University Times

Pitt team learns how to make hearts big

Using zebrafish, Pitt researchers have identified and described an enzyme inhibitor that allows them to increase the number of cardiac progenitor cells and therefore influence the size of the developing heart. The findings were reported online in the journal Nature Chemical Biology.

Senior author Michael Tsang, professor in the School of Medicine’s Department of Microbiology and Molecular Genetics, said, “This gives us a better understanding of heart development during the embryonic stage and has implications for adult disease.”

Tsang noted zebrafish offer powerful advantages for studying embryonic development because their transparent embryos develop rapidly, are small and easy to handle and, most importantly, grow outside of the mother.

In earlier work, Tsang and his team bred a line of zebrafish with the gene for green fluorescent protein linked to a key signaling pathway of fibroblast growth factors (FGFs), a family of proteins that are essential in embryonic development.

“The transgenic zebrafish embryos allow us to actually see when a drug or compound influences FGFs because the cells glow green,” Tsang said.

For the current paper, the team focused on a small molecule called BCI, which hyperactivated FGF signaling. After determining that BCI did this by blocking the activity of the Dusp6 enzyme (a feedback regulator that would otherwise have tamped down the enhanced FGF signal), they then used BCI as a tool to find out what effect Dusp6 inhibition would have on heart development.

Zebrafish treated with BCI had a greater number of cardiac progenitor cells and, ultimately, larger hearts, Tsang said.

Unraveling the fibroblast growth factor pathway has broad implications for improving wound healing as well, Tsang said. For example, FGF2 has been used in treatment of chronic skin ulcers and following burn surgery in Japan. Thus, BCI alone or in combination with FGF2 might accelerate the healing process and improve wound repair.

 Pitt co-authors are: lead investigator Gabriela Molina, Wade Znosko and Thomas Smithgall of the Department of Microbiology and Molecular Genetics; Andreas Vogt, Pierre Queiroz de Oliveira and John Lazo of the Department of Pharmacology and Chemical Biology, and Ahmet Bakan, Ivet Bahar, Weixiang Dai and Billy Day of the Department of Pharmaceutical Sciences.  

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MEMS faculty receive grants

The Department of Mechanical Engineering and Materials Science recently announced the following grants to faculty members:

• Jung-Kun Lee has been awarded a National Science Foundation CAREER Award for his research project, “Electron Injection in Nanostructured Materials: New Paradigm of Transparent Conducting Oxides.”

The research explores novel nanocomposite materials that allow independent control of the carrier concentration and mobility of transparent conducting oxides for potential electro-optical applications.

Improvements in transparent conducting oxide conductivity have the potential to increase the energy conversion efficiencies of solar cells and raise the speed and energy efficiency of optoelectronic devices.

• Ian Nettleship was awarded a three-year, $279,027 NSF grant to carry out a research project entitled “Manufacturing the Microstructural Niche for Liver Tissue Bioreactors.”

The research aims to use the structure of natural liver tissue as a guide for the processing of a new type of bioreactor that will make both liver cells and liver tissue. Researchers will create a polymer copy of a natural liver vascular network then cast ceramic foam around it. The foam cast then will be used to culture liver cells.

According to the researchers, liver cells and tissue manufactured in this way could be used in drug testing or transplant. Larger bioreactors of this type could be used to support liver function in patients awaiting liver transplants.

• Jörg Wiezorek was awarded a three-year, $450,000 grant from the Department of Energy Office of Basic Energy Science for his research project “Electron Density Determination, Bonding and Properties of Tetragonal Ferromagnetic Intermetallics.”

This work uses transmission electron microscopy, X-ray diffraction and magnetometry along with materials theory to study relationships between the electronic structure and intrinsic properties of the tetragonal ferromagnetic intermetallics iron-palladium and iron-platinum.

Application and extension of the experimental and theoretical tools resulting from this activity could impact technologies relevant to energy production and distribution, hydrogen production and storage, advanced catalysts, shape-memory devices, superconductors and permanent magnets. 

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Drug spending rises in Part D enrollees

After enrolling in Medicare Part D, senior citizens who previously had limited or no drug coverage spent more on prescriptions and less on other medical care services such as hospitalizations and visits to the doctor’s office, according to a study by researchers from the Graduate School of Public Health.

Published in the July 2 issue of the New England Journal of Medicine, the study also found that seniors who had relatively good drug benefits prior to enrolling in Medicare Part D spent somewhat more on prescriptions and, at the same time, increased their spending on other medical care services. 

“We found that Part D led to increases in overall pharmacy spending among all beneficiaries,” said the study’s lead author, Yuting Zhang, professor of health economics at GSPH. “These increases were offset by decreases in spending on other medical care services in those with little or no drug coverage before they enrolled in Medicare Part D, which was one-third of the beneficiary population studied. The majority of Part D enrollees in our study population — those with relatively good prior prescription coverage — spent more on prescriptions as well as other medical services.” 

The purpose of Medicare Part D, which took effect in January 2006, is to subsidize the cost of prescription drugs for Medicare beneficiaries, more than 30 percent of whom had limited or no coverage for prescription drugs prior to its implementation.

Zhang and her colleagues compared prescription drug use and other medical spending among three groups of senior citizens two years before and after Part D was implemented. The groups included beneficiaries with no prior drug coverage, poor prior drug coverage ($600 maximum per year) and relatively good prior drug coverage ($1,400 maximum per year, comparable to Part D). They found that total monthly prescription drug spending increased by 74 percent among the no-coverage group; by 27 percent among the poor-coverage group; and by 11 percent among the good-coverage group. The study also found that the use of both lipid-lowering and anti-diabetic medications rose in the groups with limited or no drug coverage.

When it came to spending on other medical care services excluding drugs, the no-coverage group and poor-coverage group decreased their spending by $33 and $46 per month respectively, while the good-coverage group increased their spending by $30 per month. 

“The offset in spending by seniors with limited or no prior drug benefits could be due to improved adherence to medication, especially for those with chronic conditions. Improved access to prescription drugs provided by Part D may enable this population to better control symptoms and cut down on visits to the physician’s office or emergency room,” said Zhang. On the other hand, the lack of a similar spending offset in the good-coverage group could indicate an overuse of some medications and services by this population, she noted.

Other GSPH co-authors of the study were Julie M. Donohue and Judith R. Lave.

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New flu, old flu

The current H1N1 swine flu strain has genetic roots in an illness that sickened pigs at the 1918 Cedar Rapids Swine Show in Iowa, report infectious disease experts from the Graduate School of Public Health in the New England Journal of Medicine. Their paper, published online and slated for the July 16 print issue, describes H1N1’s nearly century-long and often convoluted journey, which may include the accidental resurrection of an extinct strain.

GSPH Dean Donald S. Burke, the paper’s senior author, said, “At the same time the 1918 flu pandemic was rapidly spreading among humans, pigs were hit with a respiratory illness that closely resembled symptoms seen in people. Early experiments confirmed that this 1918 swine virus and a human strain emerged about the same time. Since then, this ancestor virus has re-assorted genetically with other influenza strains at least four times, leading to the emergence of the new 2009 strain, which has retained some similarities to the original virus.”

In the paper, Burke and lead author Shanta M. Zimmer, professor in the School of Medicine, describe the temporary “extinction” of the H1N1 virus from humans in 1957 and its subsequent re-emergence 20 years later. They note a small 230-person outbreak of H1N1 in 1976 among soldiers in Fort Dix, New Jersey, did not extend beyond the military base.

H1N1 influenza re-emerged in 1977 among people in the former Soviet Union, Hong Kong and northeastern China.

Study of its genetic origin showed that it was not the Fort Dix strain, but was related closely to a 1950 human strain.

The authors hypothesize that concerns about the Fort Dix outbreak stimulated a flurry of research on H1N1 viruses in 1976, which led to an accidental release during laboratory studies of the 1950 strain that had been preserved as a “freezer” virus, resulting in the re-emergence of the previously extinct virus a year later.

That 1977 H1N1 strain has continued to circulate among humans as seasonal flu for the past 32 years.

Because the 2009 H1N1 strain shares common ancestry with older influenzas, some people may have partial immunity to the new pandemic virus.

The authors also go on to explain that the danger posed by a virus isn’t based solely on its lethality, but also on its ability to jump from animals to humans and to survive by mutating to adapt to its new human host. H1N1 influenza viruses have demonstrated this ability throughout their history.

“Studying the history of emergence and evolution of flu viruses doesn’t provide us with a blueprint for the future, but it does reveal general patterns, and this kind of information is critical if we are to be as prepared as possible,” said Burke.

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Sleep research presented

Sleep experts from the School of Medicine’s Department of Psychiatry recently presented findings from a variety of studies at the annual meeting of the Associated Professional Sleep Societies.

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Help for vets with insomnia

A team led by psychiatry professor Anne Germain found a brief behavioral treatment for chronic insomnia in military combat veterans led to improvement in their condition.

After two face-to-face sessions and two brief telephone calls for 20 pilot study patients over four weeks, the treatment was associated with significant improvements in chronic insomnia and high levels of patient satisfaction.

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Brain cooling may treat insomnia

Insomnia is associated with increased frontal cerebral metabolism during rapid eye movement (REM) sleep. Cerebral hypothermia, or cooling of the brain, has been found to reduce cerebral metabolism in other medical conditions, but its effects on insomnia were unknown.

A study by psychiatry professor Eric Nofzinger found patients with insomnia who received a mild hypothermic stimulus to their scalps an hour before bedtime and during the first REM cycle of sleep showed reduced brain metabolism in the frontal cortex and reduced core body temperature.

Three-quarters of the patients also reported other benefits such as less distracting thoughts before bedtime and an overall better and more refreshing sleep.

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Brain activity linked to PTSD, anxiety, depression symptoms

Increased brain activity at bedtime might contribute to sleep problems in military veterans suffering from post-traumatic stress disorder (PTSD) and primary insomnia.

Pitt researchers found veterans with PTSD and insomnia showed higher brain activity prior to bedtime compared to good sleepers, and the higher the level of brain activity, the more severe the symptoms of PTSD, anxiety and depression.

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Cord blood treatment studied

The University of Pittsburgh Cancer Institute (UPCI) has begun enrolling patients in an international study of an alternative treatment to bone marrow transplants for leukemia and lymphoma patients.

The phase III study assesses the safety and efficacy of StemEx, a product derived from stem cells taken from umbilical cord blood.

Mounzer Agha, clinical director of UPCI’s hematopoietic stem cell transplant program, said, “Using umbilical cord blood stem cells instead of a traditional bone marrow transplant opens tremendous treatment possibilities for patients with diseases like leukemia and lymphoma.”

Bone marrow transplantation is a life-saving treatment for many types of leukemia and lymphoma. However, more than half the number of patients in need of a transplant can’t find matching bone marrow donors. Previous research has shown that umbilical cord blood stem cells offer a viable therapeutic option for leukemia and lymphoma patients without the necessity of a matched donor.

With StemEx, a product of Jerusalem-based Gamida Cell Ltd., the cord blood unit is enriched with stem cells, which are critical for a successful transplantation.

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The University Times Research Notes column reports on funding awarded to Pitt researchers as well as findings arising from University research.

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