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April 4, 2013

Research Notes

Device helps swallowing problems

Those suffering from swallowing difficulties, especially stroke patients, could be evaluated more efficiently and noninvasively thanks to research undertaken by Ervin Sejdic, a faculty member in electrical and computer engineering in the Swanson School of Engineering.

He and colleagues from the University of Toronto are developing a small sensor that’s placed on the neck near the thyroid and records how a person swallows. Sejdic uses simulation modeling to posit a mathematical solution to the low diagnostic success rate of current swallowing tests.

Said Sejdic: “We’ve seen a lot of patients, especially those suffering from strokes, die from difficulty swallowing. This disorder, known medically as dysphagia, can have dire consequences like malnutrition, dehydration, pneumonia and even death. Unfortunately, current methods are often cumbersome and not as effective as they need to be.”

In their paper, Sejdic and his collaborators suggest a mathematical algorithm that works electronically “behind the scenes” to improve the images captured by his neck sensor, which is the size of a quarter and affixed using double-sided tape. He and his team tested the model sensor on 40 dysphagic patients, who were instructed to take several sips of liquid in a head-neutral position. The result was a 90 percent success rate in diagnosing dysphagia.

Today’s dysphagia evaluations make use of videofluoroscopy exams — motion X-rays prescribed by speech-language pathologists — that take snapshots of the throat, said Sejdic. These exams are effective at tracking whether food is going into one’s airway instead of the stomach (aspiration); which parts of the mouth and throat may not be working well, and whether certain positions or strategies help a person swallow better.

“Unfortunately, people eat or drink something 10 to 20 times a day,” said Sejdic. “And you can’t put a person in front of an X-ray that many times, nor does every hospital have the capability to do so.”

For stroke patients rushed into the hospital, an even more basic exam is administered. This includes simple water tests in which patients drink a glass of water and are evaluated on whether they cough or have “wet voice” (a condition where it sounds like patients are producing words through moisture). However, those tests show an even lower level of efficacy.

“These simple tests have a success rate below 50 percent,” said Sejdic. “You’re better off flipping a coin.”

Sejdic and his colleagues have been working on their model sensor for almost three years, and negotiations are under way for a clinical trial in the United States and Canada. While the researchers’ neck sensor could help all patients with dysphagia, they are specifically targeting stroke sufferers, as dysphagia occurs in 37-78 percent of those patients.

The paper appeared in IEEE Transactions of Biomedical Engineering online.

Restoring insulin production is priority

Researchers at the School of Medicine and colleagues have discovered a novel mechanism that regulates the replication of insulin-producing beta cells in the pancreas.

According to lead author Nathalie Fiaschi-Taesch, faculty member in the Division of Endocrinology and Metabolism, regenerating beta cells to restore insulin production has moved to center stage in the quest for therapies for both Type 1 and Type 2 diabetes.

Said Fiaschi-Taesch: “Ideally, we would be able to do this by collecting cells from donor pancreatic tissue and growing them in the lab or, better yet, giving a patient a pill to stimulate their own beta cells to replicate. In the past, this has proven to be very challenging. Our findings provide new insights into how one may be able to do this.”

A 2009 paper reported that a team led by Fiaschi-Taesch and others successfully induced human beta cells to replicate in the lab by elevating the level of a protein called cdk-6. In two current reports in the journal Diabetes, they continued to examine the workings of the cell cycle proteins involved in the replication machinery.

Their findings were surprising. Scientists had assumed the proteins resided in the cell’s nucleus, where they could act upon genes and molecules to stimulate — or in the case of beta cells, prevent — cell replication. Their experiments showed that the cell cycle proteins actually were in the cell’s cytoplasm, the fluid around the nucleus and contained within the cell membrane.

Increasing levels of cdk-6 led that molecule and other key (or critical) cell cycle proteins to move into the nucleus to foster replication, but in the quiescent or non-replicating cell, the only ones that remained in the nucleus were inhibitors of replication. Understanding how and why those inhibiting proteins block replication could in turn lead to ways to block their activity, providing a novel approach for reviving beta cell regeneration, Fiaschi-Taesch said.

Co-authors included researchers from Mount Sinai Medical Center.

The project was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, part of the National Institutes of Health; the Juvenile Diabetes Research Foundation; the American Diabetes Association, and Pitt.

Fewer women in science careers by choice

Women may be less likely to pursue careers in science not because they have less ability but because they have more career choices, according to a study led by Ming-Te Wang, faculty member in psychology in education in the School of Education.

Although the gender gap in mathematics has narrowed in recent decades, women still are less likely to pursue STEM (science, technology, engineering and mathematics) careers than their male counterparts. With colleagues, Wang investigated whether differences in overall patterns of math and verbal ability might play a role.

Said Wang: “Our study suggests that it’s not lack of ability or differences in ability that orients females to pursue non-STEM careers but, because they’re good at both, they can consider a wide range of occupations.”

Wang’s team examined data from 1,490 college-bound students drawn from a national longitudinal study. The students were surveyed in 12th grade and again when they were 33 years old. The survey highlighted data on several factors including participants’ SAT scores, their motivational beliefs and values, and their occupations at age 33.

“We found that students who also had high verbal abilities — a group that contained more women than men — were less likely to have chosen a STEM occupation than those who had moderate verbal abilities,” said Wang. “This shows that there’s a greater likelihood that females with high math ability also have high verbal ability, giving them more career options.”

Notably, those participants who reported feeling more able and successful at math were more likely to end up in STEM-related jobs, and this was particularly true for students who had high math and moderate verbal abilities. Therefore, mathematics may play a more integral role in these individuals’ sense of identity, drawing them toward STEM occupations.

According to Wang, this study identifies a critical link in the debate about the dearth of women in STEM fields. These findings suggest that “educators and policy makers may consider shifting the focus from trying to strengthen girls’ STEM-related abilities to trying to tap the potential of these girls who are equally skilled in both mathematics and verbal domains.”

Co-authored with researchers from the University of Michigan, the paper was published online March 19 in Psychological Science.

Wearable artificial lung to be developed here

Each year, nearly 350,000 Americans die of some form of lung disease, with another 150,000 patients needing short- and long-term care. Current breathing-support technologies are cumbersome, often requiring patients to be bedridden and sedated.

Now, with the support of a $3.4 million National Institutes of Health (NIH) grant, researchers at the School of Medicine, the Swanson School of Engineering and colleagues will develop an artificial lung to serve as a bridge to transplant or recovery in patients with acute and chronic lung failure.

Said principal investigator William J. Federspiel, engineering faculty and director of the Medical Devices Laboratory within the Pitt-UPMC McGowan Institute for Regenerative Medicine: “Our wearable lung will be designed to get patients up and moving within the hospital setting, which is important for both patient recovery and improving a patient’s status prior to a lung transplant.”

Current long-term breathing support modalities include extracorporeal membrane oxygenation (ECMO), a cardiac and respiratory technique in which blood is drained from the body, oxygenated outside of it and returned to the bloodstream. The drawback to ECMO is that it can significantly limit a patient’s mobility and, while mobile ambulatory ECMO systems are beginning to be used clinically, these systems involve unwieldy equipment.

“This project will develop a compact respiratory assist device called the Paracorporeal Ambulatory Assist Lung, known as PAAL , to replace the old techniques,” said Federspiel. “This is a wearable, fully integrated blood pump and lung designed to provide longer-term respiratory support up to one to three months while maintaining excellent blood compatibility.”

The PAAL device will complement recent efforts by the University of Maryland (which developed a wearable artificial pump-lung) by potentially improving the efficiency of the transfer of oxygen and carbon dioxide and increasing biocompatibility, Federspiel said.

Federspiel’s colleagues include faculty from Carnegie Mellon University and Mississippi State University.

Childhood asthma linked to violence exposure, gene changes

Puerto Rican children who have asthma are more likely to be exposed to violence and to have changes in a gene that is associated with stress, according to a study led by faculty members Juan C. Celedón in medicine and Niels K. Jerne in pediatrics.

Asthma rates are known to be higher among Puerto Rican children both living on the island and on the mainland. The team recruited children ages 6-14 who had four Puerto Rican grandparents from randomly selected San Juan households; 271 had physician-diagnosed asthma and wheezing in the prior year and 266 did not have asthma or a history of wheezing. Blood samples were drawn for DNA analysis, all parents completed a questionnaire and children age 9 and older answered another standard questionnaire about exposure to violence.

Researchers looked for evidence of a biochemical process called methylation of the promoter, or “on-off” switch, of a gene called ADCYAP1R1, which a previous study linked to post-traumatic stress disorder. They found that increased methylation was associated with higher odds of having asthma and with exposure to violence, and that increasing exposure to violence was linked with a greater risk of asthma. They showed also that a certain variation, or polymorphism, in the ADCYAP1R1 gene in study participants was associated with asthma, but not with methylation.

“It appears there is a subgroup of people who may be more susceptible to asthma because of exposure to violence, and we need to understand how that happens,” Celedón said.

Co-authors of the paper included other researchers from Pitt, Children’s Hospital, the University of Puerto Rico and Harvard University.

The study was funded by NIH and Children’s Hospital, and was recently published in the American Journal of Respiratory and Critical Care Medicine.

Philosophy prof wins Templeton grant

Robert Batterman, philosophy faculty member, is the principal investigator for a $510,000 three-year grant from the John Templeton Foundation for a project titled “Bridging Across Scales: Emergence and Effective Theories.”

When engineers build bridges, buildings or pipelines, or when they design ships, they usually employ equations that describe the behaviors of these objects at everyday length and time scales. They almost completely ignore details of the molecular nature of the materials (steel or oil, for example). Yet their equations work: Most often the buildings don’t fall down; the bridges don’t collapse; fluid flows through pipes, and ships don’t sink.

The small-scale, microscopic details of the steel used in bridges certainly are relevant to its strength and bending behavior. But the engineers almost completely ignore those details, for pragmatic reasons: They could pay attention to all the details and build the structures from models of materials at the level of atoms and molecules, but this would be too onerous a task.

Even so, the following questions remain: What accounts for their ability to ignore the micro-details? What explains their relative autonomy from details at lower scales?

This last question is the major focus of Batterman’s research project. It is related to current debates in both the philosophical and physics communities about whether there are any properties or phenomena that are emergent, in the sense that they cannot be explained, predicted or reduced to more basic fundamental theory. By focusing on the means for explaining the autonomy and safety of various modeling strategies and theories that characterize systems at relatively large scales, the project will settle a number of philosophical questions relating to issues about emergence and reduction.

Co-investigators are Mark Wilson, Pitt faculty member in philosophy, and Christopher Smeenk, University of Western Ontario.

Pitt faculty contribute to report that could affect Medicare pay

Adjusting Medicare payments to clinicians and hospitals on the basis of geographic regions would not give providers the right incentive to improve the efficiency of care, according to an interim report issued by the Institute of Medicine (IOM), an independent, nonprofit organization that provides health advice to decision makers.

The IOM committee is engaged in an ongoing, congressionally mandated study of regional variations in health-care spending, use and the benefits of adopting a geographic value index. A value index would raise payment rates in low-cost regions where the quality of care and health benefits are high and decrease payments in high-cost areas where the quality and benefits are low relative to their spending.

Sally Morton, chair of the Department of Biostatistics at Pitt’s Graduate School of Public Health and a member of the IOM Committee on Geographic Variation in Health Care Spending and Promotion of High-Value Care, said: “Extensive analysis by our subcontractors, review of the literature and interpretation by the committee revealed that if we want to provide high-quality care at lower cost, we need to provide incentives to those who make decisions — that is, the doctors, hospitals and health-care systems — rather than broadly at the geographic area.”

Medicare spending varies greatly across the country, even after adjusting for regional price differences. Studies indicate that regions where Medicare spends more do not report consistently better health outcomes or greater patient satisfaction. However, committee members noted that using a geographically based value index to set reimbursements could reward low-performing providers in high-performing regions and penalize high-performing providers in low-performing regions.

Yuting Zhang, a Pitt faculty member in health economics and the author of one of the subcontractor reports for the IOM committee, noted: “The effectiveness of payment reforms in reducing overutilization while maintaining access to high-quality care depends on the effectiveness of targeting. We found that there was substantial local variation in health-care utilization and spending within broad regions.

“Our analysis suggests that reimbursement policy at the regional level may be too crudely targeted to promote the best use of health care resources,” said Zhang, the lead author for the study published last November in the New England Journal of Medicine. The IOM committee commissioned this study and another study, also led by Zhang, on the variation of medication adherence in heart failure, which recently was published in JAMA Internal Medicine.

IOM committee member Amber Barnato, a faculty member in the School of Medicine, said:  “In the U.S., regions don’t have decision-making authority. That’s not true in other countries, like Canada and England, where budgets are managed regionally. In those places regional budget caps are used to equitably distribute money across the country, leaving the regional decision makers to determine how to pay the providers within their region. The closest organizational equivalent we have in the U.S. for fee-for-service Medicare is an accountable care organization — and those are very new.”

The IOM committee expects to release its final report this summer.

Discovery could mean better pneumonia treatments

Scientists at the School of Medicine discovered a new biological pathway of innate immunity that ramps up inflammation and then identified agents that can block it, leading to increased survival and improved lung function in animal models of pneumonia. They reported their findings in Nature Immunology.

Pneumonia and other infections sometimes provoke an inflammatory response from the body that is more detrimental than the disease-causing bacteria, said senior author Rama Mallampalli, vice chair for research in the Department of Medicine and director of the Acute Lung Injury Center of Excellence at Pitt.

“In our ongoing studies of pneumonia, we found infecting bacteria activate a previously unknown protein called Fbxo3 to form a complex that degrades another protein called Fbxl2, which is needed to suppress the inflammatory response,” said Mallampalli, who also is chief of the pulmonary division of the VA Pittsburgh Healthcare System. “The result is an exaggerated inflammatory response that can lead to further damage of the lung tissue, multi-organ failure and shock.”

The researchers, led by Bill B. Chen, Division of Pulmonary, Allergy and Critical Care Medicine (PACCM), conducted experiments in which mice that lacked the ability to make Fbxo3 were infected with a strain of Pseudomonas bacteria, and found that they had better lung mechanics and longer survival than mice that still made the protein. Research team members Bryan J. McVerry and Yingze Zhang, both of the Acute Lung Injury Center, found that blood samples from 16 people who had sepsis, a condition of systemic inflammation, revealed higher levels of Fbxo3 — along with other inflammatory proteins — and lower levels of Fbxl2 than samples from seven patients who did not have sepsis or lung infection. Based on the structure of Fbxo3, the researchers developed a family of small molecules with the aim of inhibiting its activity. Administration of one of them, called BC-1215, led to reduced inflammatory markers and improved lung mechanics in mouse models.

Mark T. Gladwin, chief of PACCM, said: “The F-box protein Fbxo3, and other related proteins, represent ideal targets for treatment of acute lung injury, because it controls the innate immune response, is upstream of important inflammatory signaling pathways, and is more selective than traditional drugs that regulate protein turnover.”

The team is beginning to study the effects of BC-1215 on other conditions of systemic inflammation, such as colitis and arthritis.

Co-authors included Tiffany A. Coon, Jennifer R. Glasser, Jing Zhao, Yutong Zhao, Chunbin Zou, Bryon Ellis and Frank C. Sciurba, all of the Acute Lung Injury Center.

The study was funded by the U.S. Department of Veterans Affairs, NIH and the American Heart Association.


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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