experiments using cells infected with prions, it's also possible that Glypican-1 is involved in other diseases of the nervous system.
"While initial experiments haven't shown any link with other neurodegenerative diseases like Alzheimer's, we're not yet completely ruling that out," said Professor Hooper.
Source
Medical Research Council
The team have found that a protein called Glypican-1 plays a key role in the development of BSE - otherwise known as Mad Cow Disease.
BSE is known to be caused by an infectious and abnormal form of the prion protein which is present on cells within the nervous system. But scientists have been unclear as to what causes the prions to become abnormal.
The new research from Leeds' Faculty of Biological Sciences provides part of the answer. The researchers have shown that the presence of Glypican-1 causes the numbers of abnormal prion proteins to rise. In experiments, when levels of Glypican-1 were reduced in infected cells, the levels of the abnormal prion reduced as well.
The discovery was a mixture of scientific detective work and luck, according to Professor of Biochemistry, Nigel Hooper.
"We were looking at how the normal prion protein functions in cells and spotted that it was interacting with something," he said. "Some lateral thinking and deduction led us to Glypican-1 and when we carried out the experiment, we found we were right."
The team believe that Glypican-1 acts as a scaffold bringing the two forms of the prion protein together and that this contact causes normal prions to mutate into the infectious form. They are seeking further funding to investigate their hypothesis.
The findings have implications for the treatment of both BSE and the human form of the disease, CJD, according to Professor Hooper.
"Now that we know the identity of one of the key molecules in the disease process, we may in the future be able to design drugs that target this."
Although the scientists mainly conducted experiments using cells infected with prions, it's also possible that Glypican-1 is involved in other diseases of the nervous system.
"While initial experiments haven't shown any link with other neurodegenerative diseases like Alzheimer's, we're not yet completely ruling that out," said Professor Hooper.
Source
Medical Research Council
'Lifeless' Prions Capable Of Evolutionary Change And Adaptation Shown By Scripps Florida Scientists
Scientists from The Scripps Research Institute have determined for the first time that prions, bits of infectious protein devoid of DNA or RNA that can cause fatal neurodegenerative disease, are capable of Darwinian evolution.
The study from Scripps Florida in Jupiter shows that prions can develop large numbers of mutations at the protein level and, through natural selection, these mutations can eventually bring about such evolutionary adaptations as drug resistance, a phenomenon previously known to occur only in bacteria and viruses. These breakthrough findings also suggest that the normal prion protein - which occurs naturally in human cells - may prove to be a more effective therapeutic target than its abnormal toxic relation.
The study was published in the December 31, 2009 issue of the journal Science Express, an advance, online edition of the prestigious journal Science.
"On the face of it, you have exactly the same process of mutation and adaptive change in prions as you see in viruses," said Charles Weissmann, M.D., Ph.D., the head of Scripps Florida's Department of Infectology, who led the study. "This means that this pattern of Darwinian evolution appears to be universally active. In viruses, mutation is linked to changes in nucleic acid sequence that leads to resistance. Now, this adaptability has moved one level down - to prions and protein folding - and it's clear that you do not need nucleic acid for the process of evolution."
Infectious prions (short for proteinaceous infectious particles) are associated with some 20 different diseases in humans and animals, including mad cow disease and a rare human form, Creutzfeldt-Jakob disease. All these diseases are untreatable and eventually fatal. Prions, which are composed solely of protein, are classified by distinct strains, originally characterized by their incubation time and the disease they cause. Prions have the ability to reproduce, despite the fact that they contain no nucleic acid genome.
Mammalian cells normally produce cellular prion protein or PrPC. During infection, abnormal or misfolded protein - known as PrPSc - converts the normal host prion protein into its toxic form by changing its conformation or shape. The end-stage consists of large assemblies (polymers) of these misfolded proteins, which cause massive tissue and cell damage.
"It was generally thought that once cellular prion protein was converted into the abnormal form, there was no further change," Weissmann said. "But there have been hints that something was happening. When you transmit prions from sheep to mice, they become more virulent over time. Now we know that the abnormal prions replicate, and create variants, perhaps at a low level initially. But once they are transferred to a new host, natural selection will eventually choose the more virulent and aggressive variants."
Drug Resistance
In the first part of the study, Weissmann and his colleagues transferred prion populations from infected brain cells to culture cells. When transplanted, cell-adapted prions developed and out-competed their brain-adapted counterparts, confirming prions' ability to adapt to new surroundings, a hallmark of Darwinian evolution. When returned to brain, brain-adapted prions again took over the population.
To confirm the findings and to explore the issue of evolution of drug resistance, Weissmann and his colleagues used the drug swainsonine or swa, which is found in plants and fungi, and has been shown to inhibit certain prion strains. In cultures where the drug was present, the team found that a drug-resistant sub-strain of prion evolved to become predominant. When the drug was withdrawn, the sub-strain that was susceptible to swainsonine again grew to become the major component of the population.
Weissmann notes that the findings have implications for the development of therapeutic targets for prion disease. Instead of developing drugs to target abnormal proteins, it could be more efficient to try to limit the supply of normally produced prions - in essence, reducing the amount of fuel being fed into the fire. Weissmann and his colleagues have shown some 15 years ago that genetically engineered mice devoid of the normal prion protein develop and function quite normally (and are resistant to prion disease!).
"It will likely be very difficult to inhibit the production of a specific natural protein pharmacologically," Weissmann said, "You may end up interfering with some other critical physiological process, but nonetheless, finding a way to inhibit the production of normal prion protein is a project currently being pursued in collaboration with Scripps Florida Professor Corinne Lasmezas in our department."
Quasi-Species
Another implication of the findings, according to the study, is that drug-resistant variants either exist in the prion population at a low level prior to exposure or are generated during exposure to the drug. Indeed, the researchers found some prions secreted by infected cells were resistant to the drug before exposure, but only at levels less than one percent.
The scientists show that prion variants constantly arise in a particular population. These variants, or "mutants", are believed to differ in the way the prion protein is folded. As a consequence, prion populations are, in fact, comprised of multiple sub-strains.
This, Weissmann noted, is reminiscent of something he helped define some 30 years ago - the evolutionary concept of quasi-species. The idea was first conceived by Manfred Eigen, a German biophysicist who won the Nobel Prize in Chemistry in 1967. Basically stated, a quasi-species is a complex, self-perpetuating population of diverse and related entities that act as a whole. It was Weissmann, however, who provided the first confirmation of the theory through the study of a particular bacteriophage - a virus that infects bacteria - while he was director of the Institut f??r Molekularbiologie in Z??rich, Switzerland.
"The proof of the quasi-species concept is a discovery we made over 30 years ago," he said. "We found that an RNA virus population, which was thought to have only one sequence, was constantly creating mutations and eliminating the unfavorable ones. In these quasi-populations, much like we have now found in prions, you begin with a single particle, but it becomes very heterogeneous as it grows into a larger population."
There are some unknown dynamics at work in the prion population that leads to this increased heterogeneity, Weissmann added, that still need to be explored.
"It's amusing that something we did 30 years has come back to us," he said. "But we know that mutation and natural selection occur in living organisms and now we know that they also occur in a non-living organism. I suppose anything that can't do that wouldn't stand much of a chance of survival."
The joint first authors of the Science study, "Darwinian Evolution of Prions in Cell Culture," are Jiali Li and Shawn Browning of The Scripps Research Institute. Other authors include Sukhvir P. Mahal and Anja M. Oelschlegel also of The Scripps Research Institute. Weissmann notes that after the manuscript was accepted by Science, an article by Ghaemmanghami et al. appeared in PLoS Pathogens that described emergence of prions resistant to a completely different drug, quinacrine, providing additional support to the Scripps Research team's conclusions.
The Scripps Research study was supported by a grant from the National Institutes of Health and by a generous donation to the Weissmann laboratory from the Alafi Family Foundation.
The study from Scripps Florida in Jupiter shows that prions can develop large numbers of mutations at the protein level and, through natural selection, these mutations can eventually bring about such evolutionary adaptations as drug resistance, a phenomenon previously known to occur only in bacteria and viruses. These breakthrough findings also suggest that the normal prion protein - which occurs naturally in human cells - may prove to be a more effective therapeutic target than its abnormal toxic relation.
The study was published in the December 31, 2009 issue of the journal Science Express, an advance, online edition of the prestigious journal Science.
"On the face of it, you have exactly the same process of mutation and adaptive change in prions as you see in viruses," said Charles Weissmann, M.D., Ph.D., the head of Scripps Florida's Department of Infectology, who led the study. "This means that this pattern of Darwinian evolution appears to be universally active. In viruses, mutation is linked to changes in nucleic acid sequence that leads to resistance. Now, this adaptability has moved one level down - to prions and protein folding - and it's clear that you do not need nucleic acid for the process of evolution."
Infectious prions (short for proteinaceous infectious particles) are associated with some 20 different diseases in humans and animals, including mad cow disease and a rare human form, Creutzfeldt-Jakob disease. All these diseases are untreatable and eventually fatal. Prions, which are composed solely of protein, are classified by distinct strains, originally characterized by their incubation time and the disease they cause. Prions have the ability to reproduce, despite the fact that they contain no nucleic acid genome.
Mammalian cells normally produce cellular prion protein or PrPC. During infection, abnormal or misfolded protein - known as PrPSc - converts the normal host prion protein into its toxic form by changing its conformation or shape. The end-stage consists of large assemblies (polymers) of these misfolded proteins, which cause massive tissue and cell damage.
"It was generally thought that once cellular prion protein was converted into the abnormal form, there was no further change," Weissmann said. "But there have been hints that something was happening. When you transmit prions from sheep to mice, they become more virulent over time. Now we know that the abnormal prions replicate, and create variants, perhaps at a low level initially. But once they are transferred to a new host, natural selection will eventually choose the more virulent and aggressive variants."
Drug Resistance
In the first part of the study, Weissmann and his colleagues transferred prion populations from infected brain cells to culture cells. When transplanted, cell-adapted prions developed and out-competed their brain-adapted counterparts, confirming prions' ability to adapt to new surroundings, a hallmark of Darwinian evolution. When returned to brain, brain-adapted prions again took over the population.
To confirm the findings and to explore the issue of evolution of drug resistance, Weissmann and his colleagues used the drug swainsonine or swa, which is found in plants and fungi, and has been shown to inhibit certain prion strains. In cultures where the drug was present, the team found that a drug-resistant sub-strain of prion evolved to become predominant. When the drug was withdrawn, the sub-strain that was susceptible to swainsonine again grew to become the major component of the population.
Weissmann notes that the findings have implications for the development of therapeutic targets for prion disease. Instead of developing drugs to target abnormal proteins, it could be more efficient to try to limit the supply of normally produced prions - in essence, reducing the amount of fuel being fed into the fire. Weissmann and his colleagues have shown some 15 years ago that genetically engineered mice devoid of the normal prion protein develop and function quite normally (and are resistant to prion disease!).
"It will likely be very difficult to inhibit the production of a specific natural protein pharmacologically," Weissmann said, "You may end up interfering with some other critical physiological process, but nonetheless, finding a way to inhibit the production of normal prion protein is a project currently being pursued in collaboration with Scripps Florida Professor Corinne Lasmezas in our department."
Quasi-Species
Another implication of the findings, according to the study, is that drug-resistant variants either exist in the prion population at a low level prior to exposure or are generated during exposure to the drug. Indeed, the researchers found some prions secreted by infected cells were resistant to the drug before exposure, but only at levels less than one percent.
The scientists show that prion variants constantly arise in a particular population. These variants, or "mutants", are believed to differ in the way the prion protein is folded. As a consequence, prion populations are, in fact, comprised of multiple sub-strains.
This, Weissmann noted, is reminiscent of something he helped define some 30 years ago - the evolutionary concept of quasi-species. The idea was first conceived by Manfred Eigen, a German biophysicist who won the Nobel Prize in Chemistry in 1967. Basically stated, a quasi-species is a complex, self-perpetuating population of diverse and related entities that act as a whole. It was Weissmann, however, who provided the first confirmation of the theory through the study of a particular bacteriophage - a virus that infects bacteria - while he was director of the Institut f??r Molekularbiologie in Z??rich, Switzerland.
"The proof of the quasi-species concept is a discovery we made over 30 years ago," he said. "We found that an RNA virus population, which was thought to have only one sequence, was constantly creating mutations and eliminating the unfavorable ones. In these quasi-populations, much like we have now found in prions, you begin with a single particle, but it becomes very heterogeneous as it grows into a larger population."
There are some unknown dynamics at work in the prion population that leads to this increased heterogeneity, Weissmann added, that still need to be explored.
"It's amusing that something we did 30 years has come back to us," he said. "But we know that mutation and natural selection occur in living organisms and now we know that they also occur in a non-living organism. I suppose anything that can't do that wouldn't stand much of a chance of survival."
The joint first authors of the Science study, "Darwinian Evolution of Prions in Cell Culture," are Jiali Li and Shawn Browning of The Scripps Research Institute. Other authors include Sukhvir P. Mahal and Anja M. Oelschlegel also of The Scripps Research Institute. Weissmann notes that after the manuscript was accepted by Science, an article by Ghaemmanghami et al. appeared in PLoS Pathogens that described emergence of prions resistant to a completely different drug, quinacrine, providing additional support to the Scripps Research team's conclusions.
The Scripps Research study was supported by a grant from the National Institutes of Health and by a generous donation to the Weissmann laboratory from the Alafi Family Foundation.
Sticky Antibodies Block Prion Disease
Antibodies that stick to a brain prion protein called PrP could be the key to treating prion diseases like variant CJD and preventing people accidentally exposed to prions from going on to develop the fatal brain disease. Using a precise visualisation technique, called X-ray crystallography, scientists have identified an antibody that has the best ability to bind to PrP in the brain. Experiments using cells in the laboratory and in mice have suggested it could stop prion infection in its tracks.
The finding is the result of a collaboration between molecular biologists at the Medical Research Council Prion Unit, University College London, and biophysicists at the University of Liverpool. The results are published in the journal PNAS, Proceedings of the National Academy of Sciences.
Prion infection depends on conversion of naturally occurring PrP into a corrupted form called PrPSc that has a different shape. This change in shape is critical for disease progression and happens when PrP comes into contact with infectious prions. PrPSc builds up causing the death of brain cells and other symptoms of prion disease.
Past research has shown that the conversion process can be interrupted by immunisation with antibodies designed to stick to PrP. This study reveals that the ability of an antibody to reduce prion infection is dependent on how well it binds to normal PrP. Whether or not the antibody sticks to PrPSc too is irrelevant. A monoclonal (designed specifically to match one target) antibody called ICSM18 has been found to be the most effective.
Professor John Collinge, Director of the MRC Prion Unit, explained the background: ''Naturally occurring prion protein is an established therapeutic target for prion disease: studies at the MRC Prion Unit have demonstrated that when we stop brain cells of infected mice making PrP, onset of disease is prevented and early damage to the brain reverses. In this research we have prevented normal PrP from getting drawn into this process by binding antibodies onto them. We have also shown that the monoclonal antibody ICSM18 has the highest therapeutic potential in cell and mouse based studies. Whether or not it will have the same impact in people who have vCJD or other prion diseases is yet to be established, but we are trying to make human versions of these antibodies for future trials in people.''
By visualising the interaction between antibody and prion protein at a molecular level using X-ray crystallography, the researchers at Liverpool's Molecular Biophysics group were able to see exactly which parts of the two proteins stick together.
Interestingly, they found that the point where the two prion proteins come together is exactly where a key building block of the protein resides at position 129. It has been known for some years, from earlier work by MRC Prion Unit scientists, that the amino acid at position 129 has a radical effect on an individual's susceptibility to prion disease. There are two common forms of prion protein present in the population with either the amino acid methionine (M) or valine (V) at position 129.
Around a third of the UK population have two M copies of the prion gene, this means they are "MM". Around 10% of people are "VV" and the remainder have the commonest "MV" genetic type. This genetic variation is one of the strongest causes of genetic susceptibility known in any human disease and every patient who has developed vCJD has been MM. Those who have the MV genotype are partially protected against developing these diseases. The crystallographic structure, that allowed the research team to look inside the molecule at atomic details, explains why this single building block is so important in determining a person's risk of developing prion disease, as the M and V proteins interact less readily than two M or two V amino acids.
Commenting on the significance of the study findings, lead partner for structural studies Professor Samar Hasnain, Max Perutz Professor of Molecular Biophysics at the University of Liverpool said:
''The key to this research has been our ability to visualise the exact crystal structure of the prion protein when it is bound to the most effective monoclonal antibody. The results announced today are a great example of research crossing disciplines to share the skills of molecular biologists and biophysicists to solve problems associated with human disease.''
Professor Hasnain acknowledged the contribution made by staff at the Daresbury Synchrotron X-ray source where crystallographic data for the difficult structure were obtained.
Original research paper: Crystal structure of human prion protein bound to a therapeutic antibody is published online in PNAS, Proceedings of the National Academy of Sciences.
This research collaboration was between scientists at the Medical Research Council Prion Unit, University College London, and a team from the Molecular Biophysics Group at the Science and Technology Facilities Council Daresbury Laboratory, which is now based in the School of Biological Sciences at the University of Liverpool biophysics.liv.ac.uk.
The Molecular Biophysics Group, formerly at STFC Daresbury Laboratory, joined the University of Liverpool on 1st April 2008. Its research interests are centred on biomolecules associated with health, energy and the environment. The main programs include proteins involved in neurodegenerative diseases, tuberculosis, drug metabolism, and the key enzymes involved in the terrestrial nitrogen cycle. The group has pioneered multiple-techniques approach for studying metalloproteins and continues to be engaged in developing new approaches using advanced X-ray sources including the next generation light sources. For further details, see biophysics.liv.ac.uk.
Medical Research Council
The finding is the result of a collaboration between molecular biologists at the Medical Research Council Prion Unit, University College London, and biophysicists at the University of Liverpool. The results are published in the journal PNAS, Proceedings of the National Academy of Sciences.
Prion infection depends on conversion of naturally occurring PrP into a corrupted form called PrPSc that has a different shape. This change in shape is critical for disease progression and happens when PrP comes into contact with infectious prions. PrPSc builds up causing the death of brain cells and other symptoms of prion disease.
Past research has shown that the conversion process can be interrupted by immunisation with antibodies designed to stick to PrP. This study reveals that the ability of an antibody to reduce prion infection is dependent on how well it binds to normal PrP. Whether or not the antibody sticks to PrPSc too is irrelevant. A monoclonal (designed specifically to match one target) antibody called ICSM18 has been found to be the most effective.
Professor John Collinge, Director of the MRC Prion Unit, explained the background: ''Naturally occurring prion protein is an established therapeutic target for prion disease: studies at the MRC Prion Unit have demonstrated that when we stop brain cells of infected mice making PrP, onset of disease is prevented and early damage to the brain reverses. In this research we have prevented normal PrP from getting drawn into this process by binding antibodies onto them. We have also shown that the monoclonal antibody ICSM18 has the highest therapeutic potential in cell and mouse based studies. Whether or not it will have the same impact in people who have vCJD or other prion diseases is yet to be established, but we are trying to make human versions of these antibodies for future trials in people.''
By visualising the interaction between antibody and prion protein at a molecular level using X-ray crystallography, the researchers at Liverpool's Molecular Biophysics group were able to see exactly which parts of the two proteins stick together.
Interestingly, they found that the point where the two prion proteins come together is exactly where a key building block of the protein resides at position 129. It has been known for some years, from earlier work by MRC Prion Unit scientists, that the amino acid at position 129 has a radical effect on an individual's susceptibility to prion disease. There are two common forms of prion protein present in the population with either the amino acid methionine (M) or valine (V) at position 129.
Around a third of the UK population have two M copies of the prion gene, this means they are "MM". Around 10% of people are "VV" and the remainder have the commonest "MV" genetic type. This genetic variation is one of the strongest causes of genetic susceptibility known in any human disease and every patient who has developed vCJD has been MM. Those who have the MV genotype are partially protected against developing these diseases. The crystallographic structure, that allowed the research team to look inside the molecule at atomic details, explains why this single building block is so important in determining a person's risk of developing prion disease, as the M and V proteins interact less readily than two M or two V amino acids.
Commenting on the significance of the study findings, lead partner for structural studies Professor Samar Hasnain, Max Perutz Professor of Molecular Biophysics at the University of Liverpool said:
''The key to this research has been our ability to visualise the exact crystal structure of the prion protein when it is bound to the most effective monoclonal antibody. The results announced today are a great example of research crossing disciplines to share the skills of molecular biologists and biophysicists to solve problems associated with human disease.''
Professor Hasnain acknowledged the contribution made by staff at the Daresbury Synchrotron X-ray source where crystallographic data for the difficult structure were obtained.
Original research paper: Crystal structure of human prion protein bound to a therapeutic antibody is published online in PNAS, Proceedings of the National Academy of Sciences.
This research collaboration was between scientists at the Medical Research Council Prion Unit, University College London, and a team from the Molecular Biophysics Group at the Science and Technology Facilities Council Daresbury Laboratory, which is now based in the School of Biological Sciences at the University of Liverpool biophysics.liv.ac.uk.
The Molecular Biophysics Group, formerly at STFC Daresbury Laboratory, joined the University of Liverpool on 1st April 2008. Its research interests are centred on biomolecules associated with health, energy and the environment. The main programs include proteins involved in neurodegenerative diseases, tuberculosis, drug metabolism, and the key enzymes involved in the terrestrial nitrogen cycle. The group has pioneered multiple-techniques approach for studying metalloproteins and continues to be engaged in developing new approaches using advanced X-ray sources including the next generation light sources. For further details, see biophysics.liv.ac.uk.
Medical Research Council
Chronic Wasting Disease Transmissible Among Rodents
For the first time, a new study demonstrates that certain rodents can be directly infected with CWD and therefore serve as animal models for further study of the disease. The researchers report their findings in the Journal of Virology.
Chronic wasting disease (CWD), also known as mad cow disease in cattle and Creutzfeldt-Jacob disease in humans, is a transmissible prion disease most commonly found in deer and elk. Conversion of the normal host protein to an abnormal disease-associated form is an important part in the tracking of prion diseases and researchers are hopeful that rodent-adapted CWD models could assist in therapeutic development.
In the study transgenic and wild-type mice in addition to Syrian, Djungarian, Chinese, Siberian and Armenian hamsters were inoculated with CWD samples retrieved from deer and elk and monitored over various amounts of time. Distinct neuropathological patterns throughout differing incubation periods were observed in Chinese hamsters and transgenic mice offering the highest susceptibility rates. Wild-type mice and Djungarian hamsters were found not to be susceptible to CWD.
"We have shown that CWD from one or more cervid species can be transmitted to Sg, Chinese, Siberian, and Armenian hamsters and to Tg mice that express Sg hamster prion protein," say the researchers. "The resulting rodent-adapted CWD models could be useful in comparative studies of TSE strains in vivo as well as for testing potential anti-TSE therapeutic agents."
(G.J. Raymond, L.D. Raymond, K.D. Meade-White, A.G. Hughson, C. Favara, D. Gardner, E.S. Williams, M.W. Miller, R.E. Race, B. Caughey. 2007. Transmission and adaptation of chronic wasting disease to hamsters and transgenic mice: evidence for strains. Journal of Virology, 81. 8: 4305-4314).
Tips from the Journals of the American Society for Microbiology
Contact: Carrie Patterson
American Society for Microbiology
Chronic wasting disease (CWD), also known as mad cow disease in cattle and Creutzfeldt-Jacob disease in humans, is a transmissible prion disease most commonly found in deer and elk. Conversion of the normal host protein to an abnormal disease-associated form is an important part in the tracking of prion diseases and researchers are hopeful that rodent-adapted CWD models could assist in therapeutic development.
In the study transgenic and wild-type mice in addition to Syrian, Djungarian, Chinese, Siberian and Armenian hamsters were inoculated with CWD samples retrieved from deer and elk and monitored over various amounts of time. Distinct neuropathological patterns throughout differing incubation periods were observed in Chinese hamsters and transgenic mice offering the highest susceptibility rates. Wild-type mice and Djungarian hamsters were found not to be susceptible to CWD.
"We have shown that CWD from one or more cervid species can be transmitted to Sg, Chinese, Siberian, and Armenian hamsters and to Tg mice that express Sg hamster prion protein," say the researchers. "The resulting rodent-adapted CWD models could be useful in comparative studies of TSE strains in vivo as well as for testing potential anti-TSE therapeutic agents."
(G.J. Raymond, L.D. Raymond, K.D. Meade-White, A.G. Hughson, C. Favara, D. Gardner, E.S. Williams, M.W. Miller, R.E. Race, B. Caughey. 2007. Transmission and adaptation of chronic wasting disease to hamsters and transgenic mice: evidence for strains. Journal of Virology, 81. 8: 4305-4314).
Tips from the Journals of the American Society for Microbiology
Contact: Carrie Patterson
American Society for Microbiology
CJD trials two years late and still waiting
Two years ago the Department of Health (UK) promised there would be immediate (fast-track) trials to treat vCJD, the human form of BSE (mad cow disease).
Two years ago American doctors said that a malaria drug might be effective against vCJD.
The delay seems to be caused by two groups of scientists who do not seem to get on, according to an article in the Times Higher Education Supplement (UK).
A few years ago, Rachel Forber, aged 21 had vCJD. She was from Liverpool, UK. She was bed-ridden and needed round-the-clock care. In fact, she was unable to recognise her loved ones. She could not tolerate sunlight or noise. She was unable to feed herself or even get dressed on her own.
Within three months of taking Quinacrine she was able to get out of bed. She could walk on her own, she was able to swim without any help.
Unfortunately, she suffered complications with her liver. She was taken off the drug. Rachel died in 2001.
According to Sir Iain Chalmers, Director of the Cochrane Centre, UK, scientists at the Medical Research Unit Prion Unit at the Institute of Neurology, London and the CJD Surveillance Unit, Edinburgh could not agree on how to run the trials.
Sir Iain Chalmers was appointed Chairman of the committee whose job it was to oversee the trials of Quinacrine. Sir Iain Chalmers resigned recently. He says he has done all he can to push the trials forward.
In the Times Higher Education Supplement he says 'Only after I accepted the position was I introduced to the longstanding, bitter relationship between the researchers. This is a problem going back many years. I am very disappointed that this feud continues. Unless the public starts to get angry about this, I can't see their interests being served as they should be.'
According to the Medical Research Council, progress is now being made. Let's hope they can sort this out. So far, the reasons and lack or progress looks pathetic.
Two years ago American doctors said that a malaria drug might be effective against vCJD.
The delay seems to be caused by two groups of scientists who do not seem to get on, according to an article in the Times Higher Education Supplement (UK).
A few years ago, Rachel Forber, aged 21 had vCJD. She was from Liverpool, UK. She was bed-ridden and needed round-the-clock care. In fact, she was unable to recognise her loved ones. She could not tolerate sunlight or noise. She was unable to feed herself or even get dressed on her own.
Within three months of taking Quinacrine she was able to get out of bed. She could walk on her own, she was able to swim without any help.
Unfortunately, she suffered complications with her liver. She was taken off the drug. Rachel died in 2001.
According to Sir Iain Chalmers, Director of the Cochrane Centre, UK, scientists at the Medical Research Unit Prion Unit at the Institute of Neurology, London and the CJD Surveillance Unit, Edinburgh could not agree on how to run the trials.
Sir Iain Chalmers was appointed Chairman of the committee whose job it was to oversee the trials of Quinacrine. Sir Iain Chalmers resigned recently. He says he has done all he can to push the trials forward.
In the Times Higher Education Supplement he says 'Only after I accepted the position was I introduced to the longstanding, bitter relationship between the researchers. This is a problem going back many years. I am very disappointed that this feud continues. Unless the public starts to get angry about this, I can't see their interests being served as they should be.'
According to the Medical Research Council, progress is now being made. Let's hope they can sort this out. So far, the reasons and lack or progress looks pathetic.
BSE Inconclusive Test Results, Statement by Dr. John Clifford, USA
"Since the USDA enhanced surveillance program for BSE began in June 2004, more than 375,000 animals from the targeted
cattle population have been tested for BSE using a rapid test. Three of these animals tested inconclusive and were
subsequently subjected to immunohistochemistry, or IHC, testing. The IHC is an internationally recognized confirmatory test
for BSE. All three inconclusive samples tested negative using IHC.
"Earlier this week, USDA's Office of the Inspector General (OIG), which has been partnering with the Animal and Plant Health
Inspection Service, the Food Safety and Inspection Service, and the Agricultural Research Service by impartially reviewing
BSE-related activities and making recommendations for improvement, recommended that all three of these samples be subjected
to a second internationally recognized confirmatory test, the OIE-recognized SAF immunoblot test, often referred to as the
Western blot test. We received final results a short time ago. Of the three samples, two were negative, but the third came
back reactive.
"Because of the conflicting results on the IHC and Western blot tests, a sample from this animal will be sent to the
OIE-recognized reference laboratory for BSE in Weybridge, England. USDA will also be conducting further testing, which will
take several days to complete.
"Regardless of the outcome, it is critical to note that USDA has in place a sound system of interlocking safeguards to
protect human and animal health from BSE-including, most significantly, a ban on specified risk materials from the human food
supply. In the case of this animal, it was a non-ambulatory (downer) animal and as such was banned from the food supply. It
was processed at a facility that handles only animals unsuitable for human consumption, and the carcass was incinerated.
"USDA's enhanced surveillance program is designed to provide information about the level of prevalence of BSE in the United
States. Since the inception of this program, we have fully anticipated the possibility that additional cases of BSE would be
found. And, in fact, we are extremely gratified that to date, more than 375,000 animals have been tested for the disease and,
with the exception of the conflicting results we have received on this one animal, all have ultimately proven to be negative
for the disease.
"USDA is committed to ensuring that our BSE program is the best that it can be, keeping pace with science and international
guidelines, and to considering recommendations made by OIG and others in this regard. We are committed to ensuring that we
have the right protocols in place-ones that are solidly grounded in science and consistently followed. After we receive
additional test results on this animal, we will determine what further steps need to be taken and what changes, if any, are
warranted in our surveillance program."
US Dept of Agriculture
cattle population have been tested for BSE using a rapid test. Three of these animals tested inconclusive and were
subsequently subjected to immunohistochemistry, or IHC, testing. The IHC is an internationally recognized confirmatory test
for BSE. All three inconclusive samples tested negative using IHC.
"Earlier this week, USDA's Office of the Inspector General (OIG), which has been partnering with the Animal and Plant Health
Inspection Service, the Food Safety and Inspection Service, and the Agricultural Research Service by impartially reviewing
BSE-related activities and making recommendations for improvement, recommended that all three of these samples be subjected
to a second internationally recognized confirmatory test, the OIE-recognized SAF immunoblot test, often referred to as the
Western blot test. We received final results a short time ago. Of the three samples, two were negative, but the third came
back reactive.
"Because of the conflicting results on the IHC and Western blot tests, a sample from this animal will be sent to the
OIE-recognized reference laboratory for BSE in Weybridge, England. USDA will also be conducting further testing, which will
take several days to complete.
"Regardless of the outcome, it is critical to note that USDA has in place a sound system of interlocking safeguards to
protect human and animal health from BSE-including, most significantly, a ban on specified risk materials from the human food
supply. In the case of this animal, it was a non-ambulatory (downer) animal and as such was banned from the food supply. It
was processed at a facility that handles only animals unsuitable for human consumption, and the carcass was incinerated.
"USDA's enhanced surveillance program is designed to provide information about the level of prevalence of BSE in the United
States. Since the inception of this program, we have fully anticipated the possibility that additional cases of BSE would be
found. And, in fact, we are extremely gratified that to date, more than 375,000 animals have been tested for the disease and,
with the exception of the conflicting results we have received on this one animal, all have ultimately proven to be negative
for the disease.
"USDA is committed to ensuring that our BSE program is the best that it can be, keeping pace with science and international
guidelines, and to considering recommendations made by OIG and others in this regard. We are committed to ensuring that we
have the right protocols in place-ones that are solidly grounded in science and consistently followed. After we receive
additional test results on this animal, we will determine what further steps need to be taken and what changes, if any, are
warranted in our surveillance program."
US Dept of Agriculture
National CJD Surveillance Unit Publishes 16th Annual Report For 2007 And Scientific Report, UK
The Sixteenth Annual Report of the National Creutzfeldt-Jakob Disease Surveillance Unit (NCJDSU) is published today. The report looks back over the period from May 1990 (when the Unit was set up) to 31 December 2007. The report outlines the Unit's work in the clinical surveillance of variant (vCJD), sporadic and iatrogenic CJD.
The key figures on the incidence of CJD are:
- between 1996 and 31 December 2007, a total of 166 cases of definite or probable vCJD had been identified in the UK;
- only one new probable or definite case of vCJD was reported in 2007;
- there were five deaths from vCJD in 2007, the same as in 2006;
- there were 56 deaths from sporadic CJD in 2007, compared to 65 in 2006. This is comparable to the mortality rates for sporadic CJD in most other countries.
We also welcome the publication of the Unit's scientific report, which provides details of the current, and planned future scientific research being undertaken by staff at the NCJDSU, in the context of the Unit's previous research and its on-going background surveillance.
Both reports are available on the NCJDSU website at cjd.ed.uk.
The NCJDSU is funded by the Department of Health and the Scottish Executive Health Department.
Department of Health, UK
The key figures on the incidence of CJD are:
- between 1996 and 31 December 2007, a total of 166 cases of definite or probable vCJD had been identified in the UK;
- only one new probable or definite case of vCJD was reported in 2007;
- there were five deaths from vCJD in 2007, the same as in 2006;
- there were 56 deaths from sporadic CJD in 2007, compared to 65 in 2006. This is comparable to the mortality rates for sporadic CJD in most other countries.
We also welcome the publication of the Unit's scientific report, which provides details of the current, and planned future scientific research being undertaken by staff at the NCJDSU, in the context of the Unit's previous research and its on-going background surveillance.
Both reports are available on the NCJDSU website at cjd.ed.uk.
The NCJDSU is funded by the Department of Health and the Scottish Executive Health Department.
Department of Health, UK
Utility Of Circulating DNA As Novel Diagnostics For Human Cancer, Mad Cow Disease And Other Conditions
Chronix Biomedical - developing and applying proprietary techniques to detect and analyze circulating nucleic acid sequences for the diagnosis and management of disease - reported that three recent studies published in peer-reviewed journals have further confirmed the potential diagnostic and prognostic utility of fragments of DNA and RNA that circulate in the blood, known as circulating nucleic acids (CNAs). Data from these studies confirm previous findings showing that CNAs can identify the presence of certain diseases in blood samples months to years before clinical symptoms appear.
"The recent publication of these three studies represents a major milestone in the recognition of CNAs as novel diagnostic tools," said Howard Urnovitz, Ph.D., CEO of Chronix. "Our ability to accurately identify and characterize the presence of significant differences in CNA levels and sequences between healthy and diseased individuals demonstrates how CNAs would be used for diagnosis and disease management in conditions as diverse as bovine spongiform encephalopathy (mad cow disease) and human cancers."
In the study appearing in the current online edition of Clinical Chemistry, scientists from Chronix applied ultra-high speed sequencing technology and proprietary data analysis tools to characterize and categorize the CNA markers present in multiple individuals. The resulting databases of CNAs associated with specific disease states can be used to identify persons with undiagnosed disease, and potentially, to track changes in disease status. For example, the study found that one of the presumed healthy volunteers was actually infected with hepatitis B.
This study follows publication in January of research from scientists at the University of Calgary, Canada, the University of G?¶ttingen, Germany and Chronix showing the ability of a simple blood test based on circulating DNA sequences to identify the presence of bovine spongiform encephalopathy (BSE) and the related condition chronic wasting disease (CWD) in live animals long before symptoms were evident. This advance is especially significant since BSE can now only be confirmed by examining the brain tissue of dead animals. Following expected confirmation in larger studies, this new approach could revolutionize testing for BSE, making it economically and logistically feasible to screen all cattle in the food chain before BSE symptoms appear. The study was published in the journal Nucleic Acids Research.
A third reported study highlights the potential utility of CNAs in the management of cancer. Dr. Urnovitz, and Brian G.M. Durie, M.D., Medical Director and co-founder of the International Myeloma Foundation, identified specific DNA sequences circulating in the blood of a patient with the bone marrow cancer multiple myeloma and tracked variations in these sequences as the patient's myeloma moved in and out of remission. There was also an unexpected finding when CNAs identified the development of a secondary cancer in this patient, before it was clinically apparent. This preliminary study is significant because it shows that CNAs can potentially be used to diagnose, monitor and manage cancer treatment. The abstract reporting this data was published in the journal Blood in connection with the December 2008 meeting of the American Society of Hematology.
"This approach opens the door to a new tool that will enable us to follow the progress of cancer treatment and give us an early warning when a myeloma patient is about to come out of remission," said Dr. Durie. "This will allow us to stay ahead of the disease instead of waiting for the patient to get sick before we can act. That capability will represent a major change in the way we treat this cancer."
Dr. Urnovitz concluded, "Even in these experiments we found unexpected results - undiagnosed hepatitis in one patient and a secondary cancer in another - confirming the utility of CNAs in finding unsuspected disease. With these multiple proof-of-concept experiments now completed, we are embarking on the studies needed to further confirm and commercialize this powerful new approach with important applications in personalized medicine and human health."
Chronix intends to work with a number of industry partners to develop and commercialize its CNA technology for diagnostic and prognostic applications. These emerging markets for novel genetic-based assays have multi-billion dollar potential. Because the Chronix technology can identify early changes in disease status, it also can be used to generate surrogate measures for drug development studies aimed at distinguishing responder and non-responder patient subgroups. The company has recently initiated discussions with potential pharmaceutical partners.
About Chronix Biomedical
Chronix Biomedical is pioneering a breakthrough approach to the diagnosis and management of chronic diseases and cancer. It has developed proprietary technology that measures and categorizes circulating nucleic acids, DNA sequences circulating in the blood that are associated with specific changes in disease and health status. Using advanced genome analysis methods, proprietary data tools and disease-specific databases, Chronix has demonstrated the utility of its diagnostic and prognostic approach in mad cow disease and multiple myeloma, and studies in other diseases are underway. The company plans to collaborate with a variety of partners to develop and market its DNA-based assays that have the potential to transform the management of a broad range of cancers and other conditions. Chronix is headquartered in San Jose, California and has research facilities in Germany.
"The recent publication of these three studies represents a major milestone in the recognition of CNAs as novel diagnostic tools," said Howard Urnovitz, Ph.D., CEO of Chronix. "Our ability to accurately identify and characterize the presence of significant differences in CNA levels and sequences between healthy and diseased individuals demonstrates how CNAs would be used for diagnosis and disease management in conditions as diverse as bovine spongiform encephalopathy (mad cow disease) and human cancers."
In the study appearing in the current online edition of Clinical Chemistry, scientists from Chronix applied ultra-high speed sequencing technology and proprietary data analysis tools to characterize and categorize the CNA markers present in multiple individuals. The resulting databases of CNAs associated with specific disease states can be used to identify persons with undiagnosed disease, and potentially, to track changes in disease status. For example, the study found that one of the presumed healthy volunteers was actually infected with hepatitis B.
This study follows publication in January of research from scientists at the University of Calgary, Canada, the University of G?¶ttingen, Germany and Chronix showing the ability of a simple blood test based on circulating DNA sequences to identify the presence of bovine spongiform encephalopathy (BSE) and the related condition chronic wasting disease (CWD) in live animals long before symptoms were evident. This advance is especially significant since BSE can now only be confirmed by examining the brain tissue of dead animals. Following expected confirmation in larger studies, this new approach could revolutionize testing for BSE, making it economically and logistically feasible to screen all cattle in the food chain before BSE symptoms appear. The study was published in the journal Nucleic Acids Research.
A third reported study highlights the potential utility of CNAs in the management of cancer. Dr. Urnovitz, and Brian G.M. Durie, M.D., Medical Director and co-founder of the International Myeloma Foundation, identified specific DNA sequences circulating in the blood of a patient with the bone marrow cancer multiple myeloma and tracked variations in these sequences as the patient's myeloma moved in and out of remission. There was also an unexpected finding when CNAs identified the development of a secondary cancer in this patient, before it was clinically apparent. This preliminary study is significant because it shows that CNAs can potentially be used to diagnose, monitor and manage cancer treatment. The abstract reporting this data was published in the journal Blood in connection with the December 2008 meeting of the American Society of Hematology.
"This approach opens the door to a new tool that will enable us to follow the progress of cancer treatment and give us an early warning when a myeloma patient is about to come out of remission," said Dr. Durie. "This will allow us to stay ahead of the disease instead of waiting for the patient to get sick before we can act. That capability will represent a major change in the way we treat this cancer."
Dr. Urnovitz concluded, "Even in these experiments we found unexpected results - undiagnosed hepatitis in one patient and a secondary cancer in another - confirming the utility of CNAs in finding unsuspected disease. With these multiple proof-of-concept experiments now completed, we are embarking on the studies needed to further confirm and commercialize this powerful new approach with important applications in personalized medicine and human health."
Chronix intends to work with a number of industry partners to develop and commercialize its CNA technology for diagnostic and prognostic applications. These emerging markets for novel genetic-based assays have multi-billion dollar potential. Because the Chronix technology can identify early changes in disease status, it also can be used to generate surrogate measures for drug development studies aimed at distinguishing responder and non-responder patient subgroups. The company has recently initiated discussions with potential pharmaceutical partners.
About Chronix Biomedical
Chronix Biomedical is pioneering a breakthrough approach to the diagnosis and management of chronic diseases and cancer. It has developed proprietary technology that measures and categorizes circulating nucleic acids, DNA sequences circulating in the blood that are associated with specific changes in disease and health status. Using advanced genome analysis methods, proprietary data tools and disease-specific databases, Chronix has demonstrated the utility of its diagnostic and prognostic approach in mad cow disease and multiple myeloma, and studies in other diseases are underway. The company plans to collaborate with a variety of partners to develop and market its DNA-based assays that have the potential to transform the management of a broad range of cancers and other conditions. Chronix is headquartered in San Jose, California and has research facilities in Germany.
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