Health Features

Health: A Promising Pipeline

Each year, we introduce readers to promising medical studies, grants and discoveries that are moving clinical practice forward, sometimes by leaps and bounds. The inspiring work of local researchers shows us how bright the future of medicine is across a wide range of disciplines. Bravo to our hard-working scientists!

reversing autistic behaviors
Autism spectrum disorder is composed of neurodevelopmental disorders that manifest as difficulty with social interaction and communication, along with excessive repetitive behaviors. While some medications address some of the symptoms, no drug therapies exist to treat the underlying condition. Saint Louis University researchers report that treating mice with a compound called SR1078 reduces the obsessive compulsive autistic behavior.

Researchers now know that certain genes tend to be underexpressed (underactive) in the brains of autistic children, as is RORA, an activator of gene expression that has been shown to regulate those key genes.

The compound being developed and tested by Thomas Burris, Ph.D., SLU chair of pharmacology and physiology, increases the activity of RORA, thereby increasing activity in the underperforming genes and raising them to the function of a normal brain. The test mice, which were bred to excessively groom themselves, reduced grooming to normal levels when given the SR1078 compound,”says Burris.

He and his team believe that by directly targeting a protein to regulate other genes, they can avoid the side effects of antipsychotic drugs and help the autistic brain perform at more normal levels. The compound will be used to create an oral medication at the correct dose and safety profile before clinical trials with people begin. Burris recently received a National Institutes of Health grant to continue his work. Says Burris, “Our goal is to stimulate genes stifled by the autism spectrum disorder. This field currently offers very few pharmacological options. We hope this will be the start of developing therapies that will get closer to treating autism’s root cause.”

early childhood depression
The brains of children who suffer clinical depression as preschoolers develop abnormally, say researchers at Washington University School of Medicine. Their gray matter—the tissue that connects brain cells, carries signals between cells, and is involved in vision, hearing, memory, decision-making and emotion— is lower and thinner at the cortex, where the brain processes emotion.

This finding has shown researchers that a life experience, such as an episode of depression, can change the actual anatomy of the brain. First author Dr. Joan Luby, professor of child psychiatry, says they previously thought the brain developed in a predetermined way. “It may help explain why children and others who are depressed have difficulty regulating their moods and emotions,” Luby says.

For the study, 193 children were included, 90 of whom had been diagnosed with depression as preschoolers. Researchers did clinical evaluations and performed MRI scans at three points in their development. “Changes reflect an actual difference in brain maturation that emerges over the course of development,” Luby notes.

She explains that normally, children develop gray matter until puberty and as the brain gets more efficient at communication, unnecessary cells die off. Her study showed a much steeper drop-off in gray matter in the kids who had been depressed, with the greatest loss correlated to the most severe depression. The researchers want to determine if early intervention can make brain development in this population healthier.

A new study just starting will focus on treatment with parent-child psychotherapy. Researchers are looking for 250 caregiver parents and their preschoolers for a randomized study evaluating the effectiveness of 18 weeks of psychotherapy for the parent and child. Visit eedvp.wustl.edu for more information.

novel geriatric solution
America is aging at an unprecedented rate, but the number of board-certified geriatric specialists isn’t keeping up. A promising alternative for Missouri has come in the form of a $2.5 million, threeyear Department of Health and Human Services grant for Saint Louis University to train primary care providers in geriatrics.

Dr. John Morley, SLU director of geriatric medicine and the project’s director, is working with co-director Marla Berg-Weger, Ph.D., SLU professor of social work, to create The Gateway Geriatric Education Center Workforce Enhancement Program. The idea is to assemble a team of community partners to refer geriatric patients to health professionals who can help them access timely treatment. “This will compensate for our lack of geriatric infrastructure,” says Morley. “We have developed a computer-based diagnosis and management system for physicians and other professionals to catch treatable geriatric issues.”

among the initiatives:
>> Educating 1,100 health care students and providers on a team approach to improving care for older adults. Non-geriatric trained health professionals can be trained to use the Rapid Geriatric Assessment System to evaluate for frailty, loss of muscle, anorexia of aging and cognitive dysfunction.

>> Designating three faculty members from universities in the state annually as Geriatric Leadership Scholars, who will receive specialized training and mentoring.

>> Training 5,000 patients, family members and care providers to improve quality of life for geriatric patients through diet, exercise and social stimulation.

>> Teaching 220 health care professionals how to deliver a non-drug treatment called Cognitive Stimulation Therapy for Alzheimer’s disease and related disorders.

As the new program is expanded over underserved areas in St. Louis and surrounding regions, Morley expects the health of older Missourians to improve measurably. For more information, visit aging.slu.edu.

implantable devices to block pain
A novel technology is enabling scientists to implant flexible devices to activate and, in theory, block pain signals. At Washington University School of Medicine, Robert Gereau IV, Ph.D., director of the Washington University Pain Center, is encouraged. “A new field called optogenetics is allowing us to create a device called a microLED, which stimulates a light-sensitive gene to turn on pain pathways,” he says. “The paper we just published is a proof of concept that light activation can turn on neurons in the pain pathway. Another type of gene is inhibitory to cells to stop pain. If we can insert an on-switch protein into a neuron, we could also insert off-switch neurons into the pain pathway to turn off the pain signals before they reach the brain.”

Once they find the right switch to turn off pain in mice, they will begin the process of translating that to people. Their big advance, Gereau says, has been the microLED, which can be sutured in place in contoured, moving parts of the body: the spine, brain, bladder, stomach and heart. Earlier versions were rigid and impeded movement. This soft, flexible, miniaturized implant can then be powered wirelessly with radiofrequency energy from a small outside transmitter attached to the patient’s wrist, for example.

The Pain Center’s goal is to develop non-addictive options for chronic pain control. Gereau says bringing this technology to clinical practice is still years off, but it looks promising.

opioid use & depression
In a study published in January, researchers at Saint Louis University found that opioid pain medications used for longer than 30 days increased the risk of new onset depression. “The U.S. leads the world in opioid consumption,” says lead investigator Jeffrey Scherrer, Ph.D., SLU associate professor for family and community medicine. Opioids are pain medications that include codeine, morphine, Vicodin, OxyContin and fentanyl. Vicodin, Scherrer says, accounts for 90 percent of the prescriptions. “There is a place for opioids in acute pain management, but not long term. What we found in our study of three large patient populations is that after about 30 days of use, opioids may lead to changes in neuroanatomy, causing depression symptoms and a decrease in testosterone—and the effect is independent of dosage.”

Scherrer says several papers have demonstrated similar problems with continued opioid use. “Patients whose depression was in remission were twice as likely to experience a return of their depression when they started opioids. Plus, patients with chronic pain and a history of depression are more vulnerable to opioid abuse and to needing greater doses.”

An additional study alarms Scherrer with its findings that patients being treated for depression who had taken opioids became resistant to depression treatments. He says physicians should look to other treatments for chronic pain after 30 days since there is no evidence that opioids are effective long-term, and doctors should also screen patients for depression frequently.

improving radiation therapy for vets
A new program, headed by Washington University School of Medicine, will monitor quality and safety of radiation therapy at VA health centers nationwide, which serve more than 8 million a year. Dr. Jeff Michalski of Siteman Cancer Center at Barnes-Jewish Hospital, is heading the initiative, called the Radiation Oncology Practice Assessment Program. It will provide continuous feedback on the progress, quality and safety of each veteran’s cancer therapy.

Approximately 60 percent of cancer patients receive some form of radiation therapy. In the first year, this program will assess practice across 40 radiation oncology centers in VA hospitals, including Puerto Rico. “One of the questions for assessing each center is: Are patients enrolled in clinical trials? The standards we are developing can help identify circumstances for which clinical trials might be appropriate,” says Michalski. The first year, they will focus on lung and prostate cancer. The next, head and neck cancers, and then gastrointestinal cancers, which together represent the majority of cancers seen at VA hospitals, he says.

His teams will be doing on-site reviews to measure performance from patient outcome perspectives: Was the treatment effective? VA radiation oncologists will have complete and consistent records of each patient’s therapy and the response to treatment, including survival and tumor recurrence. Michalski says rather than analyzing physician performance, this system focuses on letting doctors see how changes in clinical practice, radiation planning, delivery technology and radiation dose prescription impact the success of the therapy. “The overreaching goal is to make sure our veterans receive consistent quality of care for their radiation oncology, regardless of the VA hospital in which it is performed.”

antacid ingredient stops tumors
Engineers at Washington University have found a way to keep a cancerous tumor from growing by using nanoparticles of calcium carbonate, the main ingredient in antacid tablets. The research team is being led by Avik Som, an M.D./Ph.D. student, and Samuel Achilefu, Ph.D., professor of radiology and biochemistry and molecular biophysics. Using two novel methods, they created nanoparticles that were injected intravenously into a mouse to treat solid tumors. The compound changed the pH (acidity) of the tumor environment from acidic to more alkaline, and kept the cancer from growing.

“Cancer kills because of metastases,” says Som, “and pH of a tumor is heavily correlated with metastasis. Tumors create acidic environments so they can grow.” Just as antacids change the pH in the stomach to decrease the ill effects of acidity, these nanoparticles do that to the tumor environment, thwarting its growth.

But making the nanoparticles is tricky, as Som explains. “If you crush an antacid tablet, you might get it down to particle sizes of one to 10 microns, still 100 times bigger than nanoparticles, which are what’s needed to plug the holes of tumors and their blood vessels.”

Som says the next steps are to determine whether there is any chronic toxic effect with the nanoparticles, and to look at how the nanoparticle delivery system can cooperate with cancer treatments. They know the delivery system can increase pH and prevent metastases in the mouse, but does it affect metastasis formation long term, and can they translate results to larger animals and ultimately to humans? “Right now, it is another tool in our arsenal to boost other treatment modalities; it’s really exciting,” says Som.

smoking cessation therapy & dna
Research is underway at Washington University School of Medicine to help smokers quit by analyzing genetic variations. The 720 participants will be interviewed about their smoking behaviors and provide DNA samples from saliva. “Only about 5 percent of smokers quit successfully without medication and counseling, and people with high-risk genetic markers are less likely to quit on their own,” says Dr. Li-Shiun Chen, assistant professor of psychiatry. She hopes to demonstrate that genetic markers can be matched to the effectiveness of certain smoking cessation therapies.

For smokers, a nicotine receptor marker on chromosome 15 is considered the high-risk marker that helps determine how the brain reacts to nicotine. Smokers with that marker are more likely to keep smoking, and about 30 percent become dependent on it. They also have higher earlier mortality. “The good news is that people with this high-risk marker are more likely to respond to treatment with nicotine replacement,” Chen says. Smokers without the marker can do well with lifestyle support and counseling.

The team also is tracking how individuals metabolize nicotine and who responds well to Chantix, which can have a side effect of nausea. The study will look at other markers that can indicate negative reactions, helping sort smoking cessation into gene types.

Participants will be placed randomly into one of three groups, with all receiving seven weeks of counseling. Groups will receive nicotine replacement patches and lozenges, Chantix or an inactive placebo.

To volunteer for the study, contact behaviorandgenetics@psychiatry.wustl.edu.

curing hepatitis b
Chronic infection with the hepatitis B virus can cause liver failure, liver cancer and death. More than 350 million worldwide are chronically infected, yet current treatments are expensive and only keep the virus under control.

With a new $2.2 million grant from the National Institutes of Health (NIH), John Tavis, Ph.D., SLU professor of molecular microbiology and immunology, says his 25-year mission to find a cure is getting close. “We’ve achieved the first stage of laboratory research and have developed a drug using a class of compounds called alpha hydroxy tropolones to help us identify about 35 inhibitors needed to block the viral activity.”

Researchers now need to develop a molecule with minimum toxicity that can be absorbed by the body and last long enough to do the job, ideally in pill form. Tavis says they just completed their first animal studies with positive results. “We hope a course of the drug will provide a cure. However, we also are looking at an intermediate step, combining our drug with an existing one, to boost its effectiveness and make it affordable for long-term maintenance.”

delayed v. immediate gratification
If we’re given a choice between having $7 now or being mailed $14 in a week, which are we likely to choose? People who consistently choose the smaller reward now may have a genetic predisposition to do so, and that tendency, according to researchers at Washington University School of Medicine, is associated with impulsive behaviors: alcohol and drug addiction, risk-taking and even obesity.

Andrey Anokhin, Ph.D., is an associate professor of psychiatry and principal investigator in a recently published twins study. “We studied 310 adolescent identical or fraternal twin pairs and asked them questions about money every two years from age 12 years to 20. The purpose of using twins was to judge the impact of genetic factors on their decisions.”

Researchers reasoned that if only the identical twins had the same response, heredity was a big factor. Similar responses with fraternal twins would indicate the behavior was more linked to a shared environment. What they found was a strong genetic component to the responses.

Says Anokhin, “The evidence is there that these lab measures of choice correlate with real-life variables, and that those who discounted delayed rewards also discounted delayed punishment, like having to deal with the consequences of their decisions. We also found that those traits only got stronger with age.”

After determining the traits are highly inheritable, they sought to identify which genes were involved and found the top three genes that played a role were linked to the brain’s neural receptors associated with mood, depression and addiction.

Further studies will have to be done to confirm the results. The takeaway for now, says Anokhin, is to realize that ages 10 through 12 constitute a sensitive developmental period for forming the ability to appreciate long-term goals. If parents and teachers are aware of this, they can develop educational protocols to help kids delay gratification at these critical points in their development.

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