University Times

Why omega-3s reduce inflammation

School of Medicine pharmacologists have found new mediators that not only can explain how omega-3 fatty acids reduce inflammation, but also hint at new treatments for diseases linked to inflammatory processes. Their findings are in the online version of Nature Chemical Biology.

There is strong evidence that omega-3 fatty acids (found in some fish, plant-derived oils and nuts) reduce inflammation and lower the risk of cardiovascular and other inflammatory diseases, but exactly how omega-3s induce such effects has remained a question. “This study has given us fresh and revealing perspective into that process,” said senior author Bruce A. Freeman, chair of the Department of Pharmacology and Chemical Biology.

In this study, also led by pharmacology and chemical biology faculty member Francisco J. Schopfer, researchers examined metabolic byproducts of omega-3 fatty acids that are produced by activated macrophages (a type of immune cell found in inflamed tissue) and discovered previously unknown biochemical mediators of inflammation.

Researchers chemically modified several derivatives of omega-3 fatty acids that were produced by immune cells to become electrophilic fatty acid oxidation products (EFOX).

The research team found that an enzyme called cyclooxygenase-2 (COX-2) mediates the transformation of omega-3 fatty acids into EFOX products, which are attracted to electrons and react with molecular targets in many cell types.

COX-2 is the molecular target of common drugs such as aspirin, ibuprofen and acetaminophen. Researchers found that cellular EFOX concentrations were significantly increased in the presence of aspirin, suggesting another mechanism for that drug’s beneficial effects.

By interacting with certain protein residues that have electrons available for chemical binding, these derivatives stimulate changes in cellular protein function and the genetic expression patterns of cells, resulting in a broad range of antioxidant and anti-inflammatory responses.

“There is a lot of evidence that supports minimizing inflammation as a fundamental therapy for many diseases,” Freeman said. “Our new insights help explain in part the multitude of beneficial actions observed for both omega-3 fatty acids and aspirin, and the discovery of this new class of omega-3 fatty acid-derived anti-inflammatory mediators could point drug development activities in new and fruitful directions.”

For example, drugs that enhance the production of EFOX could be of value, or new agents might be synthesized to induce anti-inflammatory signals similar to those induced by EFOX, Freeman explained. The researchers and their drug discovery team are working on some of these approaches.

The research team also included co-lead author Alison L. Groeger, as well as Marsha P. Cole, Steven R. Woodcock and Gustavo Bonacci, all of the Department of Pharmacology and Chemical Biology.

The study was funded by the School of Medicine, the National Institutes of Health (NIH), the American Diabetes Association and the Ri.MED Foundation.

Child abuse increase coincided with recession

The number of cases of abusive head trauma in children increased dramatically during the recession, according to a multi-center study led by Children’s Hospital.

Lead researcher Rachel Berger, a child abuse specialist and researcher at Children’s Hospital’s Child Advocacy Center, presented the results at the Pediatric Academic Societies annual meeting.

The study involved 512 patients, ages 9 days-6 years, who had abusive head trauma. It addition to Pittsburgh, the patients were treated at pediatric hospitals in Cincinnati, Columbus and Seattle.

The number of cases of abusive head trauma (shaken baby syndrome) rose from six per month before December 2007, to 9.3 per month after that. Researchers collected demographic and clinical data for all cases of unequivocal abusive head trauma before the recession (January 2004-November 2007) and cases during the recession (December 2007-December 2009).

“Our results show that there has been a rise in abusive head trauma, that it coincided with the economic recession and that it’s not a phenomenon isolated to our region but happening on a much more widespread level,” Berger said. “This suggests we may need to dramatically increase our child abuse prevention efforts now and in future times of economic hardship.”

Of the children studied, 63 percent had injuries severe enough that they had to be admitted to pediatric intensive care units; 16 percent died.

Berger and colleagues said a possible reason for the increase in abuse is that important programs such as social services often are cut during a recession and their loss can increase family stress, which is a known risk factor for abuse.

Transplant research presented

Pitt researchers were among the presenters earlier this month at the American Transplant Congress in San Diego. Among their presentations were:

Innate immunity in transplantation

Fadi Lakkis, a faculty member in surgery and immunology at the School of Medicine and scientific director of the Thomas E. Starzl Transplantation Institute, presented findings from his research on the role of innate immunity in distinguishing foreign tissues from self.

“It has been for many years assumed in transplantation that adaptive or acquired immune mechanisms, meaning antigen-specific responses, play the essential role in recognizing and rejecting donor tissue,” he said. “But our research indicates that the innate system, which is more primitive, also knows the difference between self and non-self.”

Unraveling the signals of this other recognition system could lead to another set of criteria to match donor and recipient tissues, which in turn could improve patient and donor organ survival and reduce the need for anti-rejection drugs.

This research was funded by NIH.

Quality-of-life predictors for caregivers

Larissa Myaskovsky, a faculty member in medicine and psychiatry, presented her research on quality of life for caregivers of cardiothoracic transplant recipients.

She and her team interviewed 242 adult caregivers to determine social supports, self-image, optimism, caregiver burden and quality of life. They found emotional and social quality-of-life functioning remained high for the first year after their loved ones’ transplant, but physical functioning and bodily pain worsened during that time. Optimism, mastery and family support were important predictors of physical and psychological quality of life in caregivers, but greater perceived burden predicted poorer physical quality of life.

The study was funded by the National Institute of Mental Health.

Fibrosis regulator found

Medical school researchers have discovered that a molecule that regulates gene expression plays a central role in the development of fibrosis, a condition in which organ-supporting connective tissues become thick, hard and rigid, restricting normal function. The findings are available in the April edition of the American Journal of Pathology at http://ajp.amjpathol.org/.

Early Growth Receptor-1 (EGR-1) orchestrates the response to certain growth factors and influences the activity of numerous genes, said principal investigator Carol Feghali-Bostwick, a faculty member in medicine and pathology.

“Our study shows that abnormally high levels of EGR-1 are associated with the development of fibrosis,” she said. “Therefore, controlling EGR-1 could be a potential therapy for disorders such as scleroderma and pulmonary fibrosis.”

Researchers induced fibrosis in animal and human fibroblasts (cells that give rise to connective tissue).

They found that the induced fibrosis was associated with abnormally elevated EGR-1 activity. And, when fibrosis was produced in cells and animals lacking EGR-1, the amount of fibrosis was dramatically reduced.

“We also found that, compared to healthy individuals, people who have pulmonary fibrosis had higher levels of EGR-1 in samples of their lung tissue and in their fibroblasts,” Feghali-Bostwick noted.

The findings suggest that targeting EGR-1 provides a potential therapeutic approach for organ fibrosis.

Other Pitt co-authors were Hidekata Yasuoka, Eileen Hsu, Ximena D. Ruiz and Richard A. Steinman of the Department of Medicine’s Division of Pulmonary, Allergy and Critical Care Medicine.

Funding for the study came from the National Institute of Arthritis and Musculoskeletal and Skin Diseases; the National Heart, Lung and Blood Institute; the American Lung Association; the American Heart Association Pennsylvania/Delaware affiliate, and the Uehara Memorial Foundation.

Weight gain in obese pregnant women?

How much weight obese women should safely gain during pregnancy is often controversial, with current guidelines suggesting a single range of 11-20 pounds.

A new study, published online in the American Journal of Clinical Nutrition, by Pitt’s Graduate School of Public Health and the University of California-Berkeley, suggests that optimal weight gain depends on level of obesity and that weight loss or very minimal weight gain may be detrimental to newborns’ health, except in the case of extremely obese women.

The study, which included 5,500 obese pregnant women at Magee-Womens Hospital, investigated how the amount of weight gain related to babies born too small, too large or too early.

Nearly 10 percent of the study participants lost weight during pregnancy. Weight loss was generally associated with an increased risk of preterm births and infants with restricted growth. For severely obese women, however, very minimal weight gain (less than 5 pounds) or weight loss was not detrimental to newborn health.

The study also found that women who gained a large amount of weight were at increased risk of preterm births and infants who were overgrown, suggesting that very high weight gain also is related to adverse birth outcomes.

Lisa M. Bodnar, lead author of the study and faculty member in epidemiology, obstetrics and gynecology, said: “We need to consider level of obesity and advise women accordingly.”

The authors suggest the following pregnancy weight gain ranges to optimize birth outcomes: 20-30 pounds for women with a body mass index (BMI) of 30-34.9, 5-20 pounds for women with BMIs 35-39.9, and less than 10 pounds for women with BMIs 40 and over.

Women who gain less than the suggested amounts can have healthy pregnancies provided their dietary intake is being monitored to ensure proper nutrition, say the authors.

Pitt co-authors of the study were Hyagriv N. Simhan and Katherine P. Himes of the Department of Obstetrics, Gynecology and Reproductive Sciences and Magee-Womens Research Institute.

Exercise aids learning

Regular exercise speeds learning and improves blood flow to the brain, according to a study by School of Medicine researchers that is billed as the first to examine these relationships in a non-human primate model. The findings are available in the journal Neuroscience.

Other animal studies have shown that exercise benefits cognition, but it has been unclear whether the same holds true for people. Testing the hypothesis in monkeys can provide information that is more comparable to human physiology, said senior author Judy L. Cameron, a faculty member in Pitt’s psychiatry department and a senior scientist at the Oregon National Primate Research Center at Oregon Health and Science University.

“We found that monkeys who exercised regularly at an intensity that would improve fitness in middle-aged people learned to do tests of cognitive function faster and had greater blood volume in the brain’s motor cortex than their sedentary counterparts,” Cameron said. “This suggests people who exercise are getting similar benefits.”

For the study, researchers trained monkeys to run on a treadmill at 80 percent of their individual maximal aerobic capacity for an hour each day, five days per week, for five months. Another group of monkeys sat on the immobile treadmill for a comparable amount of time.

Half of the runners went through a three-month sedentary period after the exercise period. In all groups, half of the monkeys were middle aged (10-12 years old) and the others were more mature (ages 15-17). Initially, the middle-aged monkeys were in better shape than their older counterparts, but with exercise, all the runners became more fit.

In a preliminary task, the monkeys learned to lift a cover off a small well in a testing tray to get the food inside. In a spatial delay task, a researcher placed a food reward in one of two wells and covered both wells in full view of the monkey. A screen was lowered to block the animal’s view, and then raised again. If the monkey displaced the correct cover, it got the treat. After reliably succeeding at this task, monkeys that correctly moved the designated one of two different objects placed over side-by-side wells got the food reward that lay within it.

Monkeys that exercised learned to remove the well covers twice as fast as controls, Cameron said. “Also, they were more engaged in the tasks and made more attempts to get the rewards, but they also made more mistakes.”

She noted that later in the testing period, learning rate and performance were similar among the groups, which could mean that practice at the task eventually would overshadow the impact of exercise.

When the researchers examined tissue samples from the brain’s motor cortex, they found that mature monkeys that ran had greater vascular volume than middle-aged runners or sedentary animals. But those blood flow changes reversed in monkeys that were sedentary after exercising for five months.

“These findings indicate that aerobic exercise at the recommended levels can have meaningful, beneficial effects on the brain,” Cameron said.

The research was supported by the National Institute of Aging, the National Institute on Diabetes, Digestive and Kidney Disorders and the Retirement Research Foundation.

Shoppers plan for impulse buys

Straying from the grocery list can yield some surprises in your shopping cart, but not necessarily in your wallet, say researchers from Pitt and Baylor University who have co-authored a new study. They found that shoppers often expect to buy a certain number of unplanned items, and most have a fairly accurate estimate as to how much they will spend on them. The study’s co-authors use the term “in-store slack” to describe the room shoppers leave in their budget for unplanned purchases.

Written by Jeffrey Inman, associate dean for research and faculty and Albert Wesley Frey Professor of Marketing in Pitt’s Joseph M. Katz Graduate School of Business; Karen M. Stilley, postdoctoral fellow in the Katz School, and Kirk L. Wakefield, chair of the marketing department at Baylor’s Hankamer School of Business, “Planning to Make Unplanned Purchases? The Role of In-Store Slack in Budget Deviation” will be published in the August issue of the Journal of Consumer Research.

The researchers asked shoppers at several grocery stores what they intended to purchase, how much they expected to spend on the planned items, and how much they intended to spend total. After shopping, participants provided their receipts and answered questions about themselves and their purchases. More than 75 percent of the participants included room in their mental budgets for unplanned purchases.

“Shoppers in the study indicated that they employ this strategy both because they anticipate ‘forgotten needs’ as well as because they realize that they will encounter ‘unplanned wants’ — with some respondents even explicitly indicating that they expected to make impulse purchases,” the authors write. The shoppers were remarkably accurate when predicting how much they would spend. The average budget deviation (actual spending minus planned spending) was only 47 cents.

The impact of in-store slack on the shoppers’ lists depended on how many aisles the shopper visited and their level of impulsiveness. “Less-impulsive individuals who shop most aisles tend to spend the money available from in-store slack but don’t exceed their overall budgets. In contrast, in-store slack leads to overspending for highly impulsive individuals who shop most aisles,” the authors explain.

For retailers, this research suggests that consumers who shop only specific aisles are not spending all of the money that they are prepared mentally to spend on the current trip, according to the authors. “In addition to highlighting the importance of encouraging consumers to shop more aisles, this research also affirms practices that retailers employ to encourage consumers to spend all of their mental budgets, such as offering samples (increase desire) or reminder placards as they approach the checkout lines (cue forgotten needs).”

Finally, the researchers’ mental budgeting perspective suggests that brands may be vying for a fixed amount of money that consumers have allocated for unplanned purchases. The fact that most consumers do not exceed their mental budgets despite making unplanned purchases suggests that different product categories function as substitutes (i.e., should I spend my in-store slack on ice cream or Parmesan cheese?).

Therefore, the researchers believe research should further examine whether in-store stimuli may simply serve to redirect what items consumers purchase rather than generate incremental spending.

“For the majority of consumers, having in-store slack appears to be a rational way to use the store to cue needs and preserve self-control,” the authors write, but caution that “highly impulsive individuals may want to consider planning as many specific purchases in advance as possible.”

MicroRNA’s role in fibrosis studied

A small piece of RNA appears to play a big role in the development of idiopathic pulmonary fibrosis (IPF), according to researchers at the School of Medicine. Their study is available online in the American Journal of Respiratory and Critical Care Medicine.

MicroRNAs are short strands of genetic material that are involved in regulating gene expression. They are thought to be factors in embryonic development, multiple cancers and chronic heart failure, said senior author Naftali Kaminski, a faculty member in medicine, computational biology and pathology and director of the Dorothy P. and Richard P. Simmons Center for Interstitial Lung Diseases at the School of Medicine and UPMC.

“Our research now indicates that microRNA changes also contribute to IPF,” Kaminski said. “We have identified an entirely new molecular mechanism for the disease, which gives us new ideas about how to treat it.”

In microRNA profiles in samples from healthy lung tissue and samples from  tissue  affected  by IPF, “Ten   percent of the microRNAs were different between IPF and control lungs,” said Kusum Pandit, the study’s lead author and a postdoctoral researcher in Kaminski’s lab.

The researchers particularly noted a diminished amount of a microRNA called let-7d. It was abundant in 20 samples from healthy tissue, but there was almost no expression of let-7d in the fibrotic, or scarred, areas of 40 IPF lung samples. Further experimentation showed that let-7d is inhibited by the cytokine TGF-beta, a signaling protein that promotes the development of fibrosis through several biological pathways.

Researchers also administered an antagonist that inhibits let-7d to several mice through their windpipes for a few days. When examined soon after, the lungs of the mice looked very much like what is seen in patients with early lung fibrosis. “These results suggest that by increasing let-7d in the lung, we may be able to slow down or even prevent lung fibrosis,” Kaminski said.

Osher grant funds tech lectures

The Osher Lifelong Learning Institute (OLLI) at Pitt, the OLLI at Carnegie Mellon University and the Carnegie Science Center received a $1,000 grant to develop a model OLLI/Science Center collaborative project.

The award comes from the Osher National Resource Center, which recently received a planning grant from the National Science Foundation to create a Science Education Center for the Third Age. The purpose of the grant is to increase adult knowledge and skill in science, technology, engineering and mathematics.

The project, designed to increase understanding of the science and technology of robotics and the application of robotics in society, brought three robotics lecturers to an OLLI audience at the Carnegie Science Center.

In March, Ralph Hollis, research professor of robotics and director of CMU’s Microdynamic Systems Laboratory, explored the history of robotics in his talk, “Robots and Robotics Through the Years: A Personal View.”

In April, CMU robotics faculty member Howie Choset, associate director of the Center for Robotic Assisted Search and Rescue, spoke on “Medical Robotics — The Wonder of Snake Robots and Minimally Invasive Surgery.” Choset’s group has developed a family of snakelike robots that can reach places conventional tools cannot.

The third lecture, held this month, was given by CMU Robotics Institute professor William (Red) Whittaker, who spoke on robots in space.

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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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