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Another Piece Fits in the Alzheimer's Puzzle

"Discovery consists of seeing what everybody has seen and thinking what nobody has thought."

--Albert Szent-Gyorgyi von Nagyrapolt

When Alzheimer's disease was first described in 1907, two primary pathological characteristics--neurofibrillary tangles and amyloid plaques--were identified as the disease's defining traits. Recently, Penn researchers John Q. Trojanowski, MD, PhD, and Virginia M.-Y. Lee, PhD, both professors of pathology and laboratory medicine, and their colleagues identified a new pathological feature of Alzheimer's disease--a plaque-like lesion involving a previously unidentified protein. The lesion appears to constitute as much as a quarter to a third of the volume of affected gray matter in the brains of Alzheimer's patients. The lesion is rare or absent in other degenerative brain diseases.

"This is a spectacular lesion, never before seen, that tracks closely with the disease state--more specifically than tangles and perhaps more specifically than amyloid plaques," said Trojanowski, director of Penn's Disease Center and lead author of the study report. The study was published in the July issue of the American Journal of Pathology.

In The New York Times, Lee explained why the protein was not noticed before in Alzheimer's patients. "The staining and chemical dye methods that have been used in the past to label Alzheimer's disease pathologies--primarily silver and thioflavin staining--do not pick up this lesion. A new series of antibodies we created to explore elements of the neurofibrillary tangles, however, did."

The finding has implications for diagnosis and treatment. "Perhaps one could develop an assay useful for diagnosis early in the disease state," Trojanowski said in the Times. "One of the important goals of Alzheimer's research now is figuring out how to identify the disease years before you encounter problems."

Trojanowski told CNN Today, "Our view is that if plaques and tangles were to be eliminated from the Alzheimer's brain and patients were not to get better, maybe it is because they have deposits of this other plaque. We may, in fact, have two therapies targeted at each of these abnormalities."

Reports began June 26.

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Some Kinds of Obesity Linked to Genetic Flaws

Two recently published reports assert that, in some people, obesity is caused by genetic flaws. The reports--one presented in Nature, and the other in Nature Genetics--concentrated on different genes. But experts say that the defects cause obesity only rarely, and that these findings cannot be applied to the majority of overweight people.

Nature described a case in which an 8-year-old girl weighed 190 pounds. Her 2-year-old cousin weighed 64 pounds. Scientists discovered that both children have a defect in the gene that tells fat cells to produce leptin. Thus, their leptin supply was greatly reduced.

Nature Genetics reported the case of a woman who had weighed 80 pounds at age 3. Now, in middle age, the woman is only moderately overweight. Researchers found genetic defects for an enzyme called prohormone covertase 1, or PC1. This substance helps the body make insulin, among other things.

"They're real landmark papers," commented Albert J. Stunkard, MD, DM, professor emeritus of psychiatry. But, there is "no big public health message. . . . The average middle-aged overweight woman is not likely to see much benefit from this."

Reports began June 24.

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A Bridge to Transplantation

Many end-stage heart disease patients die while waiting for a new heart to become available. But an investigational device may make it possible for some patients to have a better quality of life--and to even be discharged home--while they wait for a transplant.

The implantable VE TCI Heartmate Left Ventricular Assist Device (LVAD) works by mechanically pumping blood to the body by taking the place of a weakened left ventricle. The battery-driven LVAD weighs only two pounds and can be worn around a patient's waist or over his or her shoulder.

At the University of Pennsylvania Medical Center, 43-year-old Duke Grant received the device after he suffered a massive heart attack. The device so improved Grant's stamina that he was able to participate in the Second Annual Dash for Organ Donor Awareness, organized by the Delaware Valley Transplant Program and sponsored by several local medical institutions and businesses. Grant was accompanied by his wife and his two sons, as well as Penn physicians, nurses, and staffers. Among them was Michael A. Acker, MD, assistant professor of surgery and surgical director of Penn's Cardiac Transplant Program.

"We were all excited for him," Acker told Physician's News Digest. "Everyone marveled at the technology enabling him to be normal. Looking at his performance, you couldn't tell anything was wrong."

"To date, we have performed 30 LVAD procedures," Acker said. "Although it is a new technology, we have seen great results with it. The technology is safe, and the totally portable, battery-charged LVAD gives patients the potential to be discharged home while they wait for their new heart."

Reports began in April.

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MRI: Finding Breast Cancer the Noninvasive Way

Soon, doctors may be able to use magnetic resonance imaging, or MRI, to determine whether a breast tumor is benign or cancerous. This could reduce the need for traditional, painful biopsies.

Nature Medicine reported that researchers in Israel studied the effectiveness of MRI in detecting breast cancer by taking images of dye injected into the breast. By studying the spaces between tumor cells and how quickly and to what degree blood vessels leak around them, the researchers were able to tell which were cancerous and which were benign. Closer, leakier cells were associated with cancer.

Mitchell Schnall, MD, PhD, associate professor of radiology, praises the lead author of the work--Hadassa Degani of the Weizmann Institute for Science in Rehovot. Degani worked at the University of Pennsylvania Medical Center last year with Schnall. "[Degani has] done some careful studies to lay the groundwork for us to understand what we see in breast studies by MRI," Schnall told USA Today.

"One of the nice features of the MRI is that is detects almost all breast cancer," Schnall said in a WCAU-TV10 report. However, many benign tumors can look cancerous with MRI. The hope is that the reported procedure will "allow us to reduce the number of false positives that we get in breast MRI."

Reports began July 2.

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Assisted Suicide: The Debate Rages On

In June, the Supreme Court ruled that terminally ill patients do not have a constitutional right to medical assistance in committing suicide. At the same time, the court did not outlaw it. "The debate is going to take off," predicted Arthur L. Caplan, PhD, director of the Center for Bioethics, in the Philadelphia Daily News. "The Supreme Court did not say no. And I think the decision was wise--the ballot box is a better place to resolve this than the courtroom."

The question of doctor-assisted suicide now returns to state governments, which the Supreme Court said have the right to outlaw assisted suicides. Two states--New York and Washington--have already banned the process. Voters in Oregon are scheduled to vote in November on whether to legalize assisted suicide in their state.

"The Supreme Court, when it refused to recognize a right to assistance in dying, flung open the door to what will become a long, prolonged heated societal debate about the morality of assisted suicide," Caplan told The New York Times. "I see this not as the end of anything, but as the beginning of what is going to take years to work through."

According to the Times, polls suggest that a majority of Americans support the concept of assisted suicide, and surveys of doctors suggest that many doctors have been asked by patients for help in dying--and a significant number have obliged.

Reports began June 27.

The Best Best Clinical Practices

The University of Pennsylvania's disease management program was recently highlighted in an issue of Health Data Management. "The Philadelphia-based integrated delivery system is seeking to develop 10 disease management programs a year through the year 2000," the writer reported.

David Shulkin, MD, chief medical officer for HUP and chief quality officer for the Health System, reported that, so far this year, UPHS has implemented programs for asthma, hypertension, coronary artery disease, HIV/AIDS, and diabetes.

"We use a formal methodology for selecting diseases to manage, looking for high-volume, high-cost conditions in which we can make a difference in quality," Shulkin explained.

Shulkin said that the Health System has been shopping around for a "point-of-care" information system to complement the program. "I suspect we will be looking for a system that has some of the capabilities we want and looking for the information systems company to build precisely what we're looking for."

Shulkin pointed out that each disease management effort has its own timeline and budget. "We're looking at this as an opportunity to seize, and it happens to be consistent with what the managed care companies are looking for," Shulkin said.

The article appeared in the June issue.

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Second Best Care

Now that doctors are under so much pressure to keep health-care costs to a minimum, are they lowering their standards to the point where they are compromising patient care? David Asch, MD, and Peter Ubel, MD, both assistant professors of medicine, attempted to answer that question in a recent opinion piece published in The New England Journal of Medicine.

Asch and Ubel believe that the increasing pressure of managed care causes some doctors to steer patients into less expensive, and sometimes less effective, treatment options. Some compromises are unavoidable, Asch noted, but physicians must be aware of the difference between making a wise "economic decision" and saving money in a way that could endanger a patient's welfare.

After describing several instances in which a physician opted for a less expensive treatment for a patient, despite the fact that he or she was aware that a better, more expensive option existed, the authors stated their concerns. "We suspect that many physicians will recognize elements of their own practices in these cases. Does this mean that they are rationing care? Perhaps not, if rationing refers only to practices that are in some way unethical or unprofessional. Perhaps so, if rationing refers to any decrease in the quality of care intended to save money."

The authors expressed concern about cost containment that occurs "passively"--when the patient is not aware of the alternatives. Physicians use many rationales for these trade-offs, including the belief that "the group is more important than the individual."

"We hope to move discussion beyond the loaded questions of whether rationing is acceptable to the more constructive question of what kinds of compromise are justified," the authors concluded.

Reports began June 5.

Moore Highlights

Kenneth Moore, MD, assistant medical director of the emergency department at Presbyterian Medical Center, was the recent focus of the "Local Angle" page of The Philadelphia Inquirer's Inquirer Magazine. "This is the real ER," wrote reporter Michael Klein, who followed Moore around in the emergency department to learn the lay of the land.

Moore spoke of the emergency department "cycles" that have become all too predictable in his job. When welfare and Social Security checks come out on the first and third of the month, Moore said, the ER sees more beatings and alcohol-related injuries. And the staff is always alert to the sound of a car door slamming outside the entrance; it could be someone who would rather not be identified, dropping off a gunshot victim.

Moore was the son of a diplomat, and as a child, his family lived in Washington and northern Africa. "I was a fortunate kid," he conceded. Still, Moore sees his calling in educating poor people, who view hospitals as places to die. He also works with teenagers to teach them the consequences of their actions.

Moore tries to educate other physicians about the special needs of the poor. "I took [young doctors] to a shelter once, and one of them told the mothers to store their babies' milk in a refrigerator," Moore recalled. "How can you say that when they don't have a refrigerator?"

The article appeared July 6.

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The HC4 Report on Financial Status

The Hospital of the University of Pennsylvania finished the 1996 fiscal year with the second highest surplus of earnings over expenses in the Philadelphia area, at 13.7 percent. But that, according to the annual report of the Pennsylvania Health Care Cost Containment Council, was 5.7 percent lower than the previous year.

All told, 35 of the 55 Philadelphia-area hospitals fared worse in the 1996 fiscal year than in the previous year. The council reported that net profit margins fell to 0.3 percent for Philadelphia's hospitals, down from 1.3 percent. For suburban hospitals, however, the margin rose from 4.0 percent to 4.5 percent.

Among hospitals now associated with Penn's Health System, Holy Redeemer Hospital and Medical Center went from a margin of 6.3 percent to 6.7 percent; Phoenixville Hospital went from 7.2 percent to 4.9 percent; The Chester County Hospital went from 3.6 percent to 1.1 percent; Pennsylvania Hospital went from 2.2 percent to 0.5 percent; Presbyterian Medical Center went from 1.1 percent to 0.1 percent. The Children's Hospital of Philadelphia went from 9.5 percent to 9.0 percent.

"We're seeing a major reduction in payment for services," William N. Kelley, MD, CEO of Penn's Health System and dean of the School of Medicine, told The Philadelphia Inquirer. "Margins are going to be moving rapidly to essentially break even."

Reports began July 16.

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Phen-Fen Linked to Rare Disease

The popular diet drug combination phetermine and fenfluramine--known as "phen-fen"--was recently linked to serious, life-threatening complications. A report from the Mayo Clinic showed that 24 previously healthy women developed an unusual form of heart valve disease after taking the drug.

Most of the women with the condition experienced symptoms such as heart murmurs and shortness of breath. Echocardiograms showed unusual thickening of their heart valves. Five of the patients needed open-heart surgery, and others were put on heart medication.

Thomas Wadden, MD, professor of psychology in psychiatry and director of Penn's Weight and Eating Disorders Program, commented that "it's possible this medication did cause it in all 24 persons. We don't know, though. If you took 1,000 persons, put them on phen-fen, how many are going to develop this condition?"

Experts say that phen-fen has been a valuable tool for truly obese people. Physicians need to help patients decide whether the risks are justified. "You can control many of the health complications of obesity through weight loss, and these medications allow you to that," Wadden said.

"If you are having any symptoms such as shortness of breath or irregular heartbeat, you may want to contact your doctor." He added, "Otherwise, I don't think everyone should be overly alarmed by this."

Albert J. Stunkard, MD, DM, professor emeritus of psychiatry, reinforced that sentiment. "What you need to do is assess the risk/benefit ratio. How much risk are you willing to take for how much benefit?"

Reports began July 8

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The Waiting Game

Long waits to see the doctor may soon be a thing of the past. In today's health-care market, physicians are pressured by insurers and consumers to provide better, more efficient care to patients, or risk losing them as "customers." This message was heard loud and clear by Penn's Department of Orthopaedic Surgery. Research conducted a few months ago showed that the average patient waited 90 minutes before seeing a doctor for an office visit. But the implementation of better scheduling techniques has resulted in a waiting time between 10 to 15 minutes.

The department tracked its doctors to see how much time they spent with each patient. They found that some doctors had far too many patients lined up to see them on a given day, whereas others had too few. By dispersing visits more evenly, and by making special slots for patients who were in for short offices appointments, things ran more smoothly.

"We were asleep to consumers' needs and we have been brutally awakened," said David Shulkin, MD, chief medical officer for HUP and chief quality officer for the Health System.

Robert Fitzgerald Jr., MD, chair of the department, reported that the department has also improved its telephone systems. Phone staff were taught how to answer calls promptly and answer patients' questions efficiently. Before the training, about 10 percent of the department's calls had been lost, and now less than 1 percent are unanswered.

The article appeared July 20.