MAD COW DISEASE IS OUT THERE!    STAY INFORMED!

( Bovine Spongiform Encephalopathy - BSE )

Tuesday, May 23 2000 • New York Times • SANDRA BLAKESLEE

Chronic wasting disease transmits to humans

Comment (webmaster): According to an interview conducted by the NY Times at the Miami CJD Foundation meeting, Dr. Byron Caughey at federal Rocky Mtn labs in Hamilton, Montana has shown chronic wasting disease in deer and elk has potential to cause TSE disease in humans. Prions taken from the brains of infected deer and elk are able to convert normal human prion to the protease-resistant form, a well-studied proxy for ability to transmit disease across species. The efficiency of the process is fairly low compared to human-human conversion. Caughey and coworkers have previously established that sheep scrapie has about the same efficiency as BSE in converting human.

Reportedly, M.Miller et al. of the Colorado Division of Wildlife have a paper in press in the J of Wildlife Diseases, April or July 2000 reporting that levels of detectable CWD infection have reached the staggering level of 15% of the deer in Larimer County, Colorado. A letter sent by DOW to property owners proposes to slaughter affected and unaffected animals alike by increasing permits to 60% annual kill.

While it is too late to do anything about the hundreds of thousands of hunters and others who have eaten tainted deer and elk meat, it may be possible to limit the geographic extent of the epidemic in wildlife. Back-transmission to domestic sheep and cows is another serious possibility -- here, because the prion proteins are more similar, less of a species barrier is expected compared to humans.

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Clues to Mad Cow Disease Emerge in Study of Mutant Proteins

"Now, six years after young people in Britain started dying from a human strain of mad cow disease, scientists are still struggling to understand how the disease spreads to humans, how many more will die from it and if a similar epidemic could start in the United States spread by infected deer and elk.

While there are no firm answers, clues are being discovered on an almost weekly basis as scientists explore the nature of a mysterious infectious agent called the prion. Unlike disease-causing viruses or bacteria, prions are normal proteins found throughout the body tissues of humans and other animals. But for reasons that are not at all understood, normal prions sometimes transform themselves into tiny particles that cannot be killed with boiling water, chemical disinfectants or strong radiation.

These prions, almost impossible to destroy, accumulate in the brains of infected animals and people, destroying cells and leaving spongy holes in the tissue. The most common human form of this malady, called sporadic Creutzfeldt-Jakob disease or C.J.D., seems to arise spontaneously in the brains of about one per one million people. An estimated 300 Americans, mostly over age 50, die from it each year.

But a new variant of C.J.D. now is killing young Britons who acquired the disease from eating cattle infected with abnormal prions of their own. The cattle malady, called bovine spongiform encephalopathy or mad cow disease, has infected hundreds of thousands of animals since the mid-1980's.

Two weeks ago many of the world's leading prion researchers went to Miami to meet with the families of American victims of sporadic C.J.D. and to tell them everything that was known about prion diseases.

"It was a unique medical conference," said Cecile Sardo, secretary of the Creutzfeldt-Jakob Disease Foundation in Miami, which organized the meeting, held May 7 and 8. "When scientists get together they talk technically," she said. "They rarely talk in person to families."

Of the 125 people attending, half were family members and half were medical professionals. Dr. Stephen DeArmond, a pathologist at the University of California School of Medicine at San Francisco, explained that the normal prion protein was folded in a loopy pattern resembling corkscrews. But when it misfolds and acquires ribbon-like sheets, the prion becomes deadly. When a misfolded prion comes into contact with a healthy prion, he said, it can sometimes force the normal prion to change shape. The process continues, like a nuclear chain reaction, until the brain is destroyed.

It was recently proved beyond doubt that new variant C.J.D. was a human form of mad cow disease, said Dr. Robert Will, a neurologist and director of Britain's National C.J.D. Surveillance Unit in Edinburgh. This new disease could eventually kill tens of thousands of people in Britain or, given the many uncertainties about prion diseases and long incubation periods, it may eventually die out, he said.

Thus far 56 people in Britain, 2 in France and 1 from Ireland have died of new variant C.J.D. British health officials recently found a method that might assess the scope of the epidemic, Dr. Will said. Unlike the mis folded prions in sporadic C.J.D., which are found exclusively in brain tissue, new variant prions are found in the brain, tonsils, appendix, spleen and lymph nodes. Pathologists are examining 18,000 specimens from tonsil removed in the last two decades; 3,000 tonsils have been tested but the results have not been made public, Dr. Will said.

One of the biggest mysteries is why the new variant form of the disease attacks young people, Dr. Will said. The British victims were 13 to 53 years old, whereas sporadic C.J.D. affects much older people. Dr. Will said that one possible explanation was the widespread use of "mechanically extracted meat." After meat is removed from the carcass, he said, it is compressed with a machine not unlike an automobile crusher used in wrecking yards. Bone comes out one end and a meat-like goo at the other end.

This "meat" was once widely used in baby food and institutional school meals, Dr. Will said. It was fed to children all over the country, but the link between eating the food and getting the disease has not been proved.

No cases of new variant C.J.D. have been found in the United States, said Dr. Lawrence Schonberger of the Centers for Disease Control and Prevention. There have been a few instances of deaths of younger Americans from C.J.D., but tests of their brain tissue showed that they had sporadic forms of the disease, he said.

But according to Dr. Michael Hansen, a researcher at Consumers Union in Yonkers, deer and elk in several western states are experiencing a growing epidemic of a prion disease called chronic wasting disease.

In Larimer County, Colo., 15 percent of deer are infected, Dr. Hansen said. Some experts fear that many hunters and their families have almost certainly been exposed to the misfolded proteins from eating infected deer and elk meat, Dr. Hansen said. But it is not known if the deer version of the disease has been transmitted to humans.

Such transmission is possible, said Dr. Byron Caughey, a senior investigator at the Laboratory of Persistent Viral Diseases of the Rocky Mountain Laboratories in Hamilton, Mont. Results of experiments, to be published soon, show that the misfolded deer prion can, in a test tube, convert normal human, sheep and cattle prions into deadly prions. The rates are very low, he said, but conversions can occur.

At the end of the meeting, family members told researchers horror stories about how their loved ones had been told, wrongly, that they had Alzheimer's disease or got no satisfactory diagnoses at all. Many said that local pathologists, fearing prions, would not carry out brain biopsies and that some morticians had refused to embalm the bodies of C.J.D. victims.

Families are confused and angry, said Mel Steiger, an engineer from Salt Lake City, whose wife died of sporadic C.J.D. They want to know if there is an environmental factor, and, he said, they worry that officials in the United States are not doing enough to monitor the situation."

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May 22, 2000 • By Stephen J. Hedges • Chicago Tribune Staff Writer

Tissue imports pose hazards:  Deadly contamination found in shipments from abroad

The laboratory run by Dr. Alvero Duenas was not what it appeared to be. Each day the neonatal intensive care unit at the University of Valle Hospital in Cali, Colombia, received a call from Duenas' small non-profit agency, In Vitro, to see whether any babies had died prematurely.

Hospital workers said they thought Duenas, a retired university professor, was using the babies' kidneys for research. But after an assistant collected the kidneys, Duenas reduced some of them into a slurry of frozen cells and then shipped the vials to the U.S., where they were used to make Abbokinase, a $277 million-a-year anti-clotting drug sold by Abbott Laboratories of North Chicago.

Federal inspectors uncovered the kidney source in 1998 when they made a routine visit to BioWhittaker Inc., the Maryland company that took delivery of the cells from Duenas and sold them to Abbott. They halted the shipments after they found that kidneys were in mislabeled containers, that they weren't properly tested for disease, and that there was no proof the parents of the dead babies had given permission for the kidneys to be removed.

Abbott has stopped making Abbokinase, and BioWhittaker has suspended kidney shipments from Colombia. But the harvesting of dead infants' kidneys in Cali shows the wide reach and questionable practices associated with an expanding international supply of human body parts.

The body parts business in the U.S. has grown in the past decade from a small-time, community endeavor into a sophisticated medical industry, one that generates hundreds of millions of dollars in revenue each year. Increasingly, those businesses have turned to overseas markets, both as a source of body parts and as a market for exports.

Food and Drug Administration import records show heart valves and veins arriving from France and Canada, cartilage from Italy. Skin is shipped in from Denmark, South Africa and Japan. Heart arteries arrive from Russia. The tissue is used for research and transplants. Cells are used in the testing and manufacture of drugs. Exports of surplus bone donated to U.S. tissue banks are similarly brisk, according to tissue bank operators.

Like many aspects of the tissue industry, the import and export of human body parts, skin and corneas have been largely hidden from public view. The families that consent to tissue donation often think it will be used for transplants to help others in their community. There is no federal requirement that tissue banks disclose to families just what will happen to the tissue they collect. No federal agency watches over exports.

The FDA, which has been reluctant to aggressively regulate the domestic tissue market, has focused more attention on imports into the U.S., with some of its most notable actions coming in response to tainted tissue from overseas. Agency inspectors must approve all imports, and businesses bringing tissue into the U.S. must show it is disease-free and was given with the consent of the donor's next of kin.

The FDA relies largely on the veracity of the importer's documents, because it can't review donor records to check whether the tissue was properly screened and donated.

The dangers of the international trade in human body parts are demonstrated in a series of tragedies and mishaps involving tissue imports during the past decade. These episodes also shed light on a little-known and fast-expanding international business, one that is as much about making money as it is about helping people in need.

Karen Bissell first began to feel odd in June 1998. The back of her head hurt. Her vision would blur. Her legs and neck ached. Bissell was 39, an energetic woman who had played in the high school band, owned a motorcycle and served a stint in the Army. "She kept saying: 'I'll be OK, Mom. Don't worry, I'll get better,"' recalled Eleanor Bissell, Karen's mother. She never did.

Two months after she started feeling numb, Bissell was forced to leave her job as a finance administrator at the U.S. Department of Agriculture in Miami to return home to Denver. She alighted from the plane in a wheelchair, legally blind and very afraid. She died five weeks later.

The cause of death was Creutzfeldt-Jakob disease, which is similar to so-called mad cow disease. Because it may be borne in meat, any CJD-like death raises an alarm for health officials. As they delved into Bissell's medical history, those authorities fixated on a piece of brain-lining tissue transplanted into Bissell's neck six years earlier. The material, called dura mater, is the membrane that encases the brain and spinal cord. It is often transplanted to repair the breach neurosurgeons make in the patient's own dura mater to access the brain and neck.

In 1992, Bissell had an operation after she learned she suffered from an Arnold-Chiari malformation, a condition in which the head puts undue pressure on the spinal column. It is treatable, and doctors implanted a piece of donated dura mater to repair their incisions.

The dura mater, health officials say, came from Biodynamics International Inc. of Florida, which received it from its German partner, Pfrimmer-Viggo GmbH. Pfrimmer-Viggo had taken the tissue from the body of a German man who had suffered from a series of maladies, including brain disorders, officials say.

"He had all kinds of diseases," said Richard Hoffman, chief epidemiologist for the Colorado Department of Health and Environment. "He had heart disease [and] ... some kind of neurological disease. By any standards in the screening of donors, any patient with neurological diseases should be excluded."

Biodynamics, which has since changed its name to Tutogen Medical Inc., was cited after a 1990 FDA inspection for shortcomings in the screening of tissue donors by its German business partner. The FDA found that tissue from donors in newly independent Estonia, Lithuania and Russia was taken without family consent and was not properly checked for disease.

The FDA reported these manufacturing deficiencies to the company, but it took two years, until November 1992, for the agency to follow up with another inspection at Biodynamics in Germany. This time, the FDA concluded that "approximately 80 percent of all dura mater received and used has not been tested for conformance with serological specifications, i.e., hepatitis A, HIV."

The company says those problems were corrected long ago, and that its tissue was not the culprit in Karen Bissell's death. "We definitely have the deepest sympathy for the family," Tutogen President Manfred Krueger said. "But we strongly disagree with any conclusions that that woman was infected by any dura mater. She was born with a severe brain damage, and she was probably treated all her life on that brain disorder."

Bissell's family angrily disputes that. "That's not true at all," Eleanor Bissell said. "She had no brain damage. She was perfectly fine. When she was about 32, she started having numbness in her hands and feet." There were no complications afterward, she said, until the onset of CJD in the summer of 1998.

In 1999, Tutogen voluntarily issued a recall for all the dura mater it had distributed before 1994. It got back only four pieces. Company officials say they don't know how much had already been transplanted. There have been no other reports of adverse reactions to the transplanted dura mater, though health officials note that it can take 16 years for the disease to manifest itself.

Karen Bissell's relatives say they weren't told about the use of donated dura mater before Karen's surgery, the possible risks involved or the synthetic alternatives that are available. "It's the most horrible thing you can imagine going through," Eleanor Bissell said. "The hard part is knowing that it could have been prevented."

Imported dura mater had been associated with illness and fatalities before. More than 50 deaths worldwide have been linked to the late-1980s importation of a dura mater product called Lyodura, made in Germany. In February 1987, U.S. health authorities discovered that a 28-year-old Connecticut woman had developed CJD after getting a transplant of Lyodura.

Soon, other possible Lyodura-related cases of CJD were reported in Germany, Italy, Japan, New Zealand, Spain, Britain and the United States. As part of their investigation, officials with the U.S. Centers for Disease Control and Prevention in Atlanta found that manufacturer B Braun Melsungen AG was taking all of its donated dura mater and processing it together.

"They put it in a bucket, a huge bucket," said Dr. Ermias D. Belay of the CDC's division of viral and rickettsial diseases, who has investigated both the Lyodura and Tutogen cases. "They processed it together as a batch. All you need is one infected piece and it can infect all the other pieces."

B Braun Melsungen changed its processing method. But 57 people who received Lyodura grafts from the older tissue died from CJD, including the Connecticut woman and one other U.S. resident, according to the CDC. Most of the deaths occurred in Japan.

The CDC concluded that "an international outbreak of CJD associated with a single brand of dura mater graft is larger than previously recognized and that recipients of contaminated grafts may remain at risk for CJD for at least 16 years following receipt of grafts."

In the U.S., the dura mater problems were left largely to the CDC to investigate. Last October, a year after Karen Bissell's death, the FDA issued new dura mater guidelines. They call for businesses selling dura mater to keep detailed records of the donor's medical history and brain autopsy, and they provide special instructions for processing dura mater, including how to sterilize it. The guidelines, which apply to domestic and imported dura mater, don't have the same power as a federal regulation, making it harder for the FDA to enforce them.

In 1992, the Sklifosovsky Research Institute in Moscow became the source of a human body parts pipeline that delivered more than 5,600 pieces of tissue from 228 Russian cadavers to tissue banks and hospitals throughout the U.S. When a U.S. tissue bank executive expressed concerns about the safety of that tissue, FDA officials opened an investigation. What they found astonished them.

FDA case files reviewed by the Tribune offer a glimpse at just how lucrative, and potentially disastrous, the Russian tissue trade was. The pipeline flowed from the office of Dr. Valery Khvatov at Sklifosovsky, according to FDA investigators. In 1992, Khvatov arranged for a friend in Los Angeles, a dentist, to become his U.S. import agent, FDA records show.

Khvatov, according to tissue receipts, was charging $5,000 for each shipment of bones and tendons from the hips, knees, legs and feet. In an interview, Khvatov denied personally benefiting from the tissue trade. "It's a fairy tale," he said. "If I were taking cash, my own side would put me to jail." The institute, however, was receiving fees for shipping, he said.

Once the tissue was in the U.S., tissue banks would take the bones and charge $5,000 to $10,000 for different parts of the processed tissueÆup to $30,000, or six times Khvatov's wholesale price, for all of the tissue, according to FDA investigative summaries.

Records show that most of the tissue went to Allotech of El Paso, Texas. It distributed 3,000 pieces of tissue, according to an FDA investigative report. Two San Antonio businesses, Transplant Technologies Inc. and International Tissue Services, bought bone from Allotech, FDA records show. From those outlets, the Russian tissue was shipped to hospitals and tissue banks in 30 states, Puerto Rico and Mexico, FDA records show.

Khvatov also worked with a company called Flark Medical in Miami Beach, brought in more tissue and sold it to a tissue bank in San Diego, FDA records show. When FDA investigators researched the company in early 1994, they reported Flark's estimated annual income was $240,000 from the tissue business. Khvatov and his U.S. liaisons assured tissue banks that the cadavers were tested for diseases. But the FDA, with the help of the Pennsylvania Regional Tissue Bank, bought some of the Russian bones and found them to be contaminated.

"The samples were tested and found to be remarkably hepatitis positive," said David Kessler, who was FDA commissioner at the time and is now dean of Yale University Medical School. "We were getting the medical records, but they were all forgeries."

Those medical records often were incomplete, investigators found, and they were always in Russian. Few tissue banks in the U.S. bothered to have them translated. What's more, records showed that families of the deceased Russians were never asked for permission to take their bones.

Russian officials told the FDA that tissue can be taken from bodies there without permission. That meant no relatives were asked whether the deceased donor had used drugs, had contracted diseases such as AIDS or had engaged in "high-risk" behavior. Such questions are routinely asked of donor families in the U.S.

In late 1993, the FDA ordered a recall of all the Russian tissue, saying the tissue banks "lacked documentation about the donors' relevant medical history relative to ... hepatitis B, hepatitis C, or human immunodeficiency virus [HIV] infection." The tissue banks recovered about 90 percent of the Russian bone during the recall, FDA officials say. That still left 500 pieces of bone in circulation, and almost 100 were used in transplants, the FDA determined. There is no evidence to date that anyone has become ill from a Russian bone transplant.

The Russian case spurred the FDA's most forceful effort to regulate tissue. Kessler issued an emergency rule in 1993 that required U.S. tissue banks to screen all domestic donors and to give each donor a distinct number that would allow the agency to track the tissue. Importers also were required to get an FDA inspector's approval for each shipment based on paperwork showing that the tissue had been tested and is disease-free. In 1998, these became formal regulations.

The FDA took no legal action against those involved in the Russian imports, other than ordering recalls and issuing warning letters. FDA regulations, however, don't require doctors to tell patients about recalls. Some within the FDA wanted to pursue criminal charges, but that had never been done before. The Justice Department was reluctant to build a case, and the FDA at that time had few laws and regulations on tissue to cite for criminal charges.

The paperwork that accompanies imports isn't always a guarantee that the goods are safe. Imported cells like the ones produced in Cali by Dr. Duenas don't fall under the tissue regulations, but the FDA standards for testing are similar.

Since the early 1990s, Duenas had been shipping kidneys from Cali, each with documents purporting to show that all the FDA's procedures had been followed. Only in 1998 did FDA inspectors determine that the forms didn't fully explain how the kidneys had been screened for disease, just who gave the consent for the donation and what had caused the death of each infant.

Duenas, in an interview, said he formed In Vitro in 1990 and ran it from the university. BioWhittaker, he said, provided him with two machines to store the cells, as well as disease-testing kits and $70,000 a year, of which $48,000 was used to pay two employees.

Dead babies weighing 1 to 3.3 pounds yield the most useable kidney cells, he said. A tissue sample from one baby could fill anywhere from eight to 20 pinkie-size containers of kidney cells. Shipments of about 100 such containers were made to BioWhittaker two to five times a year, he said.

Duenas said he was gathering kidneys for his own research, and sending the leftover cells to BioWhittaker. "Do we throw the remaining cells in the sink?" he asked. "We get so many we can't use them all."

Duenas said he did not tell his colleagues he was shipping cells to BioWhittaker because "The culture is not right." Anti-American sentiment is strong in Colombia, he said, and word of his exports could have put him at risk.

Abbott ceased production of Abbokinase after the FDA questioned the safety of the Cali cells used in the drugs. BioWhittaker declined to discuss the Cali imports. But the company and Abbott have argued in letters to the FDA that the cell collection was done properly and was safe.

"Informed consent in Spanish was obtained prior to cell donation," said Rhonda Luniak, Abbott spokeswoman. "The medical information about the donor's mother was recorded, and extensive screening and testing was done."

A visit by a Tribune reporter to Duenas' lab and the sites where he collected the neonatal kidneys, however, raises questions about what was happening in Cali. University of Valle hospital workers say parental consent was not sought. Several parents, they said, had even complained about the two incisions in their babies' backs when they picked up the bodies for burial.

"We don't ask if they'll let us take a sample," said Maria Eugenia Rojas, a university hospital social worker. "But if they ask us for the cadaver immediately or if they ask us not to sample, we respect that" and don't take the kidneys. After the FDA halted the kidney imports, activity at Duenas' lab fell off and eventually stopped, hospital workers say.

As for Abbott, Luniak said it has "terminated our procurement of cells from outside the United States, and we are committed to finding a domestic source." If that source is found, she said, Abbokinase may return to the market by the end of 2001.

The export of tissue is scrutinized less than importation, and donor families in the U.S. usually have no idea that part of their loved ones may be going overseas.

U.S. doctors, for instance, prefer not to use the bones and bone powder of some elderly donors, but the same items are in demand in some foreign countries. And so, trying to increase revenue, some tissue banks seek elderly donors for tissue export. But donor records and interviews with families who donated a deceased relative's tissue reveal that tissue banks often don't inform families that parts of their loved one's body could end up in another country.

"My husband was not [registered as] an organ donor, and I did it against his wishes," said Linda Johnson of Orange, Calif., whose husband, Dennis, died five years ago. "And now I know I'm getting my comeuppance. "I did the moral thing to help other people, and then to find out they sent it to Europe."

Dennis Johnson's case was indeed just one of dozens in which tissue banks channeled the bones and tendons they harvested to Biodynamics International, which shipped them to its German plant for processing, and then sent them back to the U.S. for sale to hospitals, doctors and other outlets.

When told of the overseas trade, most donor family members interviewed by the Tribune were distressed.

Dorothy Newberry of Ocala, Fla., was among them. She agreed to donate her husband Arthur's tissue when he died in 1994. The University of Florida Tissue Bank representative called and told her that the tissue "could be used to do research to help other people, possibly save someone's life," she recalled. Newberry gave her consent. "I was so upset at that point, it was more, 'OK, let's go, because we've got to get to the funeral parlor. ...' There was just so much, it was a little overwhelming."

The tissue went to Germany and back without her knowledge. "They never said it was going to leave the country," she said. "The part that is troubling is if they're just making a profit for their own benefit. I mean, charity begins at home."