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December 6, 2001


Bioterrorism research at Pitt & CMU receives grant

The BioMedical Security Institute (BMSI), a joint initiative of Pitt's Graduate School of Public Health (GSPH) and Carnegie Mellon University, has received a $755,563 grant from the Centers for Disease Control and Prevention (CDC) for research on bioterrorism preparedness and response.

"Since the events of September 11, the relevance of bioterrorism research has become startlingly apparent, and the work being conducted here in Pittsburgh is of great importance to the national effort," said BMSI Director Samuel Watson of GSPH.

The recent CDC award provides BMSI with an additional year of funding for continuation of research projects that were first funded by the CDC in October 2000, as well as several new areas of research. Additional funds have come from the Agency for Healthcare Research and Quality, and the Defense Advanced Projects Research Agency.

Pitt research projects funded through these grants include: textual information and natural language processing (Wendy Chapman, Center for Biomedical Informatics), clinical event monitoring (Fu-Chiang Tsui, Center for Biomedical Informatics), trusted broker for information systems (Ravi Sharma, GSPH), mental health aspects of bioterrorism (Andrew Baum, School of Medicine) and syndromic detection of anthrax (Lee Harrison, GSPH and School of Medicine). The projects led by Chapman, Tsui and Sharma are part of a larger research effort to develop a computer-based surveillance system to provide early detection and warning of bioterror attacks.

BMSI and the bioterrorism preparedness and response program at GSPH are seeking one-page concept and proposal papers for submission to various federal agencies.

BMSI was established in 2000 with a mission to advance the nation's capability to detect, analyze, prevent and respond to natural events and acts of terrorism involving biological agents.



Grants awarded to researchers

The U.S. Army Medical Research and Development Command has awarded Adam Brufsky of the University of Pittsburgh Cancer Institute a $1.6 million grant to support the Pittsburgh Breast Cancer Consortium (PBCC).

The goal of PBCC — a collaboration involving the cancer institute, Magee-Womens Hospital and other partners — is the rapid clinical development of new agents for treating metastatic breast cancer.

Robert Enick of chemical and petroleum engineering has been granted $325,000 by the U.S. Department of Energy for a project that will design novel low molecular weight agents that enhance the viscosity of supercritical carbon dioxide.

The National Science Foundation has granted $300,000 to the computer science depart-ment's Daniel Mosse to investigate "new and potentially revolutionary" approaches to protecting computer networks from break-ins and abuse without lowering quality of service.

Laurie Mulvey of the University Center for Social and Urban Research has received a $2 million grant from the Administration on Children, Youth and Families to expand the Family Foundation's Early Head Start program to the East End corridor of Pittsburgh.

The area includes Bloom-field, East Hills, East Liberty, Friendship, Garfield, Home-wood, Larimar, Lawrenceville, Lemington, Lincoln and Morningside.

The National Cancer Institute has granted Jack Yalowich of pharmacology $259,130 to characterize the mechanisms and prevention of etoposide-induced leukemia.



Pitt study finds new answers to miscarriage

A genetic flaw located in the X chromosome appears to be a key component of recurrent miscarriage among some women, according to a new study.

Reporting in the American Journal of Obstetrics and Gynecology, physicians and scientists at Pitt Health Sciences schools and Magee-Womens Research Institute found that an abnormality in one of the mother's two X chromosomes may be at work in causing repeated pregnancy loss.

"This is exciting news for women who have suffered recurrent miscarriages with no idea why," said study author W. Allen Hogge, a professor of obstetrics, gynecology and reproductive sciences and an associate professor of human genetics at Pitt's School of Medicine. "Until now, even extensive testing has often been unable to pinpoint a cause." In fact, up to half of women who have had miscarriages could discover no medical explanation for their losses.

Working with the Children's National Medical Center at George Washington University, the Pittsburgh team found that the X-chromosome gene flaw is detectable in the mother's blood. No health risks, however, have been associated with this abnormality in the women themselves.

These women, who are carriers of X-linked recessive disorders, are more likely to miscarry male fetuses, said Hogge, calling the finding "statistically significant."

The study of 105 patients revealed that 14 percent of participants with previously unexplained recurrent miscarriages had X-linked recessive lethal traits, said Hogge, who is a clinical investigator at Magee-Womens Research Institute and medical director of genetics at Magee-Womens Hospital of the UPMC Health System.

Some 50 percent of male pregnancies receive the mother's anomalous X chromosome, causing the fetus to spontaneously abort. Female fetuses are less likely to be miscarried because there are two X chromosomes, and they need only be linked to one. Because of this, they have a 50-50 chance of avoiding the faulty gene.

Though there is no known cure for this genetic flaw, the availability of a blood test will be a significant improvement in risk assessment for future pregnancies, fertility and counseling, Hogge said.

In addition to Hogge, study authors included Mark C. Lanasa, Carolyn Kubik, James Harger and Tracy Posen, all of the Pitt School of Medicine; Roberta B. Ness of Pitt's Graduate School of Public Health; Nina Markovic of Pitt's School of Dental Medicine; Eric Hoffman, Children's National Medical Center, and Theodore Nagel, University of Minnesota.

The study was funded in part by grants from the National Institutes of Health and the NIH Medical Scientist Training Program at Pitt.



New tumor antigen, candidate for cancer vaccine identified

The protein cyclin B1, a newly identified tumor antigen, holds promise as a candidate for the development of a cancer vaccine, according to a Pitt study.

The new antigen will be used in future cancer vaccine trials for breast cancer, lung cancer and head and neck cancer, said Olivera Finn, co-author of the study, professor of molecular genetics and biochemistry at Pitt's School of Medicine and leader of the immunology program at the University of Pittsburgh Cancer Institute.

"We are very excited about this discovery. Identifying new tumor antigens that elicit strong responses by the immune system is imperative for the success of tumor-specific immunother-apy," Finn said. "If we can use a patient's own immune system to recognize and attack existing cancer cells and prevent future tumors from developing, we are closer to finding a more effective and less toxic treatment for cancer and to possibly preventing certain types of cancer."

In the study, cells of the immune system from healthy donors were exposed to dendritic cells generated in vitro (outside the body) that contained peptides from a breast cancer cell line. Dendritic cells are referred to as the pacemakers of the immune system — they are the first cells to recognize and process antigens. Antigens are substances that cause the immune system to make a specific immune response by producing antibodies and killer T cells.

When the researchers examined the immune responses that were generated, they determined that their target was a fragment derived from cyclin B1, a protein that regulates cell growth and proliferation. They also found that cyclin B1 was over-expressed in breast and lung cancer cells, as well as squamous cell carcinomas of the head and neck, but not in normal cells, indicating that it is a tumor antigen.

According to Finn, these findings are important because very few tumor-specific antigens have been identified in epithelial tumors, which account for over 83 percent of all human tumors.

This study was funded by grants from the Department of Defense and the National Institutes of Health. Collaborators on the study included Pitt researchers Henry Kao, Thomas K. Hoffmann, Sydney D. Finkelstein and Theresa L. Whiteside, as well as researchers from the University of Virginia in Charlottesville.

Study results were published in the November Journal of Experimental Medicine.



UPB institute director to lead study in national parks

Thomas Pauley, director of the Allegheny Institute of Natural History at Pitt's Bradford campus, and a group of scientists and students will be turning over rocks and logs and looking in streams and ponds next spring to find, examine and count amphibians and reptiles in eight national parks.

Pauley's work is part of a two-year project for the National Parks Service, which granted the institute $114,000.

"As soon as that first rain starts in the spring, we're going to have to pack it up and be over there waiting," said Pauley, a noted herpetologist. "The amphibians and reptiles will be coming out en masse." Currently, those cold-blooded animals are burrowed underground to stay warm, he said.

Amphibians, which include frogs, toads and salamanders, are very susceptible to the environment. They lack a protective covering, their eggs don't have shells and their larvae have gills so they're exposed to the environment. For these reasons and because they live on both land and water, amphibians "can tell us very quickly if there's something wrong" in the environment, Pauley said.

Amphibians also are abundant. In some places, the redback salamander, which is found in northwestern Pennsylvania, numbers between 10,000 to 20,000 salamanders per acre.

Salamanders are the best insect predators on the ground, and are food themselves for raccoons, turkeys, snakes and bears.

Reptiles are not so susceptible to environmental changes but are losing habitats because of urban sprawl. Reptiles are major predators: Snakes kill many rodents, and turtles are good scavengers.

The goal of Pauley's team is to find 90 percent of the amphibians and reptiles in Catoctin Mount Park and Monocacy National Battlefield Park, both in Maryland; Manassas Battlefield Park in Virginia; Harpers Ferry National Historic Park in West Virginia; George Washington Memorial Parkway, Rock Creek Park and Wolf Trap Farm Park, all in the Washington, D.C., area; and the Chesapeake and Ohio National Historic Park from the West Virginia and Maryland border near Cumberland, Md., to Washington, D.C.



New silicone breast implant to be studied

A new kind of silicone breast implant will be used in a clinical trial beginning at Magee-Womens Hospital that may signal a return to silicone gel implants.

The study, which is being undertaken by UPMC's division of plastic surgery, will focus on the CoheSIL implant manufactured by McGhan Medical Corp., a Santa Barbara, Calif.-based company that makes both saline- and silicone-filled breast implants.

"For a great many American women, breast reconstruction provides a tremendous psychological, physical and emotional uplift following breast cancer surgery," said Kenneth C. Shestak, study principal investigator and interim chairperson of the division of plastic surgery at Pitt's School of Medicine. "And for many more, breast augmentation may lead to a more fulfilling life through better confidence and an improved self-image."

The study is designed to examine the safety and efficacy of the new implant, which contains a silicone gel and has a more durable casing than previous models.

"Silicone has been considered by many plastic surgeons to be a more desirable alternative to saline implants for breast augmentation and reconstruction," said Shestak, who is an associate professor of surgery.

The CoheSIL implant is made of cohesive silicone gel and is encased in a silicone shell that is designed to hold its shape better than the saline implants currently in wide use, according to McGhan Medical Corp., a leading supplier of breast implants. In addition, a textured surface increases tissue adherence to stabilize the position of each implant.

Magee-Womens Hospital is seeking to enroll at least 10 women who are considering breast reconstruction surgery and who will think about receiving the CoheSIL implants.

In the late 1980s, safety concerns prompted litigation regarding silicone breast implants, and eventually led to their withdrawal for use in routine breast augmentation in the United States in 1992. However, links between the implants and a variety of health problems have been disproved, according to large collaborative studies of the medical literature in the United States and the United Kingdom. The U.S. Food and Drug Administration has designated the implants as Class III medical devices, subject to FDA approval.

Shestak, a noted plastic surgeon who has done more than 1,000 implant procedures during his 18-year career, said a review of virtually all studies published in peer-reviewed medical journals supports the safety of silicone implants. Current studies also find no connection between the use of a silicone implant and any known disease in humans.

The National Academy of Sciences' Institute of Medicine (IOM) reported in 1999 that a similar study review failed to find a basis for health concerns regarding silicone implants.

A total of 940 patients will participate in the CoheSIL study at 47 centers nationwide, with about half enrolled for augmentation and the remainder scheduled for reconstruction or revision surgery. The Magee study is restricted to breast reconstruction cases.

Women who are considering such breast surgery must be at least 18 years old and meet certain other criteria to enroll in the CoheSIL trial.

For more information on the study or to enroll, call Shane Peters, Magee-Womens Hospital at 412/641-4828.



UPMC to use surgical pen to treat atrial fibrillation

The UPMC Health System is one of nine centers in the United States to evaluate an experimental surgical "pen" for the treatment of the most common cardiac rhythm disorder, atrial fibrillation.

UPMC is the second center in the United States to perform surgery using the Medtronic Cardioblate RF Surgical Ablation System, a device that allows surgeons to "draw" lines on the heart's upper chambers, essentially creating a maze that blocks the irregular rhythms. To date, UPMC surgeons have performed the surgery in three patients.

Atrial fibrillation (AF) is an abnormal heart rhythm originating in the right and left atria. Rapid and chaotic beats, independent of the ventricles, cause patients to experience palpitations, dizziness, fatigue, chest discomfort and/or shortness of breath. Such inefficient pumping in the atria can cause blood flow to be sluggish, increasing the likelihood that clots will form that result in stroke.

AF affects more than 5.5 million worldwide. Its prevalence increases with age — almost 70 percent with AF are between 65 and 85 years of age. More than a third of those affected are considered to have chronic AF and have failed medical treatments that include drugs and techniques designed to restore normal rhythm.

The Cardioblate pen was designed to simplify an otherwise complicated and tedious surgical procedure to treat AF. While highly effective, few surgeons perform the surgery, called the Maze, because of its complexity; the surgery involves making more than 34 incisions on the inside surface of the atria and suturing these incisions to create a "maze" that interrupts the pathways of erratic electrical impulses. Using the Cardioblate pen, which at its tip delivers a cool irrigation fluid and radiofrequency energy, surgeons can "draw" lines, creating deep lesions or scars, instead of making incisions.

"With this device we think we can achieve the same effect as with the traditional maze procedure. And without the tedious cutting and sewing, the pen allows us to draw the same sort of pattern, but in less than 15 minutes. Importantly, as with the traditional maze operation, the surgeon has access to the left atria, where most of the irregular impulses originate. Outpatient ablation techniques can only address problems in the right atrium," said Marco A. Zenati, assistant professor of surgery in the Pitt medical school's division of cardiothoracic surgery, and principal investigator for the Pittsburgh study. Zenati is among only 10 or so surgeons in the United States trained to perform the modified maze with the Cardioblate pen.

Currently, use of the device is limited to those who meet criteria for entry into the study as well as to those who require cardiac surgery to correct another heart problem besides AF.

Medtronic expects data of the U.S. study, as well as data collected in Europe, to lead to approval of the device by the U.S. Food and Drug Administration (FDA) early next year. Approval would mean the device would be indicated for patients with AF.



Sleep problems may await astronauts on long missions

Astronauts traveling to distant places such as Mars may find themselves suffering from sleep problems as their missions progress, say scientists at Pitt's School of Medicine in a report in the December issue of Psychosomatic Medicine.

The researchers, led by Timothy H. Monk, professor of psychiatry at the Pitt medical school, found that the endogenous circadian pacemaker (ECP), which is the part of the brain controlling the body's cycle of sleep, wakefulness, alertness, temperature and brain chemistry, is able to maintain its 24-hour rhythm for about 90 days once removed from the natural time cues on Earth. After that time, the influence of the ECP appears to diminish significantly and the quantity and quality of sleep drops.

"Man's ability to leave Earth and travel in space raises the question of whether the human endogenous circadian pacemaker, which evolved on a planet with a 24-hour rotation, would still function well when removed from all of the natural time cues of Earth," said Monk. "Our study shows that human kind may need to find ways to trick the ECP into maintaining a strong 24-hour cycle if we are to succeed on longer missions."

According to Monk, studies of animals orbiting in microgravity and the weightlessness astronauts experience while in orbit have suggested that mechanisms which keep the ECP "on-track," such as day and night, might be weakened in space. With funding from the National Aeronautic and Space Administration and cooperation from American astronaut Jerry M. Linenger, who is a co-author of the study, the researchers set out to determine how Linenger's ECP would change as the mission progressed and how those changes would impact his sleep, alertness and performance.

Linenger lived aboard Russian Space Station Mir for nearly five months, from January to May of 1997. The mission was an eventful one with a fire aboard, coolant leaks and a near collision. He has written a book about the mission titled "Off the Planet: Surviving Five Perilous Months Aboard the Space Station Mir." While aboard Mir, Linenger recorded data on himself from three measurement blocks, each almost two weeks in duration. Linenger habitually went to bed and arose at fairly regular times. During each measurement block Linenger was required to measure his oral temperature and rate his subjective alertness five times per day, recording his results on a laptop computer.

During each "morning" of a measurement block, within one hour of waking, Linenger completed a computer-based version of the Pittsburgh Sleep Diary, which yields measures of the times of bedtime and waking, the estimated duration of unwanted wakefulness and the amount and rated quality of the sleep obtained the preceding "night."

Over the course of the mission the data showed an apparent "flattening" in the time-of-day function of Linenger's body temperature and alertness, indicating weakened ECP influence. These findings coincided with his subjective impressions. In block three, Linenger often forced himself to go to bed "by the clock" without feeling sleepy as a deliberate strategy to keep a rigid routine and to lessen the feeling of being dissociated from 24-hour time.

"Because one of the major functions of the ECP is to prepare a person for a restful night of sleep, we were particularly concerned with what would happen to the sleep variables during block three," said Monk. "We found a drop in the estimated amount of sleep Dr. Linenger got during that block, resulting mostly from an increase in the number of times he woke up during the night. This is the sort of sleep disruption we would expect when the ECP is not doing its job properly.

"The bottom line is we now know that the human body clock may lose its influence once we leave the planet for extended periods," Monk said. "We still have to determine if and how longer missions, such as to Mars, could be jeopardized by performance problems associated with poor sleep and ECP disruption. More research is needed with a greater number of subjects and better measures of ECP functioning."

The research was supported by NASA.



Cholesterol particle size, number can predict heart attack

The size and number of lipoproteins in the body can predict an individual's risk of heart attack, particularly in women, a Pitt researcher reported at a American Heart Association (AHA) meeting last month.

"The higher the number of small LDL (low-density lipoprotein) particles, the greater the woman's chances of a heart attack," said Lewis Kuller, professor and chair, department of epidemiology, Graduate School of Public Health. "We found that heart attack risk was as much as 2.45 times more likely for women who had the largest number of small LDL particles compared to women who had the lowest number of small LDL particles."

Heart disease is the No. 1 killer of women in the United States, and almost 60 percent of the people who die of a heart attack die suddenly outside of a hospital.

By assessing this new marker, researchers believe that physicians may be in a much better position to initiate therapy to reduce the risk of heart attack or prevent atherosclerosis before it becomes full-blown disease. Kuller points out that lipoprotein size and distribution can be improved not only by drug therapy, but by diet and exercise as well for many individuals.

Kuller presented results of a study that evaluated lipoprotein size and number from blood samples taken from 1,849 participants in the Cardiovascular Health Study. The project evaluated stored blood samples from patients who were followed for five to six years. Participants were aged 65 and older, with one group representing the controls, a second group that ultimately experienced heart attack and a third group free of subclinical or clinical cardiovascular disease.

Results showed that women who had experienced a heart attack had large numbers of small LDL particles. The association was stronger in women than in men.

Small LDL particles are more likely than large particles to cause the buildup of plaque along arterial walls. LDL cholesterol is often referred to as "bad" cholesterol when compared with HDL (high-density lipoprotein), or "good" cholesterol.

Although lipoproteins were once difficult and costly to measure, nuclear magnetic resonance imaging technology now makes an analysis of lipoprotein size and number a relatively simple task.

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