The study, published in the November issue of The Journal of Maternal-Fetal & Neonatal Medicine, set out to determine the diagnostic indications and predictive value of biomarkers measured in maternal blood in the first and second trimester of pregnancy. The goal was to determine whether the biomarkers could predict the subsequent development of preeclampsia. The findings of the study -- the largest of its kind ever undertaken -- will help clinicians assess the risk for preeclampsia, and monitor mothers and their unborn babies at risk for the silent killer.

Estimates indicate that preeclampsia is responsible for 76,000 maternal deaths and more than 500,000 infant deaths every year, according to the Preeclampsia Foundation. Preeclampsia occurs only during pregnancy and sometimes after delivery. It is characterized by high blood pressure and the presence of protein in maternal urine. Preeclampsia can affect the liver, kidney and brain. Sometimes mothers develop seizures (eclampsia) and suffer intracranial hemorrhage, the main cause of death in those who develop the disorder. Some women develop blindness.

“Left untreated, preeclampsia can lead to serious -- or even fatal -- complications for both the mother and baby,” said Juan Pedro Kusanovic, M.D., director of Translational Research of the Perinatology Research Branch, the National Institute of Children’s Health and Development, the National Institute of Health, and assistant professor of the School of Medicine’s Department of Obstetrics and Gynecology. He served as lead author of the study, “A prospective cohort study of the value of maternal plasma concentrations of angiogenic and anti-angiogenic factors in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia.”

The unborn babies of preeclamptic mothers are affected by the disease and may develop intrauterine growth starvation or die in utero. Many 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 for baby and mother.

The study received the Frederick P. Zuspan Award for Clinical Research by the International Society for the Study of Hypertension in Pregnancy. The award is given for the most outstanding clinical work relating to the study of hypertension in pregnancy.

“Our study found that maternal plasma concentrations of angiogenic and antiangiogenic factors, together with a combination of other demographic, biochemical and biophysical factors, are useful in assigning risk for the subsequent development of early-onset preeclampsia,” said Roberto Romero, M.D., chief of the Perinatology Research Branch of NICHD, NIH, who is one of the world’s leading experts on this condition and in the study of complications of pregnancy.

“The establishment of an accurate means to assess the risk for preeclampsia would enable health care practitioners to identify women who require more intensive monitoring to safeguard both mother and baby from this devastating condition,” said Dr. Romero, a professor of Molecular Obstetrics and Genetics with the WSU Center for Molecular Medicine and Genetics. “This study is the first of its kind in which women were prospectively followed from the beginning of pregnancy to determine if simple blood measurements can predict early onset preeclampsia. The results are very encouraging and suggest that the biomarkers studied can be used to identify women at risk in the second trimester, many weeks before the clinical onset of the disease.”

The results of the study will encourage laboratories and clinicians to use biomarkers to track the health of pregnant women. Several companies are developing rapid methods to measure these biomarkers and make them available for clinical use in hospitals throughout the world.

Dr. Romero explained that these tests would allow health care practitioners to identify women at risk and to intensify monitoring. An important challenge still lies in finding methods to treat preeclampsia. He noted that defective angiogenesis may be observed in other complications of pregnancy such as premature labor, fetal death and intrauterine growth restriction. The markers are likely to identify not only patients with preeclampsia, but those at risk for other complications of pregnancy.

“This research breaks new ground and will lead to healthier outcomes for mothers and infants,” said Valerie Parisi, M.D., M.P.H., M.B.A., interim dean of the School of Medicine. “This is a prime example of the bench-to-bedside research being conducted in the heart of Detroit.”

The $750,000, two-year grant from the National Institutes of Health was made possible through the American Recovery and Reinvestment Act of 2009, signed into law by President Barack Obama. This most recent funding will further Dr. Kowluru’s R01 study, “Role of Ras in Retinal Cell Death in Diabetes.”

Retinopathy is the most common cause of acquired blindness in diabetic patients. The condition is a result of damage to the small blood vessels in the retina, the layer of cells in the back of the eye that is responsible for sending signals to the brain.

All people with diabetes are at risk of developing retinopathy, and the risk increases the longer a person has diabetes. Between 40 percent and 45 percent of Americans with diabetes suffer from retinopathy, according to the National Eye Institute. The condition’s onset can begin with no or few symptoms.

Dr. Kowluru’s research focuses on determining the role of matrix metalloproteinases-9 (MMP-9), a member of the family of metalloproteinases that regulates major biological functions, including apoptosis and matrix degradation, in the pathogenesis of diabetic retinopathy. She believes that activation of signaling cascade of H-Ras (a small molecular weight G-protein) in diabetes activates MMP-9, accelerating capillary cell loss in the retina, and ultimately leading to the development of diabetic retinopathy. She will investigate the mechanism through which H-Ras activates MMP-9 in the retina in diabetes, and how MMP-9-dependent cellular signaling pathways contribute to the loss of capillary cells.

She explained that she expects to find that the activation of H-Ras in the retina in diabetes regulates MMP-9, and activated MMP-9 accelerates cell loss in the capillaries of the retina by damaging the mitochondria and speeding cell death.

“We believe that by understanding the role of MMP-9 in the pathogenesis of diabetic retinopathy, the compounds that neutralize MMP-9 can be identified to inhibit its development,” Dr. Kowluru said. “This should have immense clinical implications because MMP inhibitors are already being used in clinical trials for other diseases, and our results are expected to lay ground for a possibility to use them to inhibit retinopathy, the sight-threatening disease that diabetic patients fear the most.”

Mark Greenwald, Ph.D., director of the Substance Abuse Research Division and chief of the Human Pharmacology Laboratory in the Department of Psychiatry and Behavioral Neurosciences, will use the $890,000 over two years to investigate a non-drug reward system to combat cocaine addiction.

“As we develop cocaine treatment medications, it is critical to recognize that no medication will be universally effective. No ‘magic bullet’ is likely to be found or adhered to by patients,” Dr. Greenwald said. “Non-medication factors such as environmental conditions and individual differences will constrain the efficacy of any medication. Thus, tests of cocaine medications need to be conducted in synchrony with behavior therapies also taking into account individual differences in order to understand the mechanisms of interaction and potential boundary conditions of a medication’s efficacy.”

The study, Dr. Greenwald said, will develop a human laboratory model of behavioral “contingency management” treatment with cocaine abusers who are not seeking treatment and are thus more resistant to changing their drug abuse behavior. Contingency management is based on the idea that non-drug rewards such as financial incentives or vouchers are earned when the patient provides evidence of drug abstinence, like a cocaine-free urine sample. The process, he said, is generally more effective when rewards are delivered immediately, are larger and increase in value with repeated evidence of drug abstinence.

A newer form of contingency management arranges for drug-abstinent patients to draw in a lottery style for chances to earn prizes. The magnitude and probability of rewards may encourage continued abstinence, Dr. Greenwald said.

“In this laboratory model, we will investigate the relative importance of magnitude and probability of non-drug rewards in reducing actual cocaine-seeking behavior,” he said. “Subjects will be given opportunities to make choices between various cocaine and money options under medically safe and scientifically controlled experimental conditions. The results will enable us to determine the scientific basis for the efficacy of this behavioral treatment approach. It will also enable us to make preliminary recommendations on how to combine this behavioral approach with medications to optimize treatment outcomes.

“We expect to find that higher- versus lower-magnitude, and higher- versus lower-probability monetary rewards will significantly reduce cocaine-seeking,” Dr. Greenwald added. “We also experimentally vary the ‘price’ of cocaine (i.e. the response requirement the subject has to complete to earn a unit dose) when subjects choose between cocaine and money options. We expect increasing price to reduce demand for (choice of) cocaine. We will also evaluate whether drug price interacts with non-drug (money) reward magnitude and probability to influence cocaine seeking.”

The study also will evaluate the effects of selected individual factors (severity of cocaine dependence and level of pre-experimental cocaine use) on the data. “It’s important to study multiple influences on the data because cocaine abuse is a complex problem that is often resistant to change,” said Dr. Greenwald, who noted that this information could ultimately be used to tailor treatments according to the individual.

The reward system for cocaine abusers will mirror an earlier study in at least one aspect. In that experiment, Dr. Greenwald identified about a dozen “hardcore” heroin addicts who spent at least $40 per day on the drug. The addicts were placed on the heroin substitute buprenorphine, and had to report for urinalysis three times a week. Their levels of buprenorphine were decreased over the course of several weeks. If they tested negative for heroin use for consecutive days, they received a check for $30. The majority of those who received the reward for remaining “clean” stayed off of heroin longer, even though their physical environment and acquaintances did not change. Dr. Greenwald believes that the $30 “reward” somehow became more valuable in the minds of the addicts than the need for heroin or a substitute.

Those initial findings, he said, may lead to tailored treatment for addicts. Some may need a shorter course of rehabilitation and contact with those providing treatment to successfully abandon drug habits. Others may be identified in the opening rounds of rehabilitation as needing more intensive treatment or longer contact with healthcare providers for successful rehabilitation.

Dr. Greenwald expects the research to involve up to 16 cocaine abusers, but will need to screen about 100 people to find subjects to complete the study. All the subjects screened, including those who are excluded from the laboratory study for medical or psychiatric reasons, will provide clinical information, and will be asked to provide blood for genotyping that will be used for additional scientific purposes.

The National Eye Institute grant comes under the auspices of the American Recovery and Reinvestment Act of 2009, the national economic stimulus package signed into law by President Barack Obama.

Myopia, or nearsightedness, continues to pose a significant health problem with increasing prevalence and high morbidity related to pathological complications associated with high myopia. Dr. Tkatchenko’s long-term goal is to characterize the genetic network that regulates the size of the eye during postnatal development. His objective is to develop a mouse model of myopia for further study of the condition.

Significant progress in the mouse genome project and established technology for controlled manipulation of the genome makes the mouse an attractive species in which to characterize these genes and study their role in postnatal eye plasticity, he said.

Myopia has been studied for the last 32 years using animal models. These studies were conducted using monkeys, tree shrews, chickens and several other mammalian species, and the myopia was induced with diffusers or negative spectacle lenses. Using a monkey model of myopia, Dr. Tkatchenko found evidence for genetic regulation of myopia and identified several previously unknown candidate genes localized to chromosomal areas linked to human myopia. Further characterization of these genes in a monkey model, however, is limited because controlled manipulation of the monkey genome is not possible, he explained.

The only species in which researchers can perform a serious molecular genetics study is the mouse, but mice are not obvious candidates for a study on refractive eye development because they are nocturnal and have low visual acuity.

Although several recent studies -- including results from Dr. Tkatchenko’s lab -- suggest experimental myopia can be induced in mice, a detailed analysis of normal refractive eye development and response of the mouse eye to distortion of visual input is necessary to establish the feasibility of using mice for myopia research.

He will analyze normal refractive development of the mouse eye and the effect of diffusers on refractive development under different lighting conditions. This will optimize experimental conditions for induction of myopia in mice. He will also analyze the effect of diffusers on refractive eye development in various mouse strains to provide information about the role genetic background plays in myopia development.

“We expect that we will be able to optimize experimental conditions for induction of myopia in mice and find mouse strains that are most susceptible to development of experimental myopia,” Dr. Tkatchenko said.

Development of a mouse model of myopia will open new avenues for research, he said, leading to more advance molecular genetics studies. “Such molecular genetics studies are expected to provide new critical information about signaling cascades that are involved in refractive eye development and development of myopia. This will lead to development of pharmacological means to control and prevent myopia in humans.”

This latest grant comes under the auspices of the American Recovery and Reinvestment Act, the national economic stimulus package signed into law by President Barack Obama.

The PPRU at the School of Medicine has been in existence for 15 years now and is part of a national network of sites. Established in 1994 with funding from the Best Pharmaceuticals for Children Act adopted by Congress and signed into law by President George Bush, the PPRU network was created to allow the study of drugs in children.

“One of the major issues with drugs and children is that pharmaceutical companies hardly ever conduct trials in children for new drugs because the pediatric population is not a profitable one. Children only go up to 18 years, while adults can keep going to their 90s and even beyond,” Dr. Lieh-Lai explained. “We term children as ‘therapeutic orphans.’ The medications we use in treating them have mostly only been studied in adults, and practitioners who work with children just reduce the adult dose based on the child’s weight. There had been no considerations regarding the immature systems of children, which make them metabolize drugs differently.”

With passage of the BPCA, the government offered drug-manufacturing companies a deal: If they agreed to fund trials in children, their exclusivity on larger money-making drugs would be extended by six months.

The PPRU receives funding in five-year cycles. For every cycle, the WSU PPRU receives $1.5 million to $1.9 million. Most of the money is used to fund the infrastructure to facilitate the conducting of drug trials in children and to carry out animal model research.

Each of the 13 national sites that make up the network is composed of physicians, clinical pharmacologists, biostatisticians, pharmacologists, study coordinators, research technicians and study managers. Most sites have a clinical research center equipped with beds to house patients for overnight drug studies, a laboratory to process samples and secure data, and sample storage facilities.

For the current funding cycle, WSU PPRU researchers are focusing on the use of codeine in mechanically ventilated infants; the pharmacokinetics of intravenous terbutaline in children with asthma; targeted drug delivery using dendrimers in rabbit internal jugular vein clots; biomarker-guided treatment of autism; the pharmacokinetics of morphine in children; azithromycin pharmacokinetics in neonatal infants; the pharmacokinetics of buspirone in children with autism; and bilirubin binding in neonatal infants given intravenous ibuprofen for treatment of patent ductus arteriosus.

“We already have some preliminary results that indicate that children handle these drugs differently than adults,” Dr. Lieh-Lai said. “These studies will help us determine the best way to treat children and avoid adverse drug effects based on knowledge obtained from trials that were actually done in children. Children are often neglected in the medical world that is dominated by adults. The efforts and studies conducted by the NICHD PPRU network will help change that.”

Over the 15-year history of the network, she said, the PPRU has conducted hundreds of drug trials in children, including the use of analgesics, antibiotics, anti-hypertensives and sedatives. Research in the unit has included genetic polymorphisms, age-related differences in drug metabolism, and pathogenesis of autism and its treatment.

“We have been very successful in investigating targeted drug delivery using dendrimers and nanoparticles in animals. The funding has helped us establish several animal models – such as a mouse model of asthma, rat model of pain, rabbit model of jugular vein clot and rabbit maternal chorioamnionitis,” she said. Funding for these pilot animal studies helped the PPRU establish a “close working relationship” with the Wayne State University Departments of Chemical Engineering, Occupational and Environmental Health Sciences, the School of Pharmacy and the Perinatology Research Branch.

The work of the PPRU has also assisted junior faculty in Dr. Lieh-Lai’s division secure additional grants to further research.

The catalyst for the study, Dr. Genik explained, was Tom Killion, Ph.D., the deputy assistant secretary for Research and Technology and the chief scientist for the U.S. Army. Dr. Killion requested an independent study to determine where the Army should invest neuroscience research dollars for the next 20 years to develop the highest impact. Dr. Killion made the request of the National Research Council, the main research arm of the National Academies of Science. That led to the selection of the nation’s leading neuroscience experts to participate in the study. Five of the 15 committee members chaired subject matter groups. Dr. Genik chaired the technology group for the 20-month study.

Once the report was completed, Dr. Genik was one of four committee members selected to make up a briefing team with the committee chair. They briefed Dr. Killion at the Pentagon, the Board of Army Science and Technology at the National Research Council, and other Army organizations, including the Army Research Lab, Army Research Institute, Medical Research and Material Command, Training and Doctrine Command, and the Office of Acquisition, Logistics and Technology.

“Being recognized as a national leader in neuroscience technology and by inclusion on the committee itself is a high honor for the department, school and the university as whole; however, this second assignment of representing the committee to all external entities is even further recognition based on performance and overall contribution to the report,” said Dr. Genik, who was the only member of the briefing team to present at all three official briefings.

“In general, I hope we are able to improve survivability and decrease the effects of combat on returning soldiers,” Dr. Genik said of the study. “I am also hoping that we can increase training efficiency and provide guidance to those writing Army doctrine for future soldiers.”

A specific example, he noted, would involve the training and evaluation of operational readiness of helicopter pilots. One of the Army’s helicopters has a crash rate that “significantly exceeds” that of other aircraft, even when considering the inherent danger of missions. Reports received by the committee indicated, from a neuroscience point-of-view, that the operational interface for the helicopter pushes the cognitive limits of pilots during training, creating an increased risk of incident should the mission include additional unfamiliar stressors, or the pilot’s cognitive abilities be affected by sleep deprivation or nutritional imbalance.

“The Army does a remarkable job of making sure soldiers have enough time to sleep and are provided more than adequate nutrition, but the soldier could greatly benefit from a feedback system that tells him when he’s at peak performance and only at 80 percent peak or 60 percent,” Dr. Genik explained. “For the bulk of assignments, far lower than peak cognitive status is sufficient, but when tasks are required for a mission that inherently taxes the limits of normal function, we hope to increase survivability by providing both the soldier and commander in the field, as well as the strategic-tactical commander, with additional information on neural status and readiness.”

Some changes are already taking place in the military. The Secretary of the Army, Dr. Genik noted, has asked for a direct report because the changes under way represent a “paradigm shift” in Army research doctrine that could affect hundred of millions of dollars in funding. The various research branches of the Army are being re-tasked to work together on issues involving neuroscience. Within the next year it’s possible that a military version of the Actigraph – a device that measures circadian sleep rhythms, energy expenditure and other factors contributing to stress -- may be tested with a small number of combat troops. The rationale behind this test would be to provide objective feedback to ground troops about their neural state based on physical exertion and sleep deprivation. The field deployment of other related testing technologies is likely at least five years away, he said.

The committee made special emphasis to separate what was considered “mission enabling” technologies from “research enabling” technologies.

“The Army is very adept at recognizing devices intended to be deployed, but so far has been somewhat slow to understand the importance of guiding technologies that lead to changes in the field, but are not deployed themselves,” Dr. Genik said. “For example, all of the published human functional magnetic resonance imaging is done with a subject in a supine or prone position. There are significant perceptual differences between this position and sitting or standing, and whether the research conclusions derived from horizontal orientation directly apply to vertical orientation is an open research question that will require a new piece of technology to answer: a vertical bore MRI machine.”

Military training and doctrine, Dr. Genik said, has a 4,000-year history. In that time, armies and their professional leaders have accumulated and absorbed practical lessons from experience and trial and error. Neuroscience has been around only about 100 years, with only the last decade or so involving significant situational observation of local mental activity.

“We discuss at length the aspects of stress, including post traumatic stress disorder, that may affect performance in the field and suggest research recommendations on personality traits that may have more resilience to specific stressors,” Dr. Genik said. “Additionally, we recommend a thorough evaluation of types of stress soldiers encounter, including physical, environmental, mental, cognitive, nutritional and others. The committee suggests these areas be evaluated for what they may have in common, as well as what may be different. For example, mental stress caused by encountering a perilous situation can be very different in both intensity and duration than physical stress that can usually be alleviated with nutrition and sleep.”

An executive summary of the report is available free from the National Academies Press at
http://www.nap.edu/catalog.php?record_id=12500