Cleft Palate Prevention…Cleft palate and lip occurs in about one in 700 newborns worldwide. This disfiguring congenital defect causes feeding difficulty for infants and later problems with speech, hearing, and dental development. Treatment costs are high and multiple surgical repairs may be needed. Researchers already know that some cases of cleft lip and palate are environmentally linked to exposures in the uterus: maternal smoking, viral infections and certain medications. In other cases, genetic variation plays a larger role. Dr. David Ornitz, professor of developmental biology at Washington University School of Medicine, led a recent study on the complex origination of cleft palate among dozens of genes in a fetus. “A cleft palate is often diagnosed late in pregnancy and treated surgically after birth,” Ornitz says. “If we understood the genetic causes of this common birth defect, we might be able to diagnose it much earlier.”

He and his team studied the fibroblast growth factor receptor 2 (FGFR2) gene, one they know is implicated in cleft palate. Studies of mice with Crouzon syndrome, a developmental disorder that includes cleft palate and is caused by mutation of FGFR2, demonstrated that the mutation prevents specific growth signals from being switched off, making it more active than normal. Interestingly, genetically engineered mice in which that gene has been permanently deactivated also developed cleft palate.

Ornitz explains that the mutation in this gene affects the activity of the receptor. “Potentially, a drug could be used in fetuses diagnosed with this mutation to either turn on or reduce this gene’s activity as needed, and decrease chances of cleft palate development,” he says. “If we could diagnose the problem early enough, potentially the drug could be administered to the fetus or to the mother early in the pregnancy.”

Beverages to Slow Alzheimer’s

Research being conducted at Saint Louis University and elsewhere around the world is showing promise that a morning drink made up of essential nutrients and taken in conjunction with Alzheimer medications can delay loss of memory and cognition. Dr. John Morely, director of the Division of Geriatrics at Saint Louis University School of Medicine and the principal investigator in both the pilot and current study, says the results are very encouraging.

“The pilot study looked at 300 people diagnosed with probable Alzheimer’s disease and taking at least one of the five drugs approved by the FDA for that condition,” Morely explains. “In addition to their drugs, each person in the study either got the Alzheimer shake or a beverage without the special active ingredients. We were the only site in the U.S. Based on results from the pilot we were able to design this larger study.”

People recruited for this study must be at least 50 years old, be diagnosed with probable Alzheimer’s disease, be on one of the five medications, and have a caregiver who will supervise and ensure they get their medications and the shake every morning. The six-month study will involve six visits attended by both the patient and caregiver, and follow-up phone calls.

The Alzheimer’s shake is a strawberry vanilla drink that comes in a juice box and is taken chilled. The extra ingredients in that drink, over and above the control beverage, includes special fatty acids and vitamins and minerals known to be building blocks for the brain, such as fish oils and amino acids. Morley says that if the benefits of the drink are confirmed in the larger study, he is hopeful that it will become something that can be used early in the disease to restore normal function and delay onset of impairment.

Sexual Abuse Victims and Addictions

There is compelling evidence that the severe stress of sexual abuse early in life increases the risk of alcohol and drug addiction later on. What has been just recently discovered is that some early sexual abuse victims have a gene variation that makes addiction less likely. Dr. Elliot Nelson, associate professor of psychiatry at Washington University School of Medicine, says these results have strong implications for preventive strategies. “If we know which individuals are at greater risk, we can develop education and treatment to prevent them from getting into trouble.”

Nelson and a team of researchers studied a set of genetic variations called the H2 haplotype. Similar to a blood type, a haplotype is a normally occurring pattern of gene variants statistically associated with one another, enabling scientists to successfully predict other genetic variations. Nelson explains: “Each individual has two copies of this haplotype, either H1 or H2, or one of each. Having one or more copies of H2 seems to be protective against alcoholism or other addictions. Two copies of H1 in young sexual abuse victims indicates a greater disposition for alcoholism, drug dependency, nicotine dependency, and some psychiatric disorders later on.”

The study, which took place in Australia, included a comparison of genetic haplotype and reports of childhood abuse beginning around age 11. Sexual abuse victims with the H1 haplotype had three times the risk of heavy drinking and alcohol dependence as those who had not been abused.

Before this study, scientists knew that about half the risk for alcoholism is determined by genes, which is why it seems to run in families. The other half of the risk comes from environmental factors like age at first drink and exposure to extreme stress, such as childhood sexual abuse. When these environmental stressors occur during key periods of brain development, genes and environment together can increase the likelihood of alcoholism.

He says that if the child was sexually abused, parents should be aware there is an increased likelihood of these problems down the road. Often people with the genetic risk for addiction are also at the greatest environmental risk, so it’s important to get a handle on these targets.

Smallpox and Bioterrorism

The world was declared free of smallpox in 1980, but concern continues about the possible use of residual stores as a tool for bioterrorism. With that in mind, scientists at Saint Louis University’s Center for Vaccine Development will head up a National Institutes of Health-funded study to evaluate the most effective way to administer an investigational vaccine for smallpox. This study, conducted at five centers across the country, should help the U.S. government more efficiently protect citizens in case of a bioterrorist attack.

Dr. Sharon Frey is a professor of infectious diseases at SLU’s School of Medicine and the principal investigator in this study. “The test for this study is whether there is a difference in immune levels between two formulations of the vaccine, one given by injection subcutaneously into the fat layer under the skin (like insulin), or intradermally between layers of skin (like a TB or allergy test), she explains. “Typically less vaccine is needed to make an immune response when it is given intradermally. If we find that giving the vaccine intradermally is safe and has as strong an immune response, we could potentially protect more people with the same amount of vaccine.” Prior to the current study, the vaccine had already been tested on more than 2,400 volunteers and found to be safe and well-tolerated.

Both of the test formulations differ from the old smallpox vaccinations we received as children because this formulation of the virus does not replicate in the body, minimizing vaccine complications such as fevers, aches and fatigue, and it leaves no scar. Neither formulation has been approved yet by the FDA, which is waiting for results from this and a subsequent study in the works. For the first study, 495 volunteers are needed who have never had a smallpox vaccination, were born after 1971, are at least 18 years old and in good health.

Early Intervention in Asthma

A recent study at Washington University School of Medicine found that parents of young children with asthma often recognize signs that an asthma attack is coming but delay home treatment until it occurs. These are missed opportunities to intervene early, relieve symptoms, and prevent a full-blown attack and possible trip to the emergency room. These attacks happen to two of every three asthmatic children each year, resulting in missed school days, ER visits and hospitalization.

The study was developed after asthma coaches working for W.U.’s School of Medicine noticed that parents were monitoring symptoms of impending attacks at home but not acting on them. Based on those observations, Dr. Jane Garbutt, Associate Professor of Medicine and Pediatrics, and her colleagues designed a study focused on 101 parents of asthmatic children between the ages of 2 and 12 years. Each time their child had an attack, the parent noticed the same group of symptoms. “Even though they noticed them consistently, they didn’t do anything about it. If they had known to give albuterol earlier, they may have been able to manage things at home and avoid a trip to the emergency room,” Garbutt notes.

Based on the result of that survey and feedback from the coaches, Dr. Kathy Rivera, a pulmonary specialist with Washington University, developed an early warning sign inventory being tested in the asthma clinics with parents to see if they can reliably catch symptoms that would trigger treatment. Says Garbutt, “One of the reasons parents may not begin treatment is that they believe they are following the doctor’s instructions. It wasn’t clear to them what symptoms should trigger treating with albuterol.”

Garbutt is conducting a follow-up study with pediatric practices, some of which will randomly be assigned coaches. The coaches will work with three behaviors: how to use rescue medicine, how to recognize if it’s working properly, and how to tell when parents should ask for help. “We now have national guidelines in place that say every asthmatic child should have a personalized action plan on how to manage the condition day-to-day and what to do if it gets worse. We’re showing the doctors that it’s very important to listen carefully to their patients and the parents. Coaching is valuable in that process.”

Brain ‘Networking’

We’ve always heard that an injury on one side of the brain causes functional problems on the opposite side of the body. That turns out to be too simplistic. Because of a new MRI scanning technique called ‘resting-state functional connectivity (FC),’ we now know that part of the deficit after a brain injury is due to impairment of activity in regions that appear normal on a clinical head CT or MRI scan. In the future, that may give clinicians treating brain injury tools to better understand the effects and provide more accurate prognosis for recovery.

Dr. Maurizio Corbetta, head of stroke and traumatic brain injury rehabilitation at Washington University School of Medicine, says that before they had the ability to measure functional connectivity, the physician’s ability to understand and predict how a patient would recover from a stroke, based on the size and location of the lesion, has been disappointingly inaccurate. He couldn’t really tell how the patient would be doing in six months. “What we learned is that the brain is highly interrelated. When we move our right hand, it lights up the left motor cortex, as we expect, but it also activates regions on the right side. All these regions are part of a ‘network’; everything we do requires the coordination of a distributed network of brain areas.” For the first time, scientists have linked the individual differences in brain injury to variations in the impairment experienced by different patients.

He says FC MRI scans measure the communication between brain regions over time. Even at rest activity in regions that are networked tends to rise and fall in unison. Corbetta says, “Using this technique with stroke patients, I can look at the lesion in the brain and ask if the deficits are correlated with impairment in the communication between brain regions. We find that communication between the two sides of the brain is critical and deficits can be correlated with failure in that communication.”

In a new study funded by the National Institutes of Health that will go on for five years, stroke patients will have serial FC scans to compare right after the stroke, at three months, and again at 12 months. By tracking how connectivity is changing over time, Corbetta and colleagues hope to develop better predictors of recovery and prognosis. He is optimistic. “If FC turns out to be predictive, we may be able to use novel methods like transcranial magnetic stimulation (TMS) through the scalp to modulate this connectivity and change the activity level in the brain, potentially influencing how someone recovers,” he says.

One Step Contouring & Firming

A newer procedure offers an excellent alternative for liposuction patients. BodyTite™ is a radiofrequency-assisted liposuction that liquefies and removes unwanted fat, and at the same time firms underlying tissue and skin. Plastic surgeon William Hart with the Hart Cosmetic and Reconstructive Surgery Institute is one of only about 25 investigators in the country using this new technology, which is not yet FDA-approved for general sale.

“This new technology has many advantages over traditional liposuction, and certainly over laser liposuction,” says Hart. “Through a single cannula, the fat can be liquefied and sucked out. At the same time, the radiofrequency energy cauterizes small blood vessels to prevent bleeding and bruising, and heats the connective tissue and skin, causing them to firm and contract. It’s done in an office surgical suite under oral sedation and local anesthetic, with hardly any downtime. Clients go back to work the next day!”

Hart says laser liposuction takes about four times as long to liquefy the same amount of fat. With laser, the fat is first melted by the laser. Then the surgeon goes back in with suction to remove the melted fat, then goes back in again with heat to tighten the skin. BodyTite condenses this three-step procedure into one, and adds the advantages of careful skin temperature monitors. On the BodyTite console, the surgeon sets the target temperature for tightening, and the machine won’t go above that, preventing burns. Hart adds that the cauterizing and temperature monitoring systems allow a fair amount of fat removal.

Hart is excited about this new technology and the results he is seeing. “The technology will be approved soon for general medical use, but I think it’s important that clients go to a plastic surgeon for this, someone who is experienced in traditional liposuction and knows the limitations of the BodyTite procedure. It won’t give a client the same flat tummy or tight skin as a tummy tuck, but we can probably achieve 50 percent of that. I stress that to my clients so they can make a decision based on realistic expectations.”

‘Healthspans’ & Lifespans

The average lifespan is about 80 or so. However, the average ‘healthspan,’ the part of our life during which we have no chronic disease, is 50. That means some of us spend 30 years with significant impairment, and one in two of us will develop some form of cancer. Researchers at the Washington University School of Medicine are studying ways to bring the two spans together by finding pathways to prevent disease. One that has shown remarkable effect on healthy lifespan is calorie restriction. Organisms from yeast to mice to humans all benefit from cutting calories. Researchers have found that in less complex organisms, restricting calories can double or even triple lifespan.

Dr. Luigi Fontana, research associate professor of medicine at Washington University and investigator at the Istituto Superiore di Sanitá in Rome, Italy, explains: “About 30 percent of animals on calorie restriction die at an advanced age without any diseases normally related to aging. In contrast, among animals on a standard diet, the great majority, 94 percent, develop and die of one or more chronic diseases such as cancer or heart disease.” Nutrition and longevity researchers at Washington University, University College in London, and the Andrus Gerontology Center at the University of Southern California reported in the April 16 edition of Science that calorie restriction influences the same molecular pathways related to aging in all studied animals. Fontana is less interested in calorie restriction for its ability to promote longer life than in promoting good health throughout life. He wants to use the discoveries about calorie restriction and other related genetic and pharmacologic breakthroughs to close that 30-year gap. A side effect could be extending the average lifespan to 100.

Now starts the hue and cry about how cutting back drastically on calories makes life less worth living. Fontana understands that despite its potential benefits, calorie restriction is unlikely to gain widespread support, and explains that their focus is not simply on calorie cutting, but a combination of mild calorie restriction, exercise and nutritional supplements like phytochemicals that can mimic some of the effects of calorie restriction.

Because obesity is reaching epidemic proportions in Western countries, that 30-year healthspan-lifespan gap could even increase. It’s even possible, according to Fontana, that healthspan will go below 50 as more people develop preventable diseases such as atherosclerosis, type 2 diabetes, and certain forms of cancer. “While research continues on different combinations and approaches to achieve what calorie restriction can provide,” he says, “if a healthy lean human wants to live a longer, healthier life, right now the only way we know to achieve that is through calorie restriction.”

Teen Drinking & Breast Disease

A recent study shows that girls and young women who drink alcohol increase their risk of benign breast disease, which increases the risk for breast cancer. “Our study clearly showed that the risk of benign breast disease increased with the amount of alcohol consumed in this age group,” says Dr. Graham Colditz, associate director of prevention and control at the Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital. It’s an indication that alcohol should be limited in adolescence and early adult years, and focuses our attention on these years as key to preventing breast cancer later in life.”

The study, published in the May issue of Pediatrics, surveyed 6,899 girls ages 9 to 15 years at the study’s start and followed them with health surveys from 1996 to 2007. It reported on their alcohol consumption and whether they had ever been diagnosed with benign breast disease. Girls and young women who drank six or seven days a week were five-and-a-half times more likely to have benign breast disease than those who didn’t drink or had less than one drink per week. Participants who reported drinking 3 to 5 days a week had three times the risk.

Says Colditz, “We already have established a clear link between alcohol and breast cancer in adult women. Now studying benign breast lesions in adolescents helps explain how it leads to breast cancer in adulthood. This makes sense in light of other studies, such as those done in Japan on people exposed to the hydrogen bomb. The younger they were exposed to radiation, the more likely they were to develop cancer.” He says hundreds of studies now show that alcohol is a known carcinogen for the breast, colon, and head and neck cancers. The current study adds to that information on whether alcohol intake in adolescence can have a bigger effect later in life.

“With this study, our understanding of how to prevent breast cancer grows. Evidence exists that regular physical activity can lower breast cancer risk. Researchers also know that a good diet and maintaining a normal weight are important to risk. Now clinicians can add limiting alcohol intake throughout life as another protector against breast cancer.” Colditz says these finding give parents more ammunition in discussing alcohol intake with their children.

Radiation Implant & Eye Cancer

Retinoblastoma is a rare cancer of the eye’s retina and primarily affects children. About 200 kids per year are diagnosed with it. Hereditary retinoblastoma usually occurs in both eyes at an average age of one year or earlier. The non-hereditary form more often affects one eye around age 2 to 3. When tumors prove resistant to chemotherapy, very young children and their parents are often faced with the choice between life without eyes and a high risk of death. But a new treatment is changing all that.

Often the tumor is found when a parent takes the child’s picture and notices that one or both eyes appear white, rather than the normal red in the image. The tumor may be fairly large when it’s first noticed. Another way it is diagnosed is in children with a drifting or lazy eye. Around 20 percent of small children have this, mostly due to a condition called strabismus, but in some cases, it is caused by a tumor. Dr. J. William Harbour, Washington University School of Medicine ophthalmologist and eye surgeon at St. Louis Children’s Hospital, says because of its rarity, any child with one eye misaligned should be sent to an ophthalmologist for a dilated exam to rule out retinoblastoma.

Harbour is one of only a few doctors nationwide to use a new approach for treating retinoblastoma. He says the standard of care for retinoblastoma is chemotherapy, followed by laser and freezing treatments to eliminate any remaining tumor. When a tumor won’t respond to chemotherapy or is too large for other treatments, he uses a plaque treatment. “The plaque looks like a bottle cap made of gold. Radiation seeds are placed on one side of the plaque, focusing the radiation right on the tumor, like a flashlight, and preventing the radiation from affecting other parts of the body,” he says.

Harbour explains that these plaques have been the standard of care for adults with melanoma of the eye, but they are only recently being used for retinoblastoma. Nevertheless, the treatment is accepted as standard and covered by insurance. During a short procedure, the plaque is sewn to the sclera, or outside white part of the eye and left in place for three days until another surgery removes it. It’s usually a one-time treatment and tolerated well by even very young children. Results are not immediate. ”It takes about six weeks for us to see the tumor shrink, and within three months, it’s gone,” he says. “We use the plaque when the tumor is too large for laser but small enough to spare the child chemotherapy. Generally, children do well and keep their sight.”

While NIH studies on adults with ocular melanoma showed the plaque therapy to be as effective in preventing the spread of the melanoma as removing the eye, it’s unlikely a study of its use in children with retinoblastoma will ever be conducted. Harbour estimates only 10 to 20 children a year in the U.S. would even need it. More important is for ophthalmologists to know this therapy is available in St. Louis.