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Uncovering BRCA1's Mode of Action

"Get wisdom: and with all thy getting get understanding."

-- Proverbs 4:7

Three years ago, researchers identified the BRCA1 gene on chromosome 17. Inherited mutations to BRCA1 were linked to dramatically elevated risks of breast and ovarian cancers in women. The connection between the flawed gene and disease, however, was made through the statistical association techniques of gene mapping and not through any understanding of the molecular activity of the gene.  

In September, University of Pennsylvania Medical Center researchers reported their finding that one way functional BRCA1 limits tumor growth is by inducing p21, another gene that inhibits cell division by blocking the DNA replication phase of the cell's reproductive cycle. "Before now, we had no idea how BRCA1 functions to suppress cancer growth," said lead researcher and senior author Wafik S. El-Deiry, MD, PhD, assistant professor of medicine and genetics at Penn and an assistant investigator with the Howard Hughes Medical Institute. El-Deiry's paper was published in Nature.  

The work "bears out the theory that BRCA1 acts by activating the transcription of other genes," said Barbara Weber, MD, associate professor of medicine with a secondary appointment in genetics and another author of the paper, in an interview with Lancet. Asked by The Lancet whether BRCA1 will activate the expression of other genes, El-Deiry replied, "Absolutely. ... It would not make sense for a transcription factor to turn on a single gene."  

Reports began September 11.

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The Philadelphia Inquirer

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Two Diet Drugs Pulled Off the Market

If something seems too good to be true, it probably is. That is the lesson learned by dieters who thought they had found an easy, safe way to lose weight via the drugs fenfluramine and dexfenfluramine. Both drugs were pulled from the market in September after five medical centers--including the University of Pennsylvania--discovered that about one-third of patients who took either drug for up to two years had mild to moderate heart valve damage. The drug fenfluramine makes up half of the combination known as "fen-phen." Phentermine, the other half, was not recalled. Dexfenfluramine is a chemical cousin of fenfluramine and is sold under the brand name Redux.  

"This is distressing to patients who have been potentially harmed," said Thomas Wadden, PhD, professor of psychology in psychiatry and director of Penn's Weight and Eating Disorders Clinic, in an interview with The Philadelphia Inquirer. "But it's also distressing for people who have lost weight and improved their health without adverse effects. I talked to some patients who were really quite upset when I told them they could no longer take the drug." Wadden reported that he found valve damage in seven of 21 patients who took standard doses of fen-phen as part of a study at Penn's clinic. However, some may have had valve damage before taking the drugs.  

The weight-loss chain Nutri/System recently announced that they are offering their clients a combination of phentermine and Prozac, which they promise is a safe combination. "I think it's ridiculous," commented Albert Stunkard, MD, DM, professor emeritus of psychiatry, in the Inquirer. "If we've learned anything in the past year, it's that these drugs are dangerous. I think it's scandalous."  

Reports began on September 16.

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A Post-Transfusion Worry: Hepatitis C

In August, government advisers recommended that anyone who had a blood transfusion before 1992 be tested for hepatitis C, a serious liver infection.  

There will soon be a massive public service campaign to educate people about the disease and direct them to places where they can receive free testing if they have no insurance. According to the public service Blood Advisory Committee, blood banks will also be required to search their records for donors who tested positive for hepatitis C after 1992, and then try to locate any recipients who received that person's blood before 1992.  

There has been much debate about whether people who may have received tainted blood must be notified, with some experts contending that contacting them causes much alarm, and that drug therapy is largely unsuccessful and sexual transmission is rare. Former Surgeon General C. Everett Koop commented that he would like to see a public-health campaign, but that he doesn't want to trigger a panic. But "in public health, you have to scare people enough to make them try to do what is possible."  

It is estimated that about 290,000 people got hepatitis C from transfusions before the tests for the virus were devised in 1990. The first test needed improvements, and it wasn't until mid-1992 that a highly effective test was used to screen blood. About 3.9 million Americans are estimated to have the "silent disease."  

Hepatitis C is a blood-borne virus that becomes chronic in 85 percent of those infected. Seventy percent eventually contract liver diseases, including cirrhosis and cancer. There is no known cure, although a treatment is available that has been shown to be effective in only 10 to 25 percent of patients.  

"I don't think anybody needs to panic and feel they must call their doctor in the morning," said Arthur L. Caplan, PhD, director of Penn's Center for Bioethics and chairman of the panel. "It is a slow-acting virus. . . . But if people are concerned, if they think they had a transfusion before 1992 [or] if they tried IV drugs even once, talk to your doctor."  

Reports began August 13.

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WTXF-TV29

Genes Give Insight into Cause of Neurodegenerative Diseases

Researchers at the University of Pennsylvania Medical Center and other institutions around the world have gained a new understanding of the underlying mechanism responsible for more than a half-dozen debilitating neurodegenerative diseases. Several related reports recently appeared in Neuron and Cell. The findings will lead to more investigation of the progression of these diseases, as well as possible interventions.  

Although the various diseases that were investigated, including Huntington's and Machado-Joseph disease, can be traced to different flawed genes, they all share a common problem in their DNA: instructions for producing the amino acid glutamine are repeated excessively along a given stretch of a gene coding for an important protein. In normal proteins, the sequence of three nucleotides that constitutes glutamine--cytosine, adenine, and guanine, or CAG--is often repeated 15 or 20 times. But in the mutant protein, the repeats increase to 50 or even 100. This genetic "stutter" alters the properties of the key proteins, causing the diseases.  

"We are beginning to realize that a cell, whether it's in the brain or another part of our body, when it becomes sick it initiates a cellular suicide," said Randall N. Pittman, PhD, associate professor of pharmacology and senior author of the Neuron paper, which deals with Machado-Joseph disease, in an interview on WTXF-TV29's Good Day Philadelphia.  

Pittman gave his prediction of what scientists will do with the new information: "Different labs are going to do different things. There are physical chemists already in Germany who are beginning to at least screen some drugs against the aggregates that they can make in a test tube."  

Reports began August 7.

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Criticizing the AMA

In August, the American Medical Association announced that it would be endorsing a line of health-care products introduced by the Sunbeam Corporation later this year. According to the AMA, the deal would finance its health, educational, and research programs. Almost immediately, however, the arrangement came under criticism.  

Mildred K. Cho, PhD, research assistant professor at Penn's Center for Bioethics at Penn, had a letter published in The New York Times in which she suggested that members of the AMA "should reconsider whether they want to remain part of a professional group that violates its own code of ethics." According to Cho, "In taking royalty payments from the sale of Sunbeam products in exchange for the use of its name in endorsements, the AMA runs roughshod over the spirit, if not the letter, of two of its policies." Those policies are: "Under no circumstances may physicians place their own financial interests above the welfare of their patients" and "A physician should not be influenced in the prescribing of drugs, devices, or appliances by a direct or indirect financial interest in a pharmaceutical firm or other supplier."  

Arthur L. Caplan, PhD, director of Penn's Center for Bioethics, told Consumers' Research Magazine that he believes the practice of nonprofits' charging for "seals of approval" is "ethically dubious."  

About a week later, the AMA aired some second thoughts. "The AMA apologizes for creating a public doubt about our motives," said Dr. P. John Seward, the organization's executive vice president, in The New York Times. Seward explained that the AMA would not be described as "a product endorser" and would not accept royalty payments. Any fees from manufacturers for its health-care information "will not be used to generate additional funds for the AMA" and no fees would be accepted "beyond the audited and publicly disclosed amounts that will be needed" for production. The AMA is also seeking to be released from its exclusive contract with Sunbeam.  

Reports began August 17.

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Exercise Strengthens Bones

Exercise can help lessen the common physical ailments that accompany getting older. A recent meeting of the American Academy of Orthopaedic Surgeons highlighted the benefits of keeping active.  

"Most individuals are aware of the cardiovascular benefits of exercise, but we are just beginning to appreciate the importance of exercise for the musculoskeletal system," said Nicholas DiNubile, MD, assistant professor of orthopaedic surgery. Exercise can decrease the risk of fracture, and even those with osteoarthritis and osteoporosis can participate. Thirty minutes of physical activity a day is enough to help seniors stay fit and avoid problems.  

"Swimming is a non-impact and non-weightbearing activity that does not place a lot of pressure on arthritic joints," DiNubile said.  

Exercise can also help people with back pain. DiNubile said that exercises aimed at strengthening the back, stomach, and leg muscles are best. "Some of the best examples are wall slides, leg raises, partial sit-ups (crunches) and back extensions."  

And those with back pain need not delay in getting started on a fitness program. "Once the initial pain subsides, people should become involved in a more active exercise program that includes stretching as well as aerobic exercises like walking, swimming, or cycling. Strength training can also be gradually introduced."  

Reports began August 1.

Chicago Tribune

Saint Paul Pioneer Press

Mother's Milk Helps Prevent Disease

It's long been known that breast milk is the ideal food for infants. It is also believed that breastfeeding promotes a strong bond between mother and infant. Breastfed babies also experience fewer and less serious incidences of disease and allergy than formula-fed babies.  

For years, researchers have tried to understand why breast milk is so beneficial. "What researchers have discovered is that breast milk is much more than just food," said Charles V. Clevenger, MD, PhD, assistant professor of pathology and laboratory medicine. "It's also a bioactive compound containing antibodies that defend against infections and hormones and growth factors that direct the infant's immune system to develop fully and appropriately."  

Clevenger's studies have shown that the hormone prolactin, which is responsible for growth and differentiation of the breast during puberty, pregnancy, and lactation, also helps stimulate immune-system cells in the infant. Prolactin is produced primarily in the pituitary gland, but Clevenger's team found that tissues in the breast are able to make the hormone, too.  

Clevenger said that, in the adult stomach, the proteins that constitute the antibodies, hormones, and growth factors in breast milk would not survive exposure to the digestive acids.  

"But infants are different from adults, and one of the ways they are different is that their stomachs don't make as much acid. ... As a result, many of the important immunostimulatory proteins in breast milk can pass through the stomach of an infant and into the intestine, from which they enter the infant's bloodstream largely intact. In an adult, these proteins would be destroyed."  

Reports began August 14.

Managed Care

On Statistics and Language

Penn's own managed care guru Alan Hillman, MD, MBA, director of the Leonard Davis Institute for Health Policy, recently gave a lengthy interview to Managed Care magazine. The topic? Understanding health care's economics.  

Hillman, who is on Managed Care's editorial board, was asked to predict what changes will take place in the future of managed care. "We'll move more toward the use of outcomes to reward quality," Hillman said. "But the reason it is so hard to do that is that statistically what one doctor does can't really be connected to the outcomes of care.  

For example, a surgeon can do all the proper things in a coronary artery bypass--a technically perfect surgery---but the patient dies on the table. Or you can have a horrible doctor who does terrible surgery and some of his outcomes are going to be good. So statistically you need to have doctors at the extremes in order to say they are 'bad' or 'good.' But the clearly bad ones, one hopes, have been kicked out by their peers. Most doctors are in the middle; they have some good outcomes and some bad outcomes. Should one doctor be rewarded for having three more good outcomes than another, when in fact it may just be the result of statistical scatter?"  

Hillman was asked to comment of the new health care vocabulary. "Disease management, case management, protocols, algorithms, practice guidelines, critical pathways. We give names very easily to things, but we don't really define them," he said. "I challenge you to go out to ten different 'experts' and ask them for a definition of managed care, or of quality, or of disease management. You'll get something totally different from each person."  

The article appeared in the August issue.

Washington Post

Houston Chronicle

Practice Makes Perfect

Chances are, a person's first weight-loss diet will not be his or her last. The majority of dieters end up "cycling" or "yo-yo dieting." A new study of people who have been successful in losing weight--and who have kept it off long-term-- shows that it takes dieters many attempts before they get it right. And just because someone has regained weight after a diet, even many times, doesn't mean that they are always doomed to fail.  

University of Pittsburgh researchers studied 800 people who shed a minimum of 30 pounds and kept the weight off for nearly six years. The participants had lost an average of 270 pounds during their lives. Nearly half of the participants, whose average age was 45, had been overweight since early childhood, and another 25 percent had put on unwanted pounds from age 12 to 18.  

The researchers said that the dieters had all tried a variety of methods, and then finally came across the combination that worked for them.  

"Most people who quit smoking successfully do it on their own, and we have learned that it takes four or five times," commented Albert Stunkard, MD, DM, professor emeritus of psychiatry, in The Washington Post. The weight study "shows that persistence [in dieting] pays off. ... It's a wonderful, optimistic message and would be very nice to counter the terrible pessimistic message that people can't lose weight."  

Stunkard added, "[The study] confirms earlier smaller studies in a very dramatic way with this large sample size."  

Reports began September 2.

The Philadelphia Inquirer

Remedying the Doctor Glut

Recently, the federal government decided to offer teaching hospitals incentives to train fewer doctors in an effort to avoid a "doctor glut" that some fear may drive up costs for patients, government insurers, and employers.  

Although some argue about whether a doctor glut really exists, it's clear that the number of physicians has increased. There were 650,000 physicians in the nation in 1995, up from 520,000 a decade ago. Physicians account for about 20 percent of the country's $1.1 trillion annual health expenditures.  

The government deal would offer hospitals reimbursement for residency slots that they eliminate. Hospitals that eliminate slots during the first year of the offer would be reimbursed 100 percent. In the remaining four years, reimbursement would taper off down to zero percent.  

"A number of us in the profession were concerned that we were producing too many doctors," said William N. Kelley, MD, CEO of Penn's Health System and dean of the School of Medicine, in an interview with The Philadelphia Inquirer.  

Pennsylvania teaching hospitals employ nearly 7,000 of the nation's 105,000 medical residents. About 4,100 of those residents practice at Philadelphia-area teaching hospitals.  

According to the Inquirer, several area hospitals said that they are considering the government's offer. Some smaller hospitals reported that they cannot spare any of their residents.  

The article appeared August 31.

The Philadelphia Daily News

A Columnist Receives a Heart Transplant

One evening in June, he was enjoying dinner and a movie with his wife. But upon returning home, things started to go awry. What Philadelphia Daily News columnist Rick Selvin initially thought was indigestion turned out to be a heart attack that landed him in the Hospital of the University of Pennsylvania.  

Selvin recalled his experiences at HUP in a lengthy feature that appeared in the Philadelphia Daily News. After a triple bypass operation, Selvin became a patient on Founders 8 as he waited for a heart transplant. There he made friends quickly with the "competition"-- the other patients awaiting hearts.  

Selvin spoke highly of HUP, giving it the nickname "Club MEDicine." "Breakfast in bed, 24-hour room service and, ahem, really good drugs." He added, "The nurses are angels of mercy who make my day-to-day existence bearable and sometimes enjoyable. They maintain a sense of humor and a confidence that decreases my apprehension by double-digit percentages."  

One of Selvin's biggest disappointments at being hospitalized was having to miss the Philadelphia Folk Festival for the first time in 35 years. A fellow patient felt similarly--he had been going to the festival for 20 years. An idea dawned on them--maybe the festival could be brought to them. With the help of the "hospital brass" and a festival publicist, it was arranged. Two acts from the festival came to perform for patients, family, friends, and staff. The event was covered by WPVI-TV6. Selvin hoped that the publicity generated by the show at HUP would draw attention to the need for donor organs.  

Shortly before the article was published, Selvin received a donor heart. He is now recuperating.  

The article appeared September 12.