More education
may benefit
women with CF

For female cystic fibrosis (CF) patients and providers, individual CF health care specialists have a significant role in helping patients gain access to educational resources that can help them improve sexual and reproductive health, according to a study by researchers at Children’s Hospital.

Women with CF face important disease-specific sexual and reproductive health concerns, including delays in puberty, increased risk of vaginal yeast infections, urinary incontinence, problems with sexual function, concerns regarding contraceptive choice, decreased fertility and adverse effects of pregnancy on their lungs.

The study, published online in Pediatrics and led by Traci Kazmerski, a pulmonology fellow, sought to find the best ways to provide women with CF effective sexual and reproductive health care by interviewing CF center directors from a nationwide sample as well as young adult women with the disease and asking them about their experiences and preferences. The findings may help guide the development of educational resources around sexual and reproductive health for women with CF.

Both CF providers and patients agreed that the CF provider has a fundamental role in providing CF-specific sexual and reproductive health care. They also believed that educational resources and provider training on sexual and reproductive health topics would improve patient care in this area.

Said Kazmerski: “Patients were clear that they want both sexual and reproductive health educational resources and for their CF providers to begin those discussions, early and routinely. Our next step is to figure out how to do this as we care for our patients with CF.”

Said co-author Elizabeth Miller, pediatrics faculty member in the School of Medicine and chief of the Division of Adolescent and Young Adult Medicine at Children’s Hospital: “This study provides some critical guidance on how to better provide sexual and reproductive health education and care for adolescents with cystic fibrosis, and encourages us to consider how to integrate such care for all adolescents with chronic medical conditions.”

Other Pitt authors were David Orenstein, Daniel Weiner, Joseph Pilewski and Sonya Borrero. A researcher from the Children’s National Health System also contributed.

The study was supported by a grant from the Cystic Fibrosis Foundation.

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Improving grafts
for bypass patients

The National Institutes of Health (NIH) has awarded David Vorp, the William Kepler Whiteford Professor of Bioengineering and associate dean for research of the Swanson School of Engineering, with a two-year grant of $417,838 for research into the use of cells from a patient’s own adipose (fat) as vascular grafts in arterial bypass surgery. This new method, which has been successful in rat subjects, would allow surgeons to perform bypass surgeries without harvesting arteries or veins from the patient or requiring the time to isolate and grow a specific cell type, such as a stem cell.

Coronary bypass procedures often use other arteries or veins as a source for grafts. Arteries that can be used safely as a bypass graft in a different location are in short supply. The great saphenous vein in the leg is one of the most common sources for arterial grafts, but repurposing veins as arterial bypass grafts can cause complications.

Said Vorp: “The vein graft, even though it is the most widely used graft material for the coronary or other small diameter artery applications, is not ideal. The problem is that veins are not arteries; they are built differently because they have different purposes in the body. Arteries pulse, and they are under higher pressure than veins. When you take a vein segment and put it under arterial conditions, it responds by thickening, which can cause the same blockage you were trying to treat.”

Vorp’s study, “An Autologous, Culture-free Adipose Cell-based Tissue Engineered Vascular Graft,” will explore ways to facilitate the translation of technology that has been under development by him and his associates for a number of years. The current methodology requires stem cells to be carefully extracted from the fat and then spend time in culture before constructing a graft, which itself spends time in additional culture. This new research will explore the potential for skipping the culture steps entirely, first by using all of the fat cells from the patient (instead of isolating and expanding the stem cells alone) and then by implanting the graft immediately instead of culturing it first. The researchers also will design a way to scale-up the process that creates their engineered graft. The method used for small-scale grafts in rats won’t work when the construct is enlarged to a human scale.

“The key focus of the study is the translational aspects,” said Vorp. “We have shown that we can regenerate a small-diameter aorta in a rat that functions for up to a year. We now need to determine how to overcome some logistical issues so that we can use this technology to help human patients, which is why we started the research in the first place. This R21 grant is really facilitating the start of that process.”

R21 research grants are designated for exploratory/developmental research, generally still in the conceptual stage. They often are awarded to high-risk and high-reward studies that have the potential to become much larger in scope. J. Peter Reuben, University of Pittsburgh Medical Center Endowed Professor, chair of plastic surgery and faculty member in bioengineering, as well as William R. Wagner, director of Pitt’s McGowan Institute for Regenerative Medicine and faculty member in surgery, bioengineering and chemical engineering, will collaborate with Vorp on the study.

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New findings on schizophrenia’s
biological processes

Using a computational model they developed, researchers at the School of Medicine have discovered more than 500 new protein-protein interactions (PPIs) associated with genes linked to schizophrenia. The findings, published in npj Schizophrenia, could lead to greater understanding of the biological underpinnings of this mental illness, as well as point the way to treatments.

Senior investigator Madhavi Ganapathiraju, biomedical informatics faculty member in the School of Medicine, noted that there have been many genome-wide association studies (GWAS) that have identified gene variants associated with an increased risk for schizophrenia, but in most cases there is little known about the proteins that these genes make, what they do and how they interact.

“GWAS studies and other research efforts have shown us what genes might be relevant in schizophrenia,” she said. “What we have done is the next step. We are trying to understand how these genes relate to each other, which could show us the biological pathways that are important in the disease.”

Each gene makes proteins and proteins typically interact with each other in a biological process. Information about interacting partners can shed light on the role of a gene that has not been studied, revealing pathways and biological processes associated with the disease and also its relation to other complex diseases.

Ganapathiraju’s team developed a computational model called High-Precision Protein Interaction Prediction (HiPPIP) and applied it to discover PPIs(?) of schizophrenia-linked genes identified through GWAS, as well as historically known risk genes. They found 504 never-before-known PPIs, and noted also that while schizophrenia-linked genes identified historically and through GWAS had little overlap, the model showed they shared more than 100 common interactors.

“We can infer what the protein might do by checking out the company it keeps,” Ganapathiraju explained. “For example, if I know you have many friends who play hockey, it could mean that you are involved in hockey, too. Similarly, if we see that an unknown protein interacts with multiple proteins involved in neural signaling, for example, there is a high likelihood that the unknown entity also is involved in the same.”

Ganapathiraju and colleagues have drawn such inferences on protein function based on the PPIs of proteins, and made their findings publicly available (severus.dbmi.pitt.edu/schizo-pi). This information can be used by biologists to explore the schizophrenia interactome with the aim of understanding more about the disease or developing new treatment drugs.

The Pitt research team included Mohamed Thahir, Adam Handen, Saumendra N. Sarkar, Robert A. Sweet, Vishwajit L. Nimgaonkar, Eileen M. Bauer and Srilakshmi Chaparala. A colleague from Dublin City University, Ireland, also contributed.

This project was funded by the Biobehavioral Research Awards for Innovative New Scientists (BRAINS) from the National Institute of Mental Health, part of NIH.

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Blue light reduces mouse organ damage

A 24-hour exposure to bright blue light before surgery reduces inflammation and organ damage at the cellular level in a mouse model, according to new research from the School of Medicine.

The finding, reported in Proceedings of the National Academy of Sciences, suggests a potential pre-treatment light therapy that could improve outcomes in patients undergoing procedures characterized by a period of blood restriction, such as liver resection or organ transplantation. The research was funded by NIH.

Said senior author Matthew R. Rosengart, faculty member in the departments of surgery and critical care medicine: “We were incredibly surprised by our results. There’s long been evidence suggesting that light and circadian rhythms profoundly influence our biology and specifically the physiological response to stress. So while we were expecting to find some correlation with light spectrum and the immune response, we were not expecting results quite so striking.”

Light is complex and consists of intensity, duration of exposure and wavelength. This study is one of the first that accounts for this complexity and derives results that could guide future clinical trials in humans.

Rosengart and his team compared what happened when mice were exposed to red light, ambient white fluorescent light similar to that in hospitals and high-intensity blue light 24 hours before kidney or liver surgery involving periods of blood restriction and restoration.

The high-intensity blue light outperformed the red and white light, attenuating cellular and organ injury through at least two cellular mechanisms. The blue light brought about a reduction in the influx of neutrophils, a type of white blood cell involved in inflammation, which can lead to organ damage and other problems. Additionally, blue light inhibited dying cells from releasing a protein called HMGB1 that triggers organ-damaging inflammation.

The team then tested whether the blue light was acting through the optic pathway or some other mechanism, like the skin. Blind mice had the same healing response regardless of whether they were exposed to blue or red light, indicating that the protective impact of blue light does, indeed, act through the optic pathway.

The team then looked at whether one color of light might disrupt the circadian rhythm, which is linked to immunity, more than another. Blood from mice exposed to red, white and blue light had similar concentrations of melatonin and corticosteroid hormones.

Furthermore, the mice under each of the lights also had similar activity levels. These data indicate that the effects of blue light were not mediated by a disruption of sleep, activity or circadian rhythms.

Rosengart stresses that mice are nocturnal animals with visual, circadian and immune biology that is distinct from humans. Thus, the results of his study should not be broadly extended to patients or hospital settings until robust clinical trials have been performed to show whether pretreatment with intensive blue light is safe.

Additional Pitt researchers on this project were Du Yuan, Richard D. Collage, Hai Huang, Xianghong Zhang, Ben C. Kautza, Anthony J. Lewis, Brian S. Zuckerbraun, Allan Tsung and Derek C. Angus.

—Compiled by Marty Levine

The University Times Research Notes column reports on funding awarded to Pitt researchers and on findings arising from University research.

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