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April 14, 2016

Research Notes

Pain, disability reduced after bariatric surgery

In the three years following bariatric surgery, the majority of patients experienced an improvement in pain and walking ability, as well as a lessening of the degree to which back or leg pain interfered with work, according to a Graduate School of Public Health-led analysis of a multi-site clinical study published in the Journal of the American Medical Association.

The study also revealed patient characteristics that indicate who is the most and least likely to experience improvements in pain and function, a finding that could allow clinicians to identify patients who may require additional interventions to improve outcomes.

The research was funded by the National Institutes of Health (NIH).

Said lead author Wendy King, faculty member in the Department of Epidemiology: “Our study found that clinically meaningful improvements in bodily pain, specific joint pain and physical function are common following bariatric surgery. In particular, walking is easier, which impacts patients’ ability to adopt a more physically active lifestyle. However, some patients continue to have significant pain and disability. This data can help patients and clinicians develop realistic expectations regarding the impact of bariatric surgery on pain and disability.”

King and her colleagues followed 2,221 patients participating in the Longitudinal Assessment of Bariatric Surgery-2, a prospective study of patients undergoing weight-loss surgery at one of 10 hospitals across the U.S. After three years, patients weighed, on average, 28 percent less than prior to surgery. The majority of the patients received Roux-en-Y gastric bypass, a surgical procedure that significantly reduces the size of the stomach and changes connections with the small intestine.

Through three years of followup, 50-70 percent of adults with severe obesity who underwent bariatric surgery reported clinically important improvements in bodily pain, physical function and usual walking speed. About three-quarters of the participants with symptoms indicative of osteoarthritis before surgery experienced improvements in knee and hip pain and function. In addition, over half of participants who had a mobility deficit prior to surgery did not have such a deficit post-surgery.

Older age, lower income, more depressive symptoms and pre-existing medical conditions, including cardiovascular disease and diabetes before surgery, were among the factors independently associated with a lower likelihood of improvement in pain and mobility post-surgery, while greater weight loss, greater reduction in depressive symptoms, and remission or improvement in several medical conditions were associated with greater likelihood of improvement.

In the first year following bariatric surgery, 3.7 percent of patients had hip, knee or ankle surgery; in the second year, 4.9 percent had such surgeries followed by another 4.6 percent in the third year. The majority were knee surgeries. The incidence of back surgeries ranged from 1.5 percent in the first year to 2.3 percent in the third year.

Three years post-surgery, 76.3 percent of patients reported that their leg and back pain interfered with their work “not at all,” up from 54.1 percent pre-surgery. Also, the average physical function score of the participants, which is based on ability to walk various distances, climb stairs, perform vigorous and moderate activities, lift and carry groceries, bathe, dress, bend and kneel, improved to the point that it was comparable to that of the general U.S. population. Resting heart rate also improved.

Said study co-author Anita Courcoulas, chief of minimally invasive bariatric and general surgery in the School of Medicine: “Functional status is an extremely important aspect of health that has not been as well-studied as other conditions that change following bariatric surgery, and this study sheds light on specific factors that may affect improvements in individuals with joint pain who undergo these procedures.”

Additional Pitt investigators on this research were Jia-Yuh Chen and Steven H. Belle. Also contributing were colleagues from Weill Cornell Medical College, Pacific University, Oregon Health & Science University, the University of Washington, the Neuropsychiatric Research Institute, East Carolina University and the National Institute of Diabetes and Digestive and Kidney Disease.


New app improves disaster response

Researchers from the Department of Anesthesiology in the School of Medicine have unveiled a new web application aimed at improving how quickly staff return to the hospital in the event of a disaster.

“Disaster Recall: Optimizing Hospital Surge Capacity” was presented at Pediatric Anesthesiology 2016, cosponsored by the Society for Pediatric Anesthesia and the American Academy of Pediatrics Section on Anesthesiology and Pain Medicine. The study surveyed 50 anesthesiology departments in U.S. children’s hospitals to determine the systems in place to recall critical staff when a disaster triggers an influx of patients.

More than half of the children’s hospitals that responded to the survey manually call or text staff during disaster situations, the study showed. Twenty-eight percent used automated text messages to cell phones; 4 percent sent automated messages via messaging applications; and 16 percent had no system at all.

Said Ali Hassanpour, a fellow in pediatric anesthesiology who led the study and designed the web application: “Most children’s hospitals surveyed have antiquated systems in place. The vast majority use a phone tree system, and that process can break down at any point. You can’t predict when you are going to have an influx of patients, but a more reliable, simpler, inexpensive system can make all the difference.”

While investigating different approaches to sending text messages, researchers determined that a dedicated SMS server via a reliable SMS gateway currently is considered the most reliable method. Email-based text messaging techniques no longer are considered reliable as they have a high latency and failure rate due to abuse by spammers.

Based on the results, researchers developed a one-touch system to automatically and simultaneously contact each member of the anesthesiology department, alerting them to a disaster and requesting their return to the hospital. Responses are recorded automatically and tallied in real time through a secure interface.

“Our approach was to find a system that could quickly and instantaneously get in touch with everyone using something everyone has, a mobile phone,” Hassanpour said. “If you can efficiently get responses to see if staff members are coming back and how fast, without having to communicate with the original person who sent the message, you eliminate unnecessary work and can focus on the patients.”

The web application is being used by the Department of Pediatric Anesthesiology at Children’s Hospital. Faculty members in medicine who also presented the study were Franklyn Cladis and Peter Davis.

Racial perceptions report to be discussed

Parents and teachers, both separately and in tandem, should engage their children in conversations on race; “color blind” approaches to parenting and teaching are misguided, according to the School of Education’s newly released report, “Understanding PRIDE in Pittsburgh: Positive Racial Identity Development in Early Education.”

The report also says that positive racial-identity concepts have been linked to favorable educational and social outcomes, including a strong sense of self-esteem as well as higher grades and standardized test scores. In contrast, negative identity concepts contribute to racial achievement gaps, including a nearly 35 percent difference in reading proficiency between African-American and Caucasian children in Pittsburgh’s public schools.

The report explores methods for building positive racial self-perceptions in underrepresented children within southwestern Pennsylvania. “Understanding PRIDE in Pittsburgh” also offers recommendations on how to move forward with improving positive racial-identity development in the region.

Among a wide range of recommended measures, the report suggests continuous parent-child and parent-teacher communication about race. Additionally, the report calls for increased partnerships between educational institutions and professional organizations throughout the region.

Mayor Bill Peduto will join Kathy Humphrey, senior vice chancellor for engagement and chief of staff, and Pitt researchers to discuss the report’s findings, recommendations and significance today at 10 a.m. in the Connolly Ballroom of Alumni Hall.

Lead researcher on the report was Kenneth Smythe-Leistico, assistant director of Pitt’s Office of Child Development.

The report brings together findings from focus groups, surveys, interviews, classroom observations and literature and curricula reviews. Some of its findings:

• Southwestern Pennsylvania has many racial inequalities to overcome. Only 33 percent of African-American third-fifth graders in Pittsburgh public schools read at a proficient level compared to 67 percent of white students. For mathematics, 17 percent of African-American students scored as “proficient” compared to 52 percent of whites.

• Children become aware of racial differences at an early age. Infants as young as 3 months old are capable of categorizing people by race. Before a child’s third birthday, he or she is able to attribute positive and negative traits to racial groups. By age 5, children are able to express race-based biases and preferences.

• Both parents and teachers understand that possessing an understanding of race is valuable to a child’s healthy development. However, they are not always clear on the best approaches to the issue and often avoid talking about race out of fear of doing harm.

• Researchers, parents and teachers alike believe institutional racism must be addressed if underrepresented children are to reach their fullest potential.

• Proactively teaching young children to recognize and appreciate cultural differences promotes positive perceptions and empathy toward others.

“Understanding PRIDE in Pittsburgh” was researched and produced by The Race and Early Childhood Collaborative — a partnership of the Office of Child Development, Center for Urban Education and Supporting Early Education and Development (SEED) Lab —within Pitt’s School of Education.

The report was supported by the Frank and Theresa Caplan Fund for Early Childhood Development and Parenting Education.

Epilepsy drug improved

Researchers at the School of Medicine and the Dietrich School of Arts and Sciences have designed a more effective version of an FDA-approved epilepsy drug with the potential for fewer side effects, according to a study published in Molecular Pharmacology. The experimental agent also could prove to be a treatment for tinnitus and other disorders caused by volatile neural signaling.

Epilepsy, in which erratic firing of nerve signals causes seizures, affects about 1 percent of people worldwide, noted senior investigator Thanos Tzounopoulos, Endowed Chair in Auditory Physiology, faculty member in otolaryngology and member of the auditory research group in the School of Medicine. Drugs to treat the disorder primarily work by influencing the transport of sodium, potassium and chloride ions across the nerve cell membrane to try to reduce the excitability of the brain cells.

Said Tzounopoulos: “Unfortunately, these drugs don’t work well in nearly a third of patients and there is a great need for better treatments. We have been able to refine an existing medication so that it acts selectively on certain nerve cell membrane transport channels, which should make it more effective.”

The available drug is called retigabine, and while it has improved symptoms for some patients, it also can lead to troublesome side effects, including retinal abnormalities, urinary retention and skin discoloration. Tzounopoulos was part of a study team that evaluated an earlier modification of retigabine, dubbed SF0034, which is being developed further by SciFluor Life Sciences in Cambridge, Massachusetts.

For the current project, Tzounopoulos and Peter Wipf, Distinguished University Professor of Chemistry, rationally redesigned several structural components of retigabine to further increase its potency. Retigabine works by activating all five types of potassium transport channels in the KCNQ category, but only two of the potassium channels, KCNQ2/3, are important for stabilizing the membrane of brain cells involved in hyperexcitability-related disorders, such as epilepsy and tinnitus. The new compound, known as RL648-81 (RL-81), targets just those channels.

When the researchers compared the three drugs head-to-head in lab tests, they found RL-81 was 15 times more potent than retigabine and three times more potent than SF0034. Because of its specificity, RL-81 also should have fewer side effects.

The experimental compound could also help people with tinnitus by preventing hyperexcitation of nerve cells in auditory pathways, Tzounopoulos noted.

Said Wipf: “At this point, the new compound is ready to be studied further in animal models of epilepsy and tinnitus and for other preclinical assessments. RL-81 appears to have great potential for the treatment of these challenging neurological conditions.”

The Pitt team also included Manoj Kumar, Nicholas Reed, Ruiting Liu and Elias Aizenman. The project was funded by the Department of Defense Joint Warfighter Medical Research Program.

Enzymatic reactions may show how cells first formed colonies

A novel investigation of how enzymatic reactions can direct the motion and organization of microcapsules may point toward a new theory of how protocells — the earliest biological cells — could have organized into colonies and thus ultimately could have formed larger, differentiated structures.

Researchers at the Swanson School of Engineering, along with collaborators in Penn State’s chemistry department, found that very simple physical and chemical processes that do not rely on complex biological machinery guided the self-assembly of the microcapsules, which served as models for the protocells. Namely, the researchers isolated a dynamic cascade of events that lead the microcapsules to organize into a well-defined colony.

Anna C. Balazs, Distinguished Professor of Chemical and Petroleum Engineering, with postdoctoral associates Oleg E. Shklyaev and Henry Shum, developed the computational modeling based on previous experiments conducted by a Penn State researcher. “Harnessing Surface-Bound Enzymatic Reactions to Organize Microcapsules in Solution” was published in Science Advances.

The researchers modeled microcapsules 10-50 micrometers in diameter, the typical size of biological cells. In this study, the microcapsules consisted of an outer shell and a fluid-filled core containing hydrogen peroxide, which gradually leaked through the shell into the surrounding fluid. The hydrogen peroxide acted as a chemical reagent for a patch of enzymes on the surface under the microcapsules. The reaction occurring at the enzymes released heat and lowered the fluid density, driving the convection of the surrounding fluid. This fluid flow carried the immersed capsules and brought them together above the enzyme-coated surface. After the reagent was consumed, the fluid flow ceased and the capsules remained localized above the patch of enzymes.

Balazs and her team were able to regulate the assembly of the microcapsules by patterning the distribution of enzymes on a bottom wall, creating different types of configurations — in this instance, circular, square and crankshaft shapes. The size and number of the capsules determined the amount of fuel available to regulate the velocities. This mechanism indicates a means of controlling where and how the capsules self-organize without external stimuli.

Said Shklyaev: “The density variation created by the secretion of a reagent and its reaction at the enzymes on the bottom wall caused the fluid flow, which resulted in the assembly of the microcapsules into colonies. No magnetic or electric fields are needed to guide the microcapsules. We only need gravity. This approach can apply both to biological applications, as well as cargo delivery into particular areas of a microchannel.”

According to Balazs, this research provides a novel approach for manipulation in small fluidic devices. Use of different catalysts would allow different flow patterns to develop depending on the chemicals present in the fluid or microcapsules. This could potentially lead to autonomous sorting of cells or assembly of large, predesigned structures from smaller building blocks.

Excitatory visual neuron wiring reconstructed


Researchers at the Pittsburgh Supercomputing Center (PSC), Harvard and the Allen Institute for Brain Science in Seattle have produced a reconstruction of an excitatory nerve-cell network in the brain. It is the largest such reconstruction to date in which scientists traced the connections among nerve cells confirmed in the living brain to respond to the same visual stimulus.

The collaborators reported their results in Nature.

One of the mysteries of brain function is how we make sense of the jumble of images that confront our eyes. Neuroscientists have discovered that most individual nerve cells in the brain respond to specific elements in the visual environment. For example, one nerve cell may fire in response to vertical lines, another in response to horizontal or slanted lines. Researchers suspected that the mammalian cortex amplifies this signal by having nerve cells that respond to similar elements excite each other. This mutual excitation may help those elements stand out and prime the network for their further processing. But scientists had no anatomical evidence that this actually happens.

To get such evidence, a team led by Harvard and Allen Institute researchers identified brain nerve cells that respond to visual elements in living mice. Then they took millions of microscope images of ultra-thin (about 40-nanometers-thick) tissue slices around these nerve cells. Car-negie Mellon University (CMU) faculty members helped them to reconnect these images into a three-dimensional volume using PSC’s AlignTK software. But because these slices are fragile, microscopic tears and other artifacts happened, requiring manual intervention to correct them. So researchers had to move back and forth between computation and manual “repair” of the images until the quality of the aligned volume was good enough to trace the connections between the nerve cells. The team found that mammalian excitatory nerve cells that respond to a given visual feature do indeed make more and larger connections to other excitatory nerve cells that are tuned to respond to similar visual elements.

Said CMU’s Greg Hood: “The challenge here was to go from a block of brain tissue to a coherent, three-dimensional digital volume that someone could then visualize on a computer and trace individual nerve-cell axons and dendrites. This involves careful cutting of the tissue block into extremely thin slices, staining them, then transferring these slices into an electron microscope where they are imaged one small area at a time. In this process there are inevitable physical distortions and, if one simply stacked the images together, nothing would line up properly. Supercomputing allows us to register these images to one another and reconstruct a well-aligned volume.”

The work involved two-photon fluorescence microscopy (to identify the nerve cells responding to a given orientation of visual lines), electron microscopy and computation. To connect the electron microscope images into a 3-D reconstruction, the scientists first had to merge thousands of individual images for each slice into a single large image of the entire slice. They next aligned the adjacent slices. They could then combine these pairwise alignments over the entire stack to calculate exactly how to correct the distortion present in each slice and place its corrected image back into an aligned stack.

The group only reconstructed 0.03 cubic millimeters of the mouse brain, a volume that would go into a teaspoon about 167,000 times. But this still resulted in about 10 million camera images, amounting to roughly 100 terabytes of raw data — about the computer storage required for nearly 30 million high-resolution, large-format photographs.

Hood’s work on this project was funded by an NIH grant to the National Center for Multiscale Modeling of Biological Systems.

Middle-aged black women need more heart screenings

Middle-aged black women have higher levels of a protein in their blood associated with a predictor of heart disease than their white counterparts, even after other factors, such as obesity, are taken into consideration, according to a study conducted by the Graduate School of Public Health and the School of Medicine.

The finding, reported in Menopause, suggests routine blood testing of black menopausal women may be warranted to determine their heart disease risk and potentially when to start therapies, such as aspirin and statins.

The research was funded by NIH through the National Institute on Aging, the National Institute of Nursing Research, the Office of Research on Women’s Health and the National Heart, Lung and Blood Institute.

Said lead author Norman C. Wang, School of Medicine faculty member: “Multiple previous studies have shown that black women are at higher risk for heart disease than white women; however, guidelines for assessing cardiovascular disease risk in asymptomatic adults do not recommend selective race- or ethnic-based risk-assessment. Our study revealed for the first time that in black, but not white, women going through menopause, higher levels of an easily measured risk factor for heart disease are associated with higher amounts of early atherosclerosis, even after accounting for other risk factors for heart disease. A clinical trial to determine whether routine screening in this population can save lives may be warranted.”

Wang and his colleagues examined medical records, blood samples and heart CT scans for 372 black and white women from Pittsburgh and Chicago enrolled in the Study of Women’s Health Across the Nation (SWAN). The women averaged just over 51 years old, were not on hormone replacement therapy and had no known heart disease when enrolled.

The researchers looked at blood levels of five biomarkers linked to inflammation. All of the biomarkers were associated with coronary artery calcification, a predictor of heart disease that is measured with a heart CT scan. When the researchers then took into account the participants’ body mass index (BMI), a measure of overall body fat, they found that obesity was a key factor linking most of the elevated inflammation biomarkers and coronary artery calcification.

Regardless of BMI, black women with higher levels of one particular biomarker, C-reactive protein, were more likely to have coronary artery calcification than whites. In fact, black women with coronary artery calcification had an average level of C-reactive protein in their blood that was almost double that of their white counterparts.

Said senior author Samar El Khoudary, faculty member in public health’s Department of Epidemiology: “We clearly demonstrated that obesity, inflammation biomarkers and coronary artery calcification are linked for both black and white midlife women, further emphasizing the need to promote lifestyle changes to combat obesity at midlife when women are subjected to many physiological and biological changes that could potentially increase their risk for heart disease. Future research should build on our findings regarding black women and C-reactive protein by testing similar associations over time, which could potentially yield interventions that can help these women avoid developing heart disease.”

The researchers noted that their study only looked at black and white women, so the results are not generalizable to other racial or ethnic groups.

Additional Pitt researchers on the study were Karen A. Matthews, Emma J.M. Barinas-Mitchell and Chung-Chou H. Chang.

Policies needed to support family caregivers of the aging, disabled

Family members and friends provide the vast majority of care for aging Americans experiencing chronic conditions, trauma or illness. Yet, according to “Addressing the Needs of Caregivers at Risk: A New Policy Strategy,” a study conducted by the Stern Center for Evidence-Based Policy, current policy efforts at the federal and state levels have not adapted to address significant health and economic risks that these caregivers experience.

Though caregivers provide support to over 90 percent of individuals receiving care at home, the study, published today by the Health Policy Institute (HPI), found that they lack access to financial policies, flexible employment and social services needed to support this important function. The study builds on the Stern Center’s earlier report, “Addressing the Health Needs of an Aging America,” published last September.

Said lead author Everette James, HPI director and the M. Allen Pond Professor of Health Policy and Management at public health: “Family members and friends play a vital role in keeping aging Americans healthy and in their homes, and dramatically reducing the cost of longterm care. Our study shows that public policy has not yet embraced these caregivers, many of whom will experience major economic losses and are often at high risk for mental and physical health problems compared to those who don’t provide care. Many caregivers simply do not have access to benefits to compensate them for the time they spend giving care or employment protections that allow them to leave work to care for their family members. And we really have no comprehensive way of providing support services, such as respite care, to everyone who needs it.”

James and his colleagues examined the impact of federal and state policy designs on family caregivers’ finances, employment and access to services and support. This included major programs such as Social Security, Medicaid and the Family and Medical Leave Act, as well as lesser-known federal programs such as the national family caregiver support program, state policies on tax credits and paid sick leave.

Said study author Meredith Hughes, a JD/MPH student at Pitt: “In several cases, such as tax benefits and Social Security, no comprehensive policy framework to address family caregivers currently exists. In other cases, such as family and medical leave, current benefits are inadequate to address caregiver needs.”

The study also found that, despite evidence of positive impacts on caregivers, programs that deliver caregiver support and services, such as respite, have not expanded to meet growing demand.

Study author Philip Rocco, postdoctoral associate in the HPI, said: “Our study of current legislation shows that Congress has not been focused on changing how we address the needs of family caregivers. By analyzing the patchwork of current programs, we’ve also identified a ‘dashboard’ of feasible policy options that could help mitigate caregiver economic and health risks.”

The study concludes by suggesting a set of policy options to address current gaps in family caregiver policy.

The Stern Center is planning a series of studies on evidence-based policies to address health and economic risks experienced by family caregivers.

—Compiled by Marty Levine


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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