University Times

Stem cell stroke therapy tested

Douglas Kondziolka, Peter J. Jannetta Professor and vice chair  of the Department of Neurological Surgery, and Lawrence Wechsler, chair of the Department of Neurology, are local leaders of a trial that is evaluating the use of stem cell therapy for stroke patients.

The trial is the first step in determining whether bone marrow stem cells injected into the brain have therapeutic value in the healing of stroke lesions.

Funded by California-based SanBio, the project will evaluate stroke therapy using SB623 cells, which are stem cells that are isolated from bone marrow and modified using recombinant DNA methods.

Kondziolka said, “Lab and animal testing of these cells have shown that they are not replacing the neurons that have been lost. Eventually, the transplanted cells disappear. But while they’re present, they appear to secrete factors that encourage the brain to repair itself by rebuilding neural connections or helping existing ones work better.”

The researchers are seeking participants ages 18-75 who have had an ischemic stroke between six months and three years before study entry.

Ischemic strokes occur when a blocked artery interrupts the flow of blood and oxygen in the brain, leading to cell death. Study candidates will undergo brain scans and be evaluated to ensure they have plateaued in their recovery from the stroke.

Participants will receive local anesthetic and light sedation for the surgical procedure, Kondziolka said. Small incisions are made in the scalp and skull and, using scans and brain-mapping technology, a probe is guided to the stroke area for deposition of the SB623 cells. Participants will be evaluated periodically for the next two years.

Two stroke survivors have received the therapy at UPMC, one of two sites conducting a safety and dose escalation study of the technique. The other testing site is at Stanford University.

The first six patients received 2.5 million cells; the next six will receive 5 million cells, and the final six, 10 million cells, Wechsler said. Between each dose escalation, the participants will be monitored to verify the process is safe.

He noted that every year 800,000 Americans have strokes, making it the fourth leading cause of death and the leading cause of adult disability. Even small changes in neurological function can have a big effect on function.

“A little gain in leg strength could mean the difference between requiring a wheelchair and walking. The ability to grip could mean being able to feed yourself,” Wechsler said. “Cell therapy for stroke and other neurological disorders holds great promise, but first we must methodically test these techniques to ensure safety before we can determine their effectiveness.”

For information on the study, contact Julia Billigen at 412/605-3959 or BilligenJB@upmc.edu.

LCAs evaluate childbirth

Researchers from Pitt and Magee-Womens Hospital have collaborated to improve sustainable childbirth procedures, both through vaginal delivery and birth by cesarean section. The study, published online in Science of the Total Environment, is the first of its kind to examine infant birth using Life Cycle Assessment (LCA), a technique that assesses the environmental impacts associated with all stages of a product’s or procedure’s life.

Melissa Bilec, a faculty member in the Swanson School of Engineering and assistant director of education and outreach at the Mascaro Center for Sustainable Innovation, said, “We are deeply interested in understanding the relationship between the delivery of medical care and our environment. We utilized LCA to make suggestions on ways to save energy, improve the health of our environment and address patient or worker safety.”

With the goal of improving the environment and patient quality, the interdisciplinary research team evaluated a number of medical devices and procedures used during birth using the four-step LCA.

The major components evaluated were the heating, ventilation and air-conditioning system in the hospital (HVAC), as well as lighting, machines, surgical instruments and disposable custom packs (such as patient gowns and toiletries) associated with each mode of birth. This included the sterilization, decontamination and waste segregation for disposable materials.

“We found that energy consumption resulting from HVAC, the impacts of the waste involved with disposable custom packs and the production of disposable custom packs contributed to the highest environmental impacts for both types of births,” said Bilec.

By using LCA, the team was able to suggest some recommendations to Magee, including HVAC control optimization, environmentally preferred purchasing, reduced reliance on disposable products and modified waste management.

Noedahn Copley-Woods, a faculty member in the School of Medicine’s Department of Obstetrics, Gynecology and Reproductive Sciences, said, “The collaboration with the Pitt engineers has been incredibly exciting for us at Magee because it’s allowed us to quantify environmental impacts that we wouldn’t have otherwise understood. This collaboration has helped direct our sustainability efforts and has generated enthusiasm among Magee employees for our greening efforts.”

The Pitt-Magee team is now studying the environmental impacts of different modes of hysterectomies to further develop its understanding of the carbon footprint of other medical procedures.

Pitt engineering graduate students Nicole Campion, Justin Deblois and Cassandra Thiel assisted with the research.

Funding for this study was provided by the National Science Foundation and the National Institutes of Health.

Birth control, infection link to be studied

A group of researchers from pediatrics and obstetrics, gynecology and reproductive sciences have been awarded $497,000 to study how the use of hormonal birth control may impair women’s ability to combat viral infections.

In an effort to better understand the relationships between hormonal contraceptives and susceptibility to HIV infection, primary investigator Thomas L. Cherpes of pediatrics will investigate changes to systemic and genital tract immune responses due to the use of oral, injectable and intrauterine forms of hormonal contraceptives.

The five-year study, Modulation of Hormonal and Systemic Immunity by Hormonal Contraceptive Use, will be conducted at the adolescent medicine clinic.

Funded by the National Institute of Child Health and Human Development, the study seeks to determine the biological plausibility of suspected associations between hormonal contraceptives and increased susceptibility to HIV so health care providers will be able to make better-informed recommendations regarding contraceptive choices for women who are at risk for HIV infection.

Co-investigators include Aletha Akers of obstetrics, gynecology and reproductive sciences and Gina Sucato and Rodolfo Vicetti Miguel of pediatrics.

Bioreactor controls inflammation

Researchers from the School of Medicine and the McGowan Institute for Regenerative Medicine report in the journal Disruptive Science and Technology that they were able to load an external bioreactor with human cells that produced anti-inflammatory proteins in a rat model of sepsis.

Senior author Yoram Vodovotz and his team loaded a small bioreactor with human liver cells engineered to make the anti-inflammatory protein sTNFR. Using an intravenous line, they pumped blood from an anesthetized rat experiencing acute but transient inflammation through the bioreactor to expose it to the engineered cells.

When the bioreactor was loaded with sTNFR-producing cells, sTNFR levels rose beyond what the animal could produce on its own and levels of its counterpart inflammation protein TNF-a and other markers of inflammation dropped. The animal’s blood pressure also improved, and markers of organ damage were reduced.

Inflammation is a necessary biological response that brings cells and proteins to the site of tissue injury to contend with foreign agents such as bacteria and the products they produce, and to begin the healing process. But sometimes, the inflammatory response escalates to create damage on its own, triggering more inflammation in a self-sustaining and dangerous cycle.

“In sepsis, for example, the inflammatory response evolves almost too quickly, but the available treatment strategies aim to prevent inflammation entirely,” said Vodovotz, who is a faculty member in the Department of Surgery and director of the McGowan Institute’s Center for Inflammation and Regenerative Modeling. “A better approach would be to turn down the response when it’s too strong, yet still have appropriate inflammation signaling to promote tissue repair.”

Vodovotz said, “This bio-hybrid device acts as a kind of inflammation thermostat. By loading it with cells that produce different amounts of sTNFR, or other inflammatory blockers, we may soon be able to tailor our interventions to carefully balance inflammation and immune responses based on the patient’s medical situation.”

His team now is exploring the effectiveness of cells engineered to produce sTNFR based on the individual production of TNF-a, rather than continuously, in order to create a disease-specific response for each patient. Such a personalized medicine therapy platform could be extended based on emerging knowledge regarding the biology of inflammation.

The Vodovotz group also is creating computer models of inflammation, which could be used to engineer the next generation of this device. The portability of the device could be particularly useful on the battlefield, where early intervention to control systemic inflammation after injury might improve the chances of survival.

Pitt co-authors of the paper included Jinling Yin of the Department of Surgery; Rami A. Namas, Maxim Mikheev and Ruben Zamora of surgery and the Center for Inflammation and Regenerative Modeling; Jörg Gerlach, Patrick Over and Matthew Young of surgery and the McGowan Institute, and Gregory M. Constantine of the departments of mathematics and statistics and the McGowan Institute.

The U.S. Department of Defense, the National Institutes of Health and the Commonwealth of Pennsylvania funded the project.

Gaming for better health?

Certain video games may be useful tools for psychological and physical therapy, say School of Medicine researchers who reviewed randomized controlled trials that tested the ability of video games to improve or promote health outcomes. Their work will appear in the June issue of the American Journal of Preventive Medicine.

Video gaming has grown into a multi-billion dollar business, and much of the research about the effects of games on health has focused on negative outcomes. Violence in some games has been linked to aggressive behavior and prolonged gaming has been linked to inactivity, obesity and repetitive strain injuries. But increasingly, video games also are being developed to encourage physical activity, distract people from chronic pain and promote health education.

Study leader Brian Primack, a faculty member in medicine and pediatrics and director of the medical school’s program for research on media and health, said, “Although it is very important to continue to assess the negative impact that video games can have on health, it also is valuable to study how the power of this technology may be used to improve health.”

Researchers identified 38 peer-reviewed journal articles that tested whether a video game could improve a particular health outcome. Some of the games aimed to improve psychological outcomes. For example, one study focused on anxiety reduction with Bejeweled, a common tile-matching puzzle game; another used Rise of Nations to lessen cognitive decline in the elderly. Some video games, such as Neverball, were used to improve physical function and stability. Another study looked at Playstation EyeToy games to help with rehabilitation from stroke.

“Of course, one of the most publicized areas of video game uses for health is in the physical activity category. Schools and public health initiatives are actively investing in these games in order to get kids active, but the evidence that they work is mixed,” Primack said. “Video games also have been tested to see if they help doctors gain skills. For example, two articles looked at whether playing video games with visuo-spatial demands help surgeons perform better at simulated laparoscopic surgery.”

Many games aim to improve health through education. Re-Mission helps adolescent cancer patients understand more about cancer, and Packy & Marlon is an interactive video game in which two adolescent elephants save a summer diabetes camp from rats and mice that have disrupted the camp’s food and diabetes supplies. Virtual reality and other video games are used for pain distraction during distressing medical procedures.

In the 38 studies identified, the researchers examined a total of 190 health outcomes and found that video games improved 69 percent of psychological therapy outcomes, 59 percent of physical therapy outcomes, 50 percent of physical activity outcomes, 46 percent of clinician skills outcomes, 42 percent of health education outcomes, 42 percent of pain distraction outcomes and 37 percent of disease self-management outcomes.

“Most of the games that have been studied thus far were aimed at children and the elderly, so there may be an opportunity to develop more for the middle-age adult population, who also like playing video games for fun,” Primack said. “We see opportunity for additional research of video games to improve health in innovative and enjoyable ways.”

Colon cancer screening effective

Colorectal cancer screening is effective at preventing cancer from developing in the left and right colon, and also prevents death due to the disease, according to an endoscopic screening study published online in the New England Journal of Medicine.

The study, which is part of the National Cancer Institute’s Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, provides the strongest evidence to date that screening reduces colorectal cancer deaths and prevents people from getting the disease, endorsing the importance of colorectal cancer screening for everyone.

The study’s lead author, Robert E. Schoen, a Pitt faculty member in medicine and epidemiology, said, “Colorectal cancer screening is effective because we’re not just searching for cancer. We’re identifying the precursors of cancer, colorectal polyps, and removing them. By doing so we are preventing cancer from developing. It’s the ultimate public health success story.”

Colorectal cancer is the second-leading cause of cancer death in the U.S., with more than 50,000 people dying from the disease each year. Progress has been made in reducing incidence and death rates from the disease, thanks in part to screening, but there is potential for an even greater reduction.

For the study, which began in 1993, 154,900 men and women ages 55-74 were randomly assigned to screening with flexible sigmoidoscopy with a repeat screening at three or five years, or to “usual care,” which means whatever screening they might receive in routine medical care with their physician. More than 86 percent of the subjects underwent a screening exam. Most subjects with abnormal sigmoidoscopy screening results then had a full colonoscopy. Overall, the screening resulted in a 21 percent reduction in cancer incidence and 26 percent decline in colorectal cancer deaths. There was a 50 percent reduction in death due to distal colon cancer, the portion of the colon that can be examined directly by the flexible sigmoidoscopy exam.

“There is still room for improvement. Our biggest obstacle is the underutilization of screening,” said Schoen. “Right now, 40 percent of the U.S. population is not getting screened, and we know screening works. We need to encourage everyone to undergo screening to save themselves from this potentially deadly disease, and to reduce the unnecessary public health burden and expense of colorectal cancer.”

This study was funded by the NIH National Cancer Institute.

ICU nighttime staffing studied

Intensive care units (ICUs) that have no or limited access to critical care doctors during the day can improve patient outcomes by having the specialists, called intensivists, staff the unit at night, according to a study led by researchers at the School of Medicine and UPMC. However, the researchers were unable to find any incremental benefit of nighttime staffing in ICUs that were staffed robustly with specialists during the day. The findings were published online in the New England Journal of Medicine and presented recently at the annual meeting of the American Thoracic Society in San Francisco.

Research has shown that daytime staffing with intensivists improves ICU patient outcomes, noted senior author Jeremy M. Kahn, a faculty member in the medical school’s Department of Critical Care Medicine. But fewer than half of all ICUs in the U.S. are manned by intensivists, while many large medical centers, particularly teaching hospitals such as UPMC, have adopted not only intensivist staffing but have extended it to a 24-hour intensivist staffing model.

“Intuition would suggest that that round-the-clock attention from an expert trained in critical care medicine would be of even greater benefit to these very ill patients,” Kahn said. “But until this project, no one had carefully examined whether that assumption would hold true. As it turns out, having some access to intensivists, who are in great demand, is the key to better outcomes. Round-the-clock intensivist staffing is only helpful in some ICUs.”

The research team reviewed admission details between 2009 and 2010 from 34 community and academic hospitals that use the Acute Physiology and Chronic Health Evaluation clinical information system, a database that collects details of patient outcomes as well as ICU staffing primarily for internal quality control monitoring. The researchers sent follow-up surveys to those hospitals and received responses from 25, which included 49 ICUs and nearly 66,000 patient admissions.

Kahn and his colleagues found that patient mortality was lower in ICUs where an intensivist was available at night only if there was no intensivist heavily involved in care during the day. In ICUs where intensivists were on duty during the day, mortality was unaffected by the presence of intensivists at night.

“There is a huge opportunity to improve survival rates in some ICUs by bringing an intensivist on board at night,” Kahn said. “However, there aren’t enough of us to staff all the ICUs that need intensivists, so hospitals with a strong intensivist presence during the day — like most academic medical centers — should consider whether additional intensivist coverage is needed at night.”

The study team included David J. Wallace, Derek C. Angus and Amber E. Barnato, all of critical care medicine.

The project was funded by the National Heart, Lung and Blood Institute, part of the National Institutes of Health.

Robotic prostatectomy raises costs

A study led by Joel B. Nelson, chair of the Department of Urology, has found that the cost of robotic-assisted laparoscopic surgery for prostate cancer is significantly higher than standard open surgery, despite little scientific evidence of long-term improved patient outcomes. The study results were published in the July issue of the journal Urology.

For their cost analysis, the researchers looked at the treatment of 473 consecutive patients from July 2009 to October 2010 at UPMC Shadyside hospital. Robotic-assisted laparoscopic radical prostatectomy (RARP) was used in 115 cases; open radical retropubic prostatectomy (RRP) was used in 358.

There was no significant difference in the mean length of stay for patients undergoing RARP vs. RRP, 1.2 and 1.4 days, respectively. However, the mean total cost per case of RARP exceeded by 62 percent the cost of RRP.

The overall cost per case for RARP exceeded the cost for RRP by almost $5,300. The major contributors to the cost gap were greater operating room supply costs and indirect costs associated with the purchase and maintenance of the robotic equipment. Operating room supply costs were almost seven times greater for RARP, while ancillary, cardiology, imaging, administrative, laboratory and pharmacy costs were not significantly different between the two approaches.

Since payment to the hospital was nearly equivalent for both types of procedures, the hospital lost $4,013 on average for each RARP case, while the payments exceeded costs by $1,325 for the standard open approach. Most of the cost difference, researchers found, was attributable to the robotic equipment and supplies.

Nelson said, “Nearly 240,000 new cases of prostate cancer are diagnosed annually, and radical prostatectomy is the most common treatment. The value of that care for patients is of particular concern to a nation struggling to control health care costs while improving outcomes.”

During the past decade, he noted, RARP has become the dominant surgical approach in the treatment of prostate cancer, with a surgeon controlling a robot’s arms remotely to remove cancerous organs through small incisions in the patient’s abdomen. Yet there is limited data to show that this technological innovation has produced better long-term patient results. “It is reasonable to question whether the increased costs of this robotic-assisted approach are justified,” said Nelson, who is also co-director of the University of Pittsburgh Cancer Institute’s prostate cancer program.

Several previous studies also demonstrated a cost advantage for the standard open surgical approach. However, those studies sometimes excluded certain costs or involved hospitals with lower surgical volumes or surgeons who were less experienced with the robotic-assisted technology, potentially skewing the cost per case.

Nelson noted that randomized clinical trials — the gold standard in scientific research — comparing RRP and RARP are lacking. But a recent review of 37 comparative prostatectomy studies found no superiority for one approach over the other in terms of functional (such as post-operative continence and potency) and oncologic outcomes for patients.

“While further studies are needed to compare the long-term outcomes of RRP vs. RARP, our study suggests that our society may be paying too high a price for what has been widely perceived as a medical advance,” said Nelson.

Other Pitt authors were Jeffrey J. Tomaszewski, Benjamin J. Davies, Stephen V. Jackman and Ronald L. Hrebinko of urology.

Research aids reactor design

The U.S. Department of Energy (DOE) awarded a three-year $875,000 grant for a team of Pittsburgh scientists to develop computational models for turbulent mixing in the VHTR (very high temperature reactor), a Generation IV nuclear reactor.

Generation IV reactors offer significant advances in sustainability, safety, reliability and economics. Their designs currently are being studied and are expected to be available commercially after 2030.

The aim is to build a computational model to better understand stresses in order to refine the VHTR lower plenum design.

Principal investigator Mark Kimber and John Brigham of the Swanson School of Engineering are collaborating with co-PI Anirban Jana of the Pittsburgh Supercomputing Center (PSC) and Milorad Dzodzo of Westinghouse Electric Co. on the project.

The focus of the study is turbulent mixing in a portion of the VHTR called the “lower plenum” — where helium that has absorbed heat from the nuclear reaction enters at speeds up to 100 meters per second and at temperatures approaching 1000º C. The high flow speed and non-uniform heating cause turbulent mixing and temperature fluctuations that affect the structural reliability.

The team will use fluid dynamics software to simulate the complicated flow dynamics and thermal stresses involved. For some of the simulations and for analyzing the large datasets that will be generated, the team expects to use PSC’s Blacklight system.

NLP automates quality analysis

Software that analyzes written text, known as natural language processing (NLP) programs, effectively can measure colonoscopy quality in an inexpensive, automated and efficient manner, according to researchers from the School of Medicine, whose findings appear in the June edition of Gastrointestinal Endoscopy.

Lead author Ateev Mehrotra, a faculty member in the Division of General Internal Medicine, said, “Gastroenterology specialty societies have called for physicians to regularly measure the quality of colonoscopy screening. However, physicians face challenges doing this because it simply takes too much time to review each medical record. Our NLP computer program can replace a human and quickly analyze electronic medical records, making the process simple and cost-effective while improving the quality of care.”

More than 24,000 colonoscopy reports from UPMC digital health records were analyzed using NLP to measure and report on the quality of care for several measures. These included an indication of the patient’s physical status, documented informed consent of patient, description of the quality of bowel preparation, notation of bowel landmarks, detection of adenoma, notation of the time the scope was withdrawn, if indication for colonoscopy is chronic diarrhea, and whether or not a biopsy sample was taken.

The analysis revealed that documentation of most quality measures was poor, with a wide range of performance across hospitals and physicians — including a threefold variation in the adenoma detection rate among doctors. Researchers also found that physicians who used a structured program to document colonoscopies scored higher than those who used dictated reports.

Study co-author Robert E.  Schoen of the Division of Gastroenterology and Hepatology said, “Our study indicates that NLP could be a means of making quality reporting on colonoscopies more common and lay the foundation for efforts to improve care.”

Melissa Saul of biomedical informatics was a co-author on the study.

The National Institutes of Health and a pilot grant from Pitt’s Clinical and Translational Science Institute and the RAND-University of Pittsburgh Health Institute provided support.

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