LLUMC Legacy: Daring to Care
UNIQUE CONTRIBUTIONS THROUGH RESEARCH
To measure the severity of a patient's lung disease or to detect whether the patient had lung disease, the first inspiration-expiration measuring device, or spirometer, was invented in 1846.
Today modern spirometry, used by most hospitals, measures the breathing capacity of the lungs. While administering the test, the technician must repeatedly encourage the patient to "breathe in...out...in...out...keep going...deeper...that's it...keep going...." This time-consuming test has taken about one hour to administer and 30 minutes to evaluate.
In 1972-73, Loma Linda University scientists developed a spirometric computer program which reduces from 30 minutes to about five seconds the time spent in analyzing, interpreting, and reporting the results. This aids the physician, a pulmonary specialist, in making a quick and accurate diagnosis.
The computer-assisted spirometer calculates the flow-volume ratio. This ratio is an accurate measure of breathing performance. On a computer monitor, the ratio is graphically displayed as a closed loop. By studying the shape of the loop, the technician can see whether the patient is fully cooperating (breathing as deeply as he can) and whether the test should be repeated. The shape of the loop also reflects the area of the lung in which the patient is having trouble; thus it can suggest diagnoses which might be overlooked by conventional spirometer tests. The loop displayed on the video screen is also recorded on a picture printout, and the computer provides an interpretation of the printout.
This unique computer program was developed by two pulmonary specialists, George G. Burton, M.D. (Class of 1961), and John E. Hodgkin, M.D. (Class of 1964). Working with them was John A. Lauer, a graduate student, who incorporated the results of his research into a master's degree project.
Grey Scale Diagnostic Ultrasound
Diagnostic ultrasound is a diagnostic tool based on the principles used in sonar: It uses harmless sound waves to "see" inside the human body. A transducer, functioning alternately as a sound transmitter and microphone, emits sound waves approximately 1,000 times a second. As these sound waves are reflected from the surface of a particular internal structure in the body, they are picked up by the transducer and converted to electrical energy and then to light, creating a black and white line-drawing on an oscilloscope. The picture is based on the time it takes for the echo to return to the transducer.
In 1972 Ernest N. Carlsen, Ph.D., M.D. (Class of 1969), developed the technique and equipment for what is known as "Grey Scale Imaging." This pioneering technological breakthrough has revolutionized diagnostic ultrasound. By the use of a scan-converter (a specialized storage tube capable of building and storing an image with various shades of grey), a "picture" is developed that can be displayed on a computer monitor. "Grey Scale" produces pictures of internal structures ranging through the spectrum from white to black, much as in an ordinary photograph. It provides a much wider range of diagnostic information than did the black and white outlines of original ultrasound.
A three-dimensional re-creation of the internal structure being studied can be developed by making a series of vertical cross sections through the body. This process might be compared to slicing a loaf of bread. The ultrasound specialist can study any of the cross sections just as one might examine any slice from a loaf of bread.
Diagnostic ultrasound can safely confirm pregnancy from three to four weeks after conception, considerably sooner than with more traditional methods. It can monitor fetal development, determine fetal age and sex, confirm multiple pregnancies, measure retardation of fetal growth or detect death. It can picture a fetal abnormality as small as a defective heart valve. Diagnostic ultrasound can see the liver, spleen, kidneys, pancreas, large blood vessels, and lymph glands in the adult. It can detect hard-to-find growths or cysts in the abdomen, help locate and identify tumors, and help diagnose internal infection and internal bleeding (if the blood pools). It can detect tumors of the heart, defective heart valves, and blood vessel ruptures; and it can determine the size of heart chambers.
Radiation Therapy Planning
Advances have been made in recent years in the development of radiation therapy equipment which greatly enhances the capabilities of the physician who specializes in cancer treatment (the radiation oncologist) and the radiation physicist. There is now available a wide variety of equipment which can produce well-defined beams of radiation of infinitely varied shapes and sizes. Precise doses of radiation can now be delivered to specific tumor sites to retard or stop tumor growth.
But radiation can damage healthy as well as diseased tissues. To minimize the harmful effects, the radiation oncologist, in consultation with the radiation physicist, must plan a program of therapy which will deliver therapeutic doses of radiation to the site of deep tumors with minimum damage to surrounding areas.
For the patient's safety, precise measurements and careful planning are extremely important. But such procedures can be complex and time-consuming.
To simplify and speed the making of such a treatment plan, scientists under the direction of James M. Slater, M.D. (Class of 1963), began in 1974 to develop a computer-based radiation therapy planning system, which uses an ultrasound scanning device and a color video screen.
This radiation treatment planning system can accept data about the patient from the ultrasound scan, computerized tomographic (CT) scans, diagnostic Xray pictures, radioactive isotope scans, and other sources. In essence, it brings together in one integrated, computerized unit all the electronic and technical hardware and all the diagnostic and anatomical treatment planning tools of the cancer treatment specialists.
As compared with older methods, this system provides a much more rapid and accurate evaluation of possible treatment alternatives; it also gives the therapist the capability of determining much more quickly the best possible radiation dose-distribution pattern for the individual patient--more quickly because all the information about the patient is immediately available and can be instantly processed by the computer.
This system is also capable of recording, for future reference, accumulated dose-distributions for patients who have been treated under several different treatment plans; thus the treatment specialist knows the total amount of radiation to which the tumor and surrounding area have been exposed.
While today there are many similar integrated radiation therapy planning systems in leading hospitals, Slater pioneered interfacing diagnostic tools with the computer system, now one of the most versatile and complete systems in the world.
Chosen to be members of the United States delegation to Vienna, Austria, in March 1975, Slater and William T. Chu, Ph.D., presented their research in developing this system to the International Atomic Energy Agency Symposium of Advances in Biomedical Dosimetry. Their exhibit entitled "Computerized Radiotherapy Planning System" won first prize at the Third International European Congress of Radiologists, held in Edinburgh, Scotland, in June 1975.
Fetal Studies
Lawrence D. Longo, M.D. (Class of 1954), distinguished professor of physiology, obstetrics and gynecology, and pediatrics, and head of the Division of Perinatal Biology at Loma Linda University School of Medicine, has developed a world-renowned research center for fetal-newborn developmental physiology. The Division consists of a group of biomedical scientists, postdoctoral fellows, and graduate students devoted to investigating the biology of the developing infant. The faculty of the Division constitutes a multi-disciplinary group with a unique and broad perspective that is ideal for research and for training new investigators. Without exception, they are national and international leaders in their disciplines.
Some of the questions Longo and his associates address are: Why are some infants born with cerebral palsy, mental retardation, epilepsy, and other disorders? What is the biochemical basis for these developmental abnormalities? Why are infants who are malnourished or anemic, who live at high altitude, or whose mothers smoke smaller than normal? What are the biological implications of their growth retardation? How can the fetal and newborn cerebral blood vessels be regulated, so as to deliver oxygenated blood optimally?
Dr. Longo has published more than 300 scholarly papers in scientific journals and has written a number of governmental reports, including the section in the Surgeon General's report on smoking and health hazards to the mother and fetus. He also played a key role in legislation that required warning labels on cigarette packages regarding the hazards of smoking in relation to heart disease, lung disease, and problems for the pregnant woman and her fetus. Dr. Longo also served on the scientific advisory panel of the Environmental Protection Agency, which made recommendations leading to enactment of the Clean Air Act.
In 1988 Longo received a NATO professorship from the scientific research council of the Italian government. He has served as scientific consultant to such organizations as the National Institutes of Health, National Research Council, and National Science Foundation.
Fighting Osteoporosis
David Baylink, M.D. (Class of 1957), distinguished professor of medicine and professor of orthopaedic surgery and biochemistry, is leading the battle against osteoporosis. Osteoporosis, one of the deadliest diseases among the elderly, destroys the body's skeletal structure, leaving bones porous, brittle, and weak. It is the eighth leading cause of death in the elderly, affecting 10 million women and several million men in the U.S.
"We're talking about a major health problem," says Dr. Baylink. "Osteoporosis, contrary to common belief, is not only a preventable and treatable, but also can be accurately diagnosed. A battery of diagnostic procedures can determine the presence of osteoporosis."
Dr. Baylink directs a large basic-sciences research laboratory based largely on the problems observed in his clinic patients. He has linked the treatment of the disease with "growth factors," chemical substances in the body that, like hormones, help regulate the growth of tissue, especially the growth and renewal of bone. Bone, he says, is the body's main storage depot for growth factors. Dr. Baylink is the author of 500 scholarly papers and director of the Loma Linda University osteoporosis clinic, one of the largest clinics of its kind in the world.
Research to Benefit Open Heart Surgery
Three honors were awarded in 1975 to a six-member interdepartmental research team under the direction of Brian S. Bull, M.D. (class of 1961), at that time chair of the Department of Pathology. Their research demonstrated a method which significantly increases the safety and success of open-heart surgery.
During open heart surgery, heparin, an anticoagulant medication, is used to prevent clotting of the blood. After surgery another medicine, protamine, is used to neutralize the effects of the anticoagulant. The traditional approach has been for the anesthesiologist to follow strict guidelines based on the patient's body weight and body surface area to calculate the heparin and protamine doses.
The Loma Linda University team concluded that the traditional weight/surface area method could lead to dangerous clotting or other hazards because of wide variability in patient response. They developed a method of individualizing the medication dosage, depending on how a sample of the patient's blood responds to the heparin and protamine during the first few minutes of surgery. During their research the team developed mathematical calculations to plot an individual dose-response curve from which the correct doses could then be determined. (This has since been computerized.)
An exhibit describing these advances was prepared for the 1975 national meeting of the American Society of Anesthesiologists. Twenty-five scientific exhibits were accepted for display. Judged on the basis of their value in presenting new scientific concepts and methods, the exhibit--"The Laboratory Control of Heparin and Protamine Therapy in Cardiovascular Bypass"--won first prize by unanimous vote of the judging committee.
A paper by the same team--"Evaluation of Tests Used to Monitor Heparin Therapy during Extracorporeal Circulation"--was selected for inclusion in the 1976 Yearbook of Anesthesiology, a compilation of summaries of the year's best articles published in the field of anesthesiology. This honor was followed by a third.
A member of the team, Ralph A. Korpman, M.D. (Class of 1974), a medical student at the time he wrote the computer simulation program, received first prize for the best research done during the year by a medical student in a University Department of Pathology--the Sheard Sanford Award. He received the award and presented his findings at the joint 1975 spring meeting of the American Society of Clinical Pathologists and the American College of Pathologists.
In 1990 another Sheard Sanford Medical Student Award was presented to Patricia M. Kopko, a junior medical student. Also, her paper, "Thrombin Generation in Nonclottable Mixtures of Blood and Nonionic Contrast Agents" also published in Radiology (1990, Volume 174, pages 459-461), and accompanied by a lengthy editorial saying the paper was of "critical importance."
Kopko's research, also performed in Dr. Bull's laboratory, will help physicians performing Xray examinations of blood vessels to avoid potential complications. According to Dr. Bull, the singling out of a paper, by co-publishing it simultaneously with an editorial on the same topic, is an unusual honor accorded only to papers deemed to be highly significant. Ms. Kopko was presented the award at the national fall meeting of the American Society of Clinical Pathologists in Dallas, Texas, in October, 1990.
Citation Classics
One of the ways the scientific community's acceptance of research projects can be measured is by the number of citations a research paper receives from other scientists in the same discipline. Every time another scientist refers to a particular paper in support of his own work, the citation is recorded by organizations such as the Science Citation Index (SCI). SCI thus identifies the papers that stand out in a particular field. Eventually, if a paper is cited often enough over a 10 to 20-year period, it will be designated a Citation Classic. Three papers written from Loma Linda University by faculty members, both in the Department of Pathology and Laboratory Medicine, have achieved this distinction.
In 1958 Albert E. Hirst, Jr., M.D. (class of 1942, department cchair 1963-73), together with V. J. Johns, Jr., M.D., and S.W. Kime, Jr., M.D., completed a paper entitled "Dissecting Aneurysm of the Aorta: A review of 505 Cases." This paper (Medicine 37:217-79, 1958) is a collective review of 505 cases of dissecting aneurysm of the aorta, emphasizing historical aspects, clinical pathologic correlations, unusual manifestations, course, and treatment of the disease. It took Dr. Hirst and his team six years to complete the paper. This paper was named a Citation Classic in July 1981.
In 1965 Brian S. Bull, M.D. (class of 1961; department chair 1973Ð1994), together with M. A. Schneiderman and G. Brecher, described a method for the machine counting of platelets in human blood, using small samples of platelet-rich plasma. (American Journal of Clinical Pathology, 44:678-88, 1965.) The method included correction factors by which the resultant count could be transformed into a whole blood platelet count. It has rendered rapid and reproducible platelet counts with a minimum of technologist involvement, and thus has served the medical and scientific community well. This scholarly paper became a Citation Classic in October 1980.
In 1968 Brian S. Bull, M.D., together with M. L. Rubenberg, M.D., J. V. Dacie, M.D. (now Sir John Dacie), and M. C. Brain, M.D., wrote a paper entitled "Microangiopathic haemolytic anaemia: mechanisms of red-cell fragmentation: in vitro studies." This paper (Brit. J. Haematol. 14:643-52, 1968) describes how red cells fragment during intervascular clotting. With the use of a circulatory model created by Dr. Bull, the instant of red-cell fragmentation was captured on film. The paper's popularity, in part, may be due to its very graphic pictures of red-cell destruction. In February 1986 this paper was named a Citation Classic.