tagged w/ National Institutes of Health
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What if the Surgeon General were to declare “stupidity” a disease and the National Institutes of Health were to declare a National Emergency and manpower and money were utilized to eliminate stupidity from the human condition? That would be cool!
Years ago, as a young city hall reporter in my hometown of Clinton, Iowa, at the end of a contentious debate over whether or not Clinton would remain the largest city in the state without even a basic building code (it would), one of my favorite council members gave me a quote that I will never forget. As the building code ordinance was defeated yet again, the councilman leaned over to the press table and sighed these words.
“If only stupidity were painful…”
http://deepbrainmedia.com/2012/02/09/lets-declare-a-national-war-on-stupidity-treat-it-as-a-disease-2/What if the Surgeon General were to declare “stupidity” a disease and the... more
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PCRM | PHYSICIANS COMMITTEE FOR RESPONSIBLE MEDICINE...
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Government Announces Plan to Replace Animals in Toxicity Testing
December 20, 2011
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The Environmental Protection Agency, the National Institutes of Health, and the Food and Drug Administration just announced a joint effort to use high-throughput robotics—instead of animals—to test 10,000 chemicals and drugs for potential toxicity. I’ve asked PCRM’s Chad Sandusky, Ph.D., to provide details:
Current testing is largely based on experiments on animals—rodents, rabbits, dogs—and uses methods that are cruel, time-consuming, expensive, and in some cases use thousands of animals in a single test. For example, a reproductive toxicity study uses 2,600 animals and requires a minimum of two years at a cost of $380,000. PCRM toxicologists and government affairs staff have pushed government and industry scientists to implement nonanimal methods.
The new method was developed after the National Research Council issued a mandate (often referred to as Tox21) several years ago to replace antiquated animal-based (in vivo) toxicity testing with testing using mostly human cells and tissues. At PCRM’s toxicology department, we are convinced this will offer not only a dramatic reduction in animal use, but also a faster and cheaper approach to safety testing.
While Congress has been drafting revisions to the law that regulates chemicals (known as the Toxic Substances Control Act or TSCA), we’ve met with congressional offices to make sure that new nonanimal methods are required as they become more widely available. We’ve successfully gained support for these important changes, so animal testing will be greatly reduced—and eventually eliminated—when the bill is passed.
To learn more about how replacing animals in toxicity testing with this technology will make the world a safer place for people—and for the millions of animals now used in these cruel tests—visit www.ReformToxicityTesting.org
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PCRM | PHYSICIANS COMMITTEE FOR RESPONSIBLE MEDICINE...
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Government... more
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After the public learned last winter that the National Institutes of Health was transferring old chimpanzees back into traumatic bioinvasive research, the NIH delayed the transfers. They said they would ask for recommendations from a special panel of experts. But months before that panel was scheduled to issue their report, NIH quietly demonstrated its contempt for animal welfare advocates. In September, NIH agreed to a $19 million grant program to put the chimps back on the laboratory slab.
The panel's recommendations will be issued Dec 15, at 11:00 am. But NIH has already made up its mind and approved the transfer.After the public learned last winter that the National Institutes of Health was... more
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The growing culprit behind liver disease
By Elizabeth Cohen, CNN Senior Medical Producer
June 17, 2011 6:22 a.m. EDT
Photo: Wilson Alvarado rests at the Cleveland Clinic with his wife, Patricia, by his side. He recently had a liver transplant.
STORY HIGHLIGHTS
Doctors say being either overweight or obese can lead to liver disease
About a third of the U.S. population has nonalcoholic fatty liver disease, doctor says
But most of those won't develop significant liver disease
Symptoms often don't show up until the disease has progressed, experts say
(CNN) -- The first time Wilson Alvarado got lost on the way to a neighborhood park, he told his wife, Patricia, not to worry about it -- he was 62, he told her, and just getting a little forgetful.
Patricia thought it was strange, considering the park was only a half-mile away, and he'd driven there every week for more than 30 years. Then Wilson got lost again on the way to the park. A few months later, he called Patricia from the supermarket, asking why he was there.
"I thought, well, maybe he really is just getting old," Patricia recalls. "My mother has Alzheimer's, and I thought maybe that was it."
It was easy to overlook the little memory lapses until several years later when the situation reached a head. While her husband was visiting relatives in Puerto Rico, Patricia received a phone call from his cousin saying they'd taken Wilson to the hospital because he "wasn't making any sense" and was acting so aggressive the hospital put him in restraints.
"It was really horrifying," she says.
Patricia had him put back on a plane to Buffalo, near their home in Cheektowaga, New York. His doctors explained that liver disease was behind Wilson's memory lapses and erratic behavior.
"When you think about this kind of thing, you think about dementia or Alzheimer's," she says. "You don't think about the liver."
Wilson had cirrhosis, just like alcoholics get, but in his case, fat, not alcohol, was the culprit. At 5 feet 8 inches and 185 pounds, Wilson is overweight, and too much fat in his liver eventually caused it to malfunction.
According to the Centers for Disease Control and Prevention, two-thirds of Americans are either overweight or obese, and doctors say they're seeing more and more patients like Wilson Alvarado.
"It's overwhelming how many patients we're seeing with this problem," says Dr. Naim Alkhouri, a hepatologist at the Cleveland Clinic.
Dr. William Carey, also a hepatologist at the Cleveland Clinic, adds, "This is huge. We didn't even know this disease existed 30 years ago. Now it's the most common liver disease in America."
'We won't have the ability to treat all these patients'
About a third of the U.S. population has nonalcoholic fatty liver disease, according to Dr. Michael Curry, a hepatologist at the Beth Israel Deaconess Medical Center in Boston.
Curry said most of those people -- about 80% -- will not develop significant liver disease. The other 20% will develop a disease called nonalcoholic steatohepatitis, or NASH. Of those, about 20-30% will go on to develop cirrhosis and end-stage liver disease, where the only real treatment is a liver transplant.
"That's about 6 million people. We won't have the ability to treat all those patients," Curry says. "If we even have a fraction of that number of patients, it will overwhelm liver transplant programs."
NASH is often silent, according to the National Institutes of Health. While some people have pain in the right side of their abdomen, most do not. Liver enzyme tests are sometimes normal, and even ultrasounds and CT scans don't always pick up on the disease.
"Symptoms are few and far between," the Cleveland Clinic's Carey says.
"It can sneak up on you," says Dr. Kevin Mullen, a hepatologist at the Case Western Reserve University School of Medicine. "Even your doctor might miss it."
Often symptoms don't show up until the disease has progressed. Sometimes, the first sign is a swollen stomach or ankles, or vomiting blood.
Some patients, such as Wilson Alvarado, develop brain changes called hepatic encephalopathy. As the disease progresses, the liver has a hard time filtering out toxins, which can go to the brain and cause problems such as memory lapses, trouble sleeping at night and lack of coordination.
"It might start out with minimal changes, like a few more dents in the car," Curry says.
Later, the changes can become more disturbing.
"I had a patient who put his laundry in the refrigerator," Carey says. "Another one couldn't remember the family party that had just happened that very day."
Curry adds, "One of my patients got into the shower and turned on boiling hot water and couldn't figure out how to switch it off."
Mullen says, "It really can be bizarre. They might try to sell their house for $100 or walking around the neighborhood unclothed."
Preventing nonalcoholic fatty liver disease
If a patient loses weight, eats better and exercises, he or she can often reverse the disease in its earlier stages.
"That's why we like to find these people early," says Alkhouri of the Cleveland Clinic.
However, by the time the disease has advanced to the point of cirrhosis, it's usually irreversible, he adds.
Alvarado had to have a liver transplant last month at the Cleveland Clinic, and his wife says his thinking has become more clear.
CNN's Linda Saether contributed to this report.
http://i.cdn.turner.com/cnn/2011/HEALTH/06/16/liver.disease.ep/t1larg.cleveland.clinic.jpgThe growing culprit behind liver disease
By Elizabeth Cohen, CNN Senior Medical... more
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January 21st, 2011
07:08 PM ET
Mastectomy for a preschooler
Aleisha Hunter is not your average 4-year-old. In fact, she's the youngest breast cancer survivor in Canada.
Not exactly the news her mother Melanie was expecting when she noticed a small lump in her daughter's right breast while bathing her when she was 2. Finally after trying to figure out what was causing Aleisha so much pain, at the age of 3, doctors diagnosed juvenile breast carcinoma, a very rare form of cancer.
"Certainly breast cancer has been reported in children and in adolescents, but it's very rare in prepubrescent girls," says Dr. Thomas Olson, medical director of the Aflac Cancer Center and Blood Disorders Service in Atlanta. Fewer than 5 percent of invasive breast cancers occur in women under age 40, according to The National Institute for Health. About 12.2 percent of women born today will get a breast cancer diagnosis at some time in their lives, according to The National Cancer Institute.
"There are many adult woman who have been tested and know that they carry a breast cancer gene mutation. I think it's important for them to realize that there is no evidence to support the risk of breast cancer in childhood for their daughters," says Dr. Sharon Plon, chief of Texas Children's Cancer Center Genetics Clinic.
Aleisha's physician, Dr. Nancy Down the deputy chief of surgery at North York General Hospital, decided on a radical double mastectomy for the 3- year-old because the tumor had grown quite large she told NBC. She didn't treat Aleisha with chemotherapy or radiation. "Whenever you have a rare case you go with a logical treatment. First you know you need surgery. The question is whether chemotherapy will add to that therapy, but you probably should not give chemotherapy unless you really think it will help," says Olson a pediatric oncologist.
Downs told NBC the advantage to this rare type of cancer it's slow growing, it doesn't spread as aggressively as other types and the prognosis is usually very good. She says Aleisha will have to get reconstructive surgery on her breast once she hits puberty. "If parents are suspicious of something unusual...you have to be your child's best advocate and it's important to follow-up if you are concerned about something in your child that you haven't seen resolved," says Plon.
In November Aleisha was honored as the 2010 Ambassador for Random Act of Kindness (RAK) Day in Cambridge and North Dumfries in Canada where she is from. The day encourages people to "pay it forward" and pay tribute to those who do kindnesses on that day and all yearlong.
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http://www.thesurvivorsclub.org/news-and-articles/aleisha-hunter-survives-breast-cancer-diagnosed-at-age-2-800344612January 21st, 2011
07:08 PM ET
Mastectomy for a preschooler
Aleisha Hunter is... more
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Advanced Cell Technology said on Monday it had won U.S. Food and Drug Administration approval to try out human embryonic stem cells for treating macular degeneration, a common cause of vision loss.
http://www.indiareport.com/India-usa-uk-news/reuters/Health/75415Advanced Cell Technology said on Monday it had won U.S. Food and Drug Administration... more
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Too much milk?
Studies abound, but there's no clear conclusion as to whether milk is good or bad for us.
By Chris Woolston
Los Angeles Times
July 12, 2010
PART ONE…
Few things in life look as pure and simple as a glass of milk. The ingredient list on the carton is refreshingly short too. All it says is "milk," perhaps along with some added vitamin A and vitamin D. No preservatives, no artificial colors, no high-fructose anything. Just milk.
But like many things that appear simple from the outside, there's a lot going on beneath milk's surface. That glass is swirling with natural cow hormones, which isn't surprising considering the source. Milk contains sugars found nowhere else in nature, and it offers a particular blend of nutrients — including protein, calcium, magnesium and potassium — that you can't get anywhere else.
Yet, almost 8,000 years after nomadic herders realized they could tug at the udders of slow-moving livestock, we still aren't sure how much of the stuff we should be drinking. The USDA recommends three cups of dairy a day for all adults, but the science behind milk hasn't been settled. "This is one of the most complicated and interesting areas of nutrition," says Dr. Walter Willett, chairman of nutrition at the Harvard School of Public Health, "and we don't have all of the answers."
Many high-profile nutritionists — often working with large research grants from the dairy industry — say that milk in great quantities is an essential part of the daily diet that can help prevent osteoporosis, heart disease, cancer and other illnesses. "Anything less than three glasses a day, and you won't get all of the nutrients that you need," says Connie Weaver, head of food and nutrition at Purdue University in West Lafayette, Ind. Most of Weaver's funding comes from the National Institutes of Health, but she's also supported by the National Dairy Council.
On the other side, groups promoting animal rights and veganism — including PETA and the Physicians Committee for Responsible Medicine — say that cow's milk is a nutritional nightmare that doesn't belong in the human diet. "It's gross," says Dr. Neil Barnard, author and founder of the PCRM. "Milk is nutritionally perfect for one purpose: feeding a calf," he says. "The idea that we should be drinking milk from a cow is just bizarre."
Willett, one of the world's most prominent nutrition experts, doesn't belong to either camp. From his viewpoint, one or two cups of milk each day is a safe, reasonable and nutritious goal. "But beyond that," he says, "the benefits are unclear, and there may be some risk."
One or two cups? That's not as much as the USDA recommends but more than many milk critics could possibly stomach.
Of the foods that have their own tier on the pyramid, dairy products catch a lot of grief. A PETA website says that "dairy products are a health hazard" that are linked to "allergies, constipation, obesity, heart disease, cancer and other disease." For a topper, the site says that milk is often contaminated with cow's blood and pus.
The Physicians Committee for Responsible Medicine has always singled out milk as a particularly dangerous part of the typical western diet. The PCRM website says that saturated fats in dairy products increase the risk of heart disease. It also says that the natural hormones in milk encourage cancer of the breast, prostate and ovaries. Turning popular wisdom on its head, the organization says that dairy products won't help prevent osteoporosis, the bone-thinning disease. The website highlights the Nurses Health Study, a 12-year examination of more than 77,000 women published in 1997 that found no link between reported dairy intake and the incidence of broken bones.
CONTINUED…Too much milk?
Studies abound, but there's no clear conclusion as to whether... more
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* By Sherwood Ross *
The priorities of the National Institutes of Health(NIH) in the area of bacteriology have been “catastrophically re-ordered” by emphasizing bioweapons research over non-bioweapons research, a prominent authority states.
Giving priority to bioweapons research at NIH, started under the Bush Administration and continuing under President Obama, “diverts resources from critical public-health and scientific objectives,” says Richard Ebright, Professor of Chemistry and Chemical Biology at Rutgers University, New Brunswick, N.J.
“The negative impact has been most severe in bacteriology, in which NIH research priorities have been catastrophically re-ordered—with research on bacterial bioweapons receiving more support than research on the top five bacterial causes of death combined—and in which non-bioweapons research has suffered catastrophic losses in resources and personnel,” Ebright said.
Ebright cited the examples of research into two bacterial pathogens: “Streptococcus pneumoniae and Staphylococcus aureus, which claim 40,000 and 20,000 U.S. lives each year, respectively. Each kills more Americans than HIV-AIDS (15,000 U.S. lives) “but neither of these bacterial pathogens is on the list of NIAID Priority Pathogens,” Ebright pointed out. (NIAID, the National Institute of Allergy and Infectious Diseases, is the subdivision of NIH responsible for infectious-disease research.)
“These two killer bacterial pathogens are not in NIAID’s ‘Category A’, with the anthrax bacterium and the smallpox virus, or even in NIAID’s ‘Category B’ or ‘Category C,’” Ebright says. “Something is wrong—very wrong—when NIAID fails to prioritize the top infectious cause of U.S. death,” he said in an email to this reporter.
Other top bacterial causes of U.S. deaths include Enterococcus faecium/faecalis, Clostridium difficile, Pseudomonas aeruginosa, and Mycobacterium tuberculosis. “Of these, only the last is on the NIAID Priority Pathogens list and this pathogen is only in Category C,” Ebright said.
Asked “What is the mood of the scientific life sciences community at this time toward the Administration?” Ebright responded, “Hopeful expectation” but “growing concern that, thus far, there has been more continuity [from the Bush Administration] than change.”
The scope of the government’s involvement in bioweapons research, may be gauged from its estimated expenditure of $70 billion since 9/11 and the fact that, according to Ebright, more than 400 U.S. institutions are engaged in such work.
Francis Boyle, professor of international law at the University of Illinois, Champaign, said that in constant dollars the $70 billion “is twice what they spent on the Manhattan Project to develop the A-bomb—ergo, this is a weapons program.”
Boyle, who drafted the Biological Weapons Anti-Terrorism Act of 1989 for the U.S., said President Bush “turned the NIH into a front organization for biowarfare work,” and “(President) Obama is simply continuing the Bush policies” and is “now even exporting biowarfare capabilities to Third World Countries.”
Asked about the scope of the nation’s biowarfare activities, Boyle estimated there are “about 13,000 death scientists involved…(so) Dr. (Josef) Mengele has arrived on American campuses all over and the universities’ Institutional Review Boards (to review biowarfare research programs) are a joke and a fraud, too.” (Mengele was a German SS officer and physician who, during WWII, performed diabolical experiments on prisoners at the Auschwitz-Birkenau concentration camp in Poland.)
Boyle said, “There is so much money involved that universities simply are not going to turn down these proposals no matter how reprehensible they might read…”
At his own University of Illinois, Boyle said, previous biowarfare research and development contracts with the Pentagon clearly stated: “We have selected pigs (to gas with biowarfare agents) because they have a circulatory system and a respiratory system similar to human beings.”
Boyle said, “I am sure similar type biowarfare contracts that are clearly anti-human, anti-ethical, illegal and criminal on their face alone have been approved all over (at) American universities by now. Money talks. Ethics walks.”* By Sherwood Ross *
The priorities of the National Institutes of Health(NIH) in... more
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"Quorum sensing is a cell-to-cell communication mechanism that enables bacteria to sense and respond to changes in the density of the bacteria in a given environment," said Anand Pai, graduate student in bioengineering at Duke's Pratt School of Engineering. "It regulates a wide variety of biological functions such as bioluminescence, virulence, nutrient foraging and cellular suicide.""Quorum sensing is a cell-to-cell communication mechanism that enables bacteria... more
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Posted: August 5, 2009.
By
Sam Harris
[Author’s Note: My recent op-ed in the New York Times, in which I questioned the appointment of Francis Collins as head of the NIH, inspired a fair amount of discussion in the media and on the Internet. As many of Collins’ defenders do not seem to be fully acquainted with his beliefs, or take it for granted that others won’t be, I have written a longer essay on the subject. While most of this material is new, a few passages were previously published.]
It is widely claimed that there can be no conflict, in principle, between science and religion because many scientists are themselves “religious,” and some even believe in the God of Abraham and in the truth of ancient miracles. Even religious extremists value some of the products of science—antibiotics, computers, bombs, etc.—and these seeds of inquisitiveness, we are told, can be patiently nurtured in a way that offers no insult to religious faith.
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Where do you stand with Francis Collins at the NIH?Posted: August 5, 2009.
By
Sam Harris
[Author’s Note: My recent op-ed in... more
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Francis Collins may be a great scientist, but he is not qualified to speak for the National Institutes of Health (NIH). Collins rejects any scientific understanding of the most fundamental questions of what it is to be human, questions concerning the foundations of human nature. Collins publicly and officially claims any scientific understanding of human nature is impossible. Such a claim is simply unacceptable for the head of the NIH.
(more at link)Francis Collins may be a great scientist, but he is not qualified to speak for the... more
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Sam Harris is raising questions about the ability of Francis Collins to lead the National Institutes of Health. In an Op-Ed piece for the New York Times, Harris, noted intellectual, celebrity author and founder of the Reason Project, argues that Collins rejects a scientific understanding of human nature.
Collins, a physical chemist, a medical geneticist and the former head of the Human Genome Project, is, without question, a brilliant scientist. Harris does not question his accomplishments or his credentials. Indeed, the argument against Collins is not about credentials, but about philosophy. Harris simply questions the wisdom of entrusting "the future of biomedical research in the United States to a man who sincerely believes that a scientific understanding of human nature is impossible".
Why is an understanding of human nature impossible for Collins? The answer, in a word: "God".
(more at link)Sam Harris is raising questions about the ability of Francis Collins to lead the... more
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By SAM HARRIS
Published: July 26, 2009
PRESIDENT OBAMA has nominated Francis Collins to be the next director of the National Institutes of Health. It would seem a brilliant choice. Dr. Collins’s credentials are impeccable: he is a physical chemist, a medical geneticist and the former head of the Human Genome Project. He is also, by his own account, living proof that there is no conflict between science and religion. In 2006, he published “The Language of God,” in which he claimed to demonstrate “a consistent and profoundly satisfying harmony” between 21st-century science and evangelical Christianity.
Dr. Collins is regularly praised by secular scientists for what he is not: he is not a “young earth creationist,” nor is he a proponent of “intelligent design.” Given the state of the evidence for evolution, these are both very good things for a scientist not to be.
But as director of the institutes, Dr. Collins will have more responsibility for biomedical and health-related research than any person on earth, controlling an annual budget of more than $30 billion. He will also be one of the foremost representatives of science in the United States. For this reason, it is important that we understand Dr. Collins and his faith as they relate to scientific inquiry.
What follows are a series of slides, presented in order, from a lecture on science and belief that Dr. Collins gave at the University of California, Berkeley, in 2008:
Slide 1: “Almighty God, who is not limited in space or time, created a universe 13.7 billion years ago with its parameters precisely tuned to allow the development of complexity over long periods of time.”
Slide 2: “God’s plan included the mechanism of evolution to create the marvelous diversity of living things on our planet. Most especially, that creative plan included human beings.”
Slide 3: “After evolution had prepared a sufficiently advanced ‘house’ (the human brain), God gifted humanity with the knowledge of good and evil (the moral law), with free will, and with an immortal soul.”
Slide 4: “We humans used our free will to break the moral law, leading to our estrangement from God. For Christians, Jesus is the solution to that estrangement.”
Slide 5: “If the moral law is just a side effect of evolution, then there is no such thing as good or evil. It’s all an illusion. We’ve been hoodwinked. Are any of us, especially the strong atheists, really prepared to live our lives within that worldview?”
Why should Dr. Collins’s beliefs be of concern?
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(more at link)
____________________________________________________By SAM HARRIS
Published: July 26, 2009
PRESIDENT OBAMA has nominated Francis... more
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The National Institutes of Health recently received as its director a confessed evangelical Christian, Dr. Francis S. Collins, an appointment leading some to question whether or not Collins will be scientific and objective in his management and decisions.
(more at link)
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Is it possible to be an evangelical Christianity and maintain scientific objectivity?The National Institutes of Health recently received as its director a confessed... more
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A National Academies report released Friday concludes that researchers have no need to deal with “random source” dealers of laboratory dogs.
Random source, or class B dealers are those that procure and sell dogs and cats from the general animal population to laboratories, rounding up dogs and cats from animal shelters, auctions, private individuals and other “random sources.” Class A dealers are those that sell animals bred for a life in the laboratory.
The report comes in response to a request by Congress through the National Institutes of Health for an evaluation of the need to use random source dogs and cats in NIH-funded research.
The report states that “despite new enforcement guidelines and intensified inspection efforts, not all origins of (Class B) animals are or can be traced. The USDA simply cannot assure that stolen or lost pets will not enter research laboratories via the Class B dealer system.” The U.S. Department of Agriculture licenses Class B dealers.
The findings in the report — mostly praised by both the Humane Society of the United States (HSUS) and the American Anti-Vivisection Society (AAVS) — could provide momentum in Congress to eliminate Class B dealers, whose numbers have been rapidly shrinking.
According to the report, 20 percent of cats and dogs used in research were obtained from Class B dealers in 2002; by 2008, only 3 percent were.
One of the alternative sources suggested in the report — which stopped short of ruling out the use of random source animals entirely – is for researchers to buy animals directly from pounds and shelters.
“AAVS is extremely disappointed, however, that the Committee fell short of recommending entirely against the use of random source animals, including former pets, in NIH research. The Committee suggests that if the use of random source animals is deemed necessary, one option is that NIH research laboratories actually go directly to animal pounds and shelters to acquire cats and dogs for experiments.
The AAVS says that approach, known as pound seizure, could led to problems, with laboratories focusing on poor and overcrowded shelters, and shelters that cooperated losing public trust.
“A shelter (or) pound that releases animals directly to research facilities will lose the public’s trust, and this could decrease the number of animals brought to the shelter … and increase the number of abandoned animals,” the AAVS said. “AAVS encourages Congress to eliminate Class B dealers and to address the public’s concerns about former pets ending up in research by prohibiting the provision of random source animals for research.”
The report failed to consider other means of scientific study that do not involve the invasive or harmful use of cats and dogs, AAVS said — even though such alternative methods are receiving increasing attention.
AAVS’s educational division, Animalearn ( http://www.animalearn.org/home.php) recently released a report, Dying to Learn: Exposing the supply and use of dogs and cats in higher education. To view and download the report, visit http://www.dyingtolearn.org/.A National Academies report released Friday concludes that researchers have no need to... more
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Scientists at Dana-Farber Cancer Institute have identified a previously undetected trigger point on a naturally occurring "death protein" that helps the body get rid of unwanted or diseased cells. They say it may be possible to exploit the newly found trigger as a target for designer drugs that would treat cancer by forcing malignant cells to commit suicide.
Loren Walensky, MD, PhD, pediatric oncologist and chemical biologist at Dana-Farber and Children's Hospital Boston, and colleagues report in the Oct. 23 issue of the journal Nature that they directly activated this trigger on the "executioner" protein BAX, killing laboratory cells by setting in motion their self-destruct mechanism.
The researchers fashioned a peptide (a protein subunit) that precisely matched the shape of the newly found trigger site on the killer protein, which lies dormant in the cell's interior until activated by cellular stress. When the peptide docked into the binding site, BAX was spurred into assassin mode. The activated BAX proteins flocked to the cell's power plants, the mitochondria, where they poked holes in the mitochondria's membranes, killing the cells. This process is called apoptosis, or programmed cell death.
"We identified a switch that turns BAX on, and we believe this discovery can be used to develop drugs that turn on or turn off cell death in human disease by targeting BAX," said Walensky, who is also an assistant professor of pediatrics at Harvard Medical School.
BAX is one of about two dozen proteins known collectively as the BCL-2 family. The proteins interact in various combinations leading to either the survival of a cell or its programmed self-destruction. Cancer cells have an imbalance of BCL-2 family signals that drives them to survive instead of dying on command.
The late Stanley Korsmeyer, MD, an apoptosis research pioneer and Walensky's Dana-Farber mentor, had suggested that killer proteins like BAX could be activated directly by "death domains," termed BH3, contained within a subset of BCL-2 family proteins. He hypothesized that this activating interaction was a fleeting "hit-and-run" event, making it especially challenging for scientists to study the phenomenon.
As suspected, the proposed BAX-activating interactions could not be captured by traditional methods. "When you tried to measure binding of the BH3 subunits to BAX, you couldn't detect the interaction," explained Walensky. He recognized, however, that the BH3 peptides being used in the laboratory didn't retain the coiled shape of the natural BH3 domains that participate in BCL-2 family protein interactions. Walensky and his colleagues pioneered the design of "stapled" BH3 peptides, which contain a chemical crosslink that locks the peptides into their natural coiled shape. With biologically active shape restored, the stapled BH3 peptides bound directly to BAX and triggered its killer activity.
Defining how the activating peptides docked on BAX remained a formidable catch-22. In order to solve the structure of an interaction complex, it needed to be stable enough for analysis. In this case, the BH3 binding event itself triggers BAX to change its shape and self-associate to perform its killer function, rendering the activating interaction unstable by definition.
What if, Walensky proposed, you could set up the interaction of BH3 and BAX under laboratory conditions that caused it to be more stable or proceed in slow motion? The plan was to adjust the potency of the stapled BH3 peptide so that, according to Walensky, "it was good enough to bind BAX, yet activate it just a bit more slowly so that we could actually study the interaction." The researchers would then look for any detectable shift in the three-dimensional structure of the BAX protein to help point them to the docking site.
Scientists at Dana-Farber Cancer Institute have identified a previously undetected... more
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