 
Medical Alchemy Could Cut Heart Failure Deaths
Medical Alchemy Could Cut Heart Failure DeathsResearchers at the University may have succeeded where the alchemists of old failed. Rather than turning base metals into gold, they have found a way to turn sodium channels into calcium channels. The finding could prove more valuable than gold to the millions of people who suffer from cardiovascular and neurological diseases.W.J. Lederer, MD, PhD, A.M. Gomez, PhD, and L.F. Santana, PhD, reported their findings in the Feb. 13 issue of Science. Dr. Lederer is professor of physiology at the School of Medicine and head of the Department of Molecular Biology and Biophysics at the Medical Biotechnology Center; Drs. Gomez and Santana are senior post-doctoral fellows. The researchers discovered that common neurotransmitters like adrenalin and drugs like digitalis can transmute sodium channels into calcium channels. "We found that the sodium channel can be stimulated to do something new and different by a neurotransmitter like adrenalin. It can be induced to conduct calcium," Dr. Lederer says. "A sodium channel that conducts calcium under normal conditions is without precedent." "What's more," he adds, "when the sodium channel conducts calcium in heart muscle, it significantly increases contraction. This is not academic minutia; this is truly revolutionary." Calcium movement through sodium channels is a new cell-signaling pathway, says Lederer. "Under the control of nerve activity and circulating hormones, this system can be turned on and off. Although the work was done in heart cells, the sodium channel is one of the most constant protein channels in biology, and these results may apply to all excitable cells." This finding could explain how traditional remedies such as digitalis work for conditions like heart failure. More importantly, Dr. Lederer says, the discovery provides completely novel targets for drug discovery and molecular medicine. Not only could the Maryland researchers' findings lead to development of more effective drugs to treat heart failure, they could have broad applications in developing drug therapies for a variety of nerve, brain and muscle conditions. Dr. Lederer named the new signaling pathway "slip-mode conductance" of the sodium channel. He is widely known for his discovery of calcium "sparks" that occur inside excitable cells and can account for the normal heartbeat, cardiac arrhythmias, contraction of skeletal muscle, and control of vascular tone. In February, he received the prestigious Cole Prize of the Biophysical Society for his work on calcium sparks. The slip-mode conductance research was supported in part by the National Institutes of Health's National Heart, Lung and Blood Institute and the University's Directed Research Initiative Funds, with equipment furnished by the Medical Biotechnology Center of the University's Biotechnology Institute. Jennifer Donovan
Natural Sugar-Phosphate Compound Shows Promise as Cancer Treatment
In a study of human liver cancer cells treated with inositol hexaphosphate (IP6) and transplanted into mice, Abulkalam M. Shamsuddin, MD, PhD, professor of pathology, and colleagues found that IP6 slowed or stopped the growth of liver cancer cells and shrank existing tumors three- to four-fold. The Maryland researchers reported on their findings at the American Association for Cancer Research annual meeting in March.
"IP6 does not kill cancer cells; it tames them and makes them behave like normal cells," says Dr. Shamsuddin. His research has focused on the cancer-fighting properties of the sugar-based compound for more than a decade.
Inositol hexaphosphate is a sugar molecule attached to six phosphate molecules. It is found throughout nature, in wheat and rice bran, legumes such as soybeans, and virtually every kind of mammalian cell, and it plays an important role in regulating vital cellular functions, including proliferation and differentiation.
IP6 decreases proliferation of cancer cells and causes them to differentiate, often reverting to the size, shape and structure of normal cells, Dr. Shamsuddin reports. "IP6 has striking anticancer action, both in vitro and in vivo," he says.
In the human liver cancer cell study, Dr. Shamsuddin's team treated human hepatocellular carcinoma cells with varying doses of pure IP6. The result was partial to complete inhibition of cell growth and proliferation, depending on the dose. Treated cells transplanted into mice produced no tumors over the 41 days of the experiment, while 71 percent of mice receiving untreated cancer cells developed tumors.
Mice that developed tumors from the human cancer-cell line were injected with IP6 for 12 consecutive days. After the last treatment, their tumors weighed three- to four-fold less than they had before the injections, Dr. Shamsuddin reports.
IP6 has moved in and out of medical favor since its discovery. Its antioxidant properties sparked excitement, followed by concern that IP6 binds tightly with important minerals such as calcium, magnesium, copper, iron and zinc, preventing the body from absorbing them properly. Recent studies have shown that concern to be unfounded, says Dr. Shamsuddin. It is true that when consumed, IP6 combines with various proteins and other large molecules to form insoluble compounds that are not readily absorbed or metabolized, the researcher notes. For that reason, adding IP6 to the diet would be less effective than giving it either orally or intravenously in pure form, dissolved in water says Shamsuddin.
"Although IP6 is the substance responsible for cereal's anticancer effects, intake of pure IP6 may be a more practical approach than gorging on enormous quantities of dietary fiber to prevent cancer," he remarks.
Dr. Shamsuddin also has tested IP6 on colon, lung, breast and prostate cancer cells, on leukemias, fibrosarcomas and muscle cell cancers in children.
"IP6 has a potential for use as a novel preventive measure and treatment for a variety of cancers," Dr. Shamsuddin suggests. It also holds promise for prevention and treatment of cardiovascular disease, kidney stones and possibly even immune-system disorders like AIDS, he says.
Dr. Shamsuddin's research was supported in part by the American Institute for Cancer Research.
Jennifer Donovan
Pneumococcal disease, a group of illnesses caused by the bacteria Streptococcus pneumoniae, includes the common childhood ear infection otitis media, as well as more invasive infections such as pneumonia, bacteremia, and bacterial meningitis. More than 1.3 million children under age 5 die each year worldwide as a result of pneumococcal disease.
In the United States, children ages 2 and under are at greatest risk for invasive pneumoccocal disease (160 cases per 100,000 population). Acute otitis media is the number-one reason for visits to the pediatrician (24 million visits each year). Currently, there is no vaccine available to protect young children against pneumococcal disease.
"Traditionally, we have treated these infections with penicillin and other antibiotics," says the study's author, Margaret B. Rennels, MD, infectious disease specialist at the Medical Center and professor of pediatrics in the School of Medicine. "But the alarmingly rapid emergence of strains resistant to both penicillin and cephalosporins has created an urgent need for pneumococcal vaccines that are effective in infants."
The vaccine used in the study, PNCRM7, is formulated to protect against the seven most common strains of Streptococcus pneumoniae in the United States.
In the randomized, double-blind study, 212 healthy 2-month-old infants were enrolled at centers in Baltimore, Atlanta, Nashville, and Pittsburgh. Half received PNCRM7 and half received a control vaccine. Each child was given doses at 2, 4 and 6 months and those who remained in the study also received a booster dose at 12 to 15 months. Blood samples were collected at various intervals to test for a rise in antibodies. Results showed the vaccine produced immunity against all seven strains of Streptococcus pneumoniae, was well-tolerated with only minor reactions at the injection site and caused only mild to moderate post-vaccination fever in some children.
"Primary immunization, followed by a booster dose of PNCRM7, seemed to be acceptably safe and resulted in significant rises in antibody to all seven strains," says Dr. Rennels. "If that level of immunity proves to be protective, we will have the potential to prevent up to 85 percent of invasive pneumococcal disease and 65 percent of pneumococcal otitis media in U.S. children."
Major studies are currently under way in Finland, Northern California and on a southwest Indian reservation to determine the effectiveness of this vaccine in preventing against otitis media and invasive pneumococcal disease in children. PNCRM7 is being developed by Wyeth-Lederle Vaccines and Pediatrics.
Ellen Beth Levitt
Richard F. Macko, MD, assistant professor of neurology and gerontology at the School of Medicine, won this year's Robert G. Siekert New Investigator Award in Stroke from the American Heart Association Stroke Council for his study of the effects of B-vitamin therapy on homocysteine levels and other markers of damage to the cells lining the walls of arteries.
At the 23rd International Joint Conference on Stroke and Cerebral Circulation, Dr. Macko presented results of a double-blind, placebo-controlled study of 50 non-vitamin users who had strokes. Their average age was 67. Those randomly assigned to receive treatment took 100 milligrams of B6, one milligram of B12 and five milligrams of folate daily for three months.
Levels of homocysteine and thrombomodulin dropped significantly after three months of vitamin therapy, Dr. Macko says. The vitamin regimen produced no unwanted side effects.
"We were excited to see such a change after just three months," Dr. Macko notes.
About three out of every 10 people over the age of 65 have mild to moderate elevations in blood homocysteine levels. "We don't know if lowering those levels will directly lower the risk for stroke or heart attack," the neurologist says, "but we do have evidence that there is less damage to endothelial cells when we lower homocysteine, and we do know that damage to endothelial cells is associated with stroke. Since stroke is the third most common cause of death and the leading cause of disability in older people, anything that lowers risk is worth exploring."
Dr. Macko's research also revealed an unexpected change. Another protein in blood, von Willebrand's Factor antigen (vWF), rose in study subjects receiving vitamins. The antigen plays a key role in clotting and bleeding.
Dr. Macko says he's not sure what the unanticipated rise in vWF means. "We don't know if it increases stroke risk," he says. "We do have evidence of less endothelial cell damage, so we hope that we have simply restored normal vWf synthesis."
Jennifer Donovan
FishGutsTM 1.0 for Windows and Macintosh was produced by Andrew Kane, PhD, assistant professor of pathology and associate director of the University's Aquatic Patho-biology Center Dr. Kane designed the software for researchers, veterinarians, graduate students and fish health experts. The interactive program covers basic external and internal fish anatomy, diagnostic examination techniques, fish autopsy procedures, tissue sample preparation, and instructions for completing final case reports.
Dr. Kane narrates the software, giving instructions for lethal and non-lethal fish examination methods such as skin scrapes, gill biopsy, blood sampling, organ system dissection and sample preservation. Digital movies show live, mobile fish parasites and illustrate many of the techniques.
The Aquatic Pathobiology Center provides research and holding facilities for freshwater and marine organisms. The 35,000-square-foot facility houses a fish culture area, an experiment room, two toxicological bioassay suites, necropsy and tissue preparation rooms, a research laboratory, a conference room/ library and offices. An extensive water filtration and delivery system provides fresh, brackish and marine water to various research tanks. Center researchers specialize in environmental and comparative pathology, toxicology, molecular biology, immunology and aquaculture science. Faculty members also instruct visiting graduate and veterinary exchange students in diagnostic fish and invertebrate pathology and aquatic animal medicine. The center offers toxicity testing for environmental monitoring and animal diagnostic service for aquariums and zoological institutions nationwide.
The CDs sell for $185. For more information, contact the Aquatic Pathobiology Center at http://som1.ab.umd.edu/AquaticPath/fg.
Kristy Wooley
Alumni, faculty and friends are invited to submit nominations for the two 1999 MAA-sponsored awards by Feb. 1. The Honor Award & Gold Key is awarded to a living alumnus based on outstanding contributions to medicine and distinguished service to mankind. Factors considered in the selection process include: impact of accomplishments; local, national and international recognition; supporting letters; and publications.
The MAA Service Award honors an individual who has provided outstanding service to the Association.
Letters of nomination for both awards must include curricula vitae and should be addressed to:
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