WUSTL Medicine & Healthcare News

Folic acid may reduce some childhood cancers

Jessica Martin — 2012-05-21 00:00:00

Folic acid fortification of foods may reduce the incidence of the most common type of kidney cancer and a type of brain tumors in children, finds a new study by Kimberly J. Johnson, PhD, assistant professor at the Brown School at Washington University in St. Louis, and Amy Linabery, PhD, postdoctoral fellow at the University of Minnesota.

Incidence reductions were found for Wilms’ tumor, a type of kidney cancer, and primitive neuroectodermal tumors (PNET), a type of brain cancer.

Since 1998, the U.S. Food and Drug Administration has mandated fortification of foods with folic acid because earlier studies show that prenatal consumption of folic acid significantly reduces the incidence of neural tube defects in babies.

“Our study is the largest to date to show that folic acid fortification may also lower the incidence of certain types of childhood cancer in the United States,” Johnson says.

The study, published in the current issue of Pediatrics, examined the incidence of childhood cancer pre- and post-mandated folic acid fortification.

“We found that Wilms’ tumor rates increased from 1986 to 1997 and decreased thereafter, which is an interesting finding since the downward change in the trend coincides exactly with folic acid fortification,” Johnson says.

“PNET rates increased from 1986 to 1993 and decreased thereafter. This change in the trend does not coincide exactly with folic acid fortification, but does coincide nicely with the 1992 recommendation for women of childbearing age to consume 400 micrograms of folic acid daily.”

Study authors used the 1986-2008 data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program (SEER), which has collected information on cancer cases in various areas of the U.S. since 1973. The study involved 8,829 children, from birth to age four, diagnosed with cancer.

“Declines in Wilms’ tumors and PNETs in children were detected by multiple analyses of the data,” Johnson says.

“Importantly, the reduced rates of Wilms’ tumors also were found in a smaller study conducted in Ontario, Canada, that was published in 2011.

“More research is needed to confirm these results and to rule out any other explanations.”

Julie A. Ross, PhD, professor and director of the Division of Pediatric Epidemiology & Clinical Research in the Department of Pediatrics at the University of Minnesota, was a study co-author.

Johnson notes that one concern countries face as they are deciding whether or not to fortify foods to reduce neural tube defects in newborns is the possibility that fortification may cause unintended harm, such as causing new cancers or pre-cancerous lesions.

“Here, we are showing that folic acid fortification does not appear to be increasing rates of childhood cancers, which is good news,” she says.

For the full study, “Childhood Cancer Incidence Trends in Association With Folic Acid,” visit: http://pediatrics.aappublications.org/content/early/2012/05/15/peds.2011-3418.full.pdf+html

Tychsen named Hardesty distinguished professor

Beth Miller — 2012-05-23 00:00:00

Pediatric ophthalmologist R. Lawrence Tychsen, MD, has been named the John F. Hardesty, MD, Distinguished Professor of Ophthalmology and Visual Sciences at Washington University School of Medicine in St. Louis.

Chancellor Mark S. Wrighton and Larry J. Shapiro, MD, executive vice chancellor for medical affairs and dean of the School of Medicine, announced the appointment. Tychsen will be installed May 31.

Tychsen

“Dr. Tychsen’s extraordinary dedication to children with severe visual impairments makes him an excellent selection for this professorship to honor the legacy of Dr. Hardesty,” Wrighton says. “During his more than 20 years at Washington University, Dr. Tychsen’s work has given his patients a better future, and we are pleased to honor his outstanding work this way.”

“Through his surgical techniques and incredible compassion, Larry Tychsen has changed the lives of many visually impaired children and their families,” Shapiro says. “This professorship will provide support for Larry to continue his research and his development of new treatments for ocular disorders.”

Since many of his patients have difficulty communicating or being examined, Tychsen has established the Amblyopia and Eye Movement Disorders Center and Visual Electrophysiology Laboratory at St. Louis Children’s Hospital, where he is ophthalmologist-in-chief. In the laboratory, he and his team use noninvasive electronic techniques to measure patients’ eyesight before, during and after surgery. A computer allows precise measurement of visual acuity and eye tracking, which can help determine whether a child has a problem with sensory input or motor output.

Tychsen, professor of ophthalmology and visual sciences, of pediatrics and of anatomy and neurobiology, earned an undergraduate degree in biology and philosophy and a medical degree from Georgetown University. After medical school, he completed a one-year fellowship in neuro-ophthalmology at the National Eye Institute within the National Institutes of Health (NIH). He completed a residency at the University Hospitals in Iowa City, Iowa, followed by fellowships at the University of California, San Francisco, and the Smith-Kettlewell Eye Research Institute in San Francisco. He also served in the U.S. Air Force as a flight surgeon and pediatric ophthalmologist at the School of Aerospace Medicine and the Wilford Hall Medical Center in San Antonio, Texas, before joining the faculty at Washington University School of Medicine in 1989.

Tychsen has published more than 200 peer-reviewed journal articles or book chapters. He serves on the editorial boards of several journals, as well as panels for national and international ophthalmology associations, the National Eye Institute of the NIH and the Pediatric Eye Disease investigator group, and is a consultant to the U.S. Food and Drug Administration. He has mentored numerous undergraduate and medical students over his career and has received dozens of awards, lectureships and honors. He also treats patients at Missouri Baptist Hospital and Shriner’s Hospital for Children in St. Louis.

John F. Hardesty, MD (1887-1953), was a St. Louis ophthalmologist, teacher, writer, and war hero whose heritage may be traced back to colonial and early Missouri settlers. He earned bachelor’s and medical degrees simultaneously from Saint Louis University in 1914, then spent two years as an intern and later a resident at St. Louis City Hospital.

Hardesty’s daughter, Jane Hardesty Poole, a 1961 graduate of Washington University, established the John F. Hardesty, MD, Distinguished Professorship in Ophthalmology and Visual Sciences in his honor.

“My father gave so much of himself to help families desperate to give their blind children sight,” Poole says. “I am so pleased that I can honor him in this way.”

Hardesty enlisted in the U.S. Army Medical Corps and was later transferred, at his own request, to the Seaforth Highlanders in the British Military Service. He served on the front lines of World War I until March 1918, when he was captured by the German army and held at Baden-Baden for eight months as a prisoner of war until the armistice. He received an honorable discharge as a captain in March 1919.

Hardesty joined the Saint Louis University School of Medicine faculty in 1920, and rose through the ranks to associate professor in 1934, a position he held until 1953. He served as acting chair of the Department of Ophthalmology from 1950-53.

In 1934, Hardesty wrote a pioneering thesis for membership in the prestigious American Ophthalmological Society titled “Treatment of Glaucoma by Systemic Measures.” Although the first recorded treatments for glaucoma date back to the mid-19th century, Hardesty performed research and published papers on treating the disease using “systemic” medication, or drugs introduced to the body intravenously or subcutaneously. This represented the first attempt to treat glaucoma in systemic form.

Hardesty’s idea of using epinephrine to treat glaucoma is still in use today, and his work laid the foundation for the development of the oral drug Diamox (acetazolamide) in the 1950s by Bernard Becker, MD, at Washington University School of Medicine.

In addition to his university roles, Hardesty was ophthalmologist to the St. Louis City Sanitarium from 1921-1953 and ophthalmologist-in-chief at Missouri Baptist and Bethesda General hospitals, as well as a member of the Medical Advisory Board for the State of Missouri. He also served as medical director for the St. Louis Society for the Blind.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

IUDs, implants are most effective birth control

Diane Duke Williams — 2012-05-23 00:00:00

Audio available

A study to evaluate birth-control methods has found dramatic differences in their effectiveness. Women who used birth-control pills, the patch or vaginal ring were 20 times more likely to have an unintended pregnancy than those who used longer-acting forms such as an intrauterine device (IUD) or implant.

Results of the study, by researchers at Washington University School of Medicine in St. Louis, are reported May 24 in the New England Journal of Medicine.

Birth-control pills are the most commonly used reversible contraceptive in the United States, but their effectiveness hinges on women remembering to take a pill every day and having easy access to refills.

http://youtu.be/0ci4B7BtXwI

In the study, birth-control pills and other short-term contraceptive methods, such as the contraceptive patch or ring, were especially unreliable among younger women. For those under 21 who used birth-control pills, the patch or ring, the risk of unplanned pregnancy was almost twice as high as the risk among older women. This finding suggests that increased adolescent use of longer acting contraceptive methods could prevent substantially more unplanned pregnancies.

Peipert

“This study is the best evidence we have that long-acting reversible methods are far superior to the birth-control pill, patch and ring,” says senior author Jeffrey Peipert, MD, the Robert J. Terry Professor of Obstetrics and Gynecology. “IUDs and implants are more effective because women can forget about them after clinicians put the devices in place.”

Unintended pregnancy is a major problem in the United States. About 3 million pregnancies per year — 50 percent of all pregnancies — are unplanned. The rate of unintended pregnancy in the United States is much higher than in other developed nations, and past studies have shown that about half of these pregnancies result from contraceptive failure.

IUDs are inserted into the uterus by a health-care provider. The hormonal IUD is approved for five years, and the copper IUD can be used for as long as 10 years. Hormonal implants are inserted under the skin of the upper arm and are effective for three years. Many women, however, cannot afford the upfront costs of these methods, which can be more than $500.

“We know that IUDs and implants have very low failure rates — less than 1 percent,” says Brooke Winner, MD, a fourth-year resident at Barnes-Jewish Hospital and the study’s lead author. “But although IUDs are very effective and have been proven safe in women and adolescents, they only are chosen by 5.5 percent of women in the United States who use contraception.”

Winner

Earlier contraceptive studies asked women to recall the birth-control method they used and number of pregnancies. For this study, the investigators wanted to determine whether educating women about the effectiveness of various birth-control options and having them choose a method without considering cost would reduce the rate of unintended pregnancy. Birth control was provided to women at no cost.

The study involved more than 7,500 women enrolled in the Contraceptive CHOICE project. Participants were ages 14-45 and at high risk of unintended pregnancy. The women were sexually active or planned to become sexually active in the next six months. They either were not currently using contraception or wanted to switch birth-control methods. The women also said they did not want to become pregnant for the next 12 months.

Participants in this report could choose among the following birth-control methods: IUD, implant, birth-control pills, patch, ring and contraceptive injection. The women were counseled about the contraceptive methods, including their effectiveness, side effects, risks and benefits. Participants were permitted to discontinue or switch methods as many times as desired during the study.

Investigators interviewed participants by telephone at three and six months and every six months thereafter for the remainder of the study. During each interview, participants were asked about missed periods and possible pregnancy. Any participant who thought she might be pregnant was asked to come in for a urine pregnancy test. Those who were pregnant were asked if it was intended and what contraceptive method, if any, they were using at time of conception.

Over the three-year study, 334 women became pregnant. Of these, 156 pregnancies were due to contraceptive failure. Overall, 133 (4.55 percent) of women using pills, the patch or ring had contraceptive failure, compared with 21 (0.27 percent) of women using IUDs and implants.

“This study also is important because it showed that when IUDs and implants are provided at no cost, about 75 percent of women chose these methods for birth control,” Winner says.

Women who chose an IUD or implant were more likely to be older, to have public health insurance and to have more children than women who chose other contraceptive methods. Women who chose pills, the patch or ring were more likely to have private health insurance and to not have had children previously.

“If there were a drug for cancer, heart disease or diabetes that was 20 times more effective, we would recommend it first,” he says. “Unintended pregnancies can have negative effects on women’s health and education and the health of newborns.”

Winner B, Peipert J, Qiuhong Z, Buckel C, Madden T, Allsworth J, Secura G. Effectiveness of long-acting reversible contraception. New England Journal of Medicine. Vol. 366. May 24, 2012.

Commencement 2012: New beginnings

2012-05-23 00:00:00

Robert Boston

(From left) Larry J. Shapiro, MD, executive vice chancellor for medical affairs and dean of the School of Medicine, congratulates Kristen E. Ziara Harring, for completing her medical degree at the School of Medicine Commencement Recognition Ceremony May 18 at America's Center. At the ceremony, 127 students received Doctor of Medicine, Doctor of Medicine/Master of Arts, Doctor of Medicine/Master of Science in Clinical Investigation and Doctor of Medicine/Doctor of Philosophy degrees. The programs in occupational therapy, physical therapy and audiology and communication sciences also held recognition ceremonies. For more photos of these ceremonies, visit here.

Washington University receives $3 million to design cancer-killing viruses

Julia Evangelou Strait — 2012-05-22 00:00:00

Igor Dmitriev, PhD

The illustration shows an adenovirus particle carrying metals and antibodies for cancer therapy. In this case, the metal is copper-64, a radioactive metal useful for both imaging and cancer therapy. Antibodies shown in orange and purple can target the virus to specific tissues or tumor types.

Researchers at Washington University School of Medicine in St. Louis have received a $3 million grant from the National Cancer Institute (NCI) to develop a triple threat in the fight against cancer: a single virus equipped to find, image and kill cancer cells, all at once.

Led by David T. Curiel, MD, PhD, Distinguished Professor of Radiation Oncology, the program will build on his group’s expertise with adenovirus, a virus that causes the common cold and has shown promise in cancer therapeutics and imaging.

“This is a virus that we know a lot about,” says Curiel, director of the Biologic Therapeutics Center at Washington University. “Our research seeks ways to use the virus like a nanoparticle and capitalize on all the unique capacities of the virus and our ability to manipulate it.”

Developing a three-pronged attack on cancer cells is in line with the NCI’s pursuit of a new paradigm in cancer research. Known as theragnostics, the concept is to combine therapy and diagnostics into one targeted attack on a specific cancer.

“We would like to understand the patient’s biology and direct therapy on that basis,” Curiel says. “And ideally, such a personalized treatment agent should include everything you would want it to do — it would be targeted specifically to the cancer and avoid healthy cells, it would deliver therapeutic drugs, and it would have a method to image the tumor to monitor the outcome of therapy.”

Curiel

According to Curiel, there is a focus on nanoparticles in this three-part theragnostic tool. Similar in size to viruses, nanoparticles are also heavily studied for their anti-cancer possibilities. But Curiel argues that viruses have some advantages over nanoparticles. Unlike nanoparticles that serve only as passive carriers, viruses have DNA, which offers another layer of cancer fighting or imaging potential.

“With a virus, we can alter its genes so that it expresses a protein that could be used against the cancer, or a protein that might enable us to image the tumor,” Curiel says.

And like a nanoparticle, a virus can be modified to carry different molecules, drugs and metals on its surface. Previous work by Curiel and others has identified certain proteins that would target the virus to specific tissues in the body and even specific tumor types.

In addition to targeting, Curiel and his collaborators at Louisiana State University have developed a novel way to attach heavy metals to the surface of viruses so they are visible to non-invasive X-ray imaging. In a study published in PLoS ONE last year, they demonstrated the ability to use CT scans to track the location of these metal-carrying viruses in mice.

Beyond imaging, the metal-binding viruses could also carry radioactive metals that deliver radiation therapy directly to the cancer cells while sparing healthy ones.

“Within the cancer world, this idea of theragnostics is something of a holy grail,” Curiel says. “It’s an idea that has preceded the technology. With this grant, we hope to make inroads in developing a cancer therapeutic that accomplishes all of these targeting, treating and imaging goals.”

The grant "Targeted- and Image-Based Adenovirus Cancer Therapeutic Vectors" is supported by the National Cancer Institute (NCI), part of the National Institutes of Health (NIH). Grant 1R01CA154697-01A1.

Mathis JM, Bhatia S, Khandelwal A, Kovesdi I, Lokitz SJ, Odaka Y, Takalkar AM, Terry T, Curiel DT. Genetic incorporation of human metallothionein into the adenovirus protein IX for non-invasive SPECT imaging. PLoS ONE. February 2011.

Recommendation against PSA test too drastic

Caroline Arbanas — 2012-05-21 00:00:00

A new recommendation issued today by the U.S. Preventive Services Task Force against routine PSA testing for healthy men age 50 and older goes too far, says a prostate cancer expert at the Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis.

“Routine PSA screening is not necessary for most men,” says Gerald Andriole, MD, chief of urologic surgery, who acknowledges that widespread testing has led many men with slow-growing tumors to be over diagnosed and over treated with aggressive therapies. “But that doesn’t mean that some men don’t stand to benefit. We have to take a more nuanced approach to determine which men should be screened, how frequently they should be tested and whether their cancer warrants therapy.”

In its statement against routine PSA screening, the task force says that the test does not save lives and, when positive, often leads to invasive biopsies and treatments such as surgery or radiation therapy, with side effects that can include incontinence and impotence.

Andriole

But Andriole, who also is the principal investigator of the National Cancer Institute’s Prostate, Lung, Colorectal and Ovarian (PLCO) screening trial, argues that it would be a mistake to universally dismiss the PSA test. Rather, he says the decision to screen should be left up to patients and their doctors, who should take into consideration a man’s overall health, age and other risk factors.

It would be misguided to discourage PSA testing for men who have a high risk of dying from prostate cancer, particularly those with a family history of the disease, he adds.

For men who choose to have a PSA test, Andriole urges caution if the test is abnormal. Doctors, he says, often do not need to rush to perform biopsies or recommend aggressive treatments because most prostate tumors grow slowly. In many cases, “active surveillance” may be practical, which involves periodic PSA tests and biopsies to monitor tumor growth rather than opting for immediate aggressive treatment.

Ending PSA screening all together would mean a return to the “pre-PSA” era when about a third of prostate cancers were advanced and incurable at the time of diagnosis.

“We shouldn’t have a one-size-fits-all approach to prostate cancer screening,” Andriole says. “PSA is not a perfect test but it’s the best we have, and it would be a mistake to routinely dismiss its use.”

Prostate cancer is the second most common cancer among men, after skin cancer. In 2011, nearly 241,000 U.S. men received a diagnosis of prostate cancer and an estimated 34,00 died of the disease.

Less invasive alternative to colonoscopy reduces colon cancer deaths

2012-05-21 00:00:00

A less invasive screening test for colorectal cancer reduces deaths from the disease but is probably not as effective as colonoscopy, the gold standard.

Researchers found that screening with sigmoidoscopy reduced overall colorectal cancer deaths by 26 percent and new cases by 21 percent, when compared to no screening.

The nearly 20-year study involved 154,900 patients at major centers nationwide, including about 17,000 at Washington University School of Medicine in St. Louis. Results were published online May 21, 2012, in the New England Journal of Medicine.

No studies have compared mortality outcomes between sigmoidoscopy and colonoscopy. But recent research showed that colonoscopy reduced colorectal cancer deaths by 53 percent, making it the preferred screening method, says Nicholas O. Davidson, MD, director of the Division of Gastroenterology at Washington University School of Medicine.

But sigmoidoscopy is a valid option if its less invasive nature and easier preparation prompt more people to be screened, he adds. No matter how pre-cancerous polyps are detected, their removal reduces colorectal cancer risk.

“These findings provide further evidence that regular, scheduled screening is effective in decreasing the incidence of colorectal cancer and mortality from this disease,” says Davidson, who sees patients at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine. “Taken together with findings published earlier this year from the results of screening colonoscopy, the new research strongly suggests that colorectal cancer deaths are preventable through aggressive screening programs.”

Sigmoidoscopy uses a thin, flexible tube-like instrument, called a sigmoidoscope, to view the anus, rectum and lower colon. People who opt for this screening test don’t need to undergo rigorous bowel preparation, which is required for colonoscopy and is one reason that many people avoid the test.

Sigmoidoscopy also poses a lower risk of bowel perforation (an uncommon event that occurs when the scope pokes a hole in the intestine) compared to colonoscopy, in which a similarly flexible, but longer, tube is used to view the entire colon.

Researchers estimated that if they had used colonoscopy rather than sigmoidoscopy in the study, they would have identified 16 percent more cancers. But they concede that screening with sigmoidoscopy is better than no screening at all.

Colorectal cancer is the second-leading cause of cancer-related death in the U.S. Previous research has shown that colorectal cancer cases and deaths can be reduced with a number of screening methods, including a third one called fecal occult blood testing. However, flexible sigmoidoscopy and colonoscopy are more sensitive than the blood test for detecting polyps that may lead to colorectal cancer.

The National Cancer Institute funded the new research, part of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial, at 11 sites across the U.S. The study involved men and women aged 55 through 74 who were randomly assigned to receive flexible sigmoidoscopy screening or usual care. People in the usual care group only received screening if they asked for it or if their physician recommended it.

Participants in the flexible sigmoidoscopy group were screened once on entering the study and again three years to five years later. The participants were followed for approximately 12 years to collect data on cancer diagnoses and deaths.

Overall, after an average of nearly 12 years, participants in the screening group had a 21 percent lower incidence of colorectal cancer overall and a 26 percent lower rate of colorectal cancer mortality than participants in the usual care group. This means that, over the course of 10 years, if 1,000 people received two sigmoidoscopy screenings, there would be approximately three fewer new cases and one fewer death from colorectal cancer than in a comparable group not receiving regular screenings.

“This is the second major trial that has shown that sigmoidoscopy is effective in reducing the risk of dying of colorectal cancer,” says Barnett Kramer, M.D., director of NCI’s Division of Cancer Prevention. “Sigmoidoscopy is less invasive than colonoscopy and carries a lower risk of the colon being perforated, which may make it more acceptable as a screening test to some patients. There are several effective screening tests for colorectal cancer, and the most effective screening test is the one that people choose to take.”

At the School of Medicine, the PLCO trial is led by Gerald Andriole, MD, the Robert K. Royce Distinguished Professor and chief of urologic surgery at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked fourth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

The Alvin J. Siteman Cancer Center is the only NCI-designated Comprehensive Cancer Center within a 240-mile radius of St. Louis. Siteman Cancer Center is composed of the combined cancer research and treatment programs of Barnes-Jewish Hospital and Washington University School of Medicine.

Babies’ susceptibility to colds linked to immune response at birth

Julia Evangelou Strait — 2012-05-17 00:00:00

Innate differences in immunity can be detected at birth, according to new research at Washington University School of Medicine in St. Louis. And babies with a better innate response to viruses have fewer respiratory illnesses in the first year of life.

“Viral respiratory infections are common during childhood,” says first author Kaharu Sumino, MD, assistant professor of medicine. “Usually they are mild, but there’s a wide range of responses — from regular cold symptoms to severe lung infections and even, in rare instances, death. We wanted to look at whether the innate immune response — the response to viruses that you’re born with — has any effect on the risk of getting respiratory infections during the baby’s first year.”

Sumino

Reporting in the May issue of the Journal of Allergy and Clinical Immunology, Sumino and her colleagues found that newborns with a diminished immune response to viruses experienced more respiratory infections in their first year of life than newborns whose immune response was more robust.

Using umbilical cord blood samples taken in the delivery room, the researchers measured a specific immune system response to viral infection known as interferon-gamma (IFN-gamma). IFN-gamma is released by some cells of the immune system when they encounter a virus. An important weapon in the immune system’s arsenal, IFN-gamma helps fight viruses by stopping them from replicating.

The researchers studied cord blood samples from 82 babies in St. Louis enrolled in the Urban Environment and Childhood Asthma (URECA) trial. Eighty-five percent of the infants were African-American, and all lived in an area where at least 20 percent of the residents were below the poverty level. All had at least one parent with allergies, asthma or eczema, putting them at higher risk for these conditions themselves.

As reported by their caregivers, the babies averaged four colds in their first year with 88 percent of them suffering at least one cold. But the range varied widely with some caregivers reporting no colds and a few reporting as many as nine or 10.

To measure the innate immune response, the blood samples were taken at birth, before any exposure to the environment could influence the child’s immunity. The researchers isolated monocytes, a specific type of white blood cell, from the babies’ cord blood, and infected these cells with a common respiratory virus. They then measured the amount of IFN-gamma produced by the monocytes in response to the virus.

In general, babies whose monocytes responded to the virus by producing higher levels of IFN-gamma had fewer reported colds. Likewise, babies whose monocytes produced lower IFN-gamma levels had more reported colds.

The scientists also found that newborns whose monocytes produced less IFN-gamma also experienced more ear infections, sinus infections, pneumonia, and hospitalizations due to respiratory illness during their first year. But low IFN-gamma levels were not associated with croup or "stomach flu," indicating that this system may be closely associated with respiratory viruses and not other types of infections.

In an effort to identify other indicators of viral response, the researchers measured amounts of two other immune molecules: chemokine CCL5 and STAT1. Unlike IFN-gamma, neither showed any correlation with the number of illnesses the babies experienced.

This study in infants, as well as research in mice and human cells, supports the idea that dialing up the body’s IFN-gamma signaling system may help protect against viral infection. The report’s senior author Michael J. Holtzman, MD, the Selma and Herman Seldin Professor of Medicine, is working on drug discovery in this area. Unlike a vaccine, which protects against a specific virus, a drug that improves the body’s innate immunity could help fight a broad range of viruses, including the constantly evolving seasonal flu.

“Ideally, if these results are confirmed, we would like to be able to intervene based on knowledge of the innate IFN-gamma response,” Sumino says. “We’re not there yet — measuring IFN-gamma levels is complex. But in the future, if we can develop a relatively easy way to find out if someone has a deficiency in this system, we would like to be able to give a drug that can boost the innate immune response.”

Sumino K, Tucker J, Shahab M, Jaffee KF, Visness CM, Gern JE, Bloomberg GR, Holtzman MJ. Antiviral interferon-gamma responses of monocytes at birth predict respiratory tract illness in the first year of life. Journal of Allergy and Clinical Immunology. Vol 129. No 5. May 2012. Online March 29, 2012.

This work was supported by grants from the National Institute of Allergy and Infectious Disease (NIAID) and the National Heart, Lung, and Blood Institute (NHLBI), both part of the National Institutes of Health (NIH).

Memorial service for Welch June 4

2012-05-17 00:00:00

A memorial service in honor of Michael J. Welch, PhD, who was a faculty member for more than four decades at Washington University in St. Louis, will be held at 3 p.m. June 4 in Graham Chapel.

Welch, who was professor of radiology, of chemistry, of biomedical engineering and of developmental biology, died May 6, 2012. He was the founding leader of the Oncologic Imaging Research Program at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine and a member of the cancer center’s senior leadership.

Welch, who wrote more than 550 scientific papers, contributed to the development of positron emission tomography (PET) at the university in the early 1970s.

His many accomplishments include contributions to the compounds that allow imaging of brain blood flow and creation of imaging agents for the study of many types of cancer.

Memorial contributions may be made to The Michael J. Welch Foundation, 55 Walls Drive, Fairfield, Conn., 06824. A website, mjwelchfoundation.org, also is in development. His survivors are establishing the foundation to support research in nuclear medicine.

Medical students write health-care handbook

Diane Duke Williams — 2012-05-16 00:00:00

Robert Boston

From left: Third-year medical student Nathan Moore gives Darrell Kirch, MD, president and chief executive of the Association of American Medical Colleges, a tour of Washington University School of Medicine in St. Louis with first-year medical student Elisabeth Askin. Kirch was on campus last month to give a talk titled “Can Washington University lead the way for a new excellence in academic medicine?”

Health care in America is a vast and complicated system undergoing great change. And while students in the health professions are well-trained in science and clinical medicine, they receive little to no formal education about health-care delivery models, insurance, policy or reform — leaving them unprepared for the system in which they will be working for the rest of their lives.

When Washington University School of Medicine students Elisabeth Askin and Nathan Moore wanted to learn more about the nation’s health-care system, the majority of resources they found were narrowly focused, opinion-based publications or dense reference books.

The students collaborated to produce a clear and concise guide to the U.S. health-care system called the Health Care Handbook. The book is a topical overview of the system, aimed primarily at undergraduate and graduate health professions students.

The book also is written for the interested lay public and those who do not work in health care but recognize its importance and wish to learn more about it.

Among the facts and descriptions of systems and concepts the book provides are explanations of inpatient and outpatient care delivery systems, health insurance and economics, and healthy policy and reform.

The book also explores some of the major issues facing the health-care system today, including medical errors, malpractice, conflict of interest and residency work hours.

The authors present issues and problems neutrally, offering multiple viewpoints so that readers may develop their own opinions.

The book also is written in a conversational and accessible tone. Each chapter ends with a list of suggested reading, keeping the book short while offering readers an avenue for more information. The goal of the book is not to convince students of a certain position but rather to provide them with the tools to cogently evaluate policy, controversies and news articles.

Several undergraduate, graduate and residency programs in the St. Louis area already have printed copies for their students, and medical schools in four other states also have expressed interest in using the book in their curricula.

The book should be available for purchase on Amazon.com in June. Anyone interested in using the handbook in their programs, purchasing multiple copies, or has questions or comments should contact the authors directly at HealthCareHandbook@gmail.com.

Early substance use linked to lower educational achievement

Jim Dryden — 2012-05-16 00:00:00

Audio available

iStockPhoto

Researchers have found evidence that early drug and alcohol use is associated with lower levels of educational attainment.

Studying male twins who served in the military during the Vietnam era, they found that those who began drinking or using drugs as young teens or who became dependent on alcohol, nicotine or marijuana, were less likely to finish college than those who didn’t use alcohol or drugs until later in life and never became dependent.

The study, by investigators at Washington University School of Medicine in St. Louis and the Palo Alto Veterans Affairs Health Care System, will be published in the August 2012 issue of Alcoholism: Clinical & Experimental Research but is now available online.

“We can’t say that substance dependence or early substance use causes lower educational achievement, but we do see a strong association,” says lead author Julia D. Grant, PhD, research assistant professor of psychiatry. “Even after we statistically controlled for the genes and the environmental factors that twins share, we found a relationship between substance use and educational achievement.”

Past studies about the relationship between substance use and education have delivered mixed results. But this study of 6,242 twins shows a link between fewer years of schooling and the onset of drinking before age 14.

“Studying identical and fraternal twin pairs is useful for examining things like substance use and education because we can asses the extent to which a given behavior is influenced by genetic factors and by factors related to family and environment,” Grant says. “Since identical twins share all of their genes and fraternal share about half, we can set up statistical comparisons to tease many of those factors apart.”

In the analysis, Grant’s group found that when men in the study began to drink or use drugs early in their teen years or if they became a drug addict or alcoholic, they were less likely to complete 16 years of education.

In addition, she says the men in the study were surveyed when most were in their late 30s or early 40s, a point in their lives where it was less likely they would further their education.

Veterans, she says, were a particularly good group to follow because it is rare for anyone to serve in the military without finishing high school or earning a GED. In addition, because of the G.I. Bill, veterans are less likely to have financial constraints that would prevent them from attending college.

Grant says the findings provide more evidence that early drug and alcohol use is associated with a large number of problems later in life.

“Drugs and alcohol affect many lifetime milestones such as marriage, parenthood and employment, which are closely linked to education,” she says. “These events in later life all are influenced by early substance use, and this study provides further evidence that as a society, we need to continue our public-health efforts to reduce underage drinking, smoking and use of drugs.”

Grant JD, et al. Associations of alcohol, nicotine, cannabis and drug use/dependence with educational attainment: evidence from cotwin-control analyses. Alcoholism: Clinical & Experimental Research, Early View vol. 36 (8), August 2012.

Funding for this research comes from the Department of Veterans Affairs and the National Institutes of Health (NIH).

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Surgeons restore some hand function to quadriplegic patient

Julia Evangelou Strait — 2012-05-15 00:00:00

Audio available

Eric Young

To detour around the block in this patient’s C7 spinal cord injury and return hand function, Mackinnon operated in the upper arms. There, the working nerves that connect above the injury (green) and the non-working nerves that connect below the injury (red) run parallel to each other, making it possible to tap into a functional nerve and direct those signals to a non-functional neighbor (yellow arrow).

Surgeons at Washington University School of Medicine in St. Louis have restored some hand function in a quadriplegic patient with a spinal cord injury at the C7 vertebra, the lowest bone in the neck. Instead of operating on the spine itself, the surgeons rerouted working nerves in the upper arms. These nerves still “talk” to the brain because they attach to the spine above the injury.

Following the surgery, performed at Barnes-Jewish Hospital, and one year of intensive physical therapy, the patient regained some hand function, specifically the ability to bend the thumb and index finger. He can now feed himself bite-size pieces of food and write with assistance.

The case study, published online May 15 in the Journal of Neurosurgery, is, to the authors’ knowledge, the first reported case of using nerve transfer to restore the ability to flex the thumb and index finger after a spinal cord injury.

“This procedure is unusual for treating quadriplegia because we do not attempt to go back into the spinal cord where the injury is,” says surgeon Ida K. Fox, MD, assistant professor of plastic and reconstructive surgery at Washington University, who treats patients at Barnes-Jewish Hospital. “Instead, we go out to where we know things work — in this case the elbow — so that we can borrow nerves there and reroute them to give hand function.”

Fox

Although patients with spinal cord injuries at the C6 and C7 vertebra have no hand function, they do have shoulder, elbow and some wrist function because the associated nerves attach to the spinal cord above the injury and connect to the brain. Since the surgeon must tap into these working nerves, the technique will not benefit patients who have lost all arm function due to higher injuries — in vertebrae C1 through C5.

The surgery was developed and performed by the study’s senior author Susan E. Mackinnon, MD, chief of the Division of Plastic and Reconstructive Surgery at Washington University School of Medicine. Specializing in injuries to peripheral nerves, she has pioneered similar surgeries to return function to injured arms and legs.

Mackinnon originally developed this procedure for patients with arm injuries specifically damaging the nerves that provide the ability to flex the thumb and index finger. This is the first time she has applied this peripheral nerve technique to return limb function after a spinal cord injury.

http://youtu.be/zccK4An10kA

“Many times these patients say they would like to be able to do very simple things,” Fox says. “They say they would like to be able to feed themselves or write without assistance. If we can restore the ability to pinch, between thumb and index finger, it can return some very basic independence.”

Mackinnon cautions that the hand function restored to the patient was not instantaneous and required intensive physical therapy. It takes time to retrain the brain to understand that nerves that used to bend the elbow now provide pinch, she says.

Though this study reports only one case, Mackinnon and her colleagues do not anticipate a limited window of time during which a patient with a similar spinal cord injury must be treated with this nerve transfer technique. This patient underwent the surgery almost two years after his injury. As long as the nerve remains connected to the support and nourishment of the spinal cord, even though it no longer “talks” to the brain, the nerve and its associated muscle remain healthy, even years after the injury.

Mackinnon

“The spinal cord is the control center for the nerves, which run like spaghetti all the way out to the tips of the fingers and the tips of the toes,” says Mackinnon, the Sydney M. Shoenberg Jr. and Robert H. Shoenberg Professor and director of the School of Medicine’s Center for Nerve Injury and Paralysis. “Even nerves below the injury remain healthy because they are still connected to the spinal cord. The problem is that these nerves no longer ‘talk’ to the brain because the spinal cord injury blocks the signals.”

To detour around the block in this patient’s C7 spinal cord injury and return hand function below the level of the injury, Mackinnon operated in the upper arms. There, the working nerves that connect above the injury and the non-working nerves that connect below the injury run parallel to each other, making it possible to tap into a functional nerve and direct those signals to a non-functional neighbor.

In this case, Mackinnon took a non-working nerve that controls the ability to pinch and plugged it into a working nerve that drives one of two muscles that flex the elbow. After the surgery, the bicep still flexes the elbow, but a second muscle, called the brachialis, that used to also provide elbow flexion, now bends the thumb and index finger.

“This is not a particularly expensive or overly complex surgery,” Mackinnon says. “It’s not a hand or a face transplant, for example. It’s something we would like other surgeons around the country to do.”

Detailed information for potential patients interested in nerve transfer surgery for C6 and C7 spinal cord injury will be available after 10 a.m. EDT Tuesday, May 15, 2012 at nerve.wustl.edu.

Mackinnon SE, Yee A, Ray WZ. Spinal cord injury bypass technique with nerve transfers for the restoration of hand function after spinal cord injury – case report and review of the literature. The Journal of Neurosurgery. Online May 15, 2012.

Bonni to lead anatomy and neurobiology department

Michael C. Purdy — 2012-05-15 00:00:00

Azad Bonni, MD, PhD, currently professor of neurobiology at Harvard Medical School, will be the next head of the Department of Anatomy and Neurobiology at Washington University School of Medicine in St. Louis.

Bonni

Bonni becomes the Edison Professor and head of Anatomy and Neurobiology in October 2012. Larry J. Shapiro, MD, executive vice chancellor for medical affairs and dean of the School of Medicine, made the announcement.

"The Department of Anatomy and Neurobiology has a very distinguished history of leadership and innovation in its field,” Shapiro says. “We are confident that Dr. Bonni, who has produced many remarkable insights into brain development, will support and expand those traditions.”

Bonni studies how the brain is built at the level of individual connections between nerve cells. Key areas of his research include studies of the mechanisms that regulate the development of nerve cells and their ability to connect with each other in the brain. His lab is currently focused on the role of transcriptional and ubiquitin signaling in these processes. He also investigates how those mechanisms can contribute to neurological diseases when they go awry.

“The opportunity to lead the Department of Anatomy and Neurobiology at Washington University School of Medicine is a great honor,” Bonni says. “Research at Washington University has had a lasting impact in the establishment of neuroscience as a discipline, and the Department of Anatomy and Neurobiology has played a central role.”

Previous heads of the department have included founding head Robert J. Terry, MD; Edward W. Dempsey, PhD, who went on to serve as dean of the School of Medicine; W. Maxwell Cowan, MD, DPhil, who later became vice president and chief scientific officer of the Howard Hughes Medical Institute; and Gerald D. Fischbach, MD, who later became director of the National Institute of Neurological Disorders and Strokes.

The current department head, David Van Essen, PhD, is a past president of the Society for Neuroscience. He will continue as professor of anatomy and neurobiology and lead researcher for the Human Connectome Project, a multi-institutional effort to generate a first-of-its-kind map of all the major circuits in the human brain.

“I am extremely pleased that Dr. Bonni has agreed to take on the leadership of our department,” Van Essen says. “He has an exciting vision for the future of the department and for new collaborative opportunities with other departments, and I look forward to a smooth transition as we pass the leadership reins.”

Bonni earned a medical degree in 1986 from Queen’s University in Kingston, Canada. He specialized in neurology at McGill University and became chief neurology resident at the Montreal Neurological Institute in 1990. Bonni earned a doctorate in neuroscience at Harvard University in 1996 and launched his own laboratory at Harvard Medical School in 1999, where he rose to the rank of professor in 2008. Bonni is the recipient of many honors and awards, including the Robert H. Ebert Clinical Scholar Award from the Esther A. and Joseph Klingenstein Fund, the Alfred P. Sloan Foundation Award, and the Sidney Kimmel Scholar Award.

“I envision that the major research goal of the department moving forward will be to gain a deep mechanistic understanding of brain development and function with an emphasis on mechanisms that govern neural circuit assembly and activity,” Bonni says. “Drawing on the basic science core strengths of the department, another major goal will be to apply advances in the basic biology of brain development and function toward a better understanding of neurological and psychiatric disorders.”

Bonni said he hopes to make autism spectrum disorders and intellectual disability a focus of the department in the future. He says an essential step toward this goal will be to support and expand the Department of Anatomy and Neurobiology’s connections with other preclinical and clinical departments.

“We are at an exciting phase in the field, poised to make significant discoveries in fundamental neurobiology,” he says. “This will include new insights that interface with clinical efforts in neurology and psychiatry. I can think of no better place to work toward this larger goal than Washington University.”

Genetic test identifies eye cancer tumors likely to spread

Jim Dryden — 2012-05-14 00:00:00

Audio

Harbour laboratory

Using very small amounts of tumor tissue collected by a needle biopsy, doctors can conduct gene expression profile testing to determine the likelihood that an ocular melanoma tumor will spread beyond the eye.

Researchers at Washington University School of Medicine in St. Louis have developed a genetic test that can accurately predict whether the most common form of eye cancer will spread to other parts of the body, particularly the liver.

In 459 patients with ocular melanoma at 12 centers in the United States and Canada, the researchers found the test could successfully classify tumors more than 97 percent of the time.

The study will appear in an upcoming issue of the journal Ophthalmology, but is now online.

“When the cancer spreads beyond the eye, it’s unlikely any therapy is going to be effective,” says principal investigator J. William Harbour, MD. “But it’s very possible that we can develop treatments to slow the growth of metastatic tumors. The real importance of this test is that by identifying the type of tumor a patient has, we can first remove the tumor from the eye with surgery or radiation and then get those individuals at high risk into clinical trials that might be able to help them live longer.”

Harbour believes the test should allow ocular oncologists to quickly evaluate the risks associated with particular tumors and to begin treatment the moment they can detect any spread of the cancer.

Melanoma of the eye is relatively rare, diagnosed in about 2,000 people in the United States each year. Advances in treatment have allowed surgeons to preserve patients’ vision, but when cancer spreads beyond the eye, it often is deadly.

About a decade ago, Harbour, the Paul A. Cibis Distinguished Professor of Ophthalmology and Visual Sciences, began using gene expression profiling to monitor the activity of thousands of genes in and around ocular melanoma tumors.

“At the time, we were surprised to see that based on these gene expression profiles, the tumors clustered into two groups that corresponded, almost perfectly, to patients whose cancer spread and those whose cancer was confined within the eye,” says Harbour, who directs Washington University’s Center for Ocular Oncology. “Tumors with a class 1 gene expression profile, or ‘signature,’ very rarely spread, but those with a class 2 profile frequently develop into metastatic cancer.”

Harbour

Initially, Harbour’s group identified differences in approximately 1,000 genes between class 1 and class 2 tumors, but they whittled down that number, hoping to develop a simple test that could be used easily by ophthalmologists. Eventually, they settled on about a dozen genes that could be evaluated in tumor samples collected with a needle biopsy.

“We went through a number of sophisticated algorithms and validations, and we came up with a group of 12 genes,” he says. “We also included three more genes that don’t change whether they are in tumor tissue or healthy tissue. Those genes act as our ‘controls’ in this prognostic test.”

Testing tumor tissue from his own ocular melanoma patients at the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University in St. Louis, Harbour found that the gene expression profile test was very good at identifying the two classes of tumors. Then he started recruiting other centers to test the method, too.

“It doesn’t make for a good test if it works really well for us, but it doesn’t really work for anybody else,” Harbour says.

Doctors at the other centers collected tumor samples and shipped them to Harbour’s lab. Not knowing anything about which tumor samples came from which patients, the lab then analyzed the samples and made predictions about which tumors were likely to spread. Although it can take up to five years before there is any evidence that cancer has spread beyond the eye, this study went back less than two years later and tested predictions against what actually had happened.

Almost 62 percent of those tested (276 patients) had class 1 tumors, which were unlikely to spread. About a year and a half after the samples were tested, only three of those tumors had metastasized. Meanwhile, 38 percent of those tested (170 patients) had class 2 tumors, indicating that spread of the cancer was more likely. In that group, 44 (26 percent) developed metastatic disease during the study period. Had patients been followed longer, more likely would have experienced spread of their cancer. Statistical predictions estimate that among class 2 patients, about 60 percent would have metastatic disease within three years, and approximately 80 percent in five years.

“In this relatively short study period, the test worked as well as in the larger group of patients as it had in our patients,” Harbour says. “That was important because it validated not only that our test was an accurate predictor of which patients will develop metastasis, but it also proved that the test can be performed successfully in most other clinics. At the moment, more than 70 centers around the world are using a commercially available version of the same test.”

In the past, some centers relied on a chromosome test to identify eye tumors that were likely to spread. That test looked at chromosome 3 because many ocular melanoma tumors have only one copy of that chromosome.

But the 15-gene expression profile test is more accurate. It takes a more complete “snapshot” of the entire tumor. Harbour says the results of the chromosome test can change, depending on which part of a tumor gets sampled.

“I compare it to how our brains recognize faces,” he says. “We don’t just focus on somebody’s nose. We take in all of the information from the entire face. This test takes information from the entire tumor, so if the ‘nose’ in the ‘picture’ is out of focus for some reason, it still can analyze other things.”

Another strength of the test, he says, is that it can identify which patients will need the closest monitoring.

“Here at Washington University, for example, we monitor patients with class 2 tumors every three months and can begin treatment right away if we find evidence that a tumor has spread,” he says.

On the other hand, the current study found that more than 60 percent of patients with ocular melanoma have class 1 tumors. Those patients don’t need to be followed with the same frequency.

“We won’t have to use high-intensity surveillance on everyone, only on those patients with a class 2 molecular signature, because they’re the ones at risk for metastatic cancer,” Harbour says.

Onken MD, et al. Collaborative Ocular Oncology Group report number 1: prospective validation of a multi-gene prognostic assay in uveal melanoma. Ophthalmology, vol. 119, Advance online publication. http://dx.doi.org/10.1016/j.ophtha.2012.02.017

J. William Harbour, MD, and Washington University may receive royalties based on a license of related technology by the university to Castle Biosciences Inc. This research was not funded by Castle Biosciences, Inc.

Funding for this research comes from the National Cancer Institute and the National Eye Institute of the National Institutes of Health (NIH), the Barnes-Jewish Hospital Foundation, Kling Family Foundation, Tumori Foundation, Horncreast Foundation, a Research to Prevent Blindness David F. Weeks Professorship and a Research to Prevent Blindness Inc. unrestricted grant.

Washington University receives $8 million to lead international childhood malnutrition effort

Caroline Arbanas — 2012-05-14 00:00:00

Jeffrey I. Gordon, MD, at Washington University School of Medicine in St. Louis, will lead an international team of scientists to find new ways to diagnose, treat and prevent a critical global health problem: malnutrition in infants and children. The work is funded by an $8.3 million grant from the Bill & Melinda Gates Foundation.

Gordon’s research first established a link between obesity and the trillions of friendly microbes that live in the intestine, where they extract nutrients and calories from food. His studies have shown that diet helps shape the mix of microbes in the intestine and that these microbes, in turn, influence how efficiently nutrients and calories are harvested from foods. This dynamic interplay has led Gordon to suspect that an imbalance of certain types of gut microbes conspires with an inadequate diet to trigger malnutrition.

Gordon

“A complex relationship exists between diet, gut microbial communities and the immune system in severely malnourished children,” says Gordon, the Dr. Robert J. Glaser Distinguished University Professor and director of Washington University’s Center for Genome Sciences and Systems Biology. “We now have a way to tease apart these influences. This project seeks to discover novel dietary and microbial therapeutics that can be targeted to infants and children living in countries with rampant malnutrition.”

Severe malnutrition has long been thought to stem simply from a lack of adequate food. But now scientists understand the condition is far more complex and may involve a breakdown in the way gut microbes process various components of the diet.

The community of intestinal microbes and their vast collection of genes, known as the gut microbiome, are assembled right from birth and influenced by babies’ early environments and the first foods they consume, such as breast milk. As part of the Breast Milk, Gut Microbiome and Immunity Project, Gordon will work with other scientists to evaluate the relationship among first foods, the developing community of microbes in the intestine and the developing immune system.

The new research builds on ongoing clinical studies in Africa, South Asia and South America of malnourished and healthy infants and children and their mothers. Gordon has played a key role in that research, which also is funded by the Gates Foundation.

As part of the new project, scientists will evaluate the function of gut microbial communities in malnourished and healthy infants and children living in countries where malnutrition is prevalent. They also will characterize the nutritional content and immune activity present in breast milk samples obtained from the children’s mothers during periods of exclusive and supplemental breastfeeding. In parallel, the scientists will use a preclinical discovery pipeline recently developed in Gordon’s laboratory to identify next-generation probiotics and nutrient supplements or combinations of the two (synbiotics) that may promote healthy growth in infants and children.

The investigators also will transplant communities of intestinal microbes, obtained from stool samples, from both malnourished and healthy children into germ-free mice raised under sterile conditions. These mice will harbor collections of human gut microbes that mimic those found in the children, and they will be fed the same diets as the children.

Then, using the mice, Gordon and his colleagues can carefully evaluate how various nutritional interventions influence gut microbiomes obtained from these children. They will be able to determine which microbes respond, how they respond and how they affect the overall function of the gut microbial communities. The researchers also will evaluate certain aspects of childhood development.

“It’s extremely difficult to study individual triggers for malnutrition because there are so many variables to consider,” Gordon says. “Recreating the human gut ecosystem in mice gives us a way to control these variables. The lead compounds derived from these well-controlled, pre-clinical studies then can be considered for future clinical trials in malnourished infants and children.”

Gordon’s research underscores the need understand the workings of gut microbiomes among people of different ages living in different parts of the world, especially as scientists consider manipulating intestinal microbes to improve health and nutrition. In a study published online May 9 in Nature, he and his colleagues surveyed the gut microbiomes of more than 500 healthy individuals, ranging in age from one month to more than 80 years, who lived in villages in Malawi, the Amazon region of Venezuela and in three U.S. cities.

The researchers found a similarity across cultures in the way the gut microbiome matures, especially in the first three years of life. But they also noted distinct differences in the microbiomes of babies, children and adults depending on where they lived.

The differences were most notable between individuals living in the U.S. compared to those in Malawi or Venezuela, and seemed to be linked to diet. Malawian and Venezuelan gut communities were rich in genes that break down complex sugars and starches, like those found in cassava and corn, while gut communities in individuals in the U.S., who typically eat high-protein diets, were more heavily loaded with genes for breaking down amino acids.

Other scientists involved in the Gates Foundation project include: Per Ashorn, MD, PhD, at the University of Tampere School of Medicine in Finland; Kathryn Dewey, PhD, University of California, Davis; Michael Gottlieb, PhD, Foundation for the National Institutes of Health (NIH); Rob Knight, PhD, University of Colorado, Boulder; Kenneth Maleta, PhD, University of Malawi College of Medicine; David Mills, University of California, Davis; Jeremy Nicholson, PhD, Imperial College, London; Linda Saif, PhD, The Ohio State University.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.

Volunteers needed for study to treat severe high blood pressure

Julia Evangelou Strait — 2012-05-08 00:00:00

Doctors at Washington University School of Medicine in St. Louis are seeking volunteers for a clinical trial testing an investigational device in patients with severe high blood pressure that can’t be controlled with aggressive medical treatments.

Singh

Led by interventional cardiologist Jasvindar Singh, MD, associate professor of medicine, and hypertension specialist Angela L. Brown, MD, assistant professor of medicine, the study is intended for patients who are taking at least three different types of blood pressure medications at the highest tolerated doses, but continue to have trouble controlling their blood pressure. Both doctors treat patients at Barnes-Jewish Hospital.

The investigational device targets nerves in the arteries that deliver blood to the kidneys. The kidneys play an important role in controlling blood pressure through the sympathetic nervous system – the part of the nervous system that governs the fight-or-flight response. In people with uncontrollable high blood pressure, nerves in the kidney’s arteries often fire at abnormally high rates.

Using the investigational device, doctors insert a catheter through the groin and into the kidney’s arteries, where they apply radiofrequency energy, or heat, to interrupt the signals from some of these overactive nerves. By changing the nerve firing, the kidneys may be less active in secreting chemicals that lead to blood pressure elevation.

Brown

In the current study, patients will be randomly assigned to get the procedure with the investigational device or to a control group. Patients will not know which group they are in until their six-month follow-up visit. At that time, patients in the control group will be offered the option of receiving treatment with the device, if they choose. All patients will continue taking their medications during the trial.

This study has a unique design since patients in the control group may have the option to receive treatment six months after they are enrolled in the trial. According to Singh, the design offers the potential to help all trial participants if the device demonstrates benefit.

To participate in the study, patients must first undergo screening tests to determine whether they are eligible. Their systolic blood pressure (the top number in a blood pressure reading) must average at least 160 millimeters of mercury (normal is considered 120 or less). And they must be taking at least three blood pressure medications at the highest tolerated doses.

Patients who fit the high blood pressure criteria will undergo an imaging procedure called an angiogram to be sure the anatomy of the arteries qualifies them to participate. During the angiogram, a catheter is used to inject a dye into the arteries. Those in the investigational treatment group will undergo the study procedure at the same time. Patients will not know whether they have been assigned to the control group or the treatment group right away, since they will not know whether they underwent the angiogram alone or both the angiogram plus the investigational procedure.

Patients in the study will be followed for three years. During this time, they will monitor their own blood pressure at home. And periodically, they will need to come to Barnes-Jewish Hospital for clinic visits and laboratory tests, including blood pressure recordings, blood and urine samples, and X-ray and ultrasound imaging of the kidneys’ arteries.

All costs of the investigational treatment and testing, including an overnight stay at Barnes-Jewish Hospital, will be paid for by the trial. Blood pressure medications that patients already are taking and must continue taking during the trial will not be paid for by the trial. Participants will receive small compensation for their time. For more information, contact Marjorie Palazzolo at 314-362-1962 or mpalazzo@dom.wustl.edu.

The study is sponsored by Medtronic Inc., which makes the Symplicity Catheter System.

Peck to speak at medical school Commencement

2012-05-07 00:00:00

William A. Peck, MD, the Alan A. and Edith L. Wolff Distinguished Professor of Medicine and director of the Center for Health Policy at Washington University in St. Louis, will be the keynote speaker at Washington University School of Medicine’s 2012 Commencement.

The ceremony will be held at 3 p.m. May 18 in the Ferrara Theater at the America’s Center, 701 Convention Plaza, St. Louis, Mo.

Peck was the first person to serve simultaneously as dean of the School of Medicine and as executive vice chancellor for medical affairs. In these positions, coupled with his role as president of the Washington University Medical Center, the School of Medicine became one of the nation’s leading centers for medical research and academic clinical practice. It also emerged as the most academically select medical school in the nation.

Peck

Under his leadership, the medical school established the Center for Advanced Medicine, which houses outpatient clinics, the Alvin J. Siteman Cancer Center and markedly expanded its research programs and facilities.

Since stepping down as dean and establishing the Center for Health Policy in 2003, Peck has become a nationally recognized leader in health policy, with a particular emphasis on in the disparities in access to care, rising costs, workforce shortages and errors and inefficiencies in providing medical care.

Prior to his deanship, as a renowned endocrinologist, Peck wrote more than 100 scientific publications, including original research in bone and mineral metabolism. His major scientific contributions include the development of the first method to study directly the structure, function and growth of bone cells. He also demonstrated the mechanisms that allow hormones to regulate bone cell function and examined of the causes of osteoporosis. He was featured on national media, including PBS’ McNeil Lehrer Report, ABC’s Good Morning America and CBS Morning News.

He is a member of the Institute of Medicine (of the National Academies of Science), past chair of the Association of American Medical Colleges and received an honorary Doctor of Science degree from the University of Rochester, among many other awards.

For information about other Commencement ceremonies and receptions within the School of Medicine, visit the Commencement 2012 Schedule of Events.

Multiple thought channels may help brain avoid traffic jams

Michael C. Purdy — 2012-05-06 00:00:00

Brain networks may avoid traffic jams at their busiest intersections by communicating on different frequencies, researchers at Washington University School of Medicine in St. Louis, the University Medical Center at Hamburg-Eppendorf and the University of Tübingen have learned.

Corbetta

“Many neurological and psychiatric conditions are likely to involve problems with signaling in brain networks,” says co-author Maurizio Corbetta, MD, the Norman J. Stupp Professor of Neurology at Washington University. “Examining the temporal structure of brain activity from this perspective may be especially helpful in understanding psychiatric conditions like depression and schizophrenia, where structural markers are scarce.”

The research will be published May 6 in Nature Neuroscience.

Scientists usually study brain networks — areas of the brain that regularly work together — using magnetic resonance imaging, which tracks blood flow. They assume that an increase in blood flow to part of the brain indicates increased activity in the brain cells of that region.

“Magnetic resonance imaging is a useful tool, but it does have limitations,” Corbetta says. “It only allows us to track brain cell activity indirectly, and it is unable to track activity that occurs at frequencies greater than 0.1 hertz, or once every 10 seconds. We know that some signals in the brain can cycle as high as 500 hertz, or 500 times per second.”

For the new study, conducted at the University Medical Center at Hamburg-Eppendorf, the researchers used a technique called magnetoencephalography (MEG) to analyze brain activity in 43 healthy volunteers. MEG detects very small changes in magnetic fields in the brain that are caused by many cells being active at once. It can detect these signals at rates up to 100 hertz.

“We found that different brain networks ticked at different frequencies, like clocks ticking at different speeds,” says lead author Joerg Hipp, PhD, of the University Medical Center at Hamburg-Eppendorf and the University of Tübingen, both in Germany.

For example, networks that included the hippocampus, a brain area critical for memory formation, tended to be active at frequencies around 5 hertz. Networks constituting areas involved in the senses and movement were active between 32 hertz and 45 hertz. Many other brain networks were active at frequencies between eight and 32 hertz. These “time-dependent” networks resemble different airline route maps, overlapping but each ticking at a different rate.

“There have been a number of fMRI studies of depression and schizophrenia showing ‘spatial’ changes in the organization of brain networks,” Corbettta says. “MEG studies provide a window into a much richer ‘temporal’ structure. In the future, this might offer new diagnostic tests or ways to monitor the efficacy of interventions in these debilitating mental conditions.”

Hipp JF, Hawellek DJ, Corbetta M, Siegel M, Engel AK. Large-scale cortical correlation structure of spontaneous oscillatory activity, Nature Neuroscience, May 6, 2012.

Funding from the European Union supported this research.

Washington People: Jane Garbutt

Diane Duke Williams — 2012-05-04 00:00:00

Robert Boston

Jane Garbutt, MBChB (center, right), goes over data with (from left) Randall Sterkel, MD, assistant professor of clinical pediatrics; Kathy Mandrell, research patient coordinator; and Robert Strunk, MD, the Donald Strominger Professor of Pediatrics; at a Washington University Pediatric and Adolescent Ambulatory Research Consortium planning committee meeting. Strunk calls Garbutt an “incredible jewel” for the medical school. “Her background helps us all understand how we might be able to approach treatment more effectively,” he says. “She has been able to get a large number of private pediatricians engaged in research, most recently focused on asthma care. One of my greatest accomplishments at the School of Medicine has been getting her involved in asthma research.”

Training in England gives Jane Garbutt, MBChB, a unique perspective on medical issues in the United States and how care can be provided differently.

Her hometown of Southport, England, about 20 miles from Liverpool, also offered Garbutt another advantage — an early glimpse of The Beatles.

“My dad said they wouldn’t last, but I thought they were fantastic,” says Garbutt, research associate professor of medicine at Washington University School of Medicine in St. Louis, who first saw the iconic rock group on TV when she was 10 years old.

The Beatles quickly won over the rest of the world, but Garbutt still endeavors to convince doctors to take a new look at patient care.

Medical stints in England and Canada convinced her that less treatment is sometimes better. Doctors in these two countries often question the need for immediate medical intervention and whether modern technology is necessary, Garbutt says.

Bradley Evanoff, MD, chief of the Division of General Medical Sciences, describes Garbutt as a pioneer in outpatient clinical research.

She has been successful, her colleagues say, because of her tremendous energy and intellectual curiosity.

Garbutt strives to help pediatricians in private practice find the most effective treatments for everyday medical problems. When children visit their pediatricians with common problems such as pinkeye and sinus infections, the treatments can vary greatly from doctor to doctor and from office to office.

Garbutt’s interest in solving the conundrums faced by private-practice pediatricians led her to establish a research network. The Washington University Pediatric and Adolescent Ambulatory Research Consortium (WUPAARC) now boasts 66 pediatricians and five nurse practitioners from 35 practices in the St. Louis area. WUPAARC pediatricians suggest the study questions.

“It’s not feasible to have a research assistant in every office,” Garbutt says. “It’s much more efficient if we can enroll a few patients from lots of different practices so we can share the burden of conducting research. This approach also makes our findings more applicable generally.”

In 2008, Garbutt began using her research expertise to study asthma. She is leading a large trial to evaluate if weekly calls from asthma coaches to mothers of children with the disease will help children gain better control of their disease. The coaches monitor how families are treating the symptoms and make recommendations to enhance asthma care and improve self-management.

“Jane’s expertise in the methods and logistics needed to perform research in outpatient settings is very helpful to other investigators,” says Evanoff, also the Richard A. and Elizabeth Henby Sutter Professor of Occupational, Industrial and Environmental Medicine in Medicine. “In order to move toward more evidence-based practice of medicine, it’s important to develop more practice-based evidence.”

Robert Strunk, MD, the Donald Strominger Professor of Pediatrics, calls Garbutt an “incredible jewel” for the medical school.

“Her background helps us all understand how we might be able to approach treatment more effectively,” he says. “She has been able to get a large number of private pediatricians engaged in research, most recently focused on asthma care. One of my greatest accomplishments at the School of Medicine has been getting her involved in asthma research.”

Garbutt also has investigated common medical problems in adults. A large study she and her colleagues published in February in the Journal of the American Medical Association determined that adults with sinusitis don’t recover faster or have fewer symptoms when they take antibiotics.

From barmaid to family practice physician

Garbutt has four brothers and is the oldest child. Her mother, who taught high school typing and shorthand, loved to throw parties. Her father, a scientist, redesigned workplaces and renovated properties in his second and third careers.

In her teens, Garbutt decided to become a physician and attend the University of Bristol. In England, students go straight from high school into a five-year medical training program that has more of a clinical emphasis than medical school in the United States. Garbutt chose to specialize in family practice because she enjoyed getting to know whole families. She also welcomed the challenge of using the breadth of her medical knowledge.

Throughout medical school she worked as a barmaid in a Bristol pub, giving her a crash course on interacting with the public.

“I discovered that people are basically good, and everyone has an interesting story,” she says, adding that she met her future husband, Jerry, when she served him a beer.

After a year of training similar to a residency in the United States, Garbutt and her husband moved to Toronto, where he had accepted a job in accounting at Coopers & Lybrand. Garbutt completed two years of family practice residency training in Toronto before practicing family medicine for five years.

But she always had been interested in academics and decided to return to school when her second child, Jeremy, was 18 months old. She completed a community health and epidemiology fellowship at the University of Toronto.

Trading watercolors for research methods

The couple moved again for her husband’s job, this time to St. Louis. For four years, Garbutt stayed home with their children and focused on painting with watercolors. But a stint as a community member on the School of Medicine Institutional Review Board (IRB) led to her current position.

Courtesy photo

From left: husband, Jerry; daughter, Kate; Jane Garbutt; and son, Jeremy.

On the IRB, she got to know then-chairman William Powderly, MD, adjunct professor of medicine, who introduced her to Ben Littenberg, MD, who was forming the medical school’s Division of General Medical Sciences. She was hired as a part-time fellow in research methods.

During her fellowship, she started working with local pediatricians in a study that tested antibiotics in children with acute sinusitis. She joined the full-time faculty as a research assistant professor in medicine in 2003.

In addition to her clinical research and WUPAARC responsibilities, Garbutt directs the mentor training program in clinical investigation.

Stephanie Fritz, MD, assistant professor of pediatrics, says Garbutt has been an inspiring mentor who has made her research on staph infections possible.

“Dr. Garbutt and WUPAARC have been essential to me in the development and progress of my own research program,” Fritz says.

St. Louis pediatrician Randall Sterkel, MD, who has worked with Garbutt through WUPAARC and other research projects for about eight years, says she has championed the children in St. Louis and their pediatricians through research and advocacy.

“She is a good friend and colleague, from whom I have learned a great deal,” he says. “And because she does all of this while using the Queen’s English, she always sounds more erudite than those around her.”

Fast facts about Jane Garbutt

Born: Southport, England
University position: research associate professor of medicine and pediatrics
Most recent books read: The Cookbook Collector by Allegra Goodman and The Emperor of All Maladies by Siddhartha Mukherjee
Hobbies: Reading, painting with watercolors, bridge, growing wild roses, visiting her children, spending time at cottage in Canada
Family: Husband, Jerry Garbutt, owner of Global Surgical Corp., a local company that manufactures microscopes; daughter, Kate, 29, a financial researcher in San Francisco; son, Jeremy, 26, IT sales representative in Phoenix

New technique could identify drugs that help fight broad range of viruses

Julia Evangelou Strait — 2012-05-04 00:00:00

Courtesy photo

The Drug Discovery Center, led by the study's senior author Michael J. Holtzman, MD, the Selma and Herman Seldin Professor at Washington University School of Medicine in St. Louis, uses automated systems to screen thousands of chemical compounds in a short period of time.

Results of a new study demonstrate the feasibility of a novel strategy in drug discovery: screening large numbers of existing drugs — often already approved for other uses — to see which ones activate genes that boost natural immunity.

Using an automated, high-volume screening technique, researchers at Washington University School of Medicine in St. Louis have identified a cancer drug that enhances an important natural response to viral infection in human cells.

“Over many years of research, we have developed a good understanding of the human body’s own mechanisms to fight viruses,” says the study’s first author Dhara Patel, PhD, a postdoctoral research scholar at Washington University. “Instead of targeting the virus itself, which most current antiviral drugs do, we have designed a strategy to look for chemical compounds that will enhance this innate antiviral system.”

The results of the study, led by Michael J. Holtzman, MD, the Selma and Herman Seldin Professor of Medicine, appear May 4 in PLoS ONE.

Of the 2,240 compounds the researchers tested, 64 showed increased activity in the cells’ interferon signaling pathway, an important player in the body’s response to viruses. The 64 compounds included many different classes of drugs treating conditions as diverse as depression, high blood pressure and ulcers. But the one that stood out is idarubicin, a cancer drug commonly prescribed to treat leukemia, lymphoma and breast cancer. Even at low doses, idarubicin significantly ramps up the interferon signaling system.

In treating cancer, idarubicin stops cells from dividing by blocking a protein that unwinds DNA. As long as DNA remains tightly packed, it can’t be copied. And if DNA can’t be copied, a cell can’t divide. Interestingly, though, the researchers showed that idarubicin’s antiviral effects are totally unrelated to what makes it a good cancer drug.

Patel

“We tested other cancer drugs that work the same way as idarubicin but have very different structures,” Patel says. “Although they act the same way that idarubicin does in cancer cells, they had no effect on the interferon system.”

Like many cancer drugs, idarubicin has toxic side effects, so it is unlikely to ever be prescribed for patients fighting viral infections. But, its identification demonstrates that the new strategy works.

“While idarubicin is not something you would give to a patient who has the flu, we are continuing to screen more drugs,” Patel says. “We’re starting to find compounds from different drug classes that are not so toxic and that have similar properties in enhancing interferon signaling. We’re still validating them, but we’re very excited about what we’re finding.”

Traditionally, techniques for drug discovery involve trying to enhance or inhibit a very specific interaction. To treat a particular disease, scientists might try to disable a harmful protein, or replace a missing one, for example. But such approaches assume that altering a specific interaction of interest will result in the desired effect.

“I think our technique accepts the fact that we don’t understand everything that’s going on in the cell,” Patel says. “Instead of looking at one particular interaction, we measure the downstream effects.”

She compares it to driving a car and trying to make it go faster.

“Traditionally, we would pick a specific part — a part of the car that we think is responsible for speed — and then test compounds that alter the part in a way that we think will make the car go faster,” she says. “With our approach, we don’t assume we know what is responsible for speed. Instead, we take entire cars, treat them with many different compounds, and just see which ones go faster.”

Patel says this screening technique is unusual because it can identify drugs that enhance the body’s own immune response to a broad range of viruses, unlike a vaccine, which only protects against a specific virus.

The method has also shed light on how some compounds with known antiviral properties actually fight viruses. In addition to cancer drugs, antidepressants and blood pressure medications, the initial 64 drugs they identified with increased interferon activity included some known antiviral drugs.

“We already knew some of these compounds had antiviral properties, we just didn’t know why,” Patel says. “Now we’re starting to find out how they actually work.”

Patel DA, Patel AC, Nolan WC, Zhang Y, Holtzman, MJ. High throughput screening for small molecule enhancers of the interferon signaling pathway to drive next generation antiviral drug discovery. PLoS ONE. May 4, 2012.

The full text will be available after 5 p.m. EDT Friday, May 4, 2012, at

‪http://dx.plos.org/10.1371/journal.pone.0036594‬.

This work was supported by grants from the National Institutes of Health (NIH), including the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Allergy and Infectious Disease (NIAID), and the Martin Schaeffer Fund.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Warfarin no better than aspirin for most heart failure patients

Julia Evangelou Strait — 2012-05-02 00:00:00

Results of one of the largest studies of heart failure to date show that warfarin is no better than aspirin in reducing the combined risks of brain hemorrhage, stroke and death in most heart failure patients.

The research, reported May 2 in the New England Journal of Medicine, looked at heart failure patients with a normal heart rhythm.

The results show that the combined rate of death, stroke and brain hemorrhage was not statistically different between the two groups, at 7.47 percent per year for patients taking warfarin and 7.93 percent per year for those taking aspirin.

Heart failure is a condition in which the heart can’t pump enough blood to the body. A weakened heart increases the risk of blood clots that can cause a fatal or disabling stroke. Both aspirin and warfarin reduce the risk of stroke, but they do so by different mechanisms and with different risks.

Mann

“For the first time, clinicians have reassurance that they don’t need to put people with heart failure who have a normal rhythm on anticoagulants like warfarin, which increase the risk of bleeding,” says co-author Douglas L. Mann, MD, chief of the cardiovascular division at Washington University School of Medicine in St. Louis, who treats patients at Barnes-Jewish Hospital. “We can give patients aspirin and be reassured that it’s not going to either worsen the heart failure or lead to increased risk of death.”

The decade-long WARCEF trial (Warfarin and Aspirin for Reduced Cardiac Ejection Fraction) followed 2,305 patients and compared the anticoagulant warfarin, known by the brand name Coumadin, to aspirin. Previous studies have shown that warfarin is superior to aspirin for preventing stroke in heart failure patients with atrial fibrillation, a common irregular heart beat. WARCEF is the first study to compare warfarin to aspirin for most heart failure patients – those with a normal heart rhythm.

Patients enrolled in the trial were randomly assigned to one of two groups. One group received aspirin and placebo warfarin. A second group received warfarin and placebo aspirin. Neither the patients nor clinicians knew which active drug a particular patient received until the end of the study. Since patients on warfarin require regular blood tests, all patients’ blood was monitored whether or not they were taking active warfarin.

With at least 6 million Americans living with heart failure, this study answers an important clinical question.

“Since the overall risks and benefits are similar for aspirin and warfarin, the patient and his or her doctor are free to choose the treatment that best meets their particular medical needs,” says principal investigator Shunichi Homma, MD, of Columbia University Medical Center/New York-Presbyterian Hospital. “However, given the convenience and low cost of aspirin, many may go this route.”

Aspirin makes blood cells called platelets less “sticky,” reducing their ability to clump together and form clots. Downstream of this, warfarin interferes with chemical reactions in the body’s so-called “coagulation cascade,” thereby reducing clotting. While warfarin is associated with a greater risk of bleeding, aspirin may inhibit other medications frequently prescribed to heart failure patients. Unlike aspirin, warfarin requires a prescription and patients must have regular blood tests to monitor clotting levels.

While the study found no difference in the combined risk of brain hemorrhage, stroke and death, the two drugs did differ in the risks of individual problems. Specifically, patients taking warfarin had almost half the risk of stroke compared to those taking aspirin. And patients taking warfarin had more than twice the risk of major bleeding. According to the investigators, these results cancel each other out, and point to the importance of tailoring the treatment to individual patients.

“The key decision will be whether to accept the increased risk of stroke with aspirin or the increased risk of primarily gastrointestinal hemorrhage with warfarin,” says Walter Koroshetz, MD, deputy director of the National Institute for Neurological Disorders and Stroke, which supported the trial.

However, in patients followed four years or longer, there was evidence that warfarin was more effective overall in preventing deaths, strokes and cerebral hemorrhages.

“As we analyze the data further, we hope to be able to identify whether some patients will clearly benefit from one drug versus the other over time,” Mann says.

Homma S, Thompson JLP, Pullicino PM, Levin B, Freudenberger RS, Teerlink JR, Ammon SE, Graham S, Sacco RL, Mann DL, Mohr JP, Massie BM, Labovitz AJ, Anker SD, Lok DJ, Ponikowski P, Estol CJ, Lip GYH, DiTullio MR, Mejia V, Gabriel AP, del Valle ML, Buchsbaum R, Sanford AR, Moy CS, for the WARCEF Investigators. Warfarin and aspirin in heart failure patients in sinus rhythm. New England Journal of Medicine. Online May 2, 2012.

Funding for the trial was provided by two grants from the National Institute for Neurological Disorders and Stroke (U01-NS-043975, U01-NS-039143) to Homma and Thompson as principal investigators in medicine and biostatistics. Warfarin and warfarin placebo were provided by Taro Pharmaceuticals U.S.A. Inc., Hawthorne, N.Y., and aspirin and aspirin placebo, by Bayer HealthCare LLC, Morristown, N.J. Study findings were first presented at the International Stroke Conference in February.

Kirmani, Larsen named Loeb Teaching Fellows

Beth Miller — 2012-05-02 00:00:00

Nigar Kirmani, MD, and Douglas Larsen, MD, have been selected to receive the 2012-14 Carol B. and Jerome T. Loeb Teaching Fellowships at Washington University School of Medicine.

The fellowship program was established in 2004 by a gift from the Loebs to advance clinical education and to honor local physicians committed to clinical excellence.

Strengthened by a gift from the Barnes-Jewish Hospital Foundation, the program allows the fellows to take time from their regular duties to teach clinical medicine to students and residents. The two-year fellowships begin July 1 and continue through June 30, 2014.

Applicants for the fellowships are chosen for their record of excellence in patient care and clinical teaching. Their proposals must meet new or unmet clinical teaching needs for residents and/or students and include time spent in direct teaching and in program and curriculum development.

In addition, applicants must show innovative teaching methods and a plan to continue the curriculum or project following completion of their Loeb Teaching Fellowship term. All proposals are reviewed by a selection committee appointed by Larry J. Shapiro, MD, executive vice chancellor for medical affairs and dean of the School of Medicine.

“Nigar and Doug have developed excellent programs that will give our medical students and trainees an even more experiential training opportunities,” Shapiro says. “We are grateful to the Loebs for this gift, which continues to provide innovative learning experiences for our students.”

Kirmani

To enhance the training of students, residents and fellows, Kirmani, professor of medicine will develop new physician-education programs in infection prevention and hospital epidemiology and patient safety.

She plans to develop interactive, web-based training modules that will allow trainees to access information when needed. The modules will include a pretest, a case study and a post-test.

Students will learn about infection prevention using cases of Clostridium difficile colitis, meningococcal meningitis, herpes zoster in patients with compromised immune systems, infections in patients with HIV, as well as patient safety issues such asdrug interactions and transitions of care. In addition, students will gain extensive knowledge about the use and overuse of antibiotics.

“Dr. Kirmani’s work focuses on a vital area of patient care that impacts all specialties, says Allison Whelan, MD, senior associate dean for education and professor of medicine and of pediatrics. “This will have a major impact on the care of our hospitalized patients.”

Kirmani has been course master for the infectious diseases course taken by second-year medical students since 2000. She also is program director of the infectious diseases fellowship program, an attending physician at Barnes-Jewish Hospital, is medical director of the Barnes-Jewish Hospital Home IV Therapy service and treats outpatients in the infectious diseases clinic.

Larsen

Larsen, assistant professor of neurology and of pediatrics and director of medical student education for the Division of Pediatric and Developmental Neurology, plans to implement reflective learning into the neurology clerkship, which includes about 120 third-year medical students a year.

The program will include students rotating on the pediatric and adult neurology consult services as well as the adult neurology inpatient ward service.

The program is based on a pilot Larsen implemented in 2010-2011 in which students set personal learning goals for the rotation then wrote a journal entry daily analyzing their performance. The daily reflections were submitted weekly to Larsen for feedback and comments.

At the end of the pilot, students reported improved learning, increased awareness of their own thoughts and actions and improved recall of experiences from the rotation.

Larsen will train attending physicians to read and provide feedback to the students to nurture or coach them on their path to becoming physicians.

From the personal reflections and the feedback from attending physicians, students will be able to use the reflections to monitor their process, assess their performance and make plans for improvement as they work toward their goals.

“Doug’s proposal focuses on one of the most important areas of physician training — professional development,” Whelan says. “I expect this innovative pilot program in neurology to expand to all areas of clinical training.”

Two drugs better than one to treat youth with type 2 diabetes

2012-05-01 00:00:00

A combination of two diabetes drugs is more effective than one in treating 10-17-year-olds recently diagnosed with type 2 diabetes, according to researchers at Washington University in St. Louis who participated in a multicenter clinical trial funded by the National Institutes of Health (NIH).

The Washington University School of Medicine segment of the trial was led by Neil H. White, MD, professor of pediatrics and of medicine and director of the Pediatric Clinical Research Unit and a diabetes specialist at St. Louis Children’s Hospital.

White

The Treatment Options for type 2 Diabetes in Adolescents and Youth (TODAY) study is the first major comparative effectiveness trial for the treatment of type 2 diabetes in young people using the diabetes drugs metformin and rosiglitazone. Results of the study appeared April 29 in the New England Journal of Medicine.

The study is the largest to date to provide information about the serious nature of type 2 diabetes in youth and to compare the efficacy of the available treatments, White says.

“The results suggest that even in youth who appear to have mild type 2 diabetes, early aggressive intervention is necessary to achieve the control needed to prevent the devastating health consequences of type 2 diabetes, such as coronary artery disease, stroke, kidney and eye disease and nerve damage,” White says. “The impact of these health consequences is clear in adults, but when they manifest at a younger age the personal and societal impact will be even greater.”

Results showed that metformin therapy alone was not an effective treatment for many of these youth. In fact, metformin had a much higher failure rate in study participants than has been reported in studies of adults treated with metformin alone. In addition, adding an intensive lifestyle intervention to metformin provided no more benefit than metformin therapy alone.

The study enrolled 699 youth aged 10-17 who had type 2 diabetes for less than two years and a body mass index at the 85th percentile or greater. The researchers looked at how well and for how long each of three treatment approaches controlled blood glucose levels. Participants were randomly assigned to receive metformin alone; metformin and rosiglitazone together; or metformin plus intensive lifestyle changes aimed at helping participants lose weight and increase physical activity.

The researchers found that treatment with metformin alone was inadequate for maintaining acceptable, long-term, blood glucose control in 51.7 percent of youth over an average follow-up of 46 months. The failure rate was 38.6 percent in the metformin and rosiglitazone group, a 25.3 percent reduction from metformin alone. In the metformin plus lifestyle group the failure rate was 46.6 percent.

Currently, metformin is the standard treatment for young people with type 2 diabetes and the only oral drug approved for this use by the U.S. Food and Drug Administration.

The longer a person has type 2 diabetes, the greater the likelihood of developing complications, making it critical for youth with type 2 diabetes to quickly achieve and sustain control of their blood glucose.

“The continued follow-up of these subjects will be an important component of determining the long-term impact of diabetes-related complications and heart disease and the benefits and risks of early intervention,” White says.

Study centers included: Children’s Hospital Los Angeles; Children's Hospital Colorado, Aurora; University of Oklahoma Health Sciences Center, Oklahoma City; The University of Texas Health Science Center at San Antonio; Texas Children's Hospital, Baylor College of Medicine, Houston; Washington University School of Medicine in St. Louis; Saint Louis University Health Sciences Center, St. Louis; Rainbow Babies & Children's Hospital, Cleveland; Children's Hospital of Pittsburgh; Children's Hospital of Philadelphia; Joslin Diabetes Center at SUNY Upstate Medical University, Syracuse, NY; Yale University, New Haven, Conn.; Massachusetts General Hospital, Boston; Joslin Diabetes Center, Boston; Berrie Center at Columbia University, New York City; Data Coordinating Center at George Washington University, Washington, D.C.

The TODAY study was funded by the National Institute of Digestive and Kidney Diseases, BD Bristol-Myers Squibb, Eli Lilly and Co., GlaxoSmithKline, LifeScan Inc., Pfizer Inc. and Sanofi-aventis.

Weight-loss surgery provides benefit to high-risk, severely obese patients

Caroline Arbanas — 2012-05-01 00:00:00

Among surgeries for obesity, a newer, increasingly popular procedure called sleeve gastrectomy provides more weight loss to high-risk, severely obese patients than adjustable gastric banding, a new study suggests.

The researchers followed 40 severely obese individuals who were considered high risk because of their body mass index (BMI), age and gender. Most were men over age 50 who also had diabetes or hypertension or both for two years.

The patients underwent one of two procedures to restrict the stomach size: sleeve gastrectomy or adjustable gastric banding. Regardless of the procedure, all surgeries were performed laparoscopically.

Two years after surgery, patients in both groups had lost substantial weight, but those who had had a sleeve gastrectomy shed, on average, 16 additional pounds.

The study is available online in the Journal of the Society of Laparoendosopic Surgeons.

Varela

“The gastric sleeve is an improvement in terms of total weight loss for these high-risk patients,” says study author Esteban Varela, MD, associate professor of surgery at Washington University School of Medicine in St. Louis and a bariatric surgeon at Barnes-Jewish Hospital. “There’s not a single type of obesity surgery that’s best for all patients. We think the gastric sleeve provides solid, safe results for these severely obese, high-risk patients.”

In a sleeve gastrectomy, a large part of the stomach is removed and the remaining is refashioned into a narrow tube to restrict food intake. Gastric banding involves placing an inflatable silicone ring around the upper stomach to limit food consumption.

Both procedures were safe and effective with no major complications. Patients in the sleeve gastrectomy group weighed an average 302 pounds before surgery and had a BMI of 45. These patients lost an average 65 pounds in the two years following surgery.

This compares with an average weight loss of 49 pounds for those in the gastric banding group. They began the study weighing an average 280 pounds and with a BMI of 43.

Varela conducted the study at the Dallas VA Medical Center before he joined the Washington University faculty.

Minor complications, while low in both groups, were slightly higher among patients who received the sleeve gastrectomy. They included nausea and vomiting and inflammation at the incision site. No patients in the study died, and none needed a second surgery because of complications.

One reason why sleeve gastrectomy may result in more weight loss is because hormones that induce hunger are produced in the part of the stomach that is removed, other studies have shown.

In his practice, Varela recommends sleeve gastrectomy to many of his severely obese, high-risk patients. But, he notes, every patient is different.

“The choice of weight-loss surgery begins with a conversation between patient and surgeon,” he says. “Overall health and surgical and medical history all play a role in determining the most appropriate procedure. Most experts in the field agree that there is no one-size fits-all procedure and that safety should be a priority.”

The Washington University bariatric surgery program at Barnes-Jewish Hospital is designated as a Bariatric Surgery Center of Excellence by the American Board of Bariatric Surgery.

Varela JE. Laparoscopic sleeve gastrectomy versus laparoscopic adjustable gastric banding for the treatment of severe obesity in high-risk patients. Journal of the Society of Laparoendoscopic Surgeons. December 2011.

The study was conducted with funding from the VA Health Care system.

Surveys guide doctors about when to test teens for STIs

2012-04-28 00:00:00

More than 1 million youths ages 15-24 have sexually transmitted infections (STIs) caused by Chlamydia trachomatis and Neisseria gonorrhea. Many others, however, are unaware they are infected because they have not been tested. Technology can change that, according to preliminary data from research at Washington University School of Medicine in St. Louis.

The study, by Fahd A. Ahmad, MD, a clinical and postdoctoral fellow in pediatrics, and colleagues, showed that adolescents visiting a pediatric emergency department are willing to disclose information about their sexual activity when filling out a computerized questionnaire, and this information can be used to determine whether they should be tested for STIs. In addition, adolescents said the electronic survey was quick and easy to use.

Ahmad

Results of the study will be presented April 28 at the Pediatric Academic Societies annual meeting in Boston.

Ahmad and his colleagues developed a computerized system to assess risk factors for Chlamydia and N. gonorrhea in adolescents. Patients were eligible to complete the survey even if they were being treated in the emergency department for reasons unrelated to STIs.

“We wanted to take advantage of newer technology and communication methods to achieve better health outcomes for patients visiting the emergency department,” says Ahmad, who treats patients in the emergency department at St. Louis Children's Hospital.

A total of 460 patients ages 15-21 years old completed the survey. Computer software provided a recommendation as to whether an adolescent should be tested for STIs based on a decision algorithm created by the research team. The recommendation and a summary of the patient’s answers were integrated in the electronic medical record so that the doctors and nurses in the emergency department would have access to the information and could order any needed tests.

“When we implemented the system, we found that almost half of the patients who completed the questionnaire were in need of STI testing, and that was the same whether or not their primary complaint was related to STIs,” Ahmad says.

Researchers also found that the overall rate of Chlamydia and N. gonorrhea testing in adolescents visiting the emergency department nearly doubled — from 8.8 percent to 15.1 percent — after the computerized survey was implemented, compared with rates during the previous 15 months. Twenty percent of patients who were tested had an STI and received treatment. However, many of the patients did not receive testing as recommended for a variety of reasons.

Results also showed it took a median of eight minutes for patients to complete the survey. Ninety-one percent said the system was “very easy” or “easy” to use. In addition, 83 percent said they were “very comfortable” or “comfortable” with the system’s confidentiality. Finally, 71 percent said they would prefer an electronic questionnaire rather than an in-person interview or written survey in the future.

“Computerized questionnaires are an efficient way for health care workers to collect clinically relevant information and integrate it into their practice,” Ahmad says. “This type of system could be expanded to other sensitive issues such as substance abuse.”

Genes that promote cartilage healing protect against arthritis

Jim Dryden — 2012-04-26 00:00:00

Audio

Sandell laboratory

In mice with ears that heal rapidly, cartilage (shown in the thick blue border) also regenerates and heals more quickly. Washington University researchers found that the same genes that promote healing after cartilage damage also appear to protect against osteoarthritis.

The same genes that promote healing after cartilage damage also appear to protect against osteoarthritis, a condition caused by years of wear-and-tear on the cartilage between joints, new research at Washington University School of Medicine in St. Louis shows.

Although the research was conducted in mice, the genes also are likely to be important in people.

“Our goal is to see whether we can protect cartilage in people by detecting the early biological changes that occur in osteoarthritis and prevent it from progressing to the stage where joint replacement becomes necessary,” says principal investigator Linda J. Sandell, PhD, the Mildred B. Simon Professor of Orthopaedic Surgery. “The main problem with biological treatments is that currently, we can’t detect osteoarthritis in its early stages. Better understanding of the genes that influence the disorder may help us do that.”

The researchers reported their findings in a pair of studies, published online in the journals Arthritis & Rheumatism and Osteoarthritis and Cartilage.

Osteoarthritis is the most common form of arthritis, affecting 25 million people in the United States. It is linked to the breakdown of cartilage, which acts as a shock absorber to cushion the joints. Osteoarthritis causes pain, swelling and reduced motion and is most common in the hands, knees, hips or spine.

Scientists first discovered cartilage-healing properties in some strains of laboratory mice when they pierced their ears as a means to tag and identify them. But in some mice, the holes in their ears closed and quickly healed. Because so much of the ear is made from cartilage and healing occurred so rapidly in the mice ears, the researchers suspected that these mice also may be able to regenerate cartilage in their joints.

Sandell and her team bred the mice that healed rapidly with other mice that healed more slowly, and they found that the mice that could quickly heal and regenerate cartilage in the knee also were less susceptible to osteoarthritis.

In people, a breakdown of cartilage causes the bones to rub together and damage the joint. If the damage becomes too extensive, joint replacement surgery may be necessary.

Injury to a joint is a major risk factor for osteoarthritis, but not everyone is equally susceptible.

“Some people – and these mouse studies suggest that someday we may be able to predict which people – fare much better after an injury,” Sandell says. “We want to find a way to identify the genes that protect them.”

Sandell, director of the university’s Core Center for Musculoskeletal Biology and Medicine, and co-investigator James M. Cheverud, PhD, professor of anatomy and neurobiology, now are studying several other strains of mice on the spectrum between the good healers and those that heal poorly. They’ve looked at the cartilage tissue under the microscope to determine the extent of osteoarthritis following an injury and analyzed the DNA in cartilage.

“We’ve identified genes that correlate with healing and with protection from osteoarthritis,” Sandell says. “The work is in its beginning stages, but now that we’ve found a correlation, we want to look at even more strains of mice so that we can actually map the location of the genes that cause osteoarthritis and help to repair cartilage.”

She says osteoarthritis, like several other disorders, will ultimately involve many genes that each contribute in a small way to the disease process. By looking at more strains of mice, the research team believes it will become easier to identify the subtle genetic influences on osteoarthritis risk. As they clarify which genes are protecting the mice, it will be possible to look for similar genes in humans.

Rai MF, Hashimoto S, Johnson EE, Janiszak KL, Fitzgerald J, Heber-Katz E, Cheverud JM, Sandell LJ. Heritability of articular cartilage regeneration and its association with ear-wound healing. Arthritis & Rheumatism, vol. 64 (published online). DOI 10.1002/art.34396

Hashimoto S, Rai MF, Janiszak KL, Cheverud JM, Sandell LJ. Cartilage and bone changes during development of post-traumatic osteoarthritis in selected LGXSM recombinant inbred mice. Osteoarthritis and Cartilage, vol. 20 (published online). doi: 10.1016/j.joca.2012.01.022

Funding for this research comes from an ARRA Grand Opportunity Grant and from the National Institute of Arthritis, Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH).

Bear Cub grants awarded

Caroline Arbanas — 2012-04-26 00:00:00

Robert Boston

Jerry Morrissey, PhD, research professor of anesthesiology, has received a Bear Cub grant to study the early development of kidney cancer.

Washington University in St. Louis has awarded five Bear Cub fund grants totaling $190,000 to support innovative research that has shown commercial potential.

The fund, made up of endowment income and capital from private sources, is administered through the university’s Office of Technology Management and helps scientists further develop their technology.

The grants were awarded to:

Michael Holtzman, MD, the Selma and Herman Seldin Professor of Medicine;
Jim Janetka, PhD, research assistant professor of biochemistry and molecular biophysics;
Jerry Morrissey, PhD, research professor of anesthesiology;
David Piwnica-Worms, MD, PhD, professor of radiology; and
Samuel Wickline, MD, the J. Russell Hornsby Professor of Biomedical Sciences.

Holtzman and his colleagues will evaluate the safety and effectiveness of a drug designed to block the production of mucus. In respiratory diseases like asthma, bronchitis and the flu, the body produces too much mucus, which interferes with breathing.

Holtzman and his colleagues have developed a small-molecule inhibitor of mucus production and will evaluate the compound in animal models of airway disease and infection and in human airway cells grown in the laboratory. These studies will lay the groundwork for testing the drug in clinical trials in patients.

Recurrent urinary tract infections (UTIs) are a common problem for many women. They are typically treated with antibiotics, which are not always effective, and the bacteria that cause UTIs can rapidly develop resistance to antibiotics.

As an alternative, Janetka has designed a new group of drugs called mannosides, derived from the natural sugar mannose which don’t kill the bacteria like antibiotics but prevent bacteria from binding to and entering the bladder cells where UTIs occur.

Excess sugars are usually directed to the kidney and bladder, where they are eliminated in the urine, and mannosides are excreted in the same way, making them ideal for treating and preventing chronic UTIs.

Janetka and co-workers will optimize and evaluate lead compounds in the laboratory and then in animal models in preparation for early-phase clinical trials in patients.

Morrissey and colleagues are developing rapid tests for the early detection of kidney cancer and to monitor patients for the recurrence of the disease and metastases. They had identified a pair of proteins excreted in the urine that have the potential to detect about 90 percent of all kidney cancers.

The research team will now validate the tests using monoclonal antibody-based assays in urine samples of patients who are known to have kidney cancer, and compare their results to those in patients with non-cancerous kidney diseases and in healthy patients.

Radiotracer perfusion scans of the heart are often recommended for patients experiencing chest pain or a heart attack, so doctors can measure blood flow in the heart. But the medical isotope most commonly used today is in short supply.

Piwnica-Worms and his team have discovered a novel imaging agent that binds a new medical isotope, Gallium-68. He is evaluating whether the agent can noninvasively measure blood flow in the heart using high resolution PET scans.

Piwnica-Worms will further evaluate the imaging agent and the radiopharmaceutical in animal models, conduct toxicology tests and file an investigational drug application with the U.S. Food and Drug Administration so the agent can be evaluated in patients.

Wickline has developed a nanoparticle-based agent to inhibit and break apart blood clots that can develop suddenly, blocking blood flow to organs and tissues. This type of clotting typically is associated with heart attacks, strokes, bacterial toxins, acute kidney failure, drug reactions, sickle cell disease and sepsis.

Current treatments to control clotting often cause serious bleeding problems. The new nanoparticle agent under investigation is active specifically at the site where clots occur but does not inhibit normal clotting in other parts of the body, making bleeding problems less likely.

The agent binds only to acute clots and can be imaged to give an early noninvasive diagnosis of acute heart attacks and strokes in patients with suggestive symptoms. Wickline will continue to study the agent in animal models.

Mackinnon receives two awards from American Association of Plastic Surgeons

Beth Miller — 2012-04-25 00:00:00

Susan E. Mackinnon, MD, received the Clinician of the Year award and the Research Achievement Award in Basic Science at the American Association of Plastic Surgeons’ annual meeting April 14-17, 2012, in San Francisco.

The Clinician of the Year is chosen annually by the president of the association to recognize members who have made significant clinical achievement in the field of plastic and reconstructive surgery.

The association, based in Beverley, Mass., and the oldest plastic surgery association in the world, aims to advance the science and art of plastic surgery through surgical education, research, scientific presentations and professional interaction. Membership is by invitation only.
Mackinnon has served in a variety of roles with the association, including president, president-elect, awards committee chair, vice-president and treasurer. She was the first female president in the association’s history.

Celebrating Earth Day at School of Medicine

2012-04-24 00:00:00

Tim Parker

Jim Jackson (left), project manager in Facilities Management at the School of Medicine, explains energy used in light bulbs to a visitor to the energy conservation and alternative energy station at the School of Medicine’s Earth Day festivities April 19 in the BJC Institute of Health at Washington University School of Medicine Hope Plaza. In addition to energy, visitors learned about recycling, gardening and water conservation, and transportation and clean air.

Jaffe named president of pediatric association

Beth Miller — 2012-04-23 00:00:00

David M. Jaffe, MD, was elected president of the Academic Pediatric Association at its recent annual meeting in Boston.

Jaffe is the Dana Brown Professor of Pediatrics and director of the Division of Emergency Medicine in the Department of Pediatrics at Washington University School of Medicine in St. Louis and medical director of emergency services at St. Louis Children’s Hospital, where the emergency department staff treats between 55,000 and 60,000 patients a year.

Jaffe

The 60-year-old Academic Pediatric Association is dedicated to improving the health and well-being of children and adolescents by promoting research, advancing a scholarly approach to education, developing innovations in health-care delivery, advocating for an equitable child-health agenda and fostering leadership and career development of child-health professionals.

Jaffe was chosen to lead the association for the 2012-13 term in recognition of his numerous professional achievements and dedication to the field. He was named president-elect and joined the association’s board of directors in May 2011.

Jaffe is considered a pioneer in the field of pediatric emergency medicine. He was the first pediatric emergency medicine fellow in the United States, participated in writing the first textbook and published an article in the first volume of Pediatric Emergency Care. In addition, he was a founding member of the Pediatric Emergency Medicine Collaborative Research Consortium and the federally funded Pediatric Emergency Care Applied Research Network, both multi-institutional research networks. He has long been involved in leadership and strategic planning with national pediatric emergency organizations. He has served as a mentor and faculty adviser to residents and fellows since 1985.

Jaffe’s research focuses on young children with fever, spine and brain injuries and multi-center collaborative research.

He has been named among the Best Doctors in America by Best Doctors Inc.

Jaffe earned a medical degree from the University of Chicago and completed residencies and a fellowship at Children’s Hospital of Philadelphia.

Washington People: David Warren

Caroline Arbanas — 2012-04-20 00:00:00

Robert Boston

‪David Warren, MD (right), with nurse practitioner Jodie Marcantoni. “David is an extraordinary individual because at the height of a crisis, he remains incredibly calm,” says Vicky Fraser, MD, interim chairman of the Department of Medicine.‬

Potentially deadly infections with obscure names, such as MRSA and H1N1, have become part of the public lexicon.

These infections cause particular concern in hospitals and clinics, where they can spread rampantly. David Warren, MD, medical director for infection control at Washington University School of Medicine and Barnes-Jewish Hospital, works diligently to prevent infections, but when they do occur, he pulls out all the stops to halt their spread.

Warren keeps a watchful eye out for infections that develop almost exclusively in hospitals. Critically ill patients, whether young or old, are most at risk. They often have tubes in their veins to deliver medicine, in the bladder to remove urine, or in their lungs to supply oxygen, creating an ideal environment for bacteria to flourish and infections to develop.

And in a world that is increasingly interconnected, Warren also must keep abreast of emerging global epidemics that have the potential to wreak havoc if there’s a local outbreak.

“New challenges arise every day,” says Warren, an infectious diseases specialist and associate professor of medicine. “The most difficult aspect of that reality is that you can’t easily predict what the next threat will be, but that means there’s never a dull moment, either.”

Warren, who widely is recognized for his infection-prevention efforts, operates in what can be a high-stress environment. His colleagues say that even under pressure, he maintains his composure and thinks with a clear head, all the while reassuring patients and staff and bringing situations under control.

“David is an extraordinary individual because at the height of a crisis, he remains incredibly calm,” says Vicky Fraser, MD, interim chairman of the Department of Medicine and the J. William Campbell Professor of Medicine.

“In some situations, there are unusual infections that are incredibly difficult to identify and evaluate, but David is extremely meticulous and careful in his approach,” she says. “He always gets to the root of the problem and identifies a solution, and he is responsible for many of the dramatic improvements in infection rates at the medical school and at Barnes-Jewish Hospital.”

A love for science

Growing up, Warren developed an early love for science. He originally planned to pursue a doctorate and a career doing bench research. But in college, a summer internship at the National Institutes of Health (NIH) changed his focus.

Warren worked in a laboratory making the first attempts to use gene therapy to treat severe combined immune deficiency, or SCID. This rare, inherited disorder typically is diagnosed in infancy and caused by a genetic error that destroys the body’s ability to build a functioning immune system.

Warren found the research interesting, but what he most enjoyed about his summer experience was tagging along with a pediatrician from the lab who moonlighted as the on-call pediatrician at a local community hospital.

The life of the hospital opened up a new world for Warren. He attended the deliveries of babies and a hodgepodge of pediatric emergencies.

“It was fascinating, and I found the whole idea of taking care of people and having an immediate impact on their lives to be very appealing,” Warren says. “So I changed tracks and went into medicine.”

After graduating from medical school, Warren chose Barnes-Jewish for his internal medicine residency. When he interviewed for a slot, he was swayed by the close working relationship among faculty physicians and residents.

“There’s a real sense of camaraderie, and that was the deciding factor in my decision to come here,” Warren says.

During his residency, Warren gradually gravitated toward infectious diseases. It fed his intellectual curiosity, and he enjoyed following a detective’s trail to make a diagnosis.

“Infectious diseases is not a procedure-based specialty,” Warren says. “We spend a lot of time talking to patients and hearing about their lives, looking for the small, revealing details that provide important clues to help us determine what they were exposed to.”

Finding out what patients do for a living, where they have traveled, what they have eaten and what their hobbies and lifestyle are can be vital to a diagnosis, he says.

Warren has diagnosed a number of curious infections over the years, including a steady stream of tick-borne illnesses. Missouri is known for its ticks and has one of the highest U.S. rates of tularemia, a bacterial infection spread by ticks and deer flies.

A fungal infection, histoplasmosis, also is quite common in the Mississippi River Valley, even among people who are healthy. And it is not out of the question to see tuberculosis or even cases of malaria in patients who have traveled abroad.

Honing an expertise

After an infectious diseases fellowship at the School of Medicine, Warren joined the faculty in 2001. Since then, he has honed his expertise in diagnosing and preventing health-care-associated infections.

Even though hospital stays are shorter and less frequent, patients are typically sicker and more vulnerable to infections. These include patients in the intensive care units, those with cancer and patients having surgery.

The infections that are most worrisome are those caused by strains of bacteria that are resistant to many antibiotics. These super bugs were rare decades ago but have grown increasingly common today. They include methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE). Another is the bacterium Clostridium difficile (C. diff), which causes severe diarrhea and typically develops after patients have been taking antibiotics.

“These bacteria can cause severe infections and sometimes even death,” Warren says. “And they really limit our choice of treatments. Instead of being able to prescribe an antibiotic that would be most effective, we’re faced with having to use antibiotics that potentially have more side effects, are more expensive and may not work as well.”

Part of Warren’s job is to be sure that hospital staff, including physicians, nurses and even housekeepers, are trained in infection prevention and that they consistently follow practices that have been shown to reduce infections.

Sometimes these practices are extremely low-tech, such as hand washing. But it is critical because bacteria easily can spread on the hands of health-care workers.

Warren’s own research has shown that bathing patients in the intensive care unit with soap that contains a particular antiseptic, chlorhexidine, can significantly reduce transmission of MRSA. First evaluated in the Barnes-Jewish medical and surgical ICUs, the soap was so effective at reducing new infections that it was incorporated into routine use in all of the hospital’s ICUs.

“The nurses were already bathing the patients every day, but we found that it’s what they bathed them with that made all the difference,” he says.

Courtesy photo

David Warren and family (from left): Daughter, Julia, 10, holding Zoe; David; wife, Corinna; and son, Adam, 7.

Warren also was the senior author of updated guidelines issued recently by the Infectious Diseases Society of America for the prevention and treatment of catheter-related bloodstream infections. The comprehensive guidelines, written for physicians, cover virtually every aspect of bloodstream infections in a host of different patients and are widely cited in the scientific literature.

For Jonas Marschall, MD, assistant professor of medicine, Warren is more than an expert in his field but a mentor who has guided his career.

In 2006, Marschall came to the School of Medicine from Switzerland for a research fellowship in health-care epidemiology with a focus on hospital-acquired infections. Before he arrived, he had to choose a mentor with only a limited knowledge of the faculty. Marschall selected Warren, and the choice couldn’t have been a more perfect fit, he says.

“Right from the start, he was a wonderful, caring mentor,” Marschall says.

“David also is one of the most diligent clinicians I’ve ever seen. He’s very comprehensive and considers all aspects of the patients’ care. We all benefit from his expertise.”

Fast facts about David Warren

Grew up in: Pittsburgh
Education: BS, Penn State; MD, University of Pittsburgh; MPH, Saint Louis University
Family: Wife, Corinna, MD, an internal medicine physician at St. Luke’s Hospital in Chesterfield, Mo.; daughter, Julia, 10; and son, Adam, 7
Hobbies: Bicycling, hiking and spending time with family outdoors
Favorite Missouri state park: Ha Ha Tonka in Camdenton, Mo.
Favorite family getaway: The beaches of St. Petersburg and Clearwater, Fla.

Unusual protein helps regulate key cell communication pathway

Jim Dryden — 2012-04-22 00:00:00

Lingle laboratory

Potassium ions (shown in purple) pass through the narrow opening of a large potassium channel to generate the electrical signals that allow cells to communicate with one another. Researchers at Washington University in St. Louis have shown how an unusual protein temporarily blocks these ions from the channel, which gives cells a chance to recover so they can continue firing.

Tiny pores, or channels, embedded in cell membranes are critical to the healthy functioning of cells. Charged atoms, or ions, move through these channels to generate the electrical signals that allow cells to communicate with one another.

New research at Washington University School of Medicine in St. Louis unveils some of the inner workings of certain channels involved in regulating electrical signals in nerve cells, relaxing muscle cells and “tuning” hair cells in the inner ear.

In a report published April 22 in the advance online edition of the journal Nature, the scientists have shown how an unusual protein — one lacking any definable structure — plays a key role in temporarily blocking the movement of ions through these channels after a cell fires off an electrical signal. Preventing ions from moving through the channel is important because it gives cells time to recharge so that they can continue firing.

The researchers studied large potassium channels, called BK channels, which allow potassium ions to move in and out of cells. Looking at the channels gave the Washington University researchers an opportunity to see how so-called intrinsically disordered proteins can operate in cells.

They found that an intrinsically disordered protein was responsible for inactivating the BK channel. These proteins are of particular interest to scientists because they defy the long-held notion that a protein’s precise 3-dimensional form determines its function.

Christopher J. Lingle, PhD, a professor of anesthesiology and of neurobiology, and his colleagues monitored the electrical activity of BK channels as they opened and closed. Despite the disordered nature of the unstructured protein that closes the channel, the researchers found that it nestles into a receptor inside the BK channel in a highly specific way. This lock-and-key mechanism is essential to closing, or inactivating, the channel.

“It’s a two-step process, which distinguishes it from most other inactivation mechanisms that have been described,” Lingle says. “My guess is that the part of the protein that binds to the potassium channel receptor may have to move through some very narrow spaces. It may be that by having a less-defined structure, the protein can navigate more easily through tight spaces and to get to the binding site.”

Lingle and his colleagues are currently attempting to study how the channels behave in mouse cells to learn more about the physiological effects of BK channel behavior.

Problems in regulating BK channels are known to be involved in epilepsy, asthma and cardiovascular disease. A better understanding of the way those channels operate might help scientists think about new ways to treat these conditions and determine why the disordered protein domains that regulate these channels don’t have a well-defined structure.

Gonzalez-Perez V, Zeng X-H, Henzler-Wildman K, Lingle CJ. Stereospecific binding of a disordered peptide segment mediates BK channel inactivation. Nature, vol. 483, Advance Online Publication. DOI 10.1002/art.34396

Funding for this research comes from the National Institute of General Medical Sciences of the National Institutes of Health (NIH) and the Searle Scholars Program.

Alzheimer's plaques disrupt brain networks

Michael C. Purdy — 2012-04-19 00:00:00

David Holtzman, MD

Brain plaques in a model of Alzheimer's disease significantly decrease connections among brain networks as the mice age. Red indicates higher connection levels in scans taken from a 3-month-old mouse, left, and an 11-month-old mouse, right.

Scientists studying the way Alzheimer’s takes root in the brain have identified important new similarities between a mouse model and human Alzheimer’s.

Researchers at Washington University School of Medicine in St. Louis have shown that brain plaques in mice are associated with disruption of the ability of brain regions to network with each other. This decline parallels earlier results from human studies, suggesting that what scientists learn about Alzheimer’s effects on brain networks in the mice likely will be transferable to human disease research.

The study, published in the Journal of Neuroscience, is among the first to precisely quantify the effects of Alzheimer’s disease plaques on brain networks in an animal model. Until now, scientists studying Alzheimer’s in animals have generally been limited to assessments of structural brain damage and analyses of brain cell activity levels.

“Precise measurement of changes in brain networks are critical to understanding Alzheimer’s and will likely be important in models of other neurodegenerative disorders,” says senior author David M. Holtzman, MD, the Andrew B. and Gretchen P. Jones Professor and head of the Department of Neurology. “For example, we can now test whether blocking Alzheimer’s plaques from building up in the mouse brain prevents disruptions in brain networks.”

In humans, scientists assess the integrity of brain networks by monitoring cerebral blood flow with functional magnetic resonance imaging scans. When the brain is idle, blood flow rises and falls in sync in brain regions that network with each other, a phenomenon called functional connectivity. These links are believed to be an important component of normal brain activity. In humans, problems in functional connectivity appear to presage the development of dementia.

Applying the same technique to mice can be very challenging, Holtzman says. Instead, researchers used an approach for monitoring brain blood flow in mice recently developed by the laboratory of Joseph Culver, PhD, associate professor of radiology at Washington University. The technique involves mounting a ring with light-emitting diodes on the head of a lightly anesthetized mouse. Sensors in the ring monitor light that is reflected back from hemoglobin molecules flowing through blood vessels in the brain. This data can be used to quickly assess blood flow.

Researchers applied the approach to a mouse model of Alzheimer’s disease. They found that the brain regions with the strongest network connections in young mice developed the most plaques as the mice aged. As plaques accumulated in these regions, functional connectivity declined. Scientists have already found similar results in humans using functional magnetic resonance imaging.

A link between stronger brain networking in young mice and increased signs of Alzheimer’s in older mice may seem contradictory, but it echoes earlier studies in Holtzman’s laboratory that linked higher activity levels in individual brain cells to increased plaque deposition.

Holtzman and others have speculated that the types of information and functions encoded in the activities of brain cells and their networks may affect their impact on Alzheimer’s risk. Epidemiological studies have shown that brain stimulation, such as puzzles, reading or learning, is associated with reduced risk of Alzheimer’s. Leaving the brain idle for long periods of time may increase risk.

The mice studied in the research have a mutated form of a human protein, Alzheimer’s precursor protein, that causes them to develop brain plaques. Other mouse models have mutated versions of a protein called tau that lead to the development of neurofibrillary tangles, which are another hallmark of Alzheimer’s disease.

Holtzman, Culver and colleagues plan to test functional connectivity in mouse models with mutated versions of human tau. The results may help determine the effects of additional types of protein aggregates in the brain, according to Holtzman.

“Important new insights into the normal and dysfunctional human brain have been made via studies of functional connectivity,” Holtzman says. “Being able to analyze brain function from a similar perspective in animal models, where we have much more freedom to manipulate genes and proteins, should be very helpful in our efforts to understand and treat complex conditions like Alzheimer’s disease.”

Bero AW, Bauer AQ, Stewart FR, White BR, Cirrito JR, Raichle ME, Culver JP, Holtzman DM. Bidirectional relationship between functional connectivity and amyloid-beta deposition in mouse brain. Journal of Neuroscience, March 28, 2012.

Funding from the National Institutes of Health (NIH), the Medical-Scientist Training Program, the Ellison Medical Foundation and the Cure Alzheimer’s Fund supported this research.

First gene linked to common form of psoriasis identified

Caroline Arbanas — 2012-04-19 00:00:00

National Psoriasis Foundation

Scientists led by Washington University School of Medicine in St. Louis have identified the first gene directly linked to the most common form of psoriasis. Rare mutations in the CARD14 gene, when activated by an environmental trigger, can lead to plaque psoriasis, which accounts for 80 percent of all cases of the condition.

Scientists led by Washington University School of Medicine in St. Louis have identified the first gene directly linked to the most common form of psoriasis, a chronic skin condition.

The research shows that rare mutations in the CARD14 gene, when activated by an environmental trigger, can lead to plaque psoriasis. This type of psoriasis accounts for 80 percent of all cases and is characterized by dry, raised, red patches covered with silvery scales that can be itchy and painful.

The new findings also indicate that mutations in CARD14 can be involved in the pustular form of psoriasis and in a debilitating arthritis linked to the psoriasis. The discovery may lead to more effective, targeted therapies for plaque psoriasis and other forms of the disease.

The research is published May 4 in two separate papers in The American Journal of Human Genetics.

“We have searched for almost two decades to find a single gene linked to plaque psoriasis,” says the senior author of both papers, Anne Bowcock, PhD, professor of genetics. “Individually, the rare mutations we have found likely confer a high risk for the disease, and we think they will be important in the search to find new, more effective treatments.”

Although psoriasis has long been thought to be caused by an overactive immune system, the genetic pathway uncovered by the scientists points to defects in the skin as the main culprit of the condition and to immune cells as secondary players.

Now, the researchers want to find out how common the altered pathway is in the different types of psoriasis and in patients with psoriatic arthritis. Their work suggests that in at least some patients with different forms of psoriasis, this pathway is the same.

An estimated 7.5 million Americans have psoriasis, and about 30 percent of them develop psoriatic arthritis. Like other common diseases, psoriasis runs in families and has been thought to have a genetic component, but it’s been difficult to pin down the genes involved. That’s because common variations in genes likely contribute very little to the overall genetic risk of the disease, and mutations that substantially increase a person’s risk are so rare they have been impossible to find.

With early support from the National Psoriasis Foundation, Bowcock initiated the research with co-author Alan Menter, MD, of the Psoriasis Research Institute at the Baylor University Medical Center in Dallas.

Using the latest DNA technology to sequence all of a patient’s genes, Bowcock and her colleagues uncovered a rare CARD14 mutation in a large family of northern European descent in which plaque psoriasis was prevalent. They also found the mutation in the one-third of family members who had developed psoriatic arthritis, suggesting that the same rare mutation can play a role in both conditions.

The scientists also identified another rare CARD14 mutation in an extended family from Taiwan that had a large number of plaque psoriasis cases.

But mutations in the gene do not only occur in families with a genetic predisposition.

The researchers, including the papers’ first author Catherine Jordan, an MD/PhD student at Washington University, also found a CARD14 mutation in a 3-year-old girl with a severe case of pustular psoriasis, a rare form of psoriasis. Neither of the girls’ parents had mutations in CARD14, indicating that the rare mutation was not inherited but had occurred spontaneously.

Psoriasis typically develops after an environmental trigger, which can include an infection, such as strep throat, or injury to the skin, including a cut or bug bite. Certain medications, smoking and heavy alcohol consumption also are triggers.

The young girl, from Haiti, developed psoriasis in infancy, like some members of the family with origins in northern Europe.

“This is significant because it tells us that CARD14 mutations alone are enough to lead to psoriasis, possibly after an early trigger such as an infection,” Bowcock explains. “You don’t need anything else. This really highlights the importance of finding rare mutations for common diseases like psoriasis.”

The researchers also found 15 other rare mutations in CARD14. In a finding that is statistically significant, the mutations were more common in more than 6,000 patients with psoriasis compared to 4,000 healthy controls.

The scientists showed that in specialized skin cells called keratinocytes, mutations in CARD14 increase the activity of NF-kappaB, a protein that turns on genes. This protein increases the production of certain signaling molecules that attract inflammatory cells to the skin, unleashing a vicious cycle of inflammation that is so notable in psoriasis.

Psoriasis affects the life cycle of skin cells, causing them to mature rapidly in just a few days and accumulate to form thick, scaly patches. Interestingly, in psoriasis patients with CARD14 mutations, the researchers found the gene’s activity was increased in the skin’s upper layers, which may explain the flakiness that characterizes the condition.

“Now, we have a much clearer picture of what is happening in psoriasis,” Bowcock says. “And with all kinds of new therapeutic targets that lie within the CARD14 pathway, the field is wide open.”

Collaborators include Michelle Lowes at The Rockefeller University, Alan Menter at Baylor University Medical Center, Raphaela Goldbach-Mansky at the National Institute of Arthritis and Musculoskeletal and Skin Diseases at the National Institutes of Health (NIH), in addition to scientists at the National Institute of Allergy and Infectious Diseases at NIH, Academia Sinica in Taiwan, National Taiwan University Hospital and National Taiwan University College of Medicine, University of Michigan, University of Utah School of Medicine and the University of California, San Francisco.

The research is supported by grants from the National Institutes of Health, the National Institute of Arthritis and Musculoskeletal Diseases, the National Institute of Allergy and Infectious Diseases, with additional funding from the National Psoriasis Foundation, the Arthritis Society of Canada, the Atlantic Innovation Fund, the Canadian Institute of Health Research, the Arthritis Society, the Dana Foundation and the Academia Sinica and National Science Council of Taiwan.

Some of the patient samples for the research were obtained from the National Psoriasis Victor Henschel BioBank, an initiative of the National Psoriasis Foundation.

Jordan CT, Bowcock AM et al. Rare and common variants in CARD14, an epidermal regulator of NF-kappaB, in psoriasis. The American Journal of Human Genetics. May 4, 2012.

Jordan CT, Bowcock AM et al. PSORS2 is due to mutations in CARD14. The American Journal of Human Genetics. May 4, 2012.

Kidney stone mystery solved

Caroline Arbanas — 2012-04-18 00:00:00

Alana Desai, MD

The CT image reveals the presence of kidney stones. New research provides evidence to explain why some people are more prone to the condition than others.

Kidney stones strike an estimated 1 million Americans each year, and those who have experienced the excruciating pain say it is among the worst known to man (or woman).

Now, new research by scientists at Washington University School of Medicine in St. Louis provides evidence to explain why some people are more prone to develop the condition than others. Their discovery opens the door to finding effective drug treatments and a test that could assess a person’s risk of kidney stones.

“Now, we finally have a more complete picture detailing why some people develop kidney stones and others do not,” says senior author Jianghui Hou, PhD, assistant professor of medicine. “With this information, we can begin to think about better treatments and ways to determine a person’s risk of the condition, which typically increases with age.”

The research, in mice, is now available online in the EMBO Journal, published by the European Molecular Biology Organization.

Because kidneys function the same way in mice as in humans, the new findings can help scientists understand the root causes of kidney stones in patients. The mouse model used in the study can also serve as a platform for the preclinical testing of novel treatments for the condition, the researchers say.

Most kidney stones form when the urine becomes too concentrated, allowing minerals like calcium to crystallize and stick together. Diet plays a role in the condition — not drinking enough water or eating too much salt (which binds to calcium) also increases the risk of stones.

But genes are partly to blame. A common genetic variation in a gene called claudin-14 recently has been linked to a substantial increase in risk — roughly 65 percent — of getting kidney stones. In the new study, the researchers have shown how alterations in the gene’s activity influence the development of stones.

Typically, the claudin-14 gene is not active in the kidney. The new research shows that its expression is dampened by two snippets of RNA, a sister molecule of DNA, that essentially silence the gene.

When claudin-14 is idled, the kidney’s filtering system works like it’s supposed to. Essential minerals in the blood like calcium and magnesium pass through the kidneys and are reabsorbed back into the blood, where they are transported to cells to carry out basic functions of life.

But when people eat a diet high in calcium or salt and don’t drink enough water, the small RNA molecules release their hold on claudin-14. An increase in the gene’s activity prevents calcium from re-entering the blood, the study shows.

Hou and his team have found that claudin-14 blocks calcium from entering passageways called tight junctions in cells that line the kidney and separate blood from urine.

Without a way back to the bloodstream, excess calcium goes into the urine. Too much calcium in the urine can lead to stones in the kidneys or bladder. Intense pain develops when a large stone gets stuck in the bladder, ureter or urethra and blocks the flow of urine.

Hou’s research supports the theory that people with a common variation in claudin-14 lose the ability to regulate the gene’s activity, increasing the risk of kidney stones.

He is optimistic, however, that drugs could be developed to target the short stretches of RNA that are intimately linked to claudin-14. Drugs that mimic these so-called microRNAs could keep the activity of claudin-14 in check and reduce the likelihood that stones would form.

Also, it may one day be possible to develop a diagnostic test to measure levels of the claudin-14 protein excreted in urine. Elevated levels would indicate an increased risk of stones, and people could take steps to prevent stones by modifying their diet.

“Many genes likely play a role in the formation of kidney stones,” Hou says. “But this study gives us a better idea of the way one of the major players work. Now that we understand the physiology of the condition, we can start to think about better treatments or even ways to prevent stones from developing in the first place.”

The research was funded, in part, by the National Institutes of Health (NIH) and the American Heart Association.

Hou is working with Washington University's Office of Technology Management on an invention related to work described in the paper.

Gong Y, Renigunta V, Himmerkus N, Zhang J, Renigunta A, Bleich M, Hou J. Claudin-14 regulates renal CA++ transport in response to CaSR signaling via a novel microRNA pathway. The EMBO Journal. Advance online publication Feb. 28, 2012.

WUSTL Neurofibromatosis Center to host symposium May 4

2012-04-18 00:00:00

The Washington University Neurofibromatosis (NF) Center at will host its first research symposium on May 4. The event will focus on clinical and basic science research on neurofibromatosis 1, an inherited condition that increases risk of brain tumors in children and adults.

Morning presentations will describe new advances in basic research. The morning’s keynote speaker will be Luis F. Parada, PhD, of the University of Texas Southwestern Medical School. The keynote speaker for the afternoon, which will focus on clinical research, will be Bruce Korf, MD, PhD, of the University of Alabama at Birmingham.

Speakers from Washington University include: Larry Shapiro, MD, executive vice chancellor for medical affairs and dean of the School of Medicine, and David H. Gutmann, MD, PhD, director of the Neurofibromatosis Center.

The symposium, to be held in the Eric P. Newman Education Center, will begin at 8 a.m. A reception with the speakers will be held from 4-6 p.m.

Registration is free and open to the public. To register, e-mail Taylor Ferguson at fergusont@neuro.wustl.edu or visit http://nfcenter.wustl.edu and click the link for the symposium under "NF Center News."

Study of half siblings provides genetic clues to autism

Jim Dryden — 2012-04-16 00:00:00

Audio

A child is about half as likely to develop autism if his or her half sibling has the disorder than if a full sibling does.

When a child has autism, siblings are also at risk for the disorder. New research from Washington University School of Medicine in St. Louis shows that the genetic reach of the disorder often extends to half siblings as well.

On the surface, the finding may not be surprising — half siblings share about 25 percent of their genes. But the discovery is giving scientists new clues to how autism is inherited.

The study is published online in the journal Molecular Psychiatry.

According to principal investigator John N. Constantino, MD, the new research adds to recent evidence that even though autism is far more common in males, females still can inherit and pass along genetic risk for autism.

“We found that autism risk for half siblings is about half of what it is for full siblings,” he says. “Most of the half siblings we studied had the same mothers. Given that half of the risk of transmission was lost and half was preserved among those maternal half siblings, mothers and fathers appear to be transmitting risk equally in families in which autism recurs.”

Constantino, the Blanche F. Ittleson Professor of Psychiatry and Pediatrics and director of the William Greenleaf Eliot Division of Child and Adolescent Psychiatry at Washington University and psychiatrist-in-chief at St. Louis Children’s Hospital, says the findings also suggest that in many families, the transmission of autism is the result of the effects of many genes — not just one — with each contributing a small proportion of risk.

Prior estimates of the extent to which autism is influenced by genetic factors are derived from studies of identical and fraternal twins where one, or both, are affected by the disorder. Since identical twins share 100 percent of their genes, and fraternal twins share 50 percent, inherited conditions tend to be twice as common in an identical twin pair compared to a fraternal twin pair. But twin studies of autism are too small to give precise estimates about how the disorder is inherited.

“The largest studies have included less than 300 clinically affected twin pairs,” Constantino says. “And they include girls, boys and mixed twin pairs, which complicates the testing of models of inheritance in autism because the disorder is much more common in boys than girls.”

Other studies have focused on siblings of children with autism, looking at how much more common autism recurrence is in siblings than the general population. But to derive more information on genetic structure from their family studies, Constantino’s group looked at autism recurrence in half siblings and compared it to that in full siblings.

Constantino

The researchers studied over 5,000 families in which there was a child with autism and at least one additional sibling — the families were enrolled in a national volunteer, Internet-based family registry for autism, the Interactive Autism Network (IAN). Among those families, 619 included at least one maternal half-sibling. The researchers focused on maternal half-siblings rather than paternal half siblings because these children were more likely to live full-time with their biological mothers and to share the same environmental influences between the time they were born and the age of two, the time at which the onset of autistic syndromes occur. They compared autism recurrence among the 619 maternal half siblings to the rate among 4,832 full siblings.

In an attempt to replicate their findings, the researchers also looked at a group of local St. Louis families in which maternal half siblings also were known to have been raised in the same household.

After analyzing both sets of families, the researchers found that 10 percent to 11 percent of full siblings had been diagnosed with autism, compared to 5 percent to 7 percent of half siblings.

“If transmission of autism risk was occurring equally from unaffected mothers and fathers, you would predict that maternal half siblings’ risk of autism would be about half of what we saw in full siblings,” Constantino says. “And that’s exactly what we found.”

Current statistics from the U.S. Centers for Disease Control and Prevention estimate that about one in 110 children in the United States is somewhere on the autism spectrum. Constantino says that according to the new findings, more than 60 percent of those cases of autism are likely to be inherited on the basis of genetic variations inherited from unaffected mothers and fathers.

“In 15 to 20 percent of children with autism, it appears that genetic problems aren’t inherited, rather that genes become altered in sperm cells, egg cells or in the developing embryo,” he says. “The recent discovery of these kinds of abnormalities have raised questions about the interpretation of twin studies and the extent to which autism is inherited. The current study, however, supports inheritance as a central cause for a majority of autistic syndromes and encourages a new focus on the mechanisms by which genetic susceptibility to autism can be silenced in some individuals, especially females who typically exhibit symptoms of autism at only one third of the rate seen in males.”

Constantino JN, Todorov A, Hilton C, Law P, Zhang Y, Molloy E, Fitzgerald R, Geschwind D, Autism recurrence in half siblings: strong support for genetic mechanisms of transmission in ASD. Molecular Psychiatry, vol. 17 (published online). doi: 10.1038/mp.2012.9

Funding for this research comes from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Institute of Mental Health of the National Institutes of Health (NIH).

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

School of Medicine Earth Day celebration April 19

Beth Miller — 2012-04-12 00:00:00

Robert Boston

At Earth Day festivities in 2011, Courtney Pike (left), research technician I in the Department of Internal Medicine-Cardiovascular Division, and Liz Wright (center), a graduate research assistant and a student in the MD/PhD program, talk to Changguo Tang, PhD, a staff scientist in biochemistry and molecular biophysics, about gardening and water conservation. This year's festivities will be held April 19.

Have you ever wondered where the items you put in your office recycling bin actually go? What does it take to start an eco-friendly garden at home? What if you want to ride your bike to the medical center? Learn answers to these questions and more at Washington University School of Medicine’s Earth Day celebration April 19.

From 10:30 a.m.-1:30 p.m., faculty, staff and students are encouraged to visit four booths in the Ellen S. Clark Hope Plaza outside of the BJC Institute for Health to learn about energy conservation and alternative energy; recycling; gardening and water conservation; and transportation and clean air. Each station will have information and giveaways or drawings.

At the recycling station, Garry Gilliam and Tammy Heet of Resource Management Recycling, the university’s recycling vendor, will be on hand to answer questions and explain what happens to recyclables once they leave the School of Medicine campus.

In addition, George “The Shoeman” and Julie Scaglione will collect gently worn shoes and old personal cell phones for the Shoeman Water Projects, a charity that collects shoes and cell phones that are then exported to retailers in the developing world. Funds generated from their sales provide well-drilling rigs, water purification systems and hand-pump-repair micro businesses that bring clean water to those without it.

At the energy conservation station, Jerry Pinkner, research lab manager in molecular microbiology, and Wanda Haertling, purchasing supervisor in the medical school facilities business office, will discuss how they have incorporated the use of solar energy in their homes. Representatives from Ameren Missouri and Laclede Gas Co. will be present to share energy efficiency tips.

The gardening and water conservation station will provide hands-on tips for home gardening. Volunteers will be available to talk about composting, watering devices, planting guides and more.

The transportation station will focus on biking as an alternative form of transportation and host a sign-up for April’s Car-Free Challenge. Big Shark Bicycle Co. will be on site offering bicycle tune-ups.

In case of rain, all of the stations will move to the link above the McDonnell Pediatrics Research Building atrium.

The day’s events are sponsored by the school’s Sustainability Action Team, which also will have reusable tote bags, water bottles and T-shirts for sale.

Information about activites on the Danforth Campus may be found here: http://news.wustl.edu/news/Pages/23728.aspx.

The first Earth Day, held April 22, 1970, motivated 20 million Americans to champion a healthy environment and is credited with launching the sustainability movement. More than 1 billion people now participate in Earth Day activities each year, making it the largest civic observance in the world.

Batter up! Tread the Med kicks off April 26

Beth Miller — 2012-04-12 00:00:00

Robert Boston

Participants in last fall's Tread the Med line up for fruit and water at the kickoff event.

Get out and enjoy the weather — Tread the Med’s “Most Valuable Walker” campaign at Washington University School of Medicine is ready to begin.

The kickoff celebration will be held from 11 a.m.- 1 p.m. April 26 in Hudlin Park with a ceremonial first walk led by Larry J. Shapiro, MD, executive vice chancellor for medical affairs and dean of the School of Medicine; James P. Crane, MD, associate vice chancellor for clinical affairs, and Fredbird, mascot of the St. Louis Cardinals. Participants can enjoy fresh fruit, bottled water and the music of Fanfare.

All School of Medicine employees are eligible to participate in the Tread the Med program and kickoff.

The summer campaign, which runs from April 30-Aug. 7, aims for participants to virtually walk 500 miles from Busch Stadium to Kauffman Stadium, where the Kansas City Royals play in Kansas City, which is hosting this year’s All-Star Game, then back to Busch Stadium. To be a Most Valuable Walker, participants need to walk the virtual 500 miles, or 1 million steps, in 100 days.

Incentives include a cinch pack at 250,000 steps, a bandana at 500,000 steps, a baseball T-shirt at 750,000 steps and a baseball cap at 1 million steps.

Participants in Tread the Med also will be able to purchase $10 tickets (regularly $37 each) to Tread the Med Night June 14 when the St. Louis Cardinals play the Chicago White Sox at Busch Stadium. Participants may purchase up to eight tickets. Four winners will have a chance to be on the field during batting practice, and other events are planned.

Beginning April 17, participants may enroll at healthyliving.wustl.edu/tread-the-med. Select the Tread the Med tab for a brief description of the program then click on the tab labeled "Registration" to enter your name and e-mail address and to authorize the $5 fee to be deducted from your paycheck.

The fee helps cover the cost of a pedometer, prizes and participation in the program. Following registration, participants will be asked to complete an optional survey that will help measure the program’s success. Registration closes May 4.

Early-stage lung cancer treatments evaluated in patients with breathing problems

Caroline Arbanas — 2012-04-09 00:00:00

Jeffrey Bradley, MD

A CT image shows an early-stage lung tumor. A new clinical trial will evaluate whether a limited surgical procedure or a specialized type of radiation therapy is the best treatment for patients with early-stage lung cancer who also have breathing problems.

The Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine is seeking patients for a clinical study to determine the best treatment for patients with early-stage lung cancer who also have breathing problems.

Many patients with early-stage lung cancer have emphysema, pulmonary hypertension or other breathing problems that limit their treatment options.

The study focuses on patients with the most common type of lung cancer, non-small cell lung cancer. When it is diagnosed early, the standard treatment is surgery. But the operation is especially risky for patients with poor lung function, who often have complications after surgery.

In the new trial, doctors will compare a type of radiation therapy, called stereotactic body radiation therapy, to a more limited surgical procedure. Rather than remove the entire section of the lung, surgeons will remove only a small portion, which may reduce complications after surgery.

Stereotactic body radiation therapy pinpoints high doses of radiation directly to the tumor, while reducing damage to surrounding tissues. It can also be delivered in just several treatments over seven to 10 days, compared to conventional radiation, where treatment is given over six to eight weeks.

Stereotactic body radiation therapy is the treatment of choice for patients with non-small cell lung cancer who are too frail for any surgery. But doctors don’t know whether it is better than the limited surgery for patients healthy enough for surgery but who have decreased lung function.

“Our hope is that doctors and patients will embrace this cutting-edge trial so we can clarify the optimal treatment for this group of higher-risk patients,” says study co-investigator Bryan F. Meyers, MD, chief of the Section of Thoracic Surgery. “For very frail patients, we have stereotactic body radiation therapy. For fit patients, surgery still dominates. This trial looks at people on the cusp for whom we don’t have certainty.”

Nationwide, an estimated 420 patients will be enrolled in the trial, which is sponsored by the National Cancer Institute. Traves Crabtree, MD, assistant professor of surgery, is the local principal investigator of the study.

To be eligible, patients must have an early-stage (1A or selected 1B) non-small cell lung tumor and not received other cancer treatments.
Siteman Cancer Center was involved in an earlier trial of stereotactic body radiation therapy for early-stage non-small cell lung cancer in patients too frail for surgery.

“We have one of the largest U.S. experiences with stereotactic body radiation therapy for lung cancer,” says study co-investigator Jeffrey Bradley, MD, professor of radiation oncology. “It can eradicate lung tumors in 90-95 percent of patients with early-stage cancer, double that of conventional radiation therapy. And stereotactic body radiation therapy also appears to double the survival rate in these patients, compared to conventional radiation therapy. It’s definitely a major advance in lung cancer treatment.”

Patients in the study will be randomly assigned to receive either three treatments of stereotactic body radiation therapy over seven to 10 days or the limited surgical procedure. Over the next five years, doctors will evaluate patients’ survival rates and their quality of life after treatment.

For more information about the study, call clinical nurse research coordinator, Jo Musick at (314) 747-0707.

Alvin J. Siteman Cancer Center is the only NCI-designated Comprehensive Cancer Center within a 240-mile radius of St. Louis. Siteman Cancer Center is composed of the combined cancer research and treatment programs of Barnes-Jewish Hospital and Washington University School of Medicine.

Washington People: Lilianna Solnica-Krezel

Julia Evangelou Strait — 2012-04-06 00:00:00

Robert Boston

Lilianna Solnica-Krezel, PhD, professor and head of the Department of Developmental Biology, examines zebrafish with Isabelle Roszko, PhD, postdoctoral research scholar. “She’s one of the top people in the world in using genetics to understand the very earliest stages of development,” says Herbert W. “Skip” Virgin, MD, PhD, the Edward Mallinckrodt Professor and head of the Department of Pathology and Immunology.

Growing up in the picturesque town of Sandomierz in southeastern Poland, Lilianna Solnica-Krezel, PhD, was a serious student and an uncommonly avid reader.

Though she read widely and voraciously, there always was the thought that, in communist Poland, not all the books she might want to read were allowed.

Today, Lila (pronounced “Leela”) Solnica-Krezel, professor and head of the Department of Developmental Biology at Washington University School of Medicine in St. Louis, is a leading expert in understanding the earliest stages of life’s development.

A fitting position, perhaps, for someone who spent her adolescence helping her older brother perform field biology experiments and her teenage years reading Biologia, the Polish translation of Claude Villee’s seminal textbook Biology from cover to cover, in her spare time.

“It was a brick,” Solnica-Krezel says with a laugh. “But I had a lot of time on my hands with only two government-run TV channels. I read the chapter about the kidney, and it was fascinating. Then I read the chapter about the heart, and the chapter about neurons and a chapter about genetics. I just read chapter after chapter because it was completely amazing to me how beautiful the human body is.”

Driven by her own fascination, and encouraged by supportive parents who valued education, and her brother, Bogdan, who was studying to become a doctor, Solnica-Krezel chose to pursue an intensive five-year program in biology at the University of Warsaw.

Political protest and organic chemistry

But beyond her studies, Solnica-Krezel attended the University of Warsaw at an important time in Poland’s political history. It was 1980, and the pro-democracy Solidarity movement was gaining momentum.

“We were all extremely optimistic about what was going to happen with the country,” she says. “But in my second year, things started to go wrong.”

When the university’s administration was removed for its progressive politics, Solnica-Krezel joined fellow students in a strike that occupied university buildings. They slept on and under tables, ate food brought in by supporters and showered when they could.

But even amidst such upheaval, Solnica-Krezel never lost focus. When she wasn’t engaged in long political discussions with fellow strikers, she studied the organic chemistry text she had brought along.

“One of the reasons I know organic chemistry so well is I had this book with me for the month-long strike,” she says with a laugh.

But on Dec. 12, 1981, the Solidarity movement was banned, and the strike was disbanded.

“When I woke up the next morning, the telephones did not work,” she says. “And Gen. Wojciech Jaruzelski was on TV and radio announcing martial law in Poland. That day, I went into the old city of Warsaw, and I saw tanks everywhere.”

Poland remained under martial law for two more years. But even after the strict military control was lifted, Solnica-Krezel says there was great pessimism that the situation would ever improve.

“I knew if I wanted to advance in a scientific career in Poland, I probably would have to become a party member,” she says. “And that’s what I didn’t want to do.

“I think what I bring from my experience of that period in Poland is a great appreciation for intellectual freedom.”

This political environment, combined with the knowledge that she could not do the experiments that she pored over in scientific journals, drove her to apply to graduate schools outside of Poland.

Led by curiosity

She landed at the University of Wisconsin-Madison, where she studied slime mold genetics.

But it was a paper about fruit flies (“Mutations affecting segment number and polarity in Drosophila,” by Christiane Nüsslein-Volhard and Eric Wieschaus) that she read in Nature that showed her the power of genetics in unraveling the role of genes in the early life of an organism.

The work outlined in the paper, for which the authors later received a Nobel Prize, described how switching off certain genes during development of the fruit fly led to specific defects in the embryo and allowed scientists to identify what the genes did.

“It was just beautiful logic,” Solnica-Krezel says. “I read this paper and thought, ‘I want to apply that logic to vertebrate development.’”

“And to be able to do this kind of work, and be led by my own curiosity, has been an amazing gift throughout my life,” she says.

Following her curiosity, Solnica-Krezel has devoted her career to understanding the mysterious processes that govern how a mass of cells becomes a recognizable organism — whether a fruit fly, a zebrafish or a human.

This early phase in which the embryo begins to form a body plan is called gastrulation.

“It is not birth, marriage or death, but gastrulation which is truly the most important time in your life,” Solnica-Krezel says, quoting the well-known developmental biologist Lewis Wolpert, PhD.

“When the embryo completes its first cellular divisions, it’s just a heap of cells,” she says. “I want to understand how these cells decide what to become — the head or the trunk, a brain cell or a blood cell. What are the rules? And what are the instructions that tell these cells how to move around, so that a prospective brain cell goes to the head and the embryonic heap of cells reshapes itself into an animal body?”

Developing zebrafish and scientists

Solnica-Krezel’s favorite organism for studying gastrulation is the zebrafish, and for good reason. As vertebrates, they are more closely related to humans than the fruit fly. And unlike mice, zebrafish embryos are transparent and develop outside the mother, making the cellular processes going on inside easier to observe.

Courtesy photo

From left: Husband, Andrzej Krezel, PhD; Lilianna Solnica-Krezel, PhD; sister-in-law, Krystyna Solnica; and brother, Bogdan Solnica, MD, PhD, in Santorini, Greece.

She also played an integral role in an important series of studies that established the zebrafish as a major model organism in science, alongside the long-studied fruit fly and mouse. And under Solnica-Krezel’s leadership, Washington University has established one of the largest and most automated zebrafish facilities in the world.

“She’s one of the top people in the world in using genetics to understand the very earliest stages of development,” says Herbert W. “Skip” Virgin, MD, PhD, the Edward Mallinckrodt Professor and head of the Department of Pathology and Immunology. “The quality of her work and her ability to extend the zebrafish model system into new areas is quite striking and an important mark of the kind of person we wanted in a leadership position here. She’s also a great mentor — she has recruited outstanding young people to the faculty.”

Indeed, Solnica-Krezel says one of the roles she finds most fulfilling is helping to guide younger scientists as they begin their careers.

“I knew I loved the process of scientific discovery — bringing my ideas to life, no matter how challenging that might be,” she says. “But something I didn’t appreciate until later was the amazing satisfaction of seeing my undergraduate and graduate students and postdoctoral fellows do well.

“It’s just a joy to help these young people grow as scientists and succeed.”

Fast facts about Lilianna Solnica-Krezel

Born: Jelenia Gora, Poland
Currently reading: The Best Advice I Ever Got: Lessons from Extraordinary Lives by Katie Couric; The Immortal Life of Henrietta Lacks by Rebecca Skloot; and the Polish translation of Self by Yann Martel
Hobbies: Reading, cooking, travel and raising orchids
Family: Husband, Andrzej Krezel, PhD, research associate professor of biochemistry and molecular biophysics at Washington University; brother, Bogdan Solnica, MD, PhD, a physician-scientist at Jagiellonian University in Krakow, Poland, and his family

Morris to deliver Friedman lecture

2012-04-09 00:00:00

John C. Morris, MD, the Harvey A. and Dorismae Hacker Friedman Distinguished Professor of Neurology and director of the Alzheimer’s Disease Research Center at Washington University School of Medicine, will deliver the 2012 Friedman lecture at 3 p.m. April 30 in Graham Chapel. His lecture is titled “The Aging Mind: Realities and Myths.”

A reception will follow at 5 p.m. at the Danforth University Center.

Morris, internationally known for his work on cognitive impairment, was the founding director of the Harvey A. Friedman Center for Aging. Nancy Morrow-Howell, PhD, was recently named director of the Friedman Center for Aging, which is now a part of Washington University’s Institute for Public Health.

In addition, the Alene and Meyer Kopolow Award and the Dorismae and Harvey A. Friedman Award will be presented on behalf of the Friedman Center for Aging and the Barnes-Jewish Hospital Foundation.

The event is free and open to the public. To register, go to http://bit.ly/Apr30FCA.

Problems in recycling cellular waste linked to clogged arteries

Jim Dryden — 2012-04-04 00:00:00

Audio

Semenkovich lab

In a section of a mouse aorta affected by atherosclerosis (above), inflammatory cells undergo a process called autophagy (shown in yellow), in which they digest and recycle cellular garbage. The new research shows that a breakdown in autophagy contributes to clogged arteries.

Researchers at Washington University School of Medicine in St. Louis have found that problems with a digestive process in cells can clog arteries.

The finding could provide a target for future therapies aimed at preventing or reversing atherosclerosis, a common disorder in which fat, cholesterol and other substances build up in the walls of arteries and block blood flow.

The study found that disruptions in cell digestion, called autophagy, caused drastic inflammation in artery walls, a common characteristic of atherosclerosis.

The researchers report the finding in the April 4 issue of the journal Cell Metabolism.

“Good digestion in the cell allows it to recycle garbage,” says first author Babak Razani, MD, PhD, an instructor in medicine. “If too much protein builds up or parts of the cell become dysfunctional, this digestive process recycles and reuses parts of cells and discards parts that aren’t working properly.”

Razani

The researchers note that ancient Egyptian physicians believed vascular disease was the result of an accumulation of undigested food in blood vessels. The new findings suggest that those ancient scholars were partly right.

“People have developed atherosclerosis for thousands of years, even before they ate fast food or worked at sedentary jobs,” says senior investigator Clay F. Semenkovich, MD. “The ancient hypothesis about chronic diseases said that many problems came from undigested food, and from our experiments, it looks like there is, in fact, a good deal of undigested cellular food that collects in atherosclerotic lesions.”

Razani and Semenkovich, the Herbert S. Gasser Professor of Medicine, professor of cell biology and physiology and director of the Division of Endocrinology, Metabolism and Lipid Research, worked with Herbert W. Virgin IV, MD, PhD, the Edward Mallinckrodt Professor and head of the Department of Pathology and Immunology and professor of molecular microbiology and of medicine. The interdisciplinary team studied mice with high cholesterol that develop atherosclerosis. They found that as plaques formed in the blood vessels and the atherosclerosis got worse, the mice were also having problems with cellular digestion.

“This recycling process keeps cells healthy, and a number of disease states have been linked to dysfunction in that process,” Razani says. “Atherosclerosis involves cellular dysfunction, so you could imagine that cellular recycling might be important, but no one had tested the idea.”

Semenkovich

Atherosclerosis is common in the U.S. and throughout the Western world, and heart disease linked to atherosclerosis is the leading cause of heart attack and stroke in Western countries. Nearly 800,000 heart attacks and a similar number of strokes occur each year in the U.S., causing more than one in every five deaths.

Razani says another key component of atherosclerosis is chronic inflammation in the walls of arteries, caused mainly by the accumulation of white blood cells called macrophages. And it’s in those macrophages where autophagy breaks down.

“When we disrupted the recycling of cellular waste in macrophages, the animals had much more atherosclerosis,” he says. “And the reason was that these mice had a lot more inflammation.”

Earlier studies had speculated that disrupting cellular digestion and recycling might lead to more inflammation, and in this study the researchers showed that when the cellular digestion mechanism was impaired, mice released very large amounts a key inflammatory marker called interleukin 1-beta (IL-1ß).

“When recycling was disrupted in macrophage cells, IL-1ß went through the roof,” Razani says. “We discovered that the mechanism generating that IL-1ß was a collection of proteins called an inflammasome, which is, essentially, several proteins that come together to tell the system to secrete inflammatory substances such as IL-1ß. When there is a problem with recycling of cellular waste, these inflammatory proteins go into hyper-drive.”

The more of the inflammatory substance secreted, the higher the levels of inflammation and worsened atherosclerosis. The new study suggests that vicious cycle centers on cellular digestion and recycling. The next step will involve searching for ways to ramp up the cellular digestion process. The researchers already have identified strategies that might be useful.

“One is fasting,” Semenkovich says. “In the fasting state, cells use this mechanism to recycle proteins and discard garbage. Increased autophagy may be why a low-calorie diet reduces atherosclerosis and heart attacks.”

A drug used to prevent organ rejection in transplant patients also might point the way to more effective therapies. Previous studies have found that the drug, called rapamycin, can reduce atherosclerosis in mice. The researchers are planning to test rapamycin in mice to see whether it induces cell recycling in animals with atherosclerosis.

The problem is that rapamycin has a lot of side effects, Semenkovich says. It may decrease atherosclerosis, but lipids get much worse, so people are very nervous about giving the drug to patients who already have cholesterol problems. However, if it were possible to deliver rapamycin, or a similar substance, to specific areas where plaques are located, that might be a potential strategy for treatment.

“It’s probably not the best drug to use in people, but if we can demonstrate that it is indeed reducing atherosclerosis by revving up cell digestion and recycling, then we’d have a proof of principle,” Razani says. “From there, we might be able to look for ways to deliver the drug directly to plaques or perhaps find other drugs that improve autophagy and may help prevent or delay some of the catastrophic problems associated with atherosclerosis.”

Razani B, Feng C, Coleman T, Emanuel R, Wen H, Hwang S, Ting JP, Virgin HW, Kastan MB, Semenkovich CF, Autophagy links inflammasomes to atherosclerotic progression. Cell Metabolism, vol. 15(4), April 4, 2012.

Funding for this research comes from grants awarded by the National Heart, Lung, and Blood Institute (NHLBI) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the National Institutes of Health (NIH), as well as the Physician Scientist Training Program and Cardiovascular Training Grant at Washington University.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Ultrasound screening finds more breast cancer, false positives may outweigh that benefit

Michael C. Purdy — 2012-04-04 00:00:00

Adding ultrasound exams to annual breast cancer screening can help physicians detect more cancers in women who have dense breasts and are at a higher risk of breast cancer, according to a three-year, multi-center trial appearing April 4 in the Journal of the American Medical Association.

However, ultrasound has a downside: risks of false positive results and unnecessary biopsies that may outweigh the scans’ benefits.

“In women at high risk for breast cancer with mammographically dense breasts, magnetic resonance imaging (MRI) is a more effective supplement to mammograms than ultrasound,” says co-author Dione Farria, MD, a breast imaging radiologist at the Alvin J. Siteman Cancer Center at Washington University School of Medicine and Barnes-Jewish Hospital.

The study was conducted through the American College of Radiology Imaging Network (ACRIN), with funding from The Avon Foundation and the National Cancer Institute. A portion of the 2,700 subjects were seen at the Joanne Knight Breast Health Center at the Siteman Cancer Center. All participants received yearly mammograms over the course of three years; in addition, researchers scanned the study participants annually with ultrasound.

Ultrasound detected additional cancers and substantially increased the number of recommended biopsies and follow-up studies. At the first exam, adding screening ultrasound resulted in a 15 percent increase in imaging workups and a 7.8 percent increase in biopsy recommendations. However, significantly fewer of the women sent for biopsies on the basis of ultrasound alone had cancer compared with those who had biopsies based on mammography results.

After three rounds of screening with mammography and ultrasound, 600 subjects had screening contrast-enhanced breast MRI. The additional MRI scans detected cancer in about 1.5 percent of these women, even though they had normal mammograms and ultrasounds for three years. This means the cancer yield from adding MRI scans is four times greater than that provided by adding ultrasound.

All of the ultrasounds in the study were performed by breast imaging specialists. The results may not apply to many clinical practices because they commonly rely on non-physicians or automated systems to perform ultrasound exams. Additional patient workups and false-positive (non-cancer) biopsies may occur more frequently when breast imaging specialists are not performing the studies, the researchers suggest.

Since the study recruited women who were of higher-than-average risk for breast cancer, these results do not apply to women with average risk, even if they have dense breasts.

“As physicians, we have to carefully weigh the benefits of additional tests to detect cancer against the chance of requesting potentially unnecessary biopsies,” Farria says. “We must also remember that ultrasound and MRI do not replace the need for annual mammography. They are tools physicians sometimes use to supplement mammography.”

According to the American Cancer Society, women with a 20 percent to 25 percent or higher lifetime risk for breast cancer should obtain annual breast MRI screening in addition to annual mammography.

Farria says the Joanne Knight Breast Health Center has no current plan to offer screening ultrasound for breast cancer.

Berg WA, Zhang Z, Lehrer D, Jong RA, Pisano ED, Barr RG, Bohm-Velez M, Mahoney MC, Evans WP III, Larsen LH, Morton MJ, Mendelson EB, Farria DM, Cormack JB, Marques HS, Adams A, Yeh NM, Gabrielli G. Detection of breast cancer with addition of annual screening ultrasound or a single screening MRI to mammography in women With elevated breast cancer risk. Journal of the American Medical Association, April 4, 2012.

Funding from the Avon Foundation and the National Cancer Institute supported this research.

Ob/gyn's dream for women's hospital in Africa comes true

Diane Duke Williams — 2012-04-03 00:00:00

Courtesy photo

Lewis Wall, MD (center), addresses the crowd at the grand opening of the Danja Fistula Center in Niger, Africa.

For Lewis Wall, MD, a dream has come true.

For almost 20 years, he worked doggedly to build a hospital in one of the world’s poorest countries to treat women with a devastating childbirth injury. His dream became a reality in February, when a 42-bed hospital opened in Niger, Africa. The facility is dedicated to repairing fistulas, wounds inflicted by prolonged labor, which leave women — and often girls — steadily leaking urine and sometimes feces.

“It was wonderful to be there that day,” says Wall, professor of obstetrics and gynecology at Washington University School of Medicine in St. Louis and a physician at Barnes-Jewish Hospital. “This hospital may seem small by American standards, but it will make a large difference in the lives of so many African women who have suffered needlessly for too long.”

For most of his career, Wall’s passion has been to end the scourge of fistulas in Africa. He first saw the miserable lives of women with this injury when he worked as an anthropologist in West Africa in his mid-20s.

Fistulas are easy to repair in developed countries. But in Africa, many women don’t have access to medical care during childbirth or afterward if injuries occur.

Fistulas occur in women of all ages but are more common among those who marry young and whose narrow pelvises make them susceptible to childbirth trauma. Many of these women are divorced by their husbands, cast out by their families and must eke out a meager living with no marketable skills. Often, they live humiliating, desolate lives on the edge of their villages, with only rags to catch their waste.

“When these girls get a fistula, life is basically over for them,” says Wall, who enrolled in medical school at age 27 because he decided the world needed more doctors than anthropologists. “They become social pariahs. With an inexpensive surgical repair, we are able to give them back their life and dignity. It’s astonishing.”

In 1995, after visiting a large fistula hospital in Ethiopia, Wall envisioned opening a similar hospital in West Africa, where fistulas are prevalent.

He founded the nonprofit Worldwide Fistula Fund to raise money to construct hospitals to repair fistulas. The fund has helped support and build a number of fistula centers in Africa. It also has provided money to train local doctors to perform the surgical procedure and to help raise awareness of the problem.

In Africa, girls often marry as young as 12. Many cannot deliver babies safely because their birth canals are not fully developed. These young women may labor for five or six days only to deliver a stillborn baby. The treatment for obstructed labor is a cesarean section, but this care is not available in many parts of Africa. As a result, women often develop fistulas.

In Niger, among the scattered grasslands on the edge of the Saharan desert, people grow millet and raise sheep, cattle and goats. The majority of people live on less than $1 a day. There are very few personal or private resources for medical clinics or hospitals.

Getting the Danja Fistula Center built in Niger was much harder than Wall anticipated, he says.

“I thought I was fairly realistic because I had lived in West Africa for two years,” he says. “But we had to contend with unexpected obstacles — bureaucratic hassles, insects, a lack of communication and supplies, and people who thought their own interests would be threatened.”

He also had to raise about $1 million.

Large contributions from the Trio Foundation of St. Louis, South African musician Dave Matthews and an executive at Merrill Lynch helped the Worldwide Fistula Fund reach its goal. The fund also received many small personal donations, including $35 from a potluck hosted by a group of elderly women in New York.

“This was not my individual achievement — it was from the efforts of thousands of people,” he says.

Mark Manary, MD, the Helene B. Roberson Professor of Pediatrics, understands some of the obstacles Wall faced in getting the hospital built. Manary has spent more than 15 years treating malnourished children in Africa. He started a nonprofit organization, Project Peanut Butter, that each year produces between 1,000 to 1,250 tons of a peanut-butter mixture in Africa to treat children with malnutrition.

“Wall’s work removes a huge burden, a permanent scar from the lives of thousands of African women,” Manary says. “I admire his commitment and persistence.”

Each year, about 1,000 women will have fistula surgery in the hospital, affiliated with an existing leprosy hospital run by a Christian missionary organization. Some will travel hundreds of miles in trucks and buses to get there.

Aside from repairing fistulas, the hospital will oversee outreach efforts to promote maternal health and reduce childbirth deaths. It also will educate women about microfinance to teach them about business and empowerment.

The new hospital is part of a grand vision to eradicate fistulas worldwide by building fistula centers that would serve as focus points for maternity care and public health outreach in the world’s poorest countries.

“For starters, we hope this hospital will help countless women and alleviate human suffering,” Wall says. “We also hope it will advance women’s rights and gender equality. But for now, I’m just going to enjoy this accomplishment. There still is a lot of work to d0.”

New imaging technique could speed cancer detection

2012-04-03 00:00:00

A new imaging technique relies on light and sound to create detailed, color pictures of tumors deep inside the body. The technology, called photoacoustic tomography, may eventually help doctors diagnose cancer earlier than is now possible and to more precisely monitor the effects of cancer treatment — all without the radiation involved in X-rays and CT scans or the expense of MRIs.

Clinical trials are in the planning stages, but studies in animal models have given researchers a lot to get excited about. That’s because the technology can easily penetrate the body’s tissues to visualize tumors at depths never before possible.

Wang

“This technology is potentially a game changer, both in how we monitor cancer and in how soon we know it’s there,” says biomedical engineer Lihong V. Wang, PhD., who led the team of developers at Washington University in St. Louis.

For example, the technique could reveal the presence of cancer earlier by showing oxygen use by tissues. Excessive oxygen-burning, called hypermetabolism, is a hallmark of the disease. In the early stages, there isn’t much else to go on, so photoacoustic tomography could alert physicians to the presence of the disease at its earliest stage, Wang says.

Wang will explain the technology April 3 at the annual meeting of the American Association for Cancer Research in Chicago. Wang’s presentation follows his publication of a related paper March 23 in Science.

Wang, who is affiliated with the Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine, is working with Washington University physicians to evaluate the technology for four uses: identifying the sentinel lymph nodes for breast cancer staging, which may eliminate the need for surgical lymph node biopsies; monitoring early response to chemotherapy; imaging melanomas; and imaging the gastrointestinal tract.

A major challenge for diagnosing cancer is the inability to see small tumors growing in the body. Physicians have come to accept the grayness of X-ray images and CT scans (which are based on X-rays), where structures appear as lights and shadows. But they are a poor substitute for “photographs” of our insides.

No such photographs exist because light can’t penetrate soft tissue. Tissues scatter light, which limits the ability to see anything beyond the depth of about a millimeter. But scattering doesn’t destroy the light, which can reach a depth of about 7 centimeters, or about 3 inches.

Photoacoustic imagery brings together the best of both worlds — light and sound. It converts light absorbed by soft tissues in the body into sound waves, which easily penetrate tissues. The tissue to be imaged is then irradiated by a nanosecond-pulsed laser at an optical wavelength.

Absorption of light by molecules beneath the surface creates a thermally induced pressure jump that launches sound waves, which are measured by ultrasound receivers at the body’s surface and reassembled to create what is, in effect, a photograph.

Photoacoustic images have a much higher contrast than X-ray images because there are many highly colored molecules in the body that naturally serve as contrast agents. These include hemoglobin, which changes color as it gains or loses oxygen, but also melanin, the pigment that makes moles dark, and DNA, which in its condensed form in the cell nucleus is darker than the cell cytoplasm.

With a little help from organic dyes or genes engineered to express colorful products, photoacoustic tomography can also image tissues, such as lymph nodes, that would otherwise blend in with their surroundings.

“Every issue of every top journal publishes exciting lab discoveries, but only a tiny fraction of them are ever translated into clinical practice,” he says. “My hope is that photoacoustic tomography can help translate microscopic lab discoveries into macroscopic clinical practice.”

'Positive stress' helps protect eye from glaucoma

Michael C. Purdy — 2012-04-03 00:00:00

Jeff Gidday, PhD

Scientists have found a way in mice to prevent damage to the optic nerves that normally occurs in glaucoma. Using high-power micrographs like this one of the optic nerve in cross-section, they can quantify glaucoma damage to the axons of the retinal ganglion axons passing through the nerve. In this image, those axons are green, and the branches and nuclei of the astrocytes surrounding them are red and blue, respectively.

Working in mice, scientists at Washington University School of Medicine in St. Louis have devised a treatment that prevents the optic nerve injury that occurs in glaucoma, a neurodegenerative disease that is a leading cause of blindness.

Researchers increased the resistance of optic nerve cells to damage by repeatedly exposing the mice to low levels of oxygen similar to those found at high altitudes. The stress of the intermittent low-oxygen environment induces a protective response called tolerance that makes nerve cells — including those in the eye — less vulnerable to harm.

The study, published online in Molecular Medicine, is the first to show that tolerance induced by preconditioning can protect against a neurodegenerative disease.

Stress is typically thought of as a negative phenomenon, but senior author Jeffrey M. Gidday, PhD, associate professor of neurological surgery and ophthalmology, and others have previously shown that the right kinds of stress, such as exercise and low-oxygen environments, can precondition cells and induce changes that make them more resistant to injury and disease.

Scientists previously thought tolerance in the central nervous system only lasted for a few days. But last year Gidday developed a preconditioning protocol that extended the effects of tolerance from days to months. By exposing mice to hypoxia, or low oxygen concentrations, several times over a two-week period, Gidday and colleagues triggered an extended period of tolerance. After preconditioning ended, the brain was protected from stroke damage for at least 8 weeks.

“Once we discovered tolerance could be extended, we wondered whether this protracted period of injury resistance could also protect against the slow, progressive loss of neurons that characterizes neurodegenerative diseases,” Gidday says.

To find out, Gidday turned to an animal model of glaucoma, a condition linked to increases in the pressure of the fluid that fills the eye. The only treatments for glaucoma are drugs that reduce this pressure; there are no therapies designed to protect the retina and optic nerves from harm.

Scientists classify glaucoma as a neurodegenerative disease based on how slowly and progressively it kills retinal ganglion cells. The bodies of these cells are located in the retina of the eye; their branches or axons come together in bundles and form the optic nerves. Scientists don’t know if damage begins in the bodies or axons of the cells, but as more and more retinal ganglion cells die, patients experience peripheral vision loss and eventually become blind.

For the new study, Yanli Zhu, MD, research instructor in neurosurgery, induced glaucoma in mice by tying off vessels that normally allow fluid to drain from the eye. This causes pressure in the eye to increase. Zhu then assessed how many cell bodies and axons of retinal ganglion cells were intact after three or 10 weeks.

The investigators found that normal mice lost an average of 30 percent of their retinal ganglion cell bodies after 10 weeks of glaucoma. But mice that received the preconditioning before glaucoma-inducing surgery lost only 3 percent of retinal ganglion cell bodies.

“We also showed that preconditioned mice lost significantly fewer retinal ganglion cell axons,” Zhu says.

Gidday currently is investigating which genes are activated or repressed by preconditioning. He hopes to identify the changes in gene activity that make cells resistant to damage.

“Previous research has shown that there are literally hundreds of survival genes built into our DNA that are normally inactive,” Gidday says. “When these genes are activated, the proteins they encode can make cells much less vulnerable to a variety of injuries.”

Identifying specific survival genes should help scientists develop drugs that can activate them, according to Gidday.

Neurologists are currently conducting clinical trials to see if stress-induced tolerance can reduce brain damage after acute injuries like stroke, subarachnoid hemorrhage or trauma.

Gidday hopes his new finding will promote studies of tolerance’s potential usefulness in animal models of Parkinson’s disease, Alzheimer’s disease and other neurodegenerative conditions.

“Neurons in the central nervous system appear to be hard-wired for survival,” Gidday says. “This is one of the first steps in establishing a framework for how we can take advantage of that metaphorical wiring and use positive stress to help treat a variety of neurological diseases.”

Zhu Y, Zhang L, Schmidt JF, Gidday JM. Glaucoma-induced degeneration of retinal ganglion cells prevented by hypoxic preconditioning: A model of “glaucoma tolerance.” Molecular Medicine, published online.

This study was funded by the National Institutes of Health (NIH), the American Health Assistance Foundation, the National Glaucoma Foundation, the NIH Neuroscience Blueprint Core Grant and the Spastic Paralysis Research Foundation of the Illinois-Eastern Iowa District of Kiwanis International.

Washington University School of Medicine’s 2,100 employed and volunteer faculty physicians also are the medical staff of Barnes-Jewish and St. Louis Children’s hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation, currently ranked sixth in the nation by U.S. News & World Report. Through its affiliations with Barnes-Jewish and St. Louis Children’s hospitals, the School of Medicine is linked to BJC HealthCare.

Occupational therapy students get older adults 'CarFit'

2012-04-05 00:00:00

Ray Marklin

CJ Burhans (left) and Christina Davison, both doctoral students in the Program in Occupational Therapy, work with Marie Marklin of St. Louis during the CarFit event March 31 at the School of Medicine. Drivers who came to the event were evaluated by WUSTL occupational therapy students to ensure the vehicles were properly adjusted for the driver. The 15- to 20-minute CarFit assessment measures for a proper “fit” based on a 12-point checklist, including safety belt use, steering wheel tilt, head restraint setting, positioning to air bag, line of sight over steering wheel, positioning to gas/brake pedals and other adjustments. CarFit is an educational program created by the American Society on Aging and developed in collaboration with the American Automobile Association, AARP and American Occupational Therapy Association.

Ten WUSTL faculty to receive Outstanding St. Louis Scientists Awards

Beth Miller and Diana Lutz — 2012-04-02 00:00:00

The Academy of Science of St. Louis will honor 10 faculty members from Washington University in St. Louis for their contributions and leadership in science and medicine.

The academy will present the Outstanding St. Louis Scientists Awards at its 18th annual dinner Thursday, April 19, at the Chase Park Plaza Hotel.

The awards are designed to focus attention on St. Louis individuals and institutions known around the world for scientific contributions to research, industry and quality of life.

The WUSTL winners:

Michael W. Friedlander, PhD, professor emeritus of physics in Arts & Sciences, will receive the Science Educator Award.

For more than four decades, Friedlander has played a major role in science education both locally and nationally. Each semester since 1994, he has organized a series of four “Saturday Science” public lectures in Department of Physics. The 200-seat lecture hall is often filled.

Beyond the region, Friedlander has been an influence for science understanding with his five books written for the general public. The two published by Harvard University Press describe the history of the study of cosmic rays and what is now known about these energetic particles — an area of astrophysics to which he has contributed significant original research.

Jeffrey I. Gordon, MD, the Robert J. Glazer Distinguished Professor of Pathology and Immunology and founding director of the Center for Genome Sciences and Systems Biology, will receive the Peter H. Raven Lifetime Achievement Award.

Gordon is recognized for his leadership in “establishing the field of human microbiome research.”

His work and this field are providing new understanding of the origins of our biological differences, new approaches for understanding how changes in our cultural traditions and lifestyles are impacting our health and risk for various diseases and new therapeutic approaches to illnesses previously thought to have a microbial component.

A central focus of his lab is the relationship between gut microbial communities and the nutritional status of infants, children and adults living in Westernized and non-Westernized societies.

Scott J. Hultgren, PhD, the Helen Lehbrink Stoever Professor of Molecular Microbiology and director of the Center for Women’s Infectious Disease Research, will receive the Fellows Award.

Hultgren, one of the world’s most accomplished microbiologists, studies urinary tract infections, the most common infectious complaint of women in primary outpatient clinics.

His research has changed scientists’ understanding of the molecular basis of chronic and recurrent urinary tract infections. In addition, he is developing new antibiotics and vaccines to prevent and treat the infections.

Also active in women’s health policy, Hultgren contributed to the strategic plan developed by the Office of Research in Women’s Health to set priorities for research at the National Institutes of Health (NIH). Hultgren was elected into the National Academy of Sciences in 2011.

Timothy J. Ley, MD, the Lewis T. and Rosalind B. Apple Chair in Oncology, professor of medicine and of genetics, and associate director of The Genome Institute; Elaine R. Mardis, PhD, professor of genetics and of molecular microbiology, co-director and director of technology development of The Genome Institute; and Richard K. Wilson, PhD, professor of genetics and director of The Genome Institute, will share the George Engelmann Interdisciplinary/Collaborative Science Award, a new award that recognizes outstanding achievement in science, engineering or technology that results from collaboration among two or more individuals across disciplinary and/or institutional boundaries.

Ley, Mardis and Wilson are recognized for collaborative work that has helped to lay the foundation of cancer genomic research, diagnostics and therapeutics. The academy recognizes them for their unique look at cancer, which has helped to bring in a new era of personalized medicine.

The academy also commended them for their participation in a $65 million partnership with St. Jude Children’s Hospital to define the gene mutation spectrum in pediatric cancer. That work is creating a public database that will be shared with the international scientific community to speed progress toward fighting childhood cancers.

Audrey R. Odom, MD, PhD, assistant professor of pediatrics and of molecular microbiology, will receive the Innovation Award.

Odom is dissecting a key metabolic pathway in malaria that is not found in humans and provides a novel target for drug development.

Worldwide, there is an urgent need for new drugs to treat malaria, which causes more than a million deaths per year, mostly in young children. Odom’s lab focuses on improving the fundamental understanding of the basic molecular and cellular biology of the malaria parasite to identify new antimalarial drug targets.

Mabel L. Purkerson, MD, professor emerita of medicine, will receive the Trustee Award.

For more than 40 years, Purkerson served as a clinician, teacher, investigator and administrator at the School of Medicine. The academy recognizes her as a physician/scientist, leading by example, focusing on excellence and being open to new opportunities and techniques.

She used an interdisciplinary approach to find new strategies and tools to further her research, allowing her to make substantial contributions in the field of kidney physiology. These achievements led to her becoming the first female full professor in the Department of Medicine.

Larry J. Shapiro, MD, executive vice chancellor for medical affairs and dean of the School of Medicine, will receive the academy’s individual Science Leadership Award.

The academy recognizes Shapiro for his accomplishments in transforming the medical school’s research enterprise to focus on clinical and translational research, interdisciplinary teams, visionary genomics and regional partnerships. The academy commended him for implementing BioMed 21, the university’s initiative to facilitate multidisciplinary, collaborative research and rapidly apply breakthroughs to patient care.

Stuart A. Solin, PhD, the Charles M. Hohenberg Professor of Experimental Physics, will receive the James B. Eads Award.

Solin is recognized for significant discoveries and initiatives in the fields of condensed matter physics and nanosciences. Most recently, as inventor of the EMR (Extraordinary MagnetoResistance) sensor device concept, he has seeded a hugely important area of research, which has now been taken up extensively by industry around the globe.

His work has the capacity to revolutionize data storage and retrieval in computers. Stuart has already started work on the biological and medical application of his new class of sensors. Indications are that EMR and EEC (Extraordinary Electroconductance) nanoscale sensors can be used for cancer detection.

DNA sequencing lays foundation for personalized cancer treatment

Caroline Arbanas — 2012-04-01 00:00:00

Scientists at Washington University School of Medicine in St. Louis are using powerful DNA sequencing technology not only to identify mutations at the root of a patient’s tumor – considered key to personalizing cancer treatment – but to map the genetic evolution of disease and monitor response to treatment.

“We’re finding clinically relevant information in the tumor samples we’re sequencing for discovery-oriented research studies,” says Elaine Mardis, PhD, co-director of The Genome Institute at the School of Medicine. “Genome analysis can play a role at multiple time points during a patient’s treatment, to identify ‘driver’ mutations in the tumor genome and to determine whether cells carrying those mutations have been eliminated by treatment.”

This work is helping to guide the design of future cancer clinical trials in which treatment decisions are based on results of sequencing, says Mardis, who is speaking April 1 at the opening plenary session of the American Association for Cancer Research annual meeting in Chicago. She also is affiliated with the Siteman Cancer Center at the School of Medicine and Barnes-Jewish Hospital.

Mardis

To date, Mardis and her colleagues have sequenced all the DNA – the genome – of tumor cells from more than 700 cancer patients. By comparing the genetic sequences in the tumor cells to healthy cells from the same patient, they can identify mutations underlying each patient’s cancer.

Already, information gleaned through whole-genome sequencing is pushing researchers to reclassify tumors based on their genetic makeup rather than their location in the body. In patients with breast cancer, for example, Mardis and her colleagues have found numerous driver mutations in genes that have not previously been associated with breast tumors.

A number of these genes have been identified in prostate, colorectal, lung or skin cancer, as well as leukemia and other cancers. Drugs that target mutations in these genes, including imatinib, ruxolitinib and sunitinib, while not approved for breast cancer, are already on the market for other cancers.

“We are finding genetic mutations in multiple tumor types that could potentially be targeted with drugs that are already available,” Mardis says.

She predicts, however, that it may require a paradigm change for oncologists to evaluate the potential benefits of individualized cancer therapy. While clinical trials typically involve randomly assigning patients to a particular treatment regimen, a personalized medicine approach calls for choosing drugs based on the underlying mutations in each patient’s tumor.

“Having all treatment options available for every patient doesn’t fit neatly into the confines of a carefully designed clinical trial,” Mardis acknowledges. “We’re going to need more flexibility.”

When during the course of cancer mutations develop also is likely to be important in decisions about treatment. In a recent study, Mardis and her team mapped the genetic evolution of leukemia and found clues to suggest that targeted cancer drugs should be aimed at mutations that develop early in the course of the disease.

Using “deep digital sequencing,” a technique developed at The Genome Institute, they sequenced individual mutations in patients’ tumor samples more than 1,000 times each. This provides a read-out of the frequency of each mutation in a patient’s tumor genome and allowed the researchers to map the genetic evolution of cancer cells as the disease progressed.

They found that as cancer evolves, tumors acquire new mutations but always retain the original cluster of mutations that made the cells cancerous in the first place. Their discovery suggests that drugs targeted to cancer may be more effective if they are directed toward genetic changes that occur early in the course of cancer. Drugs that target mutations found exclusively in later-evolving cancer cells likely may not have much effect on the disease because they would not kill all the tumor cells.

Mardis says that sequencing the entire genome of cancer cells is essential to piecing together an accurate picture of the way cancer cells evolve. If the researchers had sequenced only the small portion of the genome that involves genes, they would not have had the statistical power to track the frequency of mutations over time. (Only 1 to 2 percent of the genome consists of genes.)

In another study, a phase III clinical trial of post-menopausal women with estrogen-receptor positive breast cancer, the Washington University researchers have shown that sequencing can help to predict which women will respond to treatment with aromatase inhibitors. These estrogen-lowering drugs are often prescribed to shrink breast tumors before surgery. But only about half of women with estrogen-receptor positive breast cancer respond to these drugs, and doctors have not been able to predict which patients will benefit.

Interestingly, by sequencing patients’ breast tumors before and after aromatase inhibitor therapy, the researchers identified substantive genomic changes that had occurred in responsive patients, whereas the genomes of unresponsive patients remained largely unchanged by the therapy.

“No one has ever looked at treatment response at this level of resolution,” Mardis says. “It’s so obvious who is responding.”

In addition, the researchers have identified a series of mutations in the breast tumors that have corresponding small-molecule inhibitor drugs that target defective proteins. This finding indicates that for women who are not responding to aromatase inhibitors, treatment options may include combining conventional chemotherapy with the indicated small-molecule inhibitor.

“We felt it was important to show there could be therapeutic options available to patients who are resistant to aromatase inhibitors,” Mardis says. “As we move forward, we think sequencing will contribute crucial information to determining the best treatment options for patients.”

The research is funded by the National Cancer Institute, the National Human Genome Research Institute and the National Heart, Lung and Blood Institute, all of the National Institutes of Health, and the Washington University Cancer Genome Initiative.