Chief resident Siddarth Jain demonstrates how a cooling blanket is used. (Susan Urmy/Vanderbilt)

Pediatric neurologists and neonatologists in Vanderbilt’s Neonatal Intensive Care Unit (NICU) are conducting research that may better define what happens in the brains of newborns who have suffered from oxygen deprivation, and what brain cooling therapy can achieve.

Use of a “cooling cap” within six hours is now the standard of care when an otherwise healthy, full-term infant experiences a serious lack of oxygen, called anoxic brain injury. The therapy uses cool water to bring the temperature of the brain down about five degrees. Vanderbilt took part in the initial studies of the cooling cap, which was found to reduce serious long-term brain damage and death by about one-third.

Now a switch has been made to a cooling blanket instead of a cap. The blanket is as effective in its brain-protecting capacity, but it offers researchers an opportunity to better assess what is happening in the brain as it is cooled.

Easier to monitor babies’ brains

Pediatric neurology chief resident Siddharth Jain said by using a cooling blanket, the scalp is free for him to apply a full, nine-lead electro encephalogram (EEG) monitor along with a newer device called a near-infrared spectroscopy (NIRS) monitor to find out what is going on beneath a baby’s scalp.

The EEG can detect seizures, while NIRS measures how the brain uses oxygen. The information collected so far has been surprising.

“We already know the EEG detects seizures that cannot be seen in these babies. Up to 80 percent of seizures in babies with anoxic brain injury have no overt clinical signs. Other studies have shown that these babies can have between 100 and 120 seizures during the first 72 hours of life,” Jain said.

“These seizures are different than those in epilepsy. They are very aggressive in the first 48 hours and difficult to control. We don’t know for sure, but the consensus is the seizures themselves cause further damage.”

Jain is working with Barbara Engelhardt, associate professor of neonatology, to closely examine what is happening in the first 72 hours after an anoxic injury — the critical window of opportunity in which the cooling seems to have its maximum brain-preserving effect.

For this observational study, William Walsh, neonatologist and director of nurseries, switched the NICU to the cooling blanket to allow the researchers to enroll the one or two babies brought to Vanderbilt every month with anoxic brain injury.

Speeding up evaluation and treatment

The first goal is to use EEG and NIRS to more quickly and accurately predict the severity of the anoxic injury. Currently, an MRI is used to give doctors a peek at structural damage in the brain, once the initial injury has stabilized, to assess long-term changes. But the predictive value of long term damage is not very great.

Engelhardt says EEG and NIRS provide information from day one about seizure activity as well how the brain is using oxygen.

These two pieces of information can describe changes after the initial injury, and may help provide a better measure of the effects on long-term outcomes.

Enables researchers to test new therapies

A second goal is to use the monitors to test new therapies. The hope is the monitors could more quickly assess the effectiveness of therapies is controlling seizures, or better balancing nutrient consumption after injury in the hope of further reducing the risk of permanent brain damage.

“When a brain cell is injured, it can go one of two ways: it can die or recover,” Walsh said. “The goal is to limit damage to as small an area as possible.

“The cooling cap was a general way to slow down the potential for further damage, but in the 15 years we have been using it, we have learned a lot about what is happening biochemically in anoxic injury and how we can further impact that damage.”

Alison Hansen and Ethan Lee (Anne Rayner/Vanderbilt University)

A few years ago, Alison Hanson, a student in Vanderbilt’s Medical Scientist Training Program, was invited to have lunch with a visiting Nobel laureate, Aaron Ciechanover. Hanson was working on her dissertation research at the time, and she described some interesting findings to Ciechanover.

“He said, ‘That could either be a total artifact or it could be the discovery of the century,’” Hanson recalled.

It wasn’t a total artifact.

Hanson, her mentor Ethan Lee, associate professor of cell and developmental biology, and colleagues have discovered a new molecular participant in the Wnt (pronounced “wint”) signaling pathway, which plays important roles in cell growth, development and cancer.

The investigators report in the March 9 issue of Molecular Cell, that XIAP, a protein that inhibits cell death and has been the focus of recent anti-cancer drug development, promotes Wnt signaling. The findings suggest that targeting XIAP’s role in Wnt signaling — in addition to its role in cell death — may produce even better cancer therapeutics.

Wnt signaling mutations occur in most non-inherited colon cancers

Mutations that activate the Wnt signaling pathway occur in more than 90 percent of sporadic (non-inherited) colorectal cancers, and are thought to play a role in breast, liver and other major cancers. Blocking the Wnt pathway has been a desirable therapeutic target, but its complexity has made it difficult to find “druggable” targets, said Lee, associate professor of Cell and Developmental Biology.

Lee and his colleagues are interested in understanding how the Wnt signaling pathway works – with the possibility that their discoveries may identify new anti-cancer targets.

First believed to be a fluke

They focused on enzymes that might regulate the pathway, called ubiquitin ligases (proteins that add a ubiquitin “tag” to mark other proteins for degradation). Using fruit fly genes and cells, Hanson developed a screening strategy to identify ubiquitin ligases involved in Wnt signaling.

Her screen produced the strongest signal for the fruit fly equivalent of XIAP (called DIAP-1) — eliminating DIAP-1 in fruit fly cells blocked Wingless (the fruit fly equivalent of Wnt) signaling. But others had shown that eliminating DIAP-1 causes fruit fly cells to die, so Hanson and Lee suspected that the low Wnt signaling was an artifact and they moved on to other studies.

More than a year later, Hanson decided to follow up on the shelved findings. She found that reducing XIAP levels in human cells — both normal cells and colorectal cancer cells — inhibited Wnt signaling. Then she turned to frog embryos, where loss of early Wnt signaling results in headless embryos and too much early Wnt signaling causes two heads to form.

She found that knocking down XIAP resulted in frog embryos with no heads and injecting extra XIAP caused frog embryos to develop two heads.

“I was screaming,” Hanson recalled laughing. “That’s not a fluke. It’s nearly impossible to get a second axis (another head) as an artifact.”

Feeling certain that XIAP really was involved in Wnt signaling, Hanson turned to “the harder part of the project: figuring out how and why it was required for Wnt signaling,” she said.

Help from a protein called “Groucho”

The investigators discovered that XIAP acts in the nucleus, where it adds ubiquitin to a protein called Groucho. This releases Groucho’s inhibitory hold and allows the Wnt pathway to activate gene expression.

“We think of Groucho as a safety switch,” Lee said. “Because the Wnt pathway is so important in growth and proliferation — and because when it’s active it can lead to cancer — you would want something to keep it turned off, to make sure it doesn’t get turned on accidentally. That’s Groucho.

“XIAP then removes the Groucho safety switch and lets beta-catenin turn on the system.”

XIAP was already the focus of anti-cancer drug development because it blocks cell death (inhibiting XIAP should induce cell death). Most of the ongoing efforts have targeted the region of XIAP that blocks cell death, which is different from the region involved in Wnt signaling, Lee said.

Targeting both regions may be a way to develop particularly effective anti-cancer agents, he said. “Theoretically, drugs that inhibit both of XIAP’s activities would promote cell death and block cell growth and proliferation.”

Lee and his colleagues are pursuing other ubiquitin ligases and related compounds for their roles in regulating Wnt signaling.

Other contributors to the studies included research associate Heather Wallace, doctoral candidate Tanner Freeman, R. Daniel Beauchamp, J. C. Foshee Distinguished Professor of Surgical Sciences, and Laura Lee, associate professor of cell and developmental biology. The research was supported by grants from the American Cancer Society, the National Cancer Institute SPORE in GI Cancer, and the National Institute of General Medical Sciences.

Jeffrey Sosman (Vanderbilt University)

Investigators from Vanderbilt-Ingram Cancer Center (VICC) and 12 other centers in the United States and Australia have found that a new drug for patients with metastatic melanoma nearly doubled median overall survival.

More than half of patients who were treated with the novel drug vemurafenib, known commercially as Zelboraf, responded to treatment and experienced an impressive median overall survival of nearly 16 months – far longer than the typical survival of just six to 10 months for most patients whose melanoma has spread beyond the initial tumor site.

Results from the Phase II trial, led by co-principal investigators Jeffrey Sosman, director of the melanoma program and co-leader of the Signal Transduction Program at VICC, and Antoni Ribas, professor of hematology and oncology at UCLA’s Jonsson Comprehensive Cancer Center, were published in the Feb. 23 issue of the peer-reviewed New England Journal of Medicine.

“This study confirms what we have discovered in our earlier trials. Many of our patients are exhibiting a strong, immediate response to this drug and some are living significantly longer, with manageable side effects,” said Sosman, professor of medicine at Vanderbilt University Medical Center. “It was interesting to note that a few of the patients were treated with the drug for up to six months before showing convincing evidence of response.”

“This study shows that Zelboraf changes the natural history of the disease,” said Ribas. “These results tell us that this drug is having a very big impact, and this changes the way we treat metastatic melanoma.”

Approximately half of all patients with metastatic melanoma – the most deadly form of skin cancer – have a BRAF V600 mutation in their tumor. Vemurafenib is an FDA-approved oral drug which works as a kinase inhibitor of the BRAF V600 mutation.

While vemurafenib induced clinical responses in a significant number of BRAF-positive patients when it was approved last year, the initial clinical trials had not followed patients long enough to determine overall survival.

A total of 132 patients with stage IV, BRAF-positive melanoma were enrolled in the Phase II trial. All of the patients had received at least one form of systemic treatment before enrollment in the trial.

Forty-seven percent of patients had a partial response to the drug and six percent exhibited a complete response, for an overall response rate of 53 percent.

Debra Johnson’s melanoma had already spread to one of her lungs and her lymphatic system when she was referred to VICC for mutation testing. Her tumor was BRAF-positive and after more than a year on the drug, the wife and mother from New Site, Miss., says her scans are clear and there is no visible evidence of disease.

“This treatment has been an answer to my prayer,” said Johnson.

The majority of patients had at least one adverse event related to the drug, but most of these were minor. The most common side effects were joint pain, rash, sun sensitivity, fatigue and hair loss. More than a quarter of the patients (26 percent) also developed cutaneous squamous-cell carcinomas – a less serious form of skin cancer – which were surgically removed.

A Phase III trial of this same drug confirmed significant improvement in both progression-free survival and overall survival with vemurafenib over chemotherapy in an interim analysis. The Phase II study is the first to confirm the durability of the response.

While the clinical trials for vemurafenib have been positive to date, the great majority of patients eventually experience disease progression.

“We are trying to determine what is causing this drug resistance and are searching for new therapies that we can use, perhaps in combination with vemurafenib,” said Sosman.

The Phase III research was funded by Hoffmann-La Roche Pharma.

(cancer.gov)

Women infected with human immunodeficiency virus (HIV) constitute one of the populations at highest risk for human papillomavirus-induced cervical cancer. While HIV-infected women in developing countries, such as India, are living longer thanks to antiretroviral therapy, their risk of invasive cervical cancer remains high due to lack of access to affordable and accurate cervical cancer screening and prevention services.

Visual inspection of the cervix after application of dilute acetic acid (household vinegar), or VIA, is being studied as a low-tech, low-cost alternative to the traditional screening method for cervical cancer: the Pap smear (or cervical cytology). Vikrant Sahasrabuddhe, M.D., Dr.P.H., and colleagues compared the accuracy of cervical cytology with VIA for detection of cervical precancerous changes in 303 HIV-infected women in Pune, India.

In the Jan. 1 International Journal of Cancer, they report that VIA performed better than cytology in this setting, suggesting that VIA, which is easy and inexpensive, can be a good alternative or adjunct screening test for HIV-infected women.

The research was supported by grants from the National Cancer Institute, the National Institutes of Health’s Fogarty International Center and the Indian Council of Medical Research.

(iStock)

Antonis Hatzopoulos, Ph.D., and colleagues are exploring how the Wnt signaling pathway, which is known to play many roles in cardiovascular development, regulates ES cell differentiation into other cell types. They report in the Jan. 1 issue of Stem Cells and Development that multiple waves of different types of Wnt signaling –  “noncanonical” and “canonical” – regulate ES cell differentiation. Blocking the initial noncanonical Wnt signaling promoted blood cell development. Blocking the later peak of canonical Wnt signaling favored cardiovascular cell development and also activated compensatory Wnt signaling that further increased the number of cardiac progenitor cells.

The findings provide new insights on Wnt signaling during ES cell differentiation and point to a method for inducing the cells to become cardiac muscle cells.

This research was supported by grants from the National Heart, Lung and Blood Institute.

Approval for the legacy of President George W. Bush will likely rise in the estimation of historians as time goes by, say two Vanderbilt University political scientists.

A poll by CBS News and The New York Times near the end of Bush’s 2001-2009 presidency showed his approval rating at 22 percent, making him one of the most unpopular departing presidents in history.

John Geer (Vanderbilt University)

“It’s inevitable that George W. Bush’s stock will go up, in my view, because he was rated so low to begin with,” said John Geer, Gertrude Conaway Vanderbilt Professor of Political Science. “It’s common for the person in power to take some heavy knocks during their term and directly afterward.”

One issue that could make or break Bush’s reputation is how events in the Middle East unfold, said Geer and David Lewis, the William R. Kenan Jr. Professor of Political Science at Vanderbilt. Bush’s decision to invade Iraq is still debated.

“If 10 years from now Iraq is peaceful and democratic and a source of stability in the Middle East, we are going to assess Bush’s decisions much more favorably,” Lewis said. “Similarly, if there’s a terrorist attack during the Obama presidency, people will assess Bush’s presidency differently, because they’ll say he kept his eye on the ball and kept us safe.”

David Lewis (Vanderbilt University)

Democratic President Harry Truman may be the best example of Bush’s current situation with historians, Geer and Lewis said.

“Harry Truman left office with very low poll ratings, but he steadily moved up the ladder because he didn’t necessarily do what was popular, but he certainly did a lot of things to change the country and many of those changes were for the good,” Geer said.

Bush will likely get high marks for his efforts to improve education with No Child Left Behind and increasing funding for green power initiatives and the National Institutes of Health, Lewis said.

“These funding increases could turn out to be the beginning of a golden age of scientific discovery where we find the cure for cancer and save the environment,” Lewis said. “If that happens, Bush will get credit for having great vision.”

Bush’s conservative philosophy might cost him with historians, because they tend to rate presidents higher who are more active, Geer and Lewis said.

“If you truly have conservative principles, then government shouldn’t do all that much,” Geer said. “Therefore, a very successful conservative president might not have accomplished so much in the sense of active programs. Dwight Eisenhower was one of those, more a ‘hidden-hand’ president where things went well but the changes weren’t as noticeable.”

One very noticeable Bush trait that will become more appreciated over time is his courage, Geer said. In the aftermath of the Sept. 11, 2001, attacks, Bush decided he needed to be a visible president during a time when many of his advisers, and certainly his security detail, thought it was too dangerous.

“My sense is that Bush made the decision that we couldn’t act scared,” Geer said. “And for a while after 9/11 they really didn’t know what the devil was really happening and it probably made sense for the president to stay under cover.

“But Bush overrode them and insisted on taking risks and appearing in public. That’s pretty courageous.”

George W. Bush/whitehouse.gov

Vanderbilt researchers have published the findings of a recent study, looking for genetic clues to explain this AF paradox in African Americans.

AF is the most frequent sustained arrhythmia in clinical practice with more than 2.3 million Americans diagnosed with the disease. The risk of developing AF by age 80 in European-Americans is about 20 percent, while in African Americans the risk is about 10 percent.

In a study to be published in Plos ONE, researchers studied 73 African Americans with AF from the Vanderbilt-Meharry AF Registry and 71 African American controls with no history of AF.

Genome-wide association studies for AF in European-descent populations have identified three predominant genomic regions associated with increased risk — 1q21, 4q25 and 16q22, the authors write. The relationship between these regions to AF risk in African Americans is unknown. Researchers sought to generalize these three regions in African Americans to see if they could find any association with AF in this population.

“We found those regions do play an important part in determining risks of developing AF in African-Americans; however, we saw a difference in the actual SNP (single nucleotide polymorphisms),” said Jessica Delaney, research fellow in clinical pharmacology and lead author of the study.

SNPs are the most common type of genetic variation among people, and each SNP represents a difference in a single DNA building block.

“We found that while the regions are important, the European index SNPs are different from index SNPs associated with AF in African Americans,” she said.

For years, the lower incidence of AF in African Americans was thought to be due to racial disparities in health care, but research is pointing toward genetics as the cause for the apparent paradox, said Dawood Darbar, director of the Atrial Fibrillation Clinic and an author on this study and another one, published in the American Heart Journal, that investigated the differential impact of race and risk factors on the incidence of AF.

“There have been a number of studies that have clearly shown the prevalence of AF in African-Americans is about half that of European Americans,” Darbar said.

“Whether environmental or genetic, it would therefore appear that there are novel factors either protecting African Americans from AF or making whites especially prone to AF that remain undetermined.

“This and other studies strongly suggest that the racial differences in risk of AF between African Americans and whites appear to be genetically mediated.”

Understanding the genetic basis for AF is important for determining who is at risk for developing AF and discovering new therapies to treat this very common condition, which carries with it an increased risk of stroke and heart failure.

Additional authors on the Plos ONE study are Janina Jeff, Nancy Brown, Mias Pretorius, Henry Okafor, Dawood Darbar, Dan Roden and Dana Crawford.

(iStock)

Patients with schizophrenia and psychotic bipolar disorder have widespread deficits in brain structure and function, but when these deficits appear and how they progress are open questions. Lisa Williams, Ph.D., and colleagues explored structure and function of the hippocampus, a brain region essential to memory and emotional processing, in patients in the early stage of psychotic illness.

The investigators trained early psychosis patients and healthy control subjects to perform a relational memory task (which requires the “binding” together of distinct memory elements). They tested the participants during a functional magnetic resonance imaging (fMRI) scan and measured hippocampal volume and activity. They found that many of the patients with early psychosis had normal hippocampal structure and function.

The results, reported in the Jan. 15 issue of Biological Psychiatry, provide evidence that some of the brain deficits found in chronic psychosis patients are not fully present in early stages of the disease. The findings provide a rationale for early intervention to delay, reduce or prevent memory deficits and hippocampal abnormalities.

This research was supported by the National Institute of Mental Health.

(iStock)

Respiratory syncytial virus (RSV) is a leading cause of serious lower respiratory illness in infants and the elderly. However, there is no licensed RSV vaccine and therapeutic options are limited.

James Crowe Jr., M.D., and colleagues are studying the cellular life cycle of the virus. In the January/February issue of mBio, they describe the molecular mechanisms that drive the assembly of the virus into thread-like structures (filaments) at the surface of epithelial cells (the types of cells that line the airways). They show that a specific “bit” of the RSV fusion protein – an amino acid residue in the “tail” of the protein – is critical for coordinating the assembly of these filaments by mediating the incorporation of other viral proteins. Mutation of this residue prevented filament formation and the incorporation of other viral proteins into virus-like particles.

The findings, the authors suggest, could help guide the development of new antiviral therapies and also provide new insights about how the virus is released from infected cells and spreads.

The research was supported by grants from the National Institute of General Medical Sciences, the National Institute for Allergy and Infectious Diseases, the Burroughs Wellcome Fund, and the March of Dimes.

Did you know that sexually transmitted infections are on the rise in retirement homes? How about that some gay men who get the right to marry are apparently more likely to indulge in affairs, with the knowledge and consent of their partners?

This is the kind of thing that fascinates Laura Carpenter, an associate professor of sociology and Vanderbilt’s resident “sexpert.”

“I wanted to embarrass my mother,” Carpenter jokes when asked why she picked sex as her primary research interest.

“Actually, I was originally interested in gender,” she said. “But there was this interesting time in the mid-1990s when Time and Newsweek ran cover stories about born-again virgins. It was a real culture shock moment for me, and it got me to thinking how people’s opinions are very diverse about sexuality.

“What’s good and what’s bad, what’s wholesome and not so wholesome, culturally speaking, that was all kind of up for grabs.”

Laura Carpenter (Vanderbilt)

Carpenter subsequently wrote her dissertation about the loss of virginity, leading to her book Virginity Lost: An Intimate Portrait of First Sexual Experiences. Her most recent project was co-editing (with John DeLamater of the University of Wisconsin-Madison) Sex for Life: From Virginity to Viagra: How Sexuality Changes Throughout Our Lives.”

The book, published by New York University Press, is the result of efforts by Carpenter and like-minded colleagues to expand the study of sex beyond the snapshots-style research that has dominated in the past.

“Researchers have tended to zero in on topics like adolescent sexuality or sex in the gay community, little snapshots that could be broken off and analyzed,” she said.

The trouble with that approach is the loss of the big picture within individual lives, the panorama of one sexual experience impacting another and having a cumulative effect.

“If you have an unpleasant virginity loss experience and feel bad about yourself afterwards, you may be less choosy about your next sex partner, who might not care about you or giving you pleasure,” Carpenter said.

“That might set you up for another situation where you’re unable to communicate about sex. People who aren’t able to communicate about sex are among other things, more likely to get sexually transmitted infections. Having a chronic sexually transmitted infection can be a pretty unpleasant thing, and certainly affects how you might respond to later partners and how they might relate to you.”

On the other hand, a positive experience losing virginity has its own consequences.

“Once you have an orgasm it’s pretty hard to un-have an orgasm,” Carpenter said. “That causes one to recognize something about the possibilities of sex. But amassing lots of sexual experience can have downsides, too.”

The primary problem in pursuing life course sexuality studies is lack of data.

“We generally haven’t had the luxury of following people’s sex lives for 50 or 60 years. It’s much more common – and much easier – to do a survey of teenagers in a high school at any given moment,” Carpenter said.

Sex for Life book cover courtesy of New York University Press

Better data is still a ways off for logistical reasons, but researchers who take a longer-road perspective are already showing intriguing results. Meika Loe of Colgate University has an essay in Sex for Life on “Pleasure in Old Age” about the growing population of people 90 and older.

“A lot of adult children of older parents are aghast that their widowed dad who is 85 and in assisted living is fooling around with another resident down the hallway,” Carpenter said. “But under the right circumstances, it could be quite a fulfilling relationship for those two old people.”

Complicating matters, the current generation of assisted living residents hail from the pre-AIDS era and might not think to use condoms so long after their childbearing years. That has led to increased sexually transmitted infections in nursing homes.

Carpenter’s own next research project will focus on chronic disease and sexuality. There has already been research on the impact of breast and prostate cancer on the sex lives of women and men, respectively.

Carpenter would like to know more about how common diseases such as diabetes and congestive heart failure impact sex life.

“A lot of medications for heart disease and for blood pressure affect sexual response,” Carpenter said. “Also, there are some people who have diabetes and have to wear an insulin pump on their bodies and others, at the extreme stages of the disease, may lose limbs. That has to affect someone’s sex life.”

Of course, any discussion of sex is fraught with complications. There are some stakeholders with a political or moral agenda who aren’t interested in evidence that contradicts their viewpoint.

“You find this in the abstinence-only sex-ed movement,” Carpenter said. “There’s a growing body of evidence that it doesn’t prevent most teenagers from eventually having sex before they’re married, while it does make them less likely to practice safer sex or use contraception, so they’re more likely to get sexually transmitted infections. But those findings haven’t changed the approach of people who believe abstinence-only is right for moral reasons.”

One giant factor is propelling studies of sexual behavior forward, Carpenter said. That’s the self-interest of the millions of baby boomers who are starting to face their mortality.

“Not only are they looking at their own parents and realizing they have to deal with aging, but they’re realizing that old age is going to happen to them,” Carpenter said. “And they don’t want to be asexual people, no matter how they feel about how other generations may have approached sex in later life.”

Doug Schmidt (Vanderbilt University)

Our shared concern about growing our IT talent pool is undeniably on-target, writes Doug Schmidt, professor of computer science. Software development and broader engineering skills and sheer innovative capacity are at a premium globally, as well as nationwide. It’s therefore no surprise that recruiting and retaining talented IT professionals in our region is harder than we’d like. This is particularly true in such IT growth sectors as mobile applications, information security, health information systems, cyber-physical systems and cloud computing.

Karen Harris (Vanderbilt University / Steve Green)

The American Psychological Association has released the first edition of the Educational Psychology Handbook, co-edited by Vanderbilt University Peabody College faculty members Karen R. Harris and Steve Graham.

The handbook consists of three volumes that reflect the broad nature of the educational psychology field, including state-of-the-science reviews of the diverse critical theories driving research and practice. It is intended for researchers, education professionals and other practitioners of educational psychology, a field of study that seeks to improve learning by applying psychological principles and knowledge in classrooms.

“These volumes provide an in-depth investigation of the range of individual differences and cultural and contextual factors that affect student achievement, motivation and beliefs,” Harris and Graham said of the handbook, which they co-authored with Tim Urdan, professor of psychology and liberal studies at Santa Clara University. “It offers a close examination of the research driving current assessment, teacher preparation and the promotion of learning across the life span.”

Harris is professor and Currey Ingram Chair in Special Education and focuses her research on issues surrounding academic and self-regulation strategies among students who are at-risk or have severe learning challenges, particularly in the area of writing. She is the author of over 100 publications, co-author of several books and former editor of the Journal of Educational Psychology.

Steve Graham (Vanderbilt University)

Graham is also professor and Currey Ingram Chair in Special Education. His research focuses on writing difficulties and disabilities and on examining the effectiveness of specific prevention and intervention procedures to enhance writing development. He is author of numerous books and over 135 papers on handwriting, writing instruction and learning disabilities and is the former editor of both Exceptional Children and Contemporary Educational Psychology.

In 2005, Harris and Graham received the Career Research Award from the International Council for Exceptional Children. They are both investigators in the Vanderbilt Kennedy Center for Research on Education and Human Development.

Lead author Todd Rice (Daniel Dubois / Vanderbilt University)

Ventilator-dependent ICU patients are fed through a tube in the stomach continuously, but it’s never been fully understood what the best form of nutrition is, how often patients should be fed or how much they should be given.

Vanderbilt, in conjunction with the other 11 centers in the NIH/NHILBI Acute Respiratory Distress Syndrome (ARDS) network, aims to answer these questions with the hope of improving the outcomes of patients with acute lung injury (ALI).

In a study published in the Journal of the American Medical Association this week, Vanderbilt researchers report that patients with ALI who were given lower-volume enteral (tube) feedings did not have better outcomes than those who received full feedings.

Participants were randomized to receive either lower-volume (trophic) or full enteral feeding for the first six days of the study. After day six, the care of all patients who were still on mechanical ventilators received full feeding protocol.

Trophic feeding consisted of about 400 calories per day while full feeding consisted of about 1,300 calories per day.

Prior to this study there was only observational data regarding the best amount to feed patients with lung injury who were on mechanical ventilators, said Todd Rice, assistant professor of medicine and lead author on the JAMA study.

“Some studies showed if you fed more, patients had slightly better outcomes. Others showed if you fed less, they had better outcomes because feeding more causes some complications and drives inflammation, a big part of the illness,” Rice explained.

A smaller amount of food is thought to have beneficial effects on the intestines, causing them to secrete enzymes that increase blood flow, thereby protecting the integrity of intestinal membrane. Higher doses of nutrition can cause complications of diarrhea, vomiting or aspiration.

“People have spent a lot of time and effort trying to feed ICU patients what they think is the right amount of calories, and it’s hard to do,” Rice said. “Patients don’t tolerate huge feeds when they are that sick, and we spend a lot of time giving them medicines to help their gut move better, trying to get them to full feeds.

“We did all that without any real data that this was beneficial for them. We were looking to see if feeding them fully or a little bit was better and which improved outcomes in the patients.”

The results of the study indicate that in patients with ALI, initial trophic feeding for up to six days, compared with full enteral feeding, did not improve ventilator free days, 60-day mortality or infectious complications, but it was associated with fewer gastrointestinal problems, according to the JAMA article.

Rice presented his findings at the Critical Care Congress in Houston, Texas earlier this week.

Ken Galloway (John Russell/Vanderbilt)

Vanderbilt University Engineering Dean Kenneth F. Galloway attended a White House event Feb. 8 to celebrate the efforts of engineering deans for their commitment to retain and graduate more students in the field of engineering.

Harvey Murff (Vanderbilt University)

Women who eat at least three servings of fish per week have a reduced risk of developing some types of colon polyps according to a new study by Vanderbilt-Ingram Cancer Center investigators.

The research, led by first author Harvey Murff, associate professor of medicine, was published online in the American Journal of Clinical Nutrition.

The VICC researchers believe that omega-3 fats in fish may reduce inflammation in the body and help protect against the development of colon polyps. Polyps are small growths on the lining of the intestinal tract that may develop into cancer.

Earlier research in animals has suggested a link between inflammation and colon polyp formation but studies in humans have not been conclusive.

Colorectal cancer is the fourth most common cancer and the second leading cause of cancer-related death in the United States.

More than 5,300 participants were enrolled in the Tennessee Colorectal Polyp Study and received colonoscopies at Vanderbilt or the Veterans’ Affairs Tennessee Valley Health System in Nashville. Study participants completed food frequency questionnaires to determine how often they ate fish and investigators obtained urine samples from some of the patients to measure biomarkers for a hormone related to inflammation.

Women who ate the equivalent of three servings of fish per week had about a 33 percent reduction in the risk for colon polyps. They also had a lower level of a hormone called prostaglandin E2, which is linked to inflammation.

“That was the aspect of the study we were particularly excited about because prostaglandin E2 is known to be associated with adenomas or polyps in colorectal cancers,” said Murff.

Murff said fish oil appears to have the same beneficial effect as aspirin in reducing inflammation and this may protect against the formation of polyps.

“Women who ate more fish had lower numbers of polyps and they had lower levels of prostaglandin E2 which reassured us that these results may be real findings and not just a statistical fluke,” Murff explained.

While women who ate the most fish saw some protective effect, men who ate more fish did not have a reduced risk of developing colon polyps.

The VICC investigators were surprised by this difference.

“The difference between men and women may be linked to their background diet. Even though men are eating more omega-3 fatty acids they may also be eating more omega-6 fatty acids and that may be blunting the effect,” said Murff.

Omega-6 fatty acids which are found in meats, grains and seed oils, including corn, safflower and sunflower oil, may counteract the protective effect of omega-3 fatty acids.

While eating more fish appeared to be beneficial, not all types of fish contain high levels of the protective omega-3 fatty acids. Tuna, salmon and sardines are high in omega-3 acids, while tilapia and catfish have low levels.

To validate the findings from their study, the authors are currently conducting a clinical trial to determine the effect of fish oil supplementation and prostaglandin E2 production.

The National Cancer Institute funded the study through a series of research grants.

Manish Sethi (Vanderbilt University)

Defensive medicine is the practice of ordering additional but unnecessary tests and diagnostic procedures that may later help exonerate physicians from accusations of malpractice. However, these additional costs result in no significant benefit to patients’ care.

Published in the February issue of the American Journal of Orthopedics, the study suggests unnecessary costs associated with the practice of defensive medicine play a substantial role in the nation’s rising cost of health care.

The findings are from a national survey of 2,000 orthopaedic surgeons selected randomly through a list provided by the American Academy of Orthopaedic Surgeons.

Respondents were located in all 50 states and practice in a variety of settings. Of respondents, 96 percent report practicing defensive medicine, which accounts for 24 percent of all imaging studies, laboratory tests, consultations and hospital admissions among the survey’s cohort.

“Currently, our nation’s expenditure on health care is 20 percent of GDP [gross domestic product]. This figure really bothers us and served as motivation to conduct this survey,” said Manish Sethi, assistant professor of orthopaedic surgery and rehabilitation, and lead author of the study. “If defensive medicine can be curbed, we will see a dramatic reduction in health care costs, and our research makes this case.”

With a 61 percent response rate, the survey gathered data on how many medical tests, such as x-rays or ultrasounds, a physician ordered in a month and how many of those were ordered in a defensive manner.

Using the American Medical Association’s CPT (Current Procedural Terminology) billing codes as a reference point for costs, researchers calculated the average cost of each imaging test then tabulated an average cost per month.

On average, orthopaedic surgeons spent $8,485 per month on the practice of defensive medicine, a figure which equals nearly a quarter of their total practice costs.

Per year, the cost for defensive medicine averages $101,820 per respondent. When this figure is multiplied by the 20,400 orthopaedic surgeons practicing in the U.S., the average cost per year for defensive medicine procedures among this group totals $2,077,128,000.

Ordering excess tests or procedures is known as positive defensive medicine. Researchers also examined the practice of negative defensive medicine, or the practice by physicians of avoiding high-risk patients or procedures in order to limit liability.

In the past five years, 70 percent of respondents reported reducing the number of high-risk patients they treat, while 84 percent reduced or eliminated performing high-risk services and procedures.

Write-in examples of defensive medicine included closing a practice to become a consultant, no longer seeing patients in an emergency room, and not operating on patients with diabetes or heart problems.

Alex Jahangir (Vanderbilt University)

“It becomes an access of care issue,” said Alex Jahangir, assistant professor of orthopaedic surgery and rehabilitation, and a study author. “Patients are now losing access to physicians if they happen to be a diabetic, obese, or a smoker with heart problems. Their care will be delayed; the costs will increase because they have to be flown to a tertiary center. Negative defensive medicine is a big part of the problem.”

Sethi was previously involved in a similar study of orthopaedic surgeons in Massachusetts that found comparable results, but this is the first to demonstrate defensive medicine practices are common nationwide.

Sethi and Jahangir propose that reforms should focus more on evidence-based medicine than liability policies.

“We believe an evidence-based approach is the best approach,” Sethi said. “If we can develop standards of practice that are accepted across the nation, physicians won’t need to order these additional x-rays and MRIs to protect themselves, and we know costs will go down.”

Media contact: Craig Boerner, (615) 322-4747

In a collaborative project for institutions in the Clinical and Translational Science Awards (CTSA) consortium, Paul Harris, Ph.D., and colleagues designed ResearchMatch, a web-based national recruitment registry to help match individuals who wish to participate in clinical research studies with researchers actively searching for volunteers (www.researchmatch.org). In the January issue of Academic Medicine, the investigators describe ResearchMatch’s design, technical infrastructure, workflow model and utilization metrics. As of June 2011, ResearchMatch had registered 15,871 volunteer participants from all 50 states and 751 researchers from 61 CTSA institutions (current numbers on the website show 20,192 volunteers, 1010 researchers and 67 institutions).

ResearchMatch has proven successful in connecting volunteers with researchers, and the developers are currently evaluating regulatory and workflow options to open access to researchers at non-CTSA institutions.

This research was supported by the National Center for Research Resources.

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Genome-wide association studies (GWAS) have identified hundreds of genetic variants that increase a person’s susceptibility for complex diseases. Although these variants have added to our understanding of disease pathology, they usually account for only a small proportion of disease risk.

Zhongming Zhao, Ph.D., and colleagues have developed an approach to identify gene variants that act together – for example in a biological pathway – and have a joint effect on disease risk. Their method builds on the generalized additive model (gamGWAS). It eliminates a previously identified problem in the analysis of gene sets (the long gene bias) and does not require genotyping data from the original GWAS, which reduces computational burden.

The investigators used gamGWAS to analyze two existing schizophrenia GWAS datasets from the International Schizophrenia Consortium and the Genetic Association Information Network. They report in the February Journal of Medical Genetics that gamGWAS confirmed previous findings in these datasets and also pointed to new immune-related pathways that may have roles in schizophrenia.

This research was supported by the National Institute of Mental Health, a NARSAD Maltz Investigator Award and a NARSAD Young Investigator Award.