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University of Pittsburgh

March 22, 2012

Research Notes

Gene mutations found in fibroids

Mutations in a regulatory gene are present in two-thirds of uterine fibroids, according to researchers at the School of Medicine and Magee-Womens Research Institute (MWRI). Their findings, which shed light on the pathways that allow the noncancerous tumors to develop, were reported recently in PLoS One.

Fibroids can cause heavy bleeding, anemia, pain and infertility. They affect a quarter of all women, and are the most common cause of hysterectomy in the United States, said senior author Aleksandar Rajkovic, a faculty member in the Department of Obstetrics, Gynecology and Reproductive Sciences and an MWRI investigator.

“Medical therapies for fibroids have had little success because we don’t really understand how or why they develop,” he said. “Our first step to unraveling this process was to determine if there are differences between the genes of fibroid cells and those of the neighboring normal tissue.”

The research team sequenced the genomes of fibroid and healthy uterine tissue from five women who had hysterectomies. They found that three of them had fibroids with mutations in a regulatory gene called MED12, Rajkovic said.

They then checked for MED12 mutation in 143 uterine fibroids of different individuals obtained from a biobank and found them in two-thirds of the samples. Normal uterine tissue samples did not contain mutations.

“This means that something happens in the uterus that causes MED12 mutation that, in turn, leads to the growth and formation of the fibroid tumor,” Rajkovic said. “We don’t know what causes the gene alteration but we can now target the activity of MED12 pathway genes and proteins to see if we can abolish fibroid growth so that one day women might be able to avoid surgical treatment of fibroids.”

The researchers also are looking for other mutations that could explain fibroid development in the other third of patients.

Pitt co-authors included Megan McGuire, Alexander Yatsenko, Lori Hoffner and Urvashi Surti, all of the Department of Obstetrics, Gynecology and Reproductive Sciences and MWRI.

Terahertz bandwidth generated

Research performed in the lab of physics and chemistry faculty member Hrvoje Petek has demonstrated a physical basis for terahertz bandwidth (1 trillion cycles per second) — the portion of the electromagnetic spectrum between infrared and microwave light.

Up until now, studies on electronic and optical devices with materials that are the foundations of modern electronics — such as radio, TV and computers — have generally relied on nonlinear optical effects, producing devices whose bandwidth has been limited to the gigahertz frequency region of 1 billion cycles per second.

In a paper published March 4 in Nature Photonics, Petek and colleague Muneaki Hase of the University of Tsukuba in Japan, a visiting scientist in Petek’s lab, detailed their success in generating a frequency comb — dividing a single color of light into a series of evenly spaced spectral lines for a variety of uses — that spans a more than 100 terahertz bandwidth by exciting a coherent collective of atomic motions in a semiconductor silicon crystal.

“The ability to modulate light with such a bandwidth could increase the amount of information carried by more than 1,000 times when compared to the volume carried with today’s technologies,” said Petek. “Needless to say, this has been a long-awaited discovery in the field.”

To investigate the optical properties of a silicon crystal, Petek’s team investigated the change in reflectivity after excitation with an intense laser pulse. Following the excitation, the team observed that the amount of reflected light oscillates at 15.6 terahertz, the highest mechanical frequency of atoms within a silicon lattice. This oscillation caused additional change in the absorption and reflection of light, multiplying the fundamental oscillation frequency by up to seven times to generate the comb of frequencies extending beyond 100 terahertz.

Petek and his team were able to observe the production of such a comb of frequencies from a crystalline solid for the first time.

The team is currently investigating the coherent oscillation of electrons, which could further extend the ability of harnessing light-matter interactions from the terahertz to the petahertz (1 quadrillion hertz) frequency range.

The research was funded by a grant from the National Science Foundation.

More information on Petek’s research is at www.ultrafast.phyast.pitt.edu/Home.html.

Optimism rules in the ICU

Family members of patients in the intensive care unit (ICU) tend to be overly optimistic about the possibility of recovery despite being told that the prognosis is grim, according to a study led by School of Medicine researchers. The findings, reported in the March 6 issue of the Annals of Internal Medicine, indicate that family members try to sustain hope and tend to harbor beliefs that their loved one will defy medical odds.

Because family members often are called upon to act as surrogate decision-makers for patients too ill to communicate their own wishes, it is imperative that they have a reasonably accurate perception of the patient’s prognosis, said Douglas B. White, a faculty member in the Department of Critical Care Medicine.

“Research has shown us that prognostic information influences treatment decisions near the end of life,” he said. “But there’s evidence of disconnect between what the doctor says and how the surrogates interpret the meaning.”

For the study, the team surveyed 80 surrogate decision-makers at three ICUs in San Francisco. The participants read statements such as “He will definitely survive,” “He has a 90 percent chance of surviving,” “He has a 5 percent chance of surviving” and “He will definitely not survive,” and then noted their interpretation of the survival odds on a scale marked in 10 percent intervals from 0 to 100 percent.

After completing the questionnaire, they were interviewed about their responses. The participants were assured that the statements were hypothetical and not related to their own loved one’s prognosis.

The researchers found that participants accurately interpreted statements when the prognosis generally was good. However, with poor prognoses, 40 percent of surrogates interpreted the 50 percent survival chance more optimistically than stated, and nearly two-thirds interpreted a 5 percent survival chance more optimistically than stated.

When asked to explain overly optimistic expectations, participant responses included: “I hold on to hope strongly”; “There is still hope”; “We are talking about my father in this case, not just any patient,” and “They’re not giving you a real figure.”

White noted, “Our research indicates that in the ICU setting, family members want to see the glass as half full, even if it’s really nearly empty. They accurately interpreted statements conveying good prognoses, which means it’s not a simple misunderstanding of numbers that explains their misperceptions. Instead, they appear to be biased to optimism as a coping strategy to deal with the highly stressful situation of having a loved one near death.”

He said many participants didn’t realize they had been overly optimistic until it was pointed out. That disconnect might be very difficult to overcome in the real world of the ICU, where unrealistic optimism could lead to caregiver decisions that do not reflect the patient’s values.

Seo Yeon Hong and Lisa A. Weissfield of the Graduate School of Public Health Department of Biostatistics were among the paper’s co-authors.

The research was funded by the National Heart, Lung and Blood Institute, the Greenwall Foundation and the University of California Berkeley–University of California San Francisco joint medical program.

Better brain scans developed

A powerful new imaging technique called High Definition Fiber Tracking (HDFT) will allow doctors to see clearly for the first time neural connections broken by traumatic brain injury (TBI) and other disorders, much like X-rays show a fractured bone, report Pitt researchers.

Co-senior author Walter Schneider, a psychology faculty member at Pitt’s Learning Research and Development Center (LRDC) who led the team that developed the technology, said that data from MRI scanners is processed through computer algorithms to reveal the wiring of the brain in detail and to pinpoint breaks in the cables, called fiber tracts. Each tract contains millions of neuronal connections.

“In our experiments, HDFT has been able to identify disruptions in neural pathways with a clarity that no other method can see,” Schneider said. “With it, we can virtually dissect 40 major fiber tracts in the brain to find damaged areas and quantify the proportion of fibers lost relative to the uninjured side of the brain or to the brains of healthy individuals. Now, we can clearly see breaks and identify which parts of the brain have lost connections.”

Co-senior author David O. Okonkwo, a faculty member in the Department of Neurological Surgery and a UPMC neurosurgeon, said: “There are about 1.7 million cases of TBI in the country each year, and all too often conventional scans show no injury or show improvement over time even though the patient continues to struggle. Until now, we have had no objective way of identifying how the injury damaged the patient’s brain tissue, predicting how the patient would fare or planning rehabilitation to maximize the recovery.”

In the Journal of Neurosurgery, the researchers describe the case of a 32-year-old man who wasn’t wearing a helmet when his all-terrain vehicle crashed. Initially, his CT scans showed bleeding and swelling on the right side of the brain, which controls left-sided body movement. A week later, while the man was still in a coma, a conventional MRI scan showed brain bruising and swelling in the same area. When he awoke three weeks later, the man couldn’t move his left leg, arm and hand.

HDFT scans of the study patient’s brain were performed four and 10 months after he was injured; he also had another scan performed with current state-of the-art diffusion tensor imaging, an imaging modality that collects data points from 51 directions, while HDFT is based on data from 257 directions. For the latter, the injury site was compared to the healthy side of his brain, as well as to HDFT brain scans from six healthy individuals.

Only the HDFT scan identified a lesion in a motor fiber pathway of the brain that correlated with the patient’s symptoms of left-sided weakness, including mostly intact fibers in the region controlling his left leg and extensive breaks in the region controlling his left hand. The patient recovered movement in his left leg and arm six months after the accident, but still could not use his wrist and fingers effectively 10 months later.

Okonkwo noted that the patient and his family were relieved to learn that there was evidence of brain damage to explain his ongoing difficulties. The team continues to evaluate and validate HDFT’s utility as a brain-imaging tool, so it is not yet routinely available.

“We have been wowed by the detailed, meaningful images we can get with this technology,” Okonkwo said. “HDFT has the potential to be a game-changer in the way we handle TBI and other brain disorders.”

Memory loss, language problems, personality changes and other brain changes occur with TBI, which the researchers are exploring with HDFT in other research protocols.

Co-authors included lead author Samuel L. Shin, Allison J. Hricik, Megan Maserati and Ava M. Puccio of the Department of Neurological Surgery; Timothy Verstynen, Sudhir Pathak and Kevin Jarbo of LRDC, and Sue R. Beers of the Department of Psychiatry.

The study was funded by the Defense Advanced Research Projects Agency.

Supernovae origins explained

Pitt researchers have discovered the origins of an important kind of exploding stars, type Ia supernovae, which can help researchers measure galaxy distances.

A paper detailing this research has been accepted for publication in Astrophysical Journal Letters.

Principal investigator Carlos Badenes, a faculty member in physics and astronomy, detailed the ways in which his team used the Sloan Digital Sky Survey (SDSS) — a collection of multicolor images and more than a million spectra covering more than a quarter of the sky — to determine what kinds of stars produce type Ia supernovae explosions.

Co-author Dan Maoz of Tel-Aviv University said, “We knew that two stars had to be involved in such an explosion, and that one of them had to be a white dwarf. But there were two possibilities for what the second star is, which is what we sought to discover.”

According to Badenes, the second could be a “normal star,” like the sun, or it could be another white dwarf, which is a smaller, denser, faint star composed of electron-degenerate matter. The team suspected the latter, as two white dwarfs within the same star system would revolve around one another at half a million miles an hour, speeding up and getting closer and closer until one day they would merge, most likely producing the fireworks of type Ia supernovae.

Maoz said, “There were obvious reasons to suspect that type Ia supernovae come from the merging of a double white dwarf, but our biggest question was whether there were enough double white dwarfs out there to produce the number of supernovae that we see.”

Because white dwarfs are extremely small and faint, there is no hope of seeing them in distant galaxies. Therefore, Badenes and Maoz turned to the only place where they could be seen: the part of the Milky Way galaxy within about 1,000 light-years of the sun. To find the star’s companion, the team needed two spectra to measure the velocity between the two. However, SDSS only took one spectrum of most objects. The team decided to make use of a little-known feature in the SDSS spectra to separate each one into three or more subspectra. Although the reprocessing of the data was challenging, said Badenes, the team was able to compile a list of more than 4,000 white dwarfs within a year, each of which had two or more high-quality subspectra.

“We found 15 double white dwarfs in the local neighborhood and then used computer simulations to calculate the rate at which double white dwarfs would merge,” said Badenes. “We then compared the number of merging white dwarfs here to the number of type Ia supernovae seen in distant galaxies that resemble the Milky Way.” They found that, on average, a double white dwarf merger event occurs in the Milky Way about once a century.

“That number is remarkably close to the rate of type Ia supernovae we observe in galaxies like our own,” said Badenes. “This suggests that the merger of a double white dwarf system is a plausible explanation for type Ia supernovae.”

For more information on the SDSS, go to www.sdss.org/.

Osteoporosis screening varies

A study led by medicine faculty member Susan Greenspan found that screening strategies to identify nursing home residents who are eligible for osteoporosis treatment vary widely.

The study, published in the Journal of the American Geriatrics Society, sought to identify nursing home patients who would benefit from pharmacologic treatment of osteoporosis, which could decrease their risk for bone fractures.

“Osteoporosis in the frail elderly can have devastating consequences, but we have yet to perfect a system for identifying those patients who would benefit most from the treatment,” Greenspan said.

The researchers evaluated a variety of osteoporosis screening strategies in more than 200 women residing in 11 long-term care facilities in the Pittsburgh area.

Osteoporosis is a disease that causes bones to become weak and break easily. Screening measures included history of bone fracture, bone mineral density by standard DEXA scanning, the fracture risk assessment tool (FRAX) with body mass index (BMI), FRAX with femoral neck bone density and heel ultrasound.

The study found that, depending on the screening strategy used, identification of treatment eligibility varied from 17 percent for clinical fracture to 98 percent for FRAX with BMI. Also, three-quarters of vertebral fractures were “silent,” meaning they caused no symptoms and were identified only through X-ray or special screening scans.

“This is worrisome because many physicians rely on bone density screening, but that approach missed half the women with vertebral fractures who would be candidates for osteoporosis treatment,” Greenspan said. “Still, some form of screening for vertebral fractures is appropriate because treatment could prevent more osteoporosis damage and future fractures.”

The researchers concluded that a reasonable clinical approach would be to consider treatment for those with clinical fractures of the hip or spine, radiologic evidence for a vertebral fracture or osteoporosis by bone mineral density classification.

The study’s authors say the findings are important because the number of U.S. residents over age 85 is growing rapidly and nearly 2 million people live in long-term care facilities across the country. Nursing home residents who have fractured a bone are hospitalized more than 15 times as often as those without a fracture and have a higher mortality rate, the authors said.

Collaborators on the study were Subashan Perera, David Nace, Kimberly S. Zukowski, Mary Anne Ferchak, Carroll J. Lee, Smita Nayak and Neil M. Resnick, all of medicine.

Funding was provided by the National Institutes of Health and a private family donation.

J&J research partnership formed

The University and UPMC have entered into a partnership with Johnson & Johnson Corporate Office of Science and Technology (COSAT) to support translational research, which transforms lab findings into usable products and services.

The agreement, which allocates research money to University faculty from a mutually established fund, is designed to speed development of early-stage Pitt technologies that hold the greatest potential to benefit patients and improve services delivered by the health care system.

Pitt will lead a committee that includes representatives from COSAT and UPMC to identify projects of promise. Intellectual property or technology developed at Pitt through this program will be owned by the University and made available through licensing agreements to industry collaborators through established procedures.

Pitt and UPMC recently formed a pharmaceutical collaboration committee to address how best to work with the pharmaceutical and biotech industries, including the comingled COSAT fund. The committee is led by D. Lansing Taylor, director of Pitt’s Drug Discovery Institute and Allegheny Foundation Professor of Computational and Systems Biology, and composed of faculty from the Dietrich School of Arts and Sciences, the schools of medicine and pharmacy, and staff from the Office of Technology Management and UPMC.

Government diffusion analyzed

An analysis by the Center for Metropolitan Studies (CMS) in the Graduate School of Public and International Affairs has found Pittsburgh to be the second-most decentralized metropolitan region in the nation. Using 2007 financial data from individual governments compiled and distributed by the U.S. Census Bureau’s Census of Governments program, the center’s Metropolitan Power Diffusion Index (MPDI) measured how many separate local, county and special-district governments provided 11 common public services and how much each of those governments spent in providing those services.

The services were fire, central staff services, public buildings, highways, housing development,  community development, libraries, police, sewerage, solid waste management and water utilities.

Decentralized governments are those that have more governing bodies making decisions on public services; more centralized governments have fewer governing bodies making the same decisions.

The more individual governments there are spending greater amounts of money on the services, the higher the MPDI score. Pittsburgh scored second only to Chicago, the MPDI found.

CMS director David Y. Miller said, “The purpose of the MPDI is not to determine whether centralized or more decentralized systems are better. Part of the purpose of putting out this measurement is to allow for more analytical work to be done with this data.”

Rounding out the top 10 decentralized metropolitan regions are: St. Louis, New York, Philadelphia, Boston, Houston, Minneapolis-St. Paul-Bloomington, Denver and Cincinnati.

Researchers calculated the score for 942 micropolitan and metropolitan regions for the period 1987-2007 and found that the areas are becoming more decentralized. Having calculated MPDI scores in 1987, 1997 and 2007, the CMS found the average metropolitan region became more fragmented by 5.4 percent.

The average rate of decentralization slowed to 1.4 percent between 1997 and 2007. Of the regions analyzed in 2007, 712 (approximately 75.6 percent) had scores that made them more fragmented than they were in 1987. Of those regions, 10.7 percent were rapidly decentralizing, with rates of change in excess of 20 percent.

The CMS offers a report card of trends in governmental diffusion between 1987 and 2007 for all 942 micropolitan and metropolitan regions.

Summaries available through the CMS include analysis of trends by region and population size. The CMS also provides a downloadable database that permits researchers not only to describe variation and trends in local governance structures across metropolitan areas for 1987, 1997 and 2007, but also to use the measure as a correlate with other important demographic, environmental and socioeconomic characteristics of metropolitan regions.

To view the database, go to www.metrostudies.pitt.edu.

Treating depression after coronary bypass means better quality of life

Patients who are treated for depression through a new collaborative care model after undergoing coronary artery bypass graft (CABG) procedures showed improvements in mood and health and incurred lower health care costs, according to a Pitt study presented at the American Psychosomatic Society’s annual meeting.

The findings were presented by Bruce L. Rollman, a faculty member in the School of Medicine and principal investigator for the study.

Over 400,000 people in the United States  undergo  CABG surgery annually, and approximately one in four experiences depression afterwards. Depressed patients tend to experience delayed recovery, poorer quality of life, elevated risk of hospital readmission and death and higher health care costs than those who do not become depressed.

The Bypassing the Blues study involved 453 depressed patients who had undergone CABG and was the first comparative-effectiveness trial to examine the impact of collaborative care for treating depression following an acute cardiac event. The intervention involved a nurse care manager who telephoned patients to educate them about depression, offered various treatment options and monitored their condition in collaboration with patients’ primary care physicians (PCPs).

As reported earlier by the study team in the Journal of the American Medical Association, intervention patients reported significantly greater improvements in mood symptoms, health-related quality of life and physical functioning versus patients randomized to their PCPs’ usual care for depression.

In the first cost-effectiveness analyses for treating depression in patients with cardiovascular disease, lead author Julie Donohue, a faculty member in health policy and management at the Graduate School of Public Health, and the Bypassing the Blues Trial team examined study participants’ Medicare and other insurance claims. Researchers found that patients who underwent intervention had 12-month health care costs that were $449 lower than usual-care patients ($18,172 vs. $18,621).

“Collaborative care has emerged as an integral part of the ‘patient-centered medical home’ model to reorganize and reimburse PCPs for providing high-quality chronic illness care,” Rollman said. “Demonstrating its cost-effectiveness for post-CABG depression and other cardiovascular conditions is crucial to support its widespread adoption.”

Bypassing the Blues is a National Heart Lung Blood Institute-funded effectiveness trial conducted through the University’s Center for Research on Health Care. These economic analyses were conducted with additional support provided through a grant from the Fine Foundation.

For more information on the study, go to www.bypassingtheblues.pitt.edu.

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