School of Medicine

Wayne State University School of Medicine

Research Spotlights

Deane Aikins, Ph.D.
Feb 17, 2015

Post-traumatic stress disorder has been a recognized condition in combat veterans since 1983. Women make up 17 percent of the U.S. armed forces, and since 2001, 280,000 women in the military have been deployed for tours of duty in Iraq and in Afghanistan. Of those, 150 were killed in action and 800 were wounded.

Yet there is a paucity of knowledge about PTSD in female combat veterans.

Deane Aikins, Ph.D., associate professor of Psychiatry and Behavioral Neurosciences, is working to change that with an ongoing study of PTSD in female veterans in Michigan. He is using a combination of reliving a stressful scenario with an extremely limited use of beta blockers to train the body to reduce the physical reaction to traumatic memories.

“With PTSD, we don’t have one similar reaction in all veterans,” Dr. Aikins said. “During those times of stress, the heart rate can triple within 60 seconds of thinking about trauma. But not everyone has flashbacks. Everyone is different in their reaction to PTSD and how they react to it. In those receiving the placebo, we see the heart rate shoot up. In those we’ve tested using the beta blocker, their physiological response can be as neutral as a walk through Walmart.”

The goal is not to erase or even minimize the traumatic memory, but to teach the body to develop a different reaction to the stress associated with it. “Our hypothesis is that with this method you are weakening and uncoupling the memory association between the event and the hyper-arousal that comes with PTSD,” Dr. Aikins said. “In effect, the patient’s body learns to not be physically upset by the memory.”

Veterans in the study agree to participate in four sessions. Each receives a medical screening and writes a description of two memories, one about a pleasant or neutral event, and the second a memory of a traumatic event related to military service that still causes stress. They write descriptive paragraphs of both memories, and Dr. Aikins records a 30-second narrative of both events.

In subsequent sessions, Dr. Aikins attaches to the veterans sensors for heart rate, frown muscles and sweat monitors on fingers. Veterans listen to the pleasant or neutral tape for one minute on headphones. They are asked to keep that image in mind and then are given a placebo or a beta blocker while their vital signs are monitored for two hours. If the subject’s vital signs appear good, they receive a second pill and then are sent home with 100 milligrams of the drug or a placebo. Seventy-two hours later, the subject returns to the office to listen to the recording of the traumatic incident. They again are given the drug or placebo and vitals are monitored.

Veterans return a month – and a menstrual cycle -- later to listen to the trauma memory recording again and have a final diagnostic interview.

Researchers, Dr. Aikins explained, found the beta blocker had a better impact on females in an animal model. “We think it will work better with women. Hormones may facilitate the treatment. Women could be more adept at coping with stress. We just don’t know yet. We have some statistical detail, but it doesn’t translate to clinical practice yet. That’s why we’re conducting the study.”

To date, he said, subjects receiving the placebo appear to experience no change in their reaction to stressful memories a month later. In the group receiving the beta blocker, however, after a month their physiology does not react to the trauma as it would before treatment.

Beta blockers are often used to treat hypertension and to regulate heart rate. They also have been used by people stressed about public speaking and by athletes. They have been prescribed for PTSD as a long-term therapeutic, but that use has not been very effective, Dr. Aikins said.

“We are not looking to use the beta blocker as a long-term crutch as a coping mechanism,” he said. “We have them face the fear, then take the pill. Taking the beta blocker just this one time might be enough to undo the physical reaction to the traumatic experience.”

The stress of combat is something many civilians cannot comprehend, Dr. Aikins said. “Our service members have seen women and children used as bombs and may have had to kill those people. They have seen terrible things. These are horrible things for all of us to be confronted with. We ask them to make hard calls and do sometimes terrible things.” In addition, the stress for female veterans can also be rooted in Military Sexual Trauma as sexual assault while serving in the military.

Women in combat as members of the armed services is a relatively new phenomenon for the United States, Dr. Aikins said, with the wars in Iraq and Afghanistan. Women have been in combat areas in previous military engagements, but mainly as nurses and support personnel. “We’ve known about combat stress, what we now call PTSD, for at least 60 years,” he said. “PTSD was officially recognized in 1983, 10 years after the end of the Vietnam War. Before the wars in Iraq and Afghanistan, our scientific knowledge of combat stress physiology came from studies that included a combined total of only 700 veterans, and only 33 of those were women. There is a huge gap in military and clinical literature on combat stress on women and the female stress response.”

Female veterans are under-represented in PTSD treatment studies, Dr. Aikins said. “It’s difficult to get veterans of Iraq and Afghanistan to participate. Some feel seeking help is a stigma. Some female veterans who are victims of a sexual assault in the military may not want to relive the experience, or feel help is not available because the assault was not handled correctly by their commanders or their commanders may have been the perpetrators. It may be a sense of not knowing where to seek treatment. We do everything we can to help these warriors.”

The study, which seeks only female veterans, pays subjects $400 for their participation. Women must be younger than 45. For more information about the study, call 313-437-3953.

Banu Kumar, M.D.
Jan 15, 2015

After reviewing the histories of more than 2,000 American children who were treated with antibiotics for bone infections, a national team of pediatric researchers has come up with a surprising finding that could change the way kids receive the drugs in the future.

The large study found that children who were discharged home with oral antibiotics did just as well in overcoming their bone infections as those who were sent home on intravenous antibiotics.

“This very large clinical trial shows that oral antibiotics also cause significantly fewer complications and that there is no advantage of the more invasive prolonged intravenous therapy. Based on these very hopeful findings, clinicians who treat pediatric bone infections may want to reconsider prescribing intravenous delivery of antibiotics for patients who are being sent home for extended drug therapy,” said Banu Kumar, M.D., Children’s Hospital of Michigan chief of Pediatric Hospital Medicine and assistant professor of Pediatrics for the Wayne State University School of Medicine. Dr. Kumar led the Children’s Hospital of Michigan group participating in the study.

Published last month in the Journal of the American Medical Association Pediatrics, the results of the study (http://archpedi.jamanetwork.com/article.aspx?articleid=2022276) seem likely to challenge the long-held belief that intravenous-delivered antibiotics are more effective than pills in combating bone infections in children.

The analysis of medication records among 2,060 children at 36 U.S. hospitals also found that 15 percent of the children who received antibiotics intravenously through a peripherally inserted central catheter developed complications that later sent them back to an emergency room or required further hospitalization.

The potentially significant implications of these findings were strongly underlined in an accompanying Journal editorial that noted that on the basis of the study, “Clinicians should strongly consider transition to oral antibiotic therapy at the time of discharge for the treatment of acute osteomyelitis in otherwise healthy children.”

The study also noted that the “gravity” of the complications that can result from IV antibiotics delivery – including bloodstream infection, thromboembolism and line breakage – warrants careful reassessment by clinicians of the longtime presumption that intravenous antibiotics are just as safe as the oral version.

Dr. Kumar said the results might eventually help to spare children with bone infections the discomfort and health risks that sometimes accompany intravenous delivery of antibiotics.

“The typical course of treatment for these children is anywhere from six to 12 weeks,” Dr. Kumar said, “and that means they have to live 24/7 with a peripherally inserted central catheter inserted into their arms. It also means that their caregivers have to be trained to do the dosing two or three times a day, often for several months. Given the obvious discomfort, anxiety and risk of infection that can be part of the intravenous procedures, the possibility that we could get the same effectiveness from an orally delivered antibiotic is quite promising. Based on these very hopeful findings, clinicians who treat pediatric bone infections may want to reconsider prescribing intravenous delivery of antibiotics for patients who are being sent home for extended drug therapy.”

Dr. Kumar added that the findings are a “compelling example of how good research can improve medical care. A study like this gives us enormous hope, because it shows how the clinicians and researchers at the Children’s Hospital of Michigan are constantly striving to make standard care more tolerable and safer for kids. At the end of the day, research is an important key to the best care. We need more of these kinds of studies to show there are better ways to care for kids. Children don’t like to be poked and children don’t like to be hurt – and if there are things we can do more effectively, more safely, why not?”

Steven Lipshultz, M.D., chair of Pediatrics for the Wayne State University School of Medicine and pediatrician-in-chief at Children’s Hospital of Michigan, said he was greatly encouraged by the study, which has the potential to provide “significant cost savings” as well as improved care for pediatric patients.

“Dr. Kumar and the other researchers really hit it out of the park with this comparative effectiveness study,” Dr. Lipshultz said.  “What’s exciting for all of us at the Children’s Hospital of Michigan is to know that for the past three years or so we’ve been using this (form of oral therapy) for bone infections as part of the study, which means that we’ve been providing better care for these patients. Based on this study, that has demonstrated that in the absence of data supporting that long-term intravenous antibiotics enhance clinical outcomes when compared with oral therapy, our practice of transitioning otherwise healthy children with acute osteomyelitis to oral antibiotic therapy at the time of discharge to avoid peripherally inserted central catheter-associated complications is both right for the patient and the right thing to do. At the Children’s Hospital of Michigan, we’re doing our best every single day to connect the very latest research to clinical care so that our patients can benefit as much as possible. As Dr. Kumar and her colleagues around the country have demonstrated in this important study, children benefit most when their treatment is informed by the very latest, cutting-edge research. This is an example of how we use practice-based evidence to achieve the very best outcomes for our patients by implementing evidence-based practice.”

Nihar Nayak, D.V.M., Ph.D.
Oct 28, 2014

A team of researchers led by a Wayne State University School of Medicine associate professor of obstetrics and gynecology has published findings that provide novel insight into the cause of preeclampsia, the leading cause of maternal and infant death worldwide, a discovery that could lead to the development of new therapeutic treatments.

Nihar Nayak, D.V.M., Ph.D., is the principal investigator of the study, “Endometrial VEGF induces placental sFLT1 and leads to pregnancy complications,” published Oct. 20 in the online version of The Journal of Clinical Investigation.

“Preeclampsia is a leading cause of maternal and fetal morbidity and mortality worldwide, yet its pathogenesis is still poorly understood,” Dr. Nayak said. “Many studies have suggested that elevated circulating levels of sFlt1 (a tyrosine kinase protein that disables proteins essential to blood vessel growth) contribute to the maternal symptoms of vascular dysfunction that characterize preeclampsia, but the molecular underpinnings of sFlt1 upregulation in preeclampsia have so far been elusive. Our manuscript describes the novel, field-changing finding that vascular endothelial growth factor, or VEGF, of maternal origin can stimulate soluble sFlt1 production by the placenta and that this signaling is involved in the cause of preeclampsia.”

Preeclampsia is a sudden increase in blood pressure after the 20th week of pregnancy. Indicated by a sudden increase in blood pressure and protein in the urine, preeclampsia warning signs, in addition to elevated blood pressure, can include headaches, swelling in the face and hands, blurred vision, chest pain and shortness of breath. While the condition can manifest within a few hours, some women report few or no symptoms.

The condition is responsible for 76,000 maternal deaths and more than 500,000 infant deaths every year, according to estimates from the Preeclampsia Foundation. It can affect the liver, kidney and brain. Some mothers develop seizures (eclampsia) and suffer intracranial hemorrhage, the main cause of death in those who develop the disorder. Some women develop blindness. The babies of preeclamptic mothers are affected by the condition and may develop intrauterine growth restriction or die in utero.

Many experts believe preeclampsia results from insufficient blood supply to the uterus and placenta, causing the development of high blood pressure. The increase in maternal blood pressure is a compensatory response to improve the condition of the fetus. Preeclampsia may have evolved to protect the infant, but when the disease is out of control it threatens the health of the mother. The earlier the disease starts in pregnancy, the worse the outcome can be for the baby and mother. Women with preeclampsia often do not feel effects until the condition is severe and becomes life-threatening. Effects on the mother include cardiac problems, possible brain hemorrhage, acute renal failure, blood clotting problems and possible blindness. If left undetected, the condition can progress to eclampsia and the mother may begin convulsing. For the fetus, preeclampsia has been connected to a reduction in placental blood flow, resulting in physical and mental disability, the slowing of fetal development, and in severe cases, infants may be stillborn.

While VEGF is essential for normal embryonic development, Dr. Nayak said, his team’s research has demonstrated that even mild elevation of VEGF levels during early pregnancy can cause severe placental vascular damage and embryonic lethality. The results show that modest increases in VEGF could also be a primary trigger for elevation of placental sFlt1 expression, leading to preeclampsia.

Furthermore,  the findings indicate that sFLT1 plays an essential role in maintaining vascular integrity in the placenta in later stages of pregnancy and suggest that overproduction of sFlt1 in preeclampsia, although damaging to the mother, serves a critical protective function for the placenta and fetus by “sequestering” excess maternal VEGF.

According to the Preeclampsia Foundation, the condition, also known as toxemia or pregnancy-induced hypertension, affects 5 percent to 8 percent of pregnancies. Left untreated or undetected, preeclampsia can rapidly lead to eclampsia, one of the top five causes of maternal death and infant illness and death. Approximately 13 percent of all maternal deaths worldwide – the death of a mother every 12 minutes – have been attributed to eclampsia. The foundation reports that preeclampsia is responsible for nearly 18 percent of all maternal deaths in the United States.

Even if treated successfully, preeclampsia can bring future health problems for mothers. Women who have had preeclampsia have double the risk for heart disease and stroke over the next five to 15 years after they are treated.

The Preeclampsia Foundation estimates that in the United States about 10,500 babies die annually as a result of preeclampsia. The cost of the condition in the U.S., according to the foundation, is $7 billion annually, split between $3 billion a year in treating mothers and $4 billion a year for the cost of treating infants born prematurely because of preeclampsia.

The study, supported by the Wayne State University Perinatal Initiative, included research conducted by Stanford University School of Medicine, the University of Calgary, University of Utah and Yale University School of Medicine.

Leonard Lipovich, Ph.D.
Oct 6, 2014

The National Institutes of Health has selected Wayne State University School of Medicine researcher Leonard Lipovich, Ph.D., for its coveted Director’s New Innovator Award, a five-year, $2.3 million grant he will use from the National Cancer Institute to test a hypothesis that could lead to breakthrough methodologies to improve human health.

The project will identify primate-specific long non-coding ribonucleic acids, or lncRNAs, that are functional in cell growth and cell death, within the framework of human estrogen receptor positive breast cancer. The goal of the project, which has broad relevance to other nuclear hormone receptor pathways in human disease, is to reveal the extent to which non-conserved RNA genes contribute to cancer pathogenesis in humans.

Dr. Lipovich is a Detroit resident and an associate professor of the WSU Center for Molecular Medicine and Genetics and of the Department of Neurology.

The New Innovator Award mechanism was created by the NIH to support exceptionally creative new investigators who propose highly innovative, high-risk projects that have the potential for unusually high impact. Approximately 40 New Innovator awardees are selected each year. The small number of awards, along with the relatively high award amounts and the unconventional nature of the funded research, makes the program considerably more exclusive than the NIH’s more common R01 funding mechanism.

“Life, Death and Function: The Primate-Specific Long Non-Coding RNA Transcriptome,” will test whether evolutionarily young lncRNA genes – present in humans and some or all nonhuman primates, but absent in non-primates  – are directly functional in positioning human estrogen receptor alpha positive breast cancer cells along the apoptosis-proliferation axis.

Long non-coding RNA is abundant in human cells. Long non-coding RNA genes often lack sequence conservation even between closely related species, in contrast to protein-coding genes, which are highly conserved across distant evolutionary lineages. Over the past several years, the Lipovich lab has been highlighting the primate-specificity of lncRNAs in diverse disease systems.

Targeting primate-specific lncRNAs therapeutically should result in fewer side effects than disrupting conserved pathways that current cancer drugs use. For selective chemotherapeutic agents that kill only breast cancer cells but not normal cells, pslncRNAs constitute a promising class of targets. The reason: these RNAs are young and have not yet had the time to deeply embed themselves in conserved protein-based networks over evolutionary time. Drug side effects may be a consequence of perturbing those conserved networks, Dr. Lipovich added.

“This is nothing less than a paradigm shift in cancer biology. Ever since Richard Nixon's lost ‘War on Cancer,’ proteins – and mouse models – have dominated the study of cancer,” he said. “Here, we systematically interrogate the contribution of non-protein-coding genes to cancer, with a focus on those that do not even exist in commonly used animal models.”

He is the first researcher from Wayne State University to receive the competitive award, which is so sought after he believed office staff was joking when they informed him of the honor.

“I am on the verge of realizing that a transformative, career-changing experience is already underway,” he said.

Dr. Lipovich, a proud graduate of Stuyvesant High School in New York City, received his bachelor’s degree from Cornell University in 1998, his doctorate from the University of Washington in 2003, and joined the School of Medicine faculty in 2007, working to build an internationally visible, high-profile research program. He is the only Wayne State faculty member to be selected by The Royal Society to chair one of its International Scientific Meetings, the lncRNA meeting that will take place outside of London in September 2015. Dr. Lipovich is also a funded co-investigator of ENCODE, or Encyclopedia of DNA Elements, the international consortium that serves as the official successor to the original Human Genome Project. He is in his second decade of working with the Japan-based Functional Annotation of the Mammalian Genome, or FANTOM project, and this year he joined the CHARGE, or Cohorts for Heart and Aging Research in Genomic Epidemiology, Consortium, singlehandedly bringing all these major international efforts to Wayne State through his laboratory.

“I have been arguing ever since the late 1990s, when I was a graduate student, that primate-specific, non-coding RNA genes are not junk, and that they can cause human disease,” he said. “I am profoundly and emphatically grateful for this opportunity to finally address exactly the problem that I've spent the past 15 years studying – the functional and mechanistic contribution of primate-specific long non-coding RNA genes to human phenotypic uniqueness, including human diseases that lack non-primate animal models.

“What ultimately inspires me the most is the potential of this project to empower a new era of post-genomic therapeutics,” Dr. Lipovich added. “I have a deep and abiding interest in actually improving human health and the human condition through therapeutic targeting of disease-causing lncRNAs, such as those that will be pinpointed by the newly funded work.”

Dr. Lipovich will attend the 2014 High Risk-High Reward Research Symposium, to be held Dec. 15-17 at the NIH campus in Bethesda, Md., as part of the award. The symposium will showcase presentations, poster sessions and networking opportunities for awardees.

The research will be supported by National Cancer Institute Award 1DP2-CA196375.
Steven Lipshultz, M.D.
Jul 1, 2014

Recently published findings in Annals of Internal Medicine by Steven Lipshultz, M.D., Wayne State University professor and chair of pediatrics and pediatrician-in-chief at the Children’s Hospital of Michigan, part of the Detroit Medical Center, and colleagues could help to reduce health care charges while also protecting childhood cancer survivors from heart ailments caused by drug therapy.

That’s the “very exciting and very hopeful” bottom line of the recently published study, said co-author Dr. Lipshultz, who has spent more than 30 years studying the potential harmful impact -- or cardiotoxicity -- of drug therapies on the hearts of children who have survived cancer.

The study, “Cost-Effectiveness of the Children’s Oncology Group Long-Term Follow-up Screening Guidelines for Childhood Cancer Survivors at Risk for Treatment-Related Heart Failure,” reviewed data from patient histories to show that current standard medical guidelines for protecting childhood cancer survivors from drug treatment-related heart disease and heart failure later in life through periodic heart scans called echocardiographs are overly cautious.

According to the data, the frequency of such post-cancer screenings can be safely reduced for low-risk patients – with large cost-savings and little reduction in overall quality of patient care.

“The potential savings to be earned by reducing the frequency of echocardiographic screenings in patients who have survived childhood cancer seem quite promising,” Dr. Lipshultz said. “The data in our study on the cost-effectiveness of such screenings suggest that we could save 50 percent of the charges for this heart care screening, while also sparing these children from the rigors of needless heart scanning.”

While pointing out that total U.S. spending for health care exceeds $3 trillion a year and amounts to nearly 17 percent of the entire U.S. gross domestic product, Dr. Lipshultz described the breakthrough findings as “a classic example of how effective research in pediatric medicine can both assure the quality of patient care and help in the effort to keep medical costs under control.”

According to the findings, the guidelines for the frequency of heart scans among childhood cancer survivors – as devised in 2003 by the nation’s standard-setting Children’s Oncology Group – could be safely revised, so that instead of undergoing the scans every one, two or five years (depending on pertinent health factors), childhood cancer survivors would be scanned every two, four, five or 10 years.

While praising the study – http://annals.org/article.aspx?articleid=1872846 -- for its wide-ranging exploration of the issue, an accompanying AIM editorial noted that the new recommended frequency-of-scan schedule would lower “charges by 50 percent.”

The editorial went on to point out that “screening can be done cost-effectively and is highly likely to improve the quality and quantity of the patient’s life.” 

The study has “important implications,” Dr. Lipshultz said, for the approximately 400,000 survivors of childhood cancer in the United States in 2014.

“The National Cancer Institute has estimated that one in every 530 young adults (ages 20 to 45) is a survivor of childhood cancer,” said the veteran researcher, who has published frequently over the years on the subject of cardiotoxic effects from cancer-related drug treatment in pediatric cancer survivors. “For these patients, making sure the long-lasting impact of drug therapy doesn’t lead to heart disease and heart failure later in life is vitally important.

“For childhood cancer survivors and their families, this new study is very good news, indeed – because it shows that many of them in the low-risk category can safely reduce the frequency of their heart screenings, with a significant reduction in accompanying costs.”

Dr. Lipshultz pointed out that asking childhood cancer survivors to undergo too-frequent heart scans also carries “a social cost.”

“The risk you run, if you ask these patients to have frequent scans, is that they may start to be seen by their friends and their families and their teachers at school as ‘different’ from the other kids around them. If that happens, these cancer survivors can even become youngsters whose lives are dominated by an exaggerated focus on their heart health.”

Dr. Lipshultz also said that the new study underlines the importance of “connecting research to clinical care in everything we do.

“If you want to see why that connection is so important,” he added, “just look at the ‘miracle’ in the treatment of pediatric leukemia care in this country during the past few decades. In 1970, only about 4 percent of childhood leukemia patients survived (the most prevalent form of the disease). But today, that same survival rate is over 90 percent.  That’s been one of the biggest miracles in modern medicine – and it happened in large part because of a seamless connection that was achieved between research and clinical care.”

“As the pediatrician-in-chief, I feel very passionate about trying to connect research, education and quality patient care in every single thing we do at the Children’s Hospital of Michigan.”

Fu-Shin Yu, Ph.D.
Dec 12, 2013
Diabetes Mellitus, a metabolic disorder that affects nearly 170 million people worldwide, is characterized by chronic hyperglycemia that disrupts carbohydrate fat and protein metabolism resulting from defects in insulin secretion, insulin action or both. DM can cause long-term damage, dysfunction and even failure of various organs.

Patients with DM may develop corneal complications and delayed wound healing. This slow wound healing contributes to increased infections and the formation of bed sores and ulcers. Corneal complications include diabetic neuropathies and ocular complications that often lead to reduced vision or blindness.

A team of Wayne State University researchers recently developed several diabetic models to study impaired wound healing in diabetic corneas. Using a genome-wide cDNA array analysis, the group identified genes, their associated pathways and the networks affected by DM in corneal epithelial cells and their roles in wound closure. The findings may bring scientists one step closer to developing new treatments that may slow or thwart DM’s impact on vision.

The team, led by Fu-Shin Yu, Ph.D., professor of ophthalmology and director of research at the Kresge Eye Institute, has discovered transforming growth factor β (TGFβ) signaling as a major pathway affected by hyperglycemia in DM corneal epithelial cells. In addition, Dr. Yu and his team identified for the first time that wound-induced upregulation of TGFβ3 is dampened by hyperglycemia and that by adding TGFβ3 to the wound, epithelial wound closure was accelerated.

This discovery, published on line in the prestigious scientific journal Diabetes, may provide new treatment options for diabetic wound healing in tissues such in the cornea and skin.

“Delayed wound healing are major complications of diabetes, often leading to severe end results such as diabetic ulcers, losing a limb or going blind,” said Joan Dunbar, Ph.D., associate vice president for Technology Commercialization at Wayne State University. “Dr. Yu’s discovery of the genome-wide transcriptional analysis has allowed the development of composition and methods to treat negative effects of diabetes, which may ultimately promote healing of wounds, reduce the negative effects of diabetic neuropathies, and promote the health of the eye and maintenance of eye sight in diabetics. The findings in the cornea have a strong implication in the skin as they both have neuropathy and delayed wound healing.”

Wayne State University has filed a U.S. Provisional Patent application on Dr. Yu’s technology discovery.

Dr. Yu’s research was funded by a grant from the National Eye Institute of the National Institutes of Health, award number EY01869 and Research to Prevent Blindness. 

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