S T A N F O R D M E D I C I N E

Spring 2000

 

For Alumni
Stanford
MD

 

On the Cover

Bridging Disciplines to Squelch Cholera. 

Cover illustration by Calef Brown.

Stanford Medicine, published quarterly by Stanford University Medical Center, aims to keep readers informed about the education, research, clinical care and other goings on at the Medical Center.

 

'scope

A QUICK LOOK AT THE LATEST DEVELOPMENTS FROM STANFORD UNIVERSITY MEDICAL CENTER
 
Tobacco retail promotions dwarf other products' spending

HAMPERED BY LEGAL RESTRICTIONS ON CONSUMER ADVERTISING, U.S. tobacco companies appear to be heavily promoting their products through small retail outlets, spending significantly more than other companies to obtain prominent product displays, according to a recent study by researchers at Stanford and at Santa Clara University.

The researchers found that small retail operations are receiving significantly more money and discounts from tobacco companies to push the sale of tobacco products than they receive for other items such as soft drinks, beer, wine and snacks.

"For many years the public health community has been trying to restrict consumer advertising in magazines and billboards, but our research indicates that the real target for public health should be the retail environment," says Ellen Feighery, RN, MS, a senior research scientist at the Stanford Center for Research in Disease Prevention.

Feighery was lead author of the study, published in the October 1999 issue of the American Journal of Public Health.

The article reports what appears to be the first detailed look at tobacco industry retailer incentives. The study focused on slotting and display allowances -- fees manufacturers pay retailers to encourage them to allocate premium shelf space to a product.

The survey was conducted in November and Decem ber 1997 in 108 chain convenience stores, gas stations, grocery stores, liquor stores and tobacco stores in Santa Clara County, Calif. It showed that 62.4 percent of the stores had received slotting/display allowances from tobacco makers.

In contrast, only 16.5 percent of the stores received slotting/display allowances for placing soft drinks in premium locations most likely to appeal to consumers. And only 6.9 percent of the stores received the allowances for candy.

The tobacco companies also were more generous in their payments, according to the researchers. Of the $3,157 the average store received annually for all product types, $2,462 (78 percent) came from the tobacco companies. By contrast, only 33 percent of the stores reported that tobacco sales accounted for their highest sales volume.

"These survey results suggest that tobacco companies use generous incentives and aggressive marketing programs to motivate retailers to prominently display, promote and advertise their products to ensure the high visibility of their products and marketing materials," the researchers concluded.

As evidence of fierce competition in the retail environment, three of the country's largest cigarette makers filed a lawsuit against Philip Morris Co., accusing the giant tobacco company of hampering their ability to secure prime shelf space in retail outlets. Slotting and display fees in the tobacco industry also were the focus of a U.S. Senate antitrust hearing in September 1999.

"Perhaps the Federal Trade Commission should consider expanding its ongoing investigation of Philip Morris' merchandising practices to the tobacco industry as a whole. New policies may be needed to address the [retailer focused] marketing strategies of the tobacco industry and their impact on in-store marketing environments," the researchers say. -- MG

Clues to how stomach bugs
get around

STANFORD RESEARCHERS ARE SEARCHING IN SOME UNSAVORY PLACES TO SOLVE THE RIDDLE OF HOW A COMMON BACTERIUM THAT CAUSES STOMACH ULCERS AND PERHAPS SOME KINDS OF STOMACH CANCER JUMPS FROM ONE HUMAN TO ANOTHER. The most obvious places the bacteria may be hiding are the vomit, feces and saliva of infected people.

* Sixteen healthy people infected with Helicobacter pylori, which is carried by 50 percent of the population, volunteered for a study led by Julie Parsonnet, MD, an associate professor of infectious diseases and geographic medicine. Like the majority of those carrying the bug, these people showed no signs of infection, but evidence of the bacteria in their breath and antibodies in their blood confirmed H. pylori's presence. Ten people who tested negative for the bacteria were also studied as controls.

The volunteers were admitted to Stanford's General Clinical Research Center for 24 hours, and Parsonnet and her team collected all manner of biological samples for analysis.

* The researchers first screened normal feces from each of the 26 volunteers. Helicobacter thrives in the stomach's acidic surroundings, but its survival outside this environment is limited. Normal stools can take days to traverse the colon and, not surprisingly, the researchers found no live bacteria in these samples. But, when given a substance that induced diarrhea, 11 of the 16 infected people passed stools from which the bug could be grown.

Parsonnet believes that diarrheal stools are expelled so quickly from the small bowel and stomach that live bacteria can be transported into the external environment. According to Parsonnet, H. pylori can survive outside the body for a few hours, which may be sufficient time to infect anyone who contacts the sample.

The researchers also gave the infected people, and one uninfected volunteer, a substance to make them vomit. The results showed that vomiting is a potent way of discharging millions of infectious H. pylori into the environment. The researchers found live bacteria in samples from all of the infected individuals. The concentration of H. pylori in vomit was also much greater than in feces.

Transmission of H. pylori by this route supports what scientists already know about Helicobacter infection. Close living quarters, the presence of many siblings and poor household hygiene are factors known to increase the risk of infection. Children, who tend to vomit and "spit up" more frequently than adults, are particularly likely to transmit the bug to other children, says Parsonnet. "Imagine children in day care together; one throws up and another child is right next to him or her. Or contaminated toys are not cleaned up properly," she says.

Infection during childhood leads to more opportunities to pass the bug on to others and also increases the likelihood of serious disease, says Parsonnet. Although many people carry the bug without symptoms, a combination of factors -- such as the particular strain of H. pylori and the person's diet and genetics -- can lead to ulcers and/or stomach cancer. Infection at an early age gives the bacteria more time to wreak havoc.

Analysis of air and saliva samples completed Parsonnet's battery of tests. Although the researchers could detect traces of bacteria in the saliva of approximately half of the people carrying H. pylori, mouth-to-mouth transmission is not considered a primary route of infection. Sampling the air surrounding infected volunteers confirmed the pivotal role of vomiting in the potential spread of the bacteria. The researchers found no evidence of the bug until the onset of vomiting, when air sampled from approximately a foot in front of the volunteers yielded Helicobacter that had been exhaled in tiny aerosol droplets.

The results of the study were published in the December 15, 1999, issue of the Journal of the American Medical Association. -- KW

 

Glowing mice help screen cancer therapies

MICE THAT LIGHT UP WHEN CANCER CELLS ARE ON THE RAMPAGE AND DIM WHEN THE INVADERS ARE POISONED BY DRUGS MAY HELP RESEARCHERS PINPOINT effective new anticancer therapies and will also spare the lives of many lab mice.

* A firefly gene makes the promising technique possible. Scientists in the laboratories of Christopher Contag, PhD, assistant professor of pediatrics, and Robert Negrin, MD, associate professor of medicine, have inserted the gene into human tumor cells. When tumor cells are alive and healthy, the firefly genes glow. The researchers then inject these modified tumor cells into mice. Using an ultrasensitive video camera, the firefly light can be detected through a mouse's skin and tissues, showing up on a computer screen as colored blotches superimposed over the mouse's body.

Contag's group first developed the glowing mouse in 1995 to follow the progression of infectious diseases. He and his colleagues injected Salmonella bacteria labeled with the bi oluminescent firefly gene into mice to see where they settled in the mouse's gut and how the bacteria responded to various antibiotics. The technology has since been licensed to Xenogen, a company started by Contag and others, including his wife, Pamela Reilly Contag, PhD, who is its president and CEO.

* In the recent tumor cell study, Contag and Negrin tested three standard chemotherapy drugs against human cervical tumor cells to show that the new method is a reliable predictor of the drugs' effectiveness. They reported the results in the October 12, 1999, Proceedings of the National Academy of Sciences and in the October 1999 Neoplasia.

As the tumor invaded the mouse's abdomen, the light emitted from the mouse became more intense and spread over a greater area. Within days of giving the mouse a chemotherapeutic drug, the researchers could see the light diminish and recede, indicating that the tumor cells were dying. More than two months after the light had disappeared, testing by an alternative method confirmed that the mice remained free from cancer.

Contag and Negrin believe that the new technique will be especially useful for testing drugs to treat minimal disease -- the small number of cancer cells found early in disease or following removal of a large tumor. Recent advances in cancer diagnosis are allowing physicians to detect minimal disease earlier and earlier, so drugs that can rapidly kill these cells without further harming the patient offer a better chance of fighting the disease.

Nontoxic alternatives that will kill relatively small numbers of cancer cells before they mass into a life-threatening tumor are needed, says Contag. Drugs used to treat late-stage disease -- characterized by the presence of many rapidly dividing cancer cells -- are usually very toxic, causing unpleasant side effects.

* The researchers say they are pleased that, in addition to potentially leading to improvements in rapid drug screening, the glow-gene method will reduce the number of mice sacrificed in the name of medical research. Neither the firefly gene nor the ultrasensitive camera harms the mouse. And because the tumor cells can be seen through the animal's body, there is no need to kill the mouse and dissect it to ascertain what is happening within its tissues.

"You can follow one group of mice over time, so you use fewer animals to get more data more efficiently," says Contag.

"There is no other method that can detect so few human cells noninvasively," Negrin adds. -- KW

 

Ron Garcia named minority affairs assistant dean

THE SCHOOL OF MEDICINE'S LEADERSHIP HAS ESTABLISHED AN ADMINISTRATIVE POSITION TO ASSIST THE SCHOOL'S EFFORTS to expand opportunities in medicine for underrepresented minority students -- naming Ronald Garcia, PhD, the assistant dean for minority affairs.

"Dr. Garcia has provided remarkable leadership and vision for the School through his work at the Center of Excellence and the Health Careers Opportunity Program," says Eugene A. Bauer, MD, vice president for Stanford University Medical Center and dean of the School of Medicine. "Ron's contributions have been integral to the School's progress in promoting the recruitment and selection of underrepresented minority students, as well as to increasing the number of minority students who are seeking leadership careers in medicine," he adds.

"I am very excited about my appointment," says Garcia, who assumed the post in December 1999. "In many institutions, this position focuses primarily on minority student recruitment and retention. I embrace these areas, but I intend to get involved in other areas as well. There are major challenges in so many areas of medicine; I am very pleased to work at an institution that is willing to pursue solutions and has a long history of commitment to minority recruitment," he says.

Garcia, a senior lecturer in the Department of Medicine's Division of Family and Community Medicine since September 1987, has been program director of Stanford School of Medicine's Center of Excellence (COE) since 1992 and program director of Stanford's Health Careers Opportunity Program (HCOP) since 1996. The COE is a minority recruitment, retention, curriculum development, research and faculty development project for the School of Medicine. HCOP, a six-week summer program instituted in response to dwindling minority applications, aims to help college students who are members of minority groups strengthen their qualifications for medical school.

Garcia received three degrees at Stanford: a master's in education in 1971 and both a master's in psychology and a PhD in educational psychology in 1977. He completed a postdoctoral internship in clinical psychology at the Stanford Alcohol and Drug Treatment Center in 1988.

Since 1997 he has chaired the minority and non-minority disadvantaged students advisory panel of the Medical School's Committee on Admissions. -- JT

 

New technique restores blood flow to damaged limbs

IN THE FIRST CASE REPORT OF ITS KIND IN NORTH AMERICA, STANFORD PHYSICIANS SAY THEY HAVE USED A NEW TECHNIQUE TO GRADUALLY RESTORE BLOOD FLOW TO THE LEG AND SPARE A 16-YEAR-OLD PATIENT FROM THE PROSPECT OF AMPUTATION.

The procedure could be used to benefit patients who develop blood clots in the leg, resulting either from disease or as a side effect of heart surgery.

If adopted by more surgeons, the procedure could benefit the thousands of U.S. patients each year who develop blood clots in the leg. Historically, as many as half of the patients who have these clots surgically removed may die from complications, and as many as 22 percent may undergo limb amputation, says Kai Ihnken, MD, a general surgery resident at the School of Medicine. The procedure could spare these patients the ordeal of amputation or other possible organ damage, he says.

* The procedure involves use of a special solution that is mixed with the patient's blood and then is very slowly reinfused back into oxygen-starved tissues in the body. This process, known as controlled reperfusion, avoids injury that commonly results when blood flow is suddenly restored to tissues suffering from prolonged lack of oxygen, says Ihnken. With uncontrolled reperfusion, the onslaught of blood releases toxins that can damage cells and trigger a heart attack or cripple a limb, he says.

"The initial 30 minutes of reperfusion has to be controlled if you are to avoid injury," Ihnken says. He discussed his experience with the technique October 4 in Kamuela, Hawaii, at the 46th annual world assembly of the American College of Angiology.

The procedure was initially devised by Gerald Buckberg, MD, at the University of California, Los Angeles, who developed the method in the early 1990s as a way to rescue oxygen -starved tissue in cardiac patients and to prevent tissue death that could lead to a heart attack. Ihnken, who studied under Buckberg, surmised that if the technique could work well in the heart, it should work equally well in oxygen-starved limbs. He returned to the University of Frankfurt, where he and his colleagues adapted the technique for use in the legs. These methods of controlled reperfusion have since been used in Europe in some 40 patients who were found in imaging studies to have reduced blood flow to either the heart or legs for as much as 24 hours, Ihnken says.

Ihnken brought his experience to Stanford, first applying the technique in December 1997 in a 16-year-old San Jose youth who suffered complications during surgery to correct a heart defect. During the surgery, the boy developed a blockage in a leg artery and showed signs of losing all function in the limb, Ihnken says. Doctors feared they'd have to amputate. At that point, the surgical team decided to apply controlled reperfusion. The procedure was successful, and the patient walked out of the hospital in good shape and has continued to do well, Ihnken says.

"In the past, we always thought that if an extremity had no blood supply, the best thing to do was to get as much blood restored as soon as possible," says Christopher Zarins, MD, professor and chief of vascular surgery. "It's taken some research and investigation to discover that the concept, which makes empiric sense, isn't actually true. If the extremity has been deprived of blood for a period of time, you should restore that flow gradually, not with one big burst." Zarins and Bruce Reitz, MD, professor and chair of cardiothoracic surgery, worked with Ihnken to apply the technique at Stanford.

* During the limb procedure, doctors clamp the artery and insert a tube just above the arterial blockage to withdraw some of the patient's blood. They mix the blood in a 6-to-1 ratio with a buffered solution containing salt, glucose, protein, a free radical scavenger and other protective elements. They then slowly infuse this mixture back into the leg with a pump that maintains a relatively low pressure. The clamp is then removed, allowing the blood to flow freely. The procedure takes about 30 minutes, Ihnken says.

In addition to benefiting patients with blood clots, the procedure has the potential to help people undergoing cardiac surgery, such as emergency coronary artery bypass surgery, as well as patients receiving transplanted organs, Zarins says. Transplant recipients often experience reperfusion injury when blood flow is restored to the new organ, he says.

"I think it's very promising," Zarins says. "It's something that we have only started to do and it is still in the early phases, but the early results are very encouraging." -- RR

 

Right under our noses:
More microbial inhabitants of the mouth revealed

THE HUMAN MOUTH IS AWASH WITH BACTERIA. MOSTLY AMICABLE BUGS, THEY LIVE ON OUR TEETH AND GUMS, HELPING TO DIGEST FOOD AND TO WARD OFF ATTACK BY LESS FRIENDLY, DISEASE-CAUSING BACTERIA THAT CAN STEAL THEIR WAY IN.

Stanford researchers have now shown that more of these oral inhabitants exist than previously thought. Using a combination of old and new scientific methods to study a scraping of plaque from a healthy human mouth, the researchers found evidence of 37 unique bacteria that microbiologists had never before recorded. Some were closely related to bacteria that scientists are familiar with, but others were very different.

* Knowing more about the bacteria that reside in a normal, healthy mouth may help physicians understand changes in the bacterial population that can lead to gingivitis, periodontitis and tooth decay.

"Our data suggest that a significant proportion of the resident human bacterial flora remain poorly characterized, even within this well-studied and familiar microbial environment," says David Relman, MD, assistant professor of medicine and of microbiology and immunology at Stanford.

According to Relman, the subgingival crevice -- the deep gum pocket cradling each tooth -- has been repeatedly scrutinized in the search for microbes. Even though almost 500 bacterial strains have been identified already, Relman believes they may represent only a fraction of the bacteria living in this oral groove.

Oral bacteria have traditionally been studied by taking a scraping or sample from inside the mouth, growing the bugs in the laboratory and then identifying different species according to biochemical tests and the type of food source that each bacterium prefers. Using this method, the Relman team identified bacteria found in a sample of plaque taken from the subgingival crevice.

* They also searched the same sample using molecular techniques. Instead of nurturing the bacteria in the lab, they prepared DNA directly from the plaque and studied each genetic sequence that had a bacterial signature. Comparing the results, they found that the molecular method yielded many new bacteria. Not only did the method reveal bugs that had never before been found in the mouth, many were bugs that had not yet been documented by microbiologists.

* The team discovered 31 bacteria using the molecular method. In contrast, the traditional approach, which identifies only bacteria that can be cultivated in the lab, uncovered only six new bugs.

"Sequence-based environmental microbial surveys have taught us that cultivation methods woefully underrepresent the true extent of bacterial diversity," says Relman.

Although the cultivation method traditionally used by clinical microbiology labs did not uncover the bacterial diversity revealed by the molecular technique, the researchers found that some bacteria were more readily recovered the old way, indicating that both DNA analysis and cultivation have a role in the comprehensive study of human microbial populations.

Characterization of previously undocumented oral bacteria is part of the Relman team's larger effort to identify rare and unusual microbes that make their home in the human body -- many cohabiting benignly but some causing mysterious human disease.

Relman and colleagues published their findings in the December 7, 1999, Proceedings of the

National Academy of Sciences. -- KW

 

Researchers pool data to answer questions
about rare lung disease

BECOMING SICK CAN SEEM DOUBLY UNFAIR IF YOU HAVE A RARE DISEASE. FALLING ILL IS ALREADY A MISFORTUNE, but to make matters worse the rarity of the disease often thwarts scientific investigation that could lead to a treatment or cure.

Hoping to overcome the limitation of small numbers, Stanford has joined with five other research centers to pool data on the rare lung disease lymphangioleiomyomatosis (LAM). The goal of the LAM registry, which began operating about two years ago, is to bring together enough information to answer questions about the origin, course and cause of LAM, including the role played by genes.

* Each center will collect data on as many LAM patients as possible and monitor their health for five years. Each year, patients will be given chest X-rays, lung-function tests, exercise tests and a questionnaire to measure how the disease is affecting their quality of life. All of this information, along with samples of lung tissue and blood, will be sent to a central databank at the Cleveland Clinic in Ohio, where it will be available to other researchers in the project. The National Heart, Lung and Blood Institute is providing the funding.

Stanford was chosen as one of the six sites because Thomas Raffin, MD, professor and chief of the Division of Pulmonary and Critical Care Medicine, is one of the few LAM experts in the world.

* LAM is a relentless and often fatal disease that ravages the lungs of young and middle-aged women. In normal lungs, a sheath of smooth muscle cells surrounds the airways and, by contracting or relaxing, regulates air flow to match the body's need for oxygen. But in LAM patients, over years the smooth muscle cells begin to multiply uncontrollably. Bundles of cells can narrow the airways and block blood and lymph vessels, causing difficulty breathing, internal bleeding and fluid buildup. Proliferating muscle can pinch off the small air sacs known as alveoli, which can then form air-filled cysts. Cysts near the surface of the lungs -- known as blebs -- can rupture and cause a partial or complete collapse of the lung. Although LAM involves out-of-control cell replication and shows some similarities to the skin cancer malignant melanoma, the disease is not considered a form of cancer, Raffin says.

* For LAM patients, whose first symptom is usually shortness of breath during exercise, treatment usually does not stop the progression of the disease. Most patients develop severe breathing difficulties within 10 years of diagnosis, and less than 50 percent survive more than 20 years. Since the disease occurs almost exclusively in women of childbearing age, scientists naturally suspected the hormone estrogen was somehow involved. However, chemical treatment to block estrogen and even removal of the ovaries do not seem to slow the disease, Raffin and colleagues reported in a 1990 study published in the New England Journal of Medicine. Lung transplants can extend life for a number of years but create other problems, such as the risk of rejection and infection.

* As with so much else about LAM, the cause remains mysterious. Genes undoubtedly play a role, Raffin says, but further research is hampered not only by the rarity of patients but also by the lack of an animal model of the disease that could be studied in the laboratory. Besides humans, only bottlenose dolphins have been reported to get LAM, Raffin notes.

In the two years since the registry opened, 129 patients have enrolled, says Susan Jacobs, RN, who coordinates clinical trials in pulmonary and critical care medicine at Stanford. That may not seem impressive until you consider that only 500 or so Americans have LAM. The registry will continue accepting new patients through 2001.

With the information in the LAM registry, scientists will be able to better understand how the disease damages the lungs and to undertake longitudinal studies of LAM's progression. Researchers will also be able to evaluate the success of treatments, identify likely complications, improve diagnosis and determine how long patients survive with the disease. Blood samples should speed the hunt for genes that contribute to the disease. -- ML