University Times

Grant funds research into regeneration of tissue

The University’s McGowan Institute for Regenerative Medicine has been awarded $3.7 million for research into the process of wound healing and tissue regeneration.

The Defense Advanced Research Projects Agency grant will be used to examine the cellular and molecular systems that allow certain animals to completely regenerate lost tissue. The ultimate goal of the research is to identify ways for enhancing the capacity for wound healing and tissue restoration in humans.

Coordinating the effort is Stephen Badylak, a research professor in surgery at the School of Medicine and director of the Center for Pre-clinical Tissue Engineering at the McGowan Institute. In addition to Pitt, researchers at five other sites — Children’s Memorial Research Center in Chicago, the University of Massachusetts-Lowell, the University of Utah, Weill Medical College of Cornell University and the Wistar Institute in Philadelphia — will be involved in the study.

“We sincerely believe that the ability to promote tissue restoration in humans is not only possible, it will in fact be a reality some day,” said Badylak. “By working as a team and capitalizing on our collective expertise and experience, we’re in a better position to succeed at unlocking the regenerative potential of mammals than would be possible working in the silos of our individual labs.”

To some extent, humans already have the capacity for regeneration. For instance, certain cells, such as liver cells and red blood cells, can self-renew; and during embryonic development mammals and birds can regenerate such diverse tissues and structures as their skin and spinal cord. However, humans can’t perform the same trick of regrowing a severed limb that salamanders and newts can. In humans, the cells that respond to the site of injury form scar tissue, whereas in salamanders the responding cells are genetically programmed to become the cell types of the lost structure.

The researchers aim to prove that mammals can form the required progenitor cells for regeneration just as a salamander does. By studying salamanders and a special type of mouse that possesses unique regenerative abilities, the researchers hope to identify the specific types of cells, molecular signals, genes and cellular scaffolding required for regenerative cell growth.

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Geriatric research presented

Pitt researchers recently presented findings of a number of studies at a meeting of the American Geriatrics Society.

* Elderly women have more disability in daily living activities

Pitt Institute on Aging researcher Susan Hardy has found aging women experience more disability than aging men even though they live longer than men. Researchers studied more than 750 community-living men and women without disabilities, age 70 and older, for five years, looking at their increasing needs for assistance in four activities of daily living (ADLs) — bathing, dressing, walking and transferring.

The study found that while men experience more severe disability, requiring assistance with three or four ADLs, women experience more mild disability, requiring assistance with only one or two ADLs. However, the disability of aging women tends to require longer recovery periods.

The study found that women experienced 157 months of disability per 1,000 person-months compared to 89 months for the men.

* Irregular gait may predict future walking disability

A study of 401 older adults with an average age of 79 years showed that the variability of their gait can be used as a predictor for later walking disability. Prior studies already have determined that the speed with which an older person walks is a strong predictor for future walking disability.

This study analyzed gait speed, step length, stance time and step width and found that a faster gait speed was associated with a 9 percent lower hazard rate while a longer stance time variability was associated with a 12 percent higher hazard rate. Step length and step width variability were not found to be related to walking disability.

The researchers were Jennifer S. Brach and Jessie Van Swearingen of physical therapy, Anne Newman of epidemiology and medicine and Stephanie Studenski and Subashan Perera of medicine.

* Biofeedback aids continence

A study by Stasa D. Tadic, Lisa Rosenberg, Werner Schaefer, Derek Griffiths and Neil M. Resnick of the Department of Medicine has found that biofeedback therapy reduces the number of urinary urge incontinence episodes and improves subjective psychological symptoms in older women.

Following a 12-week course of biofeedback therapy, study participants aged 60 and over showed improvements in their perception of control, self-concept and psychological aspects related to their condition. They also had an average 41 percent reduction in urge incontinence incidents.

In addition, women with a history of depression had a greater decrease in their feelings of psychological burden than did women who had no history of depression. Among the conclusions of this interim study are the suggestion that biofeedback, in part, may target psychological mechanisms involved in urge incontinence. The greatest impact results from patients’ perception of increased control, they found.

* Poor nursing home care providers more likely to close

A study of the relationship between nursing home quality of care and their risk of closure showed that facilities with lower quality of care ratings had an increased risk of closing.

Alfred Fisher and Nicholas Castle of the School of Medicine obtained the names of every nursing facility that closed between January 1999 and July 2005, then cross-referenced the names with the on-line survey certification and reporting database to obtain quality information. The remaining 17,000 open facilities were used as controls.

Researchers looked at five clinical measures of quality — psychoactive drug use, physical restraints, catheters, contractures and pressure ulcers. “Our preliminary data suggest that our quality indicators have a significant effect on the risk of closure,” the researchers reported.

“Further, we anticipate finding a closure incidence of only 0.7%, a number low enough to ask, ‘Do nursing homes close often enough?’

“Finally, we believe that the 2002 advent of the Nursing Home Compare (NHC) system corresponded to a strengthening of the correlation between low-quality and subsequent facility closure. Such a finding would warrant recommending the use of the NHC system as a model for implementing consumer-driven quality improvements in other branches of the health care industry,” the researchers wrote.

* Light drinkers cut heart attack, death risk

A study of septuagenarians has found light-to-moderate alcohol consumption is associated with a reduction in the risk of cardiac events and an improvement in overall survival rates.

Those reporting consumption of 1-7 drinks per week showed lower risks for death and cardiac events compared to those who never drank or drank less frequently.

An analysis of a possible link with inflammatory markers in the bloodstream did not affect the strength of this association, but the relationship seemed different in men and women, with the benefit of light-to-moderate alcohol consumption appearing to be mainly confined to men with high levels of interleukin-6.

Among the researchers was Anne Newman of epidemiology.

* Dementia patients more likely to be hospitalized

Lewis H. Kuller of epidemiology and Oscar L. Lopez of neurology were among a multi-university team of researchers who found that persons with dementia were more than twice as likely to be hospitalized as those with normal cognition. Those with mild cognitive impairment (MCI) were at a 70 percent increased risk of hospitalization.

The rate of total hospitalization for those with normal cognition was 297 per 1,000 person-years, 432 for persons with MCI and 1,049 for incident dementia including 842 for Alzheimer’s disease, 1,690 for vascular dementia and 1,120 for mixed dementia.

“Careful observation and additional preventive care may help reduce this burden,” the researchers wrote.

* Exercise equals stronger bones for elderly

A Pitt study of older athletes to determine whether high- or low-impact exercise had an effect on bone mineral density (BMD) has found both types beneficial.

A study of 87 runners and swimmers who competed in the 2005 Senior Olympics in Pittsburgh showed that both groups had better bone density scores than others their age.

“Although no significant difference was observed between BMD in high- versus low-impact athletes, this data reinforces the recommendation that elderly men and women participate in exercise to help maintain BMD and reduce progression of osteoporosis,” researchers concluded.

Pitt researchers were: Nicole F. Velez, Amy Zhang, Megan Miller, Susan Greenspan and Subashan Perera, all of endocrinology.

* Walking ability: indicator of future health

Researchers from the Graduate School of Public Health have found that the ability to walk a quarter-mile was an important determinant in whether elderly persons would be alive six years later as well as how much illness and disability they would experience within that time frame.

“The ability to complete this walk was a powerful predictor of health outcomes,” said lead author Anne B. Newman, professor of epidemiology at GSPH and professor of medicine at Pitt’s School of Medicine. “In fact, we found that the people who could not complete the walk were at an extremely high risk of later disability and death.”

The study was published recently in the Journal of the American Medical Association.

Newman and her co-workers, collaborating with researchers at five other institutions, asked a group of almost 2,700 community-dwelling men and women aged 70-79 to complete — as quickly as they could without running and at a consistent pace —  ten 40-meter laps in a corridor. All of the participants previously had reported no difficulty walking a quarter of a mile, climbing one flight of stairs without resting or performing basic activities of daily living.

Participants were excluded from attempting the walk if they had an abnormal electrocardiogram, elevated blood pressure or resting heart rate or recently had a procedure for, or symptoms of, heart disease. Those participants who qualified for the quarter-mile walk were told to stop if they experienced any signs of fatigue or persistent rapid heart rate.

Of 2,680 people in the test, nearly 87 percent completed the full 400 meters, while 13 percent did not. A review of medical histories found that among those excluded from or who stopped the walk, death rates were significantly higher six years later than those who completed the walk.

In addition, of the more than 2,200 participants who did not have a clinical diagnosis of cardiovascular disease at the time of the test, those who did not complete the walk had significantly more heart-related incidents six years later than those who did complete the walk. The former group also had a significantly higher risk of persistent limitations in their mobility and related disabilities than did those who completed the full walk.

“A significant portion of people in the study could not complete the walk, even though they believed they were in fairly good health. Moreover, there was a big gap in health outcomes between people who could complete the longer walk and people who could not, with the latter being at an extremely high risk of becoming disabled or dying. What was really surprising is that these people were not aware of how limited they actually were,” said Newman, who also is a collaborator with Pitt’s Institute on Aging.

Of those who completed the walk, the slowest had a three- to four-fold higher risk of death than those in the fastest 25 percent for walk time. They also had a higher risk of cardiovascular disease-related complications and limitation in their mobility and mobility-related disabilities than those in the fastest 25 percent.

“Our study found that many people who performed well on lower extremity tests or short walking tests did not perform well on the 400-meter walking test. Although quite simple, the 400-meter walk appears to be a highly accurate way to predict whether or not someone may be experiencing early problems and needs an immediate referral into an intervention program to help them increase their activity and physical stamina,” Newman said.

This study was funded, in part, by a grant from the National Institute on Aging, National Institutes of Health. Other Pitt researchers involved were Jennifer S. Brach, physical therapy; Robert M. Boudreau and Barbara L. Naydeck, epidemiology, and Stephanie A. Studenski, medicine.

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UPB prof examines which young sex offenders respond to treatment

Research by Gregory Page, assistant professor of psychology at Pitt-Bradford, has found that demographics are no indicator of how well juvenile sex offenders may do in treatment, but some psychological factors can predict who is more likely to respond.

Page’s work, “Predicting Treatment Response With Demographic and Psychological Factors With Juvenile Sexual Offenders in Residential Treatment,” was presented in March at the 2006 American Psychology Law Society conference.

Page assessed youths when they entered a treatment facility and three months later. He reviewed demographics including the number of victims, relationship to the victims, type of sexual offense, age of victims, history of previous legal violations, previous sex offender treatment, previous psychiatric/psychological treatment, education levels, age of offender, history of previous abuse and substance usage history.

The psychological factors Page examined included anger; thinking errors associated with sexual offending behaviors such as rape and molestation; responsibility; the strength of the bond with parents and friends, and the locus of control, which represents whether the youths’ attribute responsibility to their own actions or those of others.

Page’s research revealed that none of the demographic factors were found to predict whether the youths would respond well to treatment. However, some of the psychological factors did predict treatment response.

For example, Page said the youths who did not have a good bond with their fathers or peers, were less angry and took more responsibility for their behaviors were more likely to do better in treatment. Additionally, after being in treatment for three months, those who tended to associate their own behaviors with causing positive and negative consequences and who had fewer thinking errors associated with sexual offending behaviors were more likely to be doing better in the treatment.

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Type 1 diabetics’ eye & heart disease rate unchanged

Researchers at the Graduate School of Public Health (GSPH) have discovered that while cases of premature death and a few other complications of type 1 diabetes have declined, rates of other serious diabetes-related disorders such as heart and eye disease have not improved over the past 25-30 years.

In the study, published in the journal Diabetes, investigators analyzed mortality and long-term complications such as renal failure and coronary artery disease in 906 type 1 diabetics participating in the Pittsburgh Epidemiology of Diabetes Complications Study (EDC).

The EDC is an ongoing investigation to document long-term complications of type 1 diabetes among juveniles and adolescents who were patients at Children’s Hospital between 1950 and 1980.

An analysis of mortality data showed that those diagnosed in later years lived longer. Individuals diagnosed in the 1950s had a five-fold higher rate of early death at 25 years post-diagnosis than those diagnosed in the 1970s. Some morbidity rates also were reduced.

For example, kidney failure rates declined significantly for those diagnosed more recently. At 20 years post-diagnosis, 4 percent of those diagnosed after 1964 developed renal failure compared to 16 percent among those diagnosed in the 1950s. At 30 years post-diagnosis, renal failure rates had declined from 31 percent in the 1950s to 18 percent in the 1960s.

On the other hand, there were no differences in rates of cardiovascular disease events and cardiac intervention procedures. Even when the researchers took into account the fact that procedures such as balloon angioplasty and stenting have become more common than they were in the 1950s and 1960s, their analysis found no differences in cardiovascular disease among the study population at either 20 or 30 years’ duration. Finally, there were no differences between the groups in rates of kidney dysfunction or proliferative retinopathy, a major cause of blindness in type 1 diabetics, at 20 and 25 years post-diagnosis.

Georgia Pambianco, lead study author, said, “Doctors have long considered type 1 diabetes a small blood vessel problem, so they have traditionally not focused on the potential large blood vessel complications, such as cardiovascular disease. However, our study suggests that doctors and their patients need to pay more attention to factors that affect the larger blood vessels, such as lipids and blood pressure.”

While a primary focus on blood glucose control has decreased early death significantly in type 1 diabetics, this study suggests these individuals remain significantly burdened with other serious chronic diseases. Trevor Orchard, professor of epidemiology, medicine and pediatrics at GSPH and principal investigator of the EDC, said, “We were, in fact, both surprised and disappointed that there were no improvements in cardiovascular and retinopathy disease rates, particularly because other complications improved so dramatically. Our data show that focusing solely on blood glucose control is only postponing, not preventing, some of the more significant complications of this disease.”

Orchard, who also is medical director of Pitt’s Nutrition Lipid Program, said although there have been only a few studies in children on the safety of lipid-lowering drugs, those studies found statins to be relatively safe. “This is certainly a group that could potentially benefit from more aggressive lipid control. In fact, much more focused attention needs to be paid to all cardiovascular risk factors, particularly lipids and blood pressure, and at an earlier age than we have been doing previously. This childhood-onset group is at a higher risk for cardiovascular disease even at early middle age. Waiting until they are adults to treat their lipids is too late.”

The National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health funded the research.

Other investigators include Tina Costacou, GSPH, and Demitrius Ellis and Dorothy J. Becker, Children’s Hospital.

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Nicotine patch helpful even for cheaters

Smokers who are trying to quit may be encouraged by Saul Shiffman’s study, which shows that wearing a nicotine patch can help prevent relapse, even in smokers who have cheated and smoked a cigarette.

The study, “Analyzing Milestones in Smoking Cessation: Illustration in a Nicotine Patch Trial in Adult Smokers,” appears in the May 2 Journal of Consulting and Clinical Psychology.

Shiffman and his associates not only examined the treatment’s final outcome — whether the patch worked — but also measured treatment milestones, such as momentary lapses, to discover more about why and how a nicotine patch works.

Smokers in the study were using either a high-dose NicoDerm CQ nicotine patch (35 mg, 2/3 stronger than the currently marketed 21 mg patches) or a placebo patch.

Using hand-held computers as electronic diaries, the 324 participants recorded exactly when they were craving a cigarette and if and when they lapsed and smoked one. The resulting data showed that people who wore the active patch after lapsing were 4- 6 times less likely to “cheat” again and again. The nicotine patch not only helped prevent slips, but also was more effective in preventing the slip from turning into a full relapse.

The study also analyzes mechanisms of action and could provide a better understanding of addiction treatment overall. And, it offers insight on how different techniques could be effective in different phases of treatment.

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McGowan researchers present findings

Researchers from Pitt’s McGowan Institute for Regenerative were among the participants at the first meeting of the Tissue Engineering and Regenerative Medicine International Society, held last month in Pittsburgh. Among their presentations:

* Gel may help breast cancer patients avoid radiation therapy

Women who undergo surgery for breast cancer followed by radiation therapy often experience breast deformities that can only be corrected through reconstructive surgery. McGowan researchers, in collaboration with bioengineers at Carnegie Mellon University, have developed a polymer-based therapy for breast cancer that could serve as an artificial tissue filler after surgery and a clinically effective therapy.

“Although radiation therapy is the standard treatment for breast cancer following surgery, it is expensive, time consuming and increases the cosmetic deformity caused by surgery,” said Howard D. Edington, associate professor of surgery and surgical oncology at Pitt and a faculty member at McGowan. “We sought to develop a possible alternative to radiation therapy that would not only release chemotherapy slowly to kill the cancerous cells left behind after surgery but that also would fill in the dimples and sometimes quite significant indentations that are common after breast surgery and radiation.”

The researchers encapsulated a common breast cancer chemotherapy drug, doxorubicin, in microspheres, then mixed them with a polymer gel. The gel was inserted under the skin next to the mammary glands of mice with breast cancer. The researchers found that they could successfully control the delivery of chemotherapy over a period of 30 days and that the tumors were completely eradicated compared to a control group of mice that were implanted with the gel insert without chemotherapy.

“Through further research and testing, our goal is to develop this into a clinical treatment for women undergoing breast cancer surgery,” said Edington, who also is chief of surgery at Magee-Womens Hospital. “This treatment may help decrease the occurrences of breast deformity. We believe this approach could eventually represent an alternative to breast radiation after surgery.”

Edington said clinical trials on women with breast cancer will follow additional laboratory studies. A paper detailing these results will be published in the Journal of Biomedical Materials Research.

Pitt co-authors of the study were Alicia J. DeFail, Kacey Marra and Wen-Chi C. Lee.

The study was funded by a grant from the U.S. Department of Defense.

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Pushing progenitors to build blood vessels

Using a unique combination of mechanical stimulations that accurately mimic the pressure, strain and shear forces to which blood vessels normally are subjected, researchers have demonstrated for the first time that bone marrow-derived progenitor cells can be stimulated to differentiate into mature cells.

One specific type of stimulation, called cyclic pressure, dramatically increased the differentiation of progenitor cells, according to research presented by Timothy M. Maul, a pre-doctoral fellow in bioengineering who is working in the laboratory of David Vorp, associate professor of surgery and bioengineering at the School of Medicine.

Why cyclic pressure, which mimics the hydrostatic pressure that causes the stretching of blood vessels, is able to yield greater numbers of differentiated cells is unclear. The researchers plan to look at gene expression patterns for biochemical markers and proteins that are known to influence the way cells behave to get a more accurate picture.

“Once we are able to understand exactly what is being switched on or off by mechanical stimulation, we can potentially use appropriate types and magnitudes of forces to help guide progenitor cells into becoming mature cell types useful for engineering new blood vessel tissue,” Maul said.

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Heart patch helps heal

A tissue-engineered cardiac “patch” promoted both tissue and vessel formation and improved heart function weeks after heart attack, according to researchers who tested the biodegradable material in small-animal studies.

Their findings suggest a new therapeutic option for preventing heart failure following myocardial infarction.

“The patch helps keep the tissue thick and mechanically softer, creating a more conducive environment for healing instead of scar tissue formation,” said William Wagner, associate professor of surgery, chemical engineering and bioengineering, and deputy director of the McGowan Institute.

Made of a flexible, microporous polyester urethane material that biodegrades over time, the cardiac patch promoted growth of new vessels and of smooth muscle cell bundles that may aid the contractile function of the heart, the researchers found. By comparison, rats that did not have the patch applied had profound scarring and thinning of the left ventricle wall.

According to Wagner, future studies will determine if seeding the patch with muscle-derived stem cells can bring about even greater improvements in healing and heart function.

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Long-term study to follow liver transplant patients

A $1.6 million grant from the National Institutes of Health will fund a study by researchers from the Pitt schools of nursing, medicine and pharmacy to find out which liver recipients fare best and to determine what individual and environmental factors affect adherence and outcomes.

With such information, clinicians should be able to identify patients early in the transplant process who may need individualized interventions to maximize transplant benefits.

Researchers expect to enroll 300 adult liver recipients and follow them for a year after their release from the hospital. They will collect information through interviews, self-reports, medical record reviews and monitoring of medication adherence.

Liver transplant patients tend to be more diverse in their psychosocial, behavioral and medical histories, said principal investigator Carol Stilley, an assistant professor of nursing and psychiatry at the School of Nursing and project director at its Center for Research in Chronic Disorders.

“As such, we think they may differ in their patterns of adherence, which are likely to affect health outcomes as well.”

A good prognosis depends in part on a patient’s dedication to a complicated regimen that involves multiple medications, numerous checkups, lab tests and biopsies, and abstinence from high-risk behaviors such as alcohol abuse, smoking, promiscuous sexual activity and intravenous drug use that can lead to diseases that could potentially destroy the new liver.

“In the liver transplant population, we and others have primarily studied alcohol relapse in patients who received transplants due to alcoholic cirrhosis. In this study, we will be looking at all liver transplant patients and at adherence to the entire treatment regimen, which includes much more than abstinence from alcohol. It includes taking medications on a regular basis, keeping clinic appointments and sustaining recommended lifestyle changes,” Stilley said.

The project is being conducted in collaboration with the Thomas E. Starzl Transplantation Institute.