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July 10, 2003


Artificial organ research findings presented

Clinical and basic science findings of more than a dozen studies were presented by researchers from Pitt’s McGowan Institute for Regenerative Medicine at a joint meeting of the American Society for Artificial Internal Organs and the International Society for Artificial Organs. Scientific sessions took place June 18-21 at the Hilton Washington.

Among the findings were the following:

Success reported in growing functioning liver tissue in a bioreactor

Growing functioning liver tissue in a fist-sized device that works in a way similar to kidney dialysis has kept patients in liver failure alive until donor organs have become available, according to Jörg Gerlach, professor of surgery at the School of Medicine.

“We have treated eight patients in acute liver failure — some of whom were in a coma — who were able to be bridged to transplant,” said Gerlach, who also is a faculty member of the University’s McGowan Institute for Regenerative Medicine.

Gerlach and his colleagues have been able to grow functioning liver tissue from human liver stem cells derived from organs that had been deemed unsuitable for transplant because of damage or underlying disease. Such cells have been shown to proliferate and form liver-like tissues in bioreactors, and persist in culture for many weeks.

About 25 million Americans (one in 10) have liver disease, according to the American Liver Foundation. More than 43,000 people die of liver disease yearly. Annual hospitalization costs exceed $8 billion.

Gerlach’s bioreactor could have an impact for the sickest of these patients, who often do not survive the wait for transplantation or become too sick to qualify for a transplant.

Tissue-engineered materials continue to show promise

Research on tissue-engineered materials continue to show promise as a treatment for heart defects, reported William Wagner, associate professor of surgery and bioengineering at Pitt’s School of Medicine and a deputy director of the McGowan Institute.

Researchers in Wagner’s laboratory have developed a novel, flexible and biodegradable material based on a specialized polymer that is porous to encourage the infiltration and growth of cells. This “cardiac patch” was tested in the repair of defects in adult rats.

After four weeks, the patches and nearby tissue were studied for evidence of inflammation, scarring and proper cell growth. Results show encouraging levels of repair and cell regeneration with minimal signs of inflammation.

“Future application of this material as a cellular scaffold in cardiovascular tissue engineering appears promising,” Wagner said.


Geology prof awarded NSF, NASA grants

Michael Ramsey, an assistant professor in the Department of Geology and Planetary Science, has been awarded a research grant from the National Science Foundation’s (NSF) Division of Earth Sciences Petrology and Geochemistry Program.

Ramsey’s project, “Emission Spectroscopy of Silicic Lavas: Implications for Dome Processes and Hazards,” was awarded $228,108 over the next three years. The research focuses on active explosive volcanoes using both laboratory and field-based investigations, linked together by state-of-the-art satellite remote sensing data.

The ultimate goal is to model the effects of thermal infrared emission from volcanic surfaces in order to better understand eruption processes and mitigate future volcanic hazards.

Ramsey, together with Nicholas Lancaster of the Desert Research Institute in Reno, Nev., also has been awarded a $456,719 grant from NASA’s Solid Earth and Natural Hazards Program.

The project, “Eolian processes in arid regions: Tracking land surface change using orbital data,” will be conducted over the next three years. It will attempt to advance the understanding of the dynamics of eolian (wind) processes in Saharan Africa using orbital remote sensing and field data. It will address several major aspects of the eolian sediment transport system including the source areas for large trans-Atlantic dust storms.

The eolian system generates two of the most important natural hazards in drylands currently experiencing the effects of desertification: dust storms and sand encroachment.


Pregnancy related diabetes, high blood pressure can raise heart disease risk

Women who have pregnancy-related high blood pressure conditions or diabetes can develop heart disease risk factors as soon as two years after giving birth, according to a Pitt study presented recently at the American Diabetes Association’s scientific sessions in New Orleans.

“Our study points to the importance of monitoring pregnant women for new-onset diabetes, preeclampsia and hypertension, because these conditions can leave these women with insulin resistance or continued high blood pressure after delivery, putting them at risk for cardiovascular disease,” said Zsolt Bosnyak, who led the study while a post-doctoral fellow at Pitt’s Graduate School of Public Health. He is now with the National Centre for Diabetes Care in Budapest, Hungary.

The study looked at the health status, one to three years post-delivery, in 36 women who had preeclampsia while pregnant, 33 women with hypertension (high blood pressure) while pregnant, 24 with diabetes while pregnant, and 31 controls.

Preeclampsia is a condition in which high blood pressure is accompanied by protein in the urine, usually albumin.

Women with preeclampsia or gestational diabetes had a four- to six-fold chance of being insulin resistant one to three years after delivery. Insulin resistance is a condition in which insulin is not used efficiently by the body. It often leads to diabetes, and a recent Pitt study linked it to heart disease in people with diabetes.

Co-investigator Trevor Orchard, professor of epidemiology, said: “Diabetes, preeclampsia and high blood pressure during pregnancy should be viewed as potential markers for an increase in heart disease risk factors after delivery. Pregnant women who have one or more of these conditions, and women who have had them while they were pregnant, should modify their life styles to reduce risk. Stop smoking and drinking; exercise; eat more fruit, vegetables and whole grains; cut back on fatty foods.”

The study was supported by the American Diabetes Association.


Moisture helps, hinders in particle mixing

A Pitt engineering professor and his graduate assistant have found that adding moisture to a batch of two different granular particles will either cause them to mix or separate, depending on the composition of the particles.

Joseph McCarthy, assistant professor in the Department of Chemical and Petroleum Engineering, and graduate student Hongming Li developed and tested a theory regarding particle mixing and segregating. Their findings were published last month in the journal Physical Review Letters.

Granular materials in many instances “flow” like liquids, but there are important differences that scientists don’t fully comprehend.

“It’s well known that granular materials may segregate — or unmix — due to differences in size, density, shape, etc.,” the researchers write. What is less well known is the role of cohesion. Conventional wisdom says that adding moisture to the materials to make them stick to one another more easily allows one to mix systems that would typically unmix.

McCarthy and Li tumbled red and green glass and plastic beads of different sizes and densities in a drum. The researchers also varied the particles’ wetting properties by covering some of the beads with water repellent and others with water-attracting coatings.

For some combinations, the dry beads mixed, while adding moisture caused them to segregate. For other combinations, however, the opposite occurred.

Their findings are of importance to business sectors like pharmaceuticals, metals and ceramics, in which mixing or separating granular materials such as powders needs to be controlled.

“In many instances the wetting properties and the density of a material may be fixed, but our theory lets you know exactly what size ratios to use to get a cohesive system to mix, or not mix,” said McCarthy. “And it’s not always a combination you would expect.”

In general, McCarthy said, “If like particles stick to each other when dry, then adding moisture will cause them to segregate. If dissimilar particles stick to each other, then adding moisture will cause them to mix.”

The research is sponsored by the Chemical and Transport Systems Division of the National Science Foundation and the American Chemical Society’s Petroleum Research Fund.


Researchers seeking genetic keys to mental illness

Pitt researchers have completed the first survey of the entire human genome for genes that affect the susceptibility of individuals to developing clinical depression.

George S. Zubenko, professor of psychiatry at Pitt’s School of Medicine and adjunct professor of biological sciences at Carnegie Mellon University, and his team have located a number of chromosomal regions they say hold the genetic keys to a variety of mental illnesses, including major depression and certain addictions.

The survey was done in 81 families identified by individuals with recurrent, early-onset, major depressive disorder (RE-MDD), a severe form of depression that runs in families.

The Pitt team’s findings were published July 2 in the American Journal of Medical Genetics.

Depression is the second-leading cause of disability worldwide, affecting nearly 10 percent of the population. And while scientists have made significant progress developing new drugs to treat it, studies that identify specific risk genes may lead to even more effective drugs designed to target depression in specific individuals.

Twin studies have demonstrated that genetic factors typically account for 40-70 percent of the risk for developing major depression, but finding those genes has proven to be a challenge because, as in most diseases, there are likely numerous genes involved and only individuals with certain combinations of those genes develop the disorder.

Of equal interest is a secondary finding that longevity in the families who carry these genes is significantly reduced.

The survey revealed 19 loci — small regions on chromosomes where genes reside — that appear to influence susceptibility to depressive disorders. The results extended the investigators’ previous finding that a small region of chromosome 2q containing the CREB1 gene affects the vulnerability of women to developing depression. And at least some of the 19 depression vulnerability loci appear to work in concert to affect a person’s risk of developing depression.

According to Zubenko, “Greater scrutiny of the chromosome 2 locus has provided stronger evidence for the role of CREB1 as a risk gene for depressive disorders among women. In addition, five of the new genetic loci appear to interact with the CREB1 region to affect the risk of developing clinical depression in these families.

“Women are twice as likely as men to develop depression, and genetic differences appear to account for some of that disparity,” said Zubenko. Sex-specific loci were common and preferentially affected the vulnerability of women to developing unipolar mood disorders. Evidence of at least one male-specific risk locus also was found. The sex-specific effects of particular risk genes for depression may result from the interactions of these genes and their products with sex hormones.

These findings suggest there are important differences in the molecular pathophysiology of mood disorders in men and women, or in the mechanisms that determine resistance to stressful stimuli. They also may help explain the vulnerability of women to depression during times of significant hormonal fluctuation including puberty, menstrual cycling, pregnancy and childbirth, and menopause. Conversely, age-related reductions in hormone levels may contribute to a reduced proportion of familial cases of depression among depressions that arise later in life.

Remarkably, deceased members of the 81 families died at an age eight years younger than the general population and over 40 percent died before the age of 65. This difference in mortality was spread across the lifespan, including a five-fold increase in the proportion of children who died in the first year of life and several-fold increases in deaths by suicide, homicide and liver disease. However, most premature deaths occurred from “natural causes” including heart disease, cancer and stroke.

The study received funding from the National Institute of Mental Health.


Benefit seen in repeating sigmoidoscopy 3 years after negative exam

According to findings published in the July 2 issue of the Journal of the American Medical Association (JAMA), repeating flexible sigmoidoscopy three years after a negative exam can detect advanced adenomas (pre-cancerous polyps or growths in the lining of the large intestine) and distal colon cancer, raising concern about the impact of delaying repeat screening for prolonged intervals.

“Our study found a three- to four-fold increase in detection from the initial exam compared to the next exam three years later. The findings at three years, although modest, indicate that more frequent screening for colon cancer, by detecting pre-cancerous growths, could have an impact on mortality from this disease,” said Robert Schoen, lead author of the study and associate professor of medicine and epidemiology at Pitt’s School of Medicine.

“Our findings raise concern that a longer interval between exams, such as the currently recommended 10-year interval for repeat colonoscopy after a negative exam, may result in morbidity and mortality from colorectal cancer. This is especially suggested by the fact that over 80 percent of the advanced lesions found on the repeat exam three years later were found in a region of the colon that, as far as can be determined, was well examined the first time around,” added Schoen, who also is director of colorectal and gastrointestinal cancer prevention and control research at the University of Pittsburgh Cancer Institute.

During flexible sigmoidoscopy (FSG), a doctor uses a lighted scope to examine the inside of the large intestine from the rectum through the last part of the colon, where most colon polyps develop.

“While the overall percentage of detected abnormalities was modest, these data question the notion that individuals with initial negative results can wait for prolonged periods of time to be re-screened,” said Schoen.

In the United States, colorectal cancer accounts for 11 percent of all cancers. For patients with advanced disease, five-year survival rates are 10 to 20 percent. However, when colorectal cancer is diagnosed at an early, localized stage, the five-year survival rate is 90 percent.

Co-authors include Pitt’s Joel L. Weissfeld and scientists from the National Cancer Institute, Anderson Cancer Center and the University of Minnesota.


Pharmacy awards announced

Wen Xie, an assistant professor in the School of Pharmacy’s pharmaceutical sciences department and a member of the Center for Pharmacogenetics here, recently received federal grants totaling more than $130,000 for breast cancer research.

Breast cancer is a leading cause of death in women in the United States. Estrogen is known to play an important role in breast cell growth and breast cancer formation. Current therapies to lower estrogen effects, such as estrogen deactivation and anti-estrogen agents, are effective to treat and prevent breast cancer.

A major route for the body to deactivate estrogen is through estrogen sulfation, a chemical modification that is carried out by sulfotransferases. Since the modified estrogens lose their ability to bind to the estrogen receptor, methods to increase estrogen sulfation are believed to be beneficial to deactivate estrogens. The production of sulfotransferase by the body is controlled by PXR, a member of orphan nuclear receptor family.

Since PXR determines the production of sulfotransferase, Pitt researchers hypothesize that activation of PXR by chemical or genetic means will increase the production of sulfotransferase, which will enhance estrogen deactivation and inhibit estrogen-dependent breast cancer cell growth. The traditional anti-estrogenic agents such as tamoxifen, though effective, are known to have unpleasant side effects, such as risk for endometrial cancer and deep vein thrombosis. It is anticipated that PXR activating agents may represent a novel strategy to deactivate estrogens and to treat and prevent breast cancers. 

Xie is a leading researcher in drug toxicity and drug-to-drug interactions. His research, which also focuses on the role of hormones in drug exchanges, uses a combination of cultured cells and genetically engineered animal models that include transgenic mice equipped with human genes. He is one of a few researchers in the United States using transgenic mice to study drug interactions.

Blair Capitano, assistant professor in the Department of Pharmacy and Therapeutics and the medical school’s medicine department, was recently selected to receive a 2003 Thomas E. Starzl Transplantation Institute Young Investigator Grant of $25,000 for her protocol, “Voriconazole Prophylaxis Against Aspergillosis in Lung Transplant Recipients: Pharmacokinetics and Correlation Between Plasma and Lung Concentrations With Toxicity/Efficacy.”

Pharmacokinetics describes the movement of an agent through the body. Capitano’s study will evaluate the pharmacokinetics, safety and efficacy of voriconazole, a novel agent used to prevent fungal infection in lung transplant patients. It will be the first step in utilizing pharmacokinetic and pharmacodynamic information to optimize voriconazole therapy in lung transplant patients.

Capitano’s research fo-cuses on pharmacokinetics/pharmacodynamics and application of these principles to optimize clinical outcomes and prevent the development of antimicrobial resistant pathogens.

She also received a separate grant for more than $7,000 from the General Clinical Research Center and Clinical Research and Feasibility Funds for Young Investigators for the same project.

Brian Potoski, assistant professor in the pharmacy and therapeutics department and the medicine department, is co-investigator on the project.

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