TO GET MORE...   If you are interested in publishing any of the releases in this media report or if would like to schedule an interview or get high resolution photos related to the story, please contact Claudia Costabile at ccostab1@jhmi.edu. Let us know your opinion or special request here.	HOPKINS STUDY REVEALS WHITE BLOOD CELLS CAN BOTH HURT AND HELP   In an example of biological irony, the same white blood cell chemistry known to damage kidneys used for transplants may also help prevent such damage, according to a federally funded study in genetically engineered mice at Johns Hopkins. Researchers have long known that when blood flow is cut off and then returned to transplanted kidneys or other organs, immune system cells called T lymphocytes produce toxic natural chemicals that contribute to ischemic reperfusion injury (IRI). Nature cannot distinguish between deliberate surgical wounds needed to remove and re implant a donor kidney and other kinds of organ damage in which certain toxic chemicals are needed to clean up or remove bad tissue. But in the new study published in the September issue of The Journal of Immunology, the Hopkins team reports that that T cells can also play a role in reducing cellular damage in IRI kidneys, according to Hamid Rabb, M.D., medical director of kidney and pancreas transplantation at The Johns Hopkins University School of Medicine. IRI occurs in 30 percent to 40 percent of kidneys removed from dead donors, resulting in lower kidney survival rates, shortened kidney life and a cost increase of approximately $20,000 per patient from the initial hospital stay and treatment alone, according to Rabb. Scientists therefore are interested in identifying means of preventing or rapidly treating IRI, but one barrier to greater understanding has been the inability to detect the lymphocytes in the kidney during the first critical six hours after blood flow is returned. In the Hopkins study, designed to try to find these cells and learn more about IRI, white blood cells were taken from mice that had undergone experimentally induced IRI. These cells were injected into mice engineered without a thymus gland, which produces T cells. A comparison group of genetically engineered mice got no injections. After the researchers temporarily stopped blood flow to kidneys in mice in both groups for 30 minutes, they discovered that the kidneys in the injected mice were improved compared to the other group of mice. This was an unexpected result, says Rabb. For years we have known that T cells play a role in IRI, but we assumed it was always a negative role; now we know they play a protective role as well. Rabb said further research is needed to establish the exact mechanism for this protection, but he says it makes perfect sense in theory. T cells are part of our immune system, and our immune system is designed to protect us from injury. What's surprising here is that practical experience over the years has taught us that when the immune system is activated, we have increased cell damage, says Rabb. Using a new method developed by Dolores B. Ascon, Ph.D., a postdoctoral fellow in the Department of Nephrology at Hopkins and first author on the paper, Rabb and his team successfully tracked small numbers of lymphocytes in three distinct groups of mice: normal mice, mice that underwent fake surgery without blood flow interruption to the kidneys ischemia) and mice that underwent surgery and 30 minutes of ischemia. The study showed elevated levels of T cells in the kidneys three hours after IRI compared to the normal mice. It also showed elevated levels of the chemicals tumor necrosis factor alpha (TNF alpha) and interferon gamma (IFN gamma), which are known to produce cellular damage in kidneys. These chemicals are produced by T cells. The mice that underwent fake surgery also had an elevated level of T cells when compared to the normal mice, but these cells did not release TNF alpha and IFN gamma and did not cause injury to the kidneys. In this case it appears as though the surgery triggered the movement of T cells to the region, but since there was no ischemia, these cells did not produce TNF alpha and IFN gamma, says Rabb. This only further illustrates the complexity of the role T cells play in IRI. Other contributors to this study are Sergio Lopez Briones, Ph.D; Manchang Liu, M.D., Ph.D; Miguel Ascon, Ph.D; Vladimir Savransky, M.D., Ph.D.; and Mark J. Soloski, Ph.D; all of the Department of Medicine at Johns Hopkins School of Medicine, and Robert B. Colvin of the Department of Pathology at Harvard Medical School. This study was supported by grants from the National Institutes of Health.   WHO GETS A HEART TRANSPLANT? CRITERIA EXPAND TO COVER OLDER ADULTS AND SOME CANCER PATIENTS   Elderly men and women with heart failure and men with treated prostate cancer are among those who have been historically denied heart transplantation. Now, under new guidelines co authored by a Hopkins cardiologist and issued today by the International Society for Heart and Lung Transplantation (ISHLT), they can and should be considered. "People who once would die because they did not qualify now have a chance to get a new heart," says Stuart Russell, M.D., who served on the ISHLT committee revising the guidelines. "Research now suggests they are actually good candidates," he adds. ISHLT guidelines, which date back to 1992 and were last updated in 1997, restricted access for cancer patients who been tumor free for less than five years or had weakened immune systems from cancer therapy that precluded them from taking anti rejection drugs for a transplanted organ. The new recommendations allow some people with slow growing or treated cancers to qualify, and they raise the qualifying age cap from 65 to 70. Support for the new criteria, says Russell, comes from research confirming that transplant recipients over age 65 have a 90 percent survival rate one year post transplant. After 10 years, he says, 50 percent are still alive. "Too often, people suffering from heart failure and cancer give up on the prospect of a long, productive life, thinking they have exhausted all treatment options possible, and even their primary physicians are not aware that transplantation is a viable option," says Russell, an associate professor at The Johns Hopkins University School of Medicine and its Heart Institute. Russell has been personally involved in the care of more than 360 heart transplantation patients, including 13 at Hopkins so far in 2006 and another 18 in 2005. He began work on revising the guidelines at the April 2005 annual meeting of the ISHLT. The expanded criteria follow changes in 2002 guidelines for organ donation, which permitted transplantation of hearts from those over 50, even when the hearts were enlarged or the arteries feeding it were clogged, provided the clot was removed. And they are likely to increase demand for already scarce donor organs. As of Sept. 1, at least 2,885 Americans were on waiting lists for a heart transplant, according to the latest figures from the United Network for Organ Sharing, the international coordinating body that impartially distributes donated organs. Up to 20 percent of those on the list to receive a heart will die while waiting, Russell notes. The guidelines, posted at www.ishlt.org, reaffirm the organizations view that demand for transplantations is unlikely to ever be fully met and that more resources are needed to slow down the progression of heart failure and prevent the need for transplant surgery in the first place. Russell says new drugs, implantable defibrillators and pacemakers, and smaller heart pumps can assist a weakened heart for longer periods, or until a donor new organ becomes available. He estimates that the relaxed guidelines could result in up to 15 more heart transplantations for patients in the region served by Hopkins in southeastern Pennsylvania, Maryland and northern Virginia, none of whom would have qualified for an organ under the old restrictions. Nationally, he estimates, up to 400 more patients could now qualify and receive a new heart.   PSST! COFFEE DRINKERS: FRUIT FLIES HAVE SOMETHING TO TELL YOU ABOUT CAFFEINE   In their hunt for genes and proteins that explain how animals discern bitter from sweet, a team of John Hopkins researchers began by testing whether mutant fruit flies prefer eating sugar over sugar laced with caffeine. Using a simple behavioral test, the researchers discovered that a single protein missing from the fly-equivalent of our taste buds caused them to ignore caffeine's taste and consume the caffeine as if it were not there. "No, you won't see jittery Drosophila flitting past your bananas to slurp your morning java anytime soon," says Craig Montell, Ph.D., a professor of biological chemistry in the Institute of Basic Biomedical Sciences at Johns Hopkins. "The bottom line is that our mutant flies willingly drink caffeine-laced liquids and foods because they can't taste its bitterness -- their taste receptor cells don't detect it." The Johns Hopkins flies, genetically mutated to lack a certain taste receptor protein, have been the focus of studies to sort out how animals taste and why we like the taste of some things but are turned off by the taste of others. By color-coding sweet and bitter substances eaten by fruit flies and examining the coloring that shows up in their translucent bellies, the Johns Hopkins team hoped to learn whether flies missing a specific "taste-receptor" protein changed their taste preferences. "Normally," Montell explains, "when given the choice between sweet and bitter substances, flies avoid caffeine and other bitter-tasting chemicals. But flies missing this particular taste-receptor protein, called Gr66a, consume caffeine because their taste-receptor cells don't fire in response to it." The discovery, which is the first ever example of a protein required for both caffeine tasting and caffeine-induced behavior, was published Sept. 19 in Current Biology. For the study, Montell and his colleagues kept 50 fruit flies away from food overnight and for breakfast gave the starved flies 90 minutes to eat as much as they wanted of either or both of two concoctions: a blue-colored mixture of sugar and agar and a red-colored mixture of caffeine, sugar and agar. The researchers then flipped the flies onto their backs and looked at the color of their bellies to see what they ate - blue indicating a preference for eating sugar, red indicating a preference for bitter caffeine, and purple indicating no preference. Flies missing the critical taste receptor protein Gr66a consumed the bitter caffeine solution to the same extent as the sugar-only solution. Montell and colleagues conclude that Gr66a is crucial for the normal caffeine avoidance behavior and without it, flies are seemingly indifferent to the bitter taste. The researchers went on to examine whether this indifference to bitter was due to the taste nerves on the fly's "tongue" or some malfunction in the fly's brain. Chemical stimulants trigger taste receptor cells to send an electrical current to the brain where the information is processed and often leads to a change in behavior, such as the decision to eat or avoid. With fine tools, the research team recorded electrical currents in those cells known to contain the Gr66a caffeine taste receptor in the fly's equivalent of the taste buds - dubbed the taste bristles. Applying sugar to the taste bristles of normal flies, or to mutant flies missing the Gr66a protein, causes the neurons to produce electrical current "spikes" at a frequency of about 20 spikes per second. Other bitter compounds like quinine generated electrical current spikes at about the same frequency in the mutants. Only flies missing the Gr66a taste receptor protein were unable to generate any current spikes when given caffeine. "This is a clear demonstration that Gr66a is functioning in the taste receptor cells and is not a 'general sensor' for bitter compounds, but is required more specifically for the caffeine response," says Montell. "This indicates that flies have different receptors for the response to other types of bitter compounds," he says. "We also tested whether the flies avoided the related bitter compounds found in tea and cocoa -- chocolate -- and found that Gr66a also is required for the response to the compound in tea, but not for the one in chocolate," he says. Fruit flies often are used as experimental organisms because they grow quickly and are easy to manipulate genetically. Now that Montell and his colleagues have a mutant fly that is unable to taste caffeine, they hope to further examine the other genes and molecules involved in the caffeine response and better understand the biochemistry behind caffeine-induced behavior in other organisms, namely humans. The researchers were funded by the Polycystic Kidney Disease Foundation and the National Institute of Deafness and Communicative Disorders of the National Institutes of Health. Authors on this paper: Seok Jun Moon, Michael Köttgen, Yuchen Jiao, Hong Xu and Montell, all of Hopkins.   BACTERIA GET OFF EASY IN SINUS INFECTIONS   Researchers at Johns Hopkins have evidence that curbed activity from several key chemicals on the inner lining of the nose are linked to chronic sinusitis that fails to respond to the usual current treatments. An estimated 32 million Americans know the misery of persistent inflammation of the moist tissue that lines the nose and sinus cavities.The result is clogged passages and recurring infections, according to the U.S. Centers for Disease Control and Prevention. Because nearly one in 10 of those treated see symptoms return within weeks or months after drugs or surgery fail to keep the sinus passages open, scientists have long suspected that these resistant cases had some underlying problem with the immune system contributing to the ailment. In a study described on Sept. 19 at the annual scientific sessions of the American Academy of Otolaryngology, Head and Neck Surgery, the Johns Hopkins team found that in chronic sufferers who failed to respond to treatment, the activity of at least four genes in the body's nasal immune defense system were severely decreased, and their production of two proteins critical to this defense was 20 to 200 times less than normal. Comparing nasal epithelial cell samples from nine patients who benefited from surgery with nine who did not, the Johns Hopkins team discovered suppressed levels of human beta defensin 2 (HBD2) and mannose binding lectin (MBL) in those whose symptoms returned. The proteins are naturally produced in the nose whenever the immune system detects foreign bacteria or fungi, binding to invading pathogens, inactivating them and making them easily disposed of. An earlier study published by the same team in the March-April issue of the American Journal of Rhinology also showed that sinus tissue from people with chronic sinusitis that resisted treatment had 30 times lower than normal activity of a so-called toll-like receptor gene, TLR9. Inside the nose, researchers say, toll-like receptor proteins (TLRs) detect invading bacteria and other pathogens in the air by attaching to their trace byproducts. Once a threat is identified, the receptors stimulate the epithelial cells to produce antibiotic proteins, such as HBD2 and MBL, to fight the invading organisms. This innate response helps prevent airborne bacteria or fungi from settling in the nose and sinus cavities, causing infection. "Colonization with microorganisms is a common problem in patients with chronic sinusitis and polyps, but the reasons for this are incompletely understood," says Andrew Lane, M.D., an associate professor at The Johns Hopkins University School of Medicine and director of its rhinology and sinus surgery center. "Now we are uncovering new clues as to what might be wrong and perhaps, ultimately, how it might be treated. "The nose's first line of defense is the epithelium, and when the local innate immune function is curtailed, infections can get a head start, which might serve to worsen the sinus inflammation. "The potential is there to manipulate these chemical receptors and proteins to see if this makes patients more responsive to conventional therapy," says Lane. The study, led by Lane, was believed to be the first to determine levels of each TLR - there are 10 - by directly measuring messenger RNA expression in sinusitis patients and those more fortunate to not have it. Scientists have known for more than a year that TLRs were present in both the healthy and sinusitis-wracked nose, but not which receptors or proteins were more important than others in the condition's chronic form. That study involved 30 men and women, mostly from the Baltimore region, who had surgery for chronic sinusitis at Johns Hopkins. (Another 10 had no sinus problem and served as study controls.) Those who underwent surgery did so after standard therapy using antibiotics, decongestants and steroids had failed to stop their symptoms and keep their infections from coming back. Indeed, 20 participants in the study had developed nasal polyps, which have no known cause and are especially hard to treat, researchers say. They note that polyps must often be surgically removed to allow the sinuses to drain normally. All patients were monitored for a minimum of six months to see if any symptoms or polyps returned. Thirteen in the surgery group had recurrent inflammation within three months to one year after surgery, while the rest remained symptom free. The Johns Hopkins team took samples during surgery of the mucous membrane lining the nose, and using real-time polymerase chain reaction, analyzed the samples for any genetic differences between the groups. "Surgically treating sinusitis is much like plumbing, in the sense that we try to restore normal sinus cavity drainage pathways," adds study presenter Murugappan Ramanathan Jr., M.D., a resident in otolaryngology-head and neck surgery at Johns Hopkins. "But for the intractable cases, surgery may fail because the problem is not so much about plumbing as it is inflammation, and for this we need research at the molecular level to find a solution." Funding for this study was provided in part by the National Institutes of Health, including the National Institute on Deafness and Other Communication Disorders, and the National Institute of Allergy and Infectious Diseases, with additional funding coming from the American Rhinologic Society. Besides Lane and Ramanathan, other researchers involved in this research, conducted solely at Johns Hopkins, were Quynh Ai Truong-Tran, Ph.D., and Robert Schleimer, Ph.D.   LOW AND HIGH BMI INCREASES RISK OF DEATH   While studies have linked being either underweight or overweight to poor health, the effect of being overweight or obese on the risk of dying has been a topic of recent controversy. Researchers have long used the body-mass index (BMI), weight in kilograms divided by the square of height in meters, as a measure of the appropriateness of weight in relation to height. Researchers from Yonsei University, in Seoul, South Korea, and the Johns Hopkins Bloomberg School of Public Health report in one of the largest studies to date (over 1.2 million study participants) that having either a high or low BMI increases risk of death. The researchers found that the effect of BMI on the risk of dying varied among major causes of death and that the risk of death from being overweight or obese was greater in younger people. The study is published in the Aug. 24, 2006, edition of the New England Journal of Medicine. "The relationship between being underweight or overweight and the risk of death is controversial because, of the few studies on this topic, most were not able to pinpoint at what BMI the risk of death increased. The results from these other studies were also mixed; some of them did not show an increase in risk of death," said Sun Ha Jee, PhD, lead author of the study and an associate professor of epidemiology at Yonsei University. The authors examined the effect of body weight on the risk of death of more than 1.2 million 30- to 95-year-old Koreans over a 12-year time span. They looked at death from any cause and those from specific diseases, such as cancer, atherosclerotic cardiovascular disease and respiratory disease. The study participants, who were part of the Korean Cancer Prevention Study, had an average BMI of 23.2, regardless of sex; the majority of participants had a BMI below 25, which is considered a normal weight. By comparison, the average BMI in the United States is currently 27.8 for men 20 years and older and 28.1 for women 20 years and older. Compared to normal-weight Koreans, underweight, overweight and obese men and women had higher rates of death. Men and women who had never smoked with a BMI of 23.0 to 24.9 had the lowest risk of death from any cause. The researchers found that the relationship of BMI with risk of dying varied among the major causes of death considered. The risk of death from cancer increased beginning at BMI levels of 26.0-28.0 and rose further at higher levels, according to the researchers. Risk for death from respiratory causes was highest at the lowest BMI values and decreased with higher BMI values, whereas the risk of death from atherosclerotic cardiovascular disease increased progressively with higher BMI values. Information on cardiovascular risk factors showed an increasingly unfavorable profile with increasing BMI values. Study participants younger than 50 years of age had the highest relative risk of death associated with a high BMI. The researchers report no evidence of an increased risk of death for 65-year-old and above, obese individuals. "Past studies were conducted primarily in Western populations and we did not know if these results would apply in Asian populations, which tend to be thinner but have a higher percentage of body fat than do their Western counterparts," said Jonathan M. Samet, MD, senior author of the study and professor and chair of the Bloomberg School's Department of Epidemiology. The amount of respiratory causes of death, such as tuberculosis, pneumonia, chronic obstructive pulmonary disease and asthma, differ between Koreans and inhabitants of Western countries. Jee, who is also an adjunct associate professor at the Bloomberg School, noted that the study results cannot be generalized to other populations. "Body-Mass Index and Mortality in Korean Men and Women" was supported by grants from the National Cancer Institute, the National Institutes of Health, the Department of Health and Human Services and the Korean Seoul City Research and Development program. In addition to Jee and Samet, the study is co-authored by Eliseo Guallar, MD, DrPH, and Jae Woong Sull, PhD, with the Bloomberg School of Public Health, Jungyong Park, PhD, and Heechoul Ohrr, MD, with Yonsei University, and Sang-Yi Lee, MD, with Cheju National University and National Health Insurance Corporation, Korea.   RESEARCHERS FIND A BETTER BLOOD TEST FOR PROSTATE CANCER   New studies of a blood protein recently identified at Johns Hopkins, early prostate cancer antigen-2 (EPCA-2), may change the way men are screened for prostate cancer -- a disease that kills tens of thousands of men every year. Current standards of screening and testing for prostate cancer focus on the blood protein prostate-specific antigen (PSA) along with a digital rectal examination. Men who have more than 2.5 nanograms per milliliter of PSA are considered at risk for prostate cancer. However, PSA testing often erroneously highlights noncancerous conditions (false positives) and can miss some cases of cancer (false negatives), according to Robert H. Getzenberg, Ph.D., a professor of urology and director of research at the James Buchanan Brady Urological Institute at The Johns Hopkins University School of Medicine. Due to elevated PSA levels, approximately 1.6 million men undergo prostatic biopsies in the United States annually, and roughly 80 percent of these men have negative results, according to Getzenberg, lead author of the study. He says that of the entire population of men in the United States who have been tested for PSA, an estimated 25 million have elevated PSA levels and a biopsy of the prostate that did not reveal any prostate cancer. Conversely, roughly 15 percent of men with prostate cancer go undetected because their PSA levels are below the cutoff level, according to Getzenberg. In a study to be published online Aug. 24 in Lancet, Getzenberg and a team of Johns Hopkins researchers introduce evidence in support of EPCA-2 testing as a more accurate way to identify cancer in the prostate. "A blood test based on EPCA-2 may greatly improve our ability to accurately detect prostate cancer early and minimize the number of false positives, therefore lowering the number of unnecessary biopsies," says Getzenberg. "In addition, this is the first time we have a test that effectively distinguishes between men with cancer confined to the prostate and those whose disease has spread outside of the gland." Getzenberg and his team measured EPCA-2 levels in the blood of 330 Johns Hopkins patients separated into several groups: men with normal PSA levels and no evidence of disease, men with elevated PSA levels but who had negative biopsies, men with a common noncancerous prostate condition known as benign prostatic hypertrophy (BPH) who did not receive biopsies for prostate cancer, men with prostate cancer but with normal PSA levels, men with prostate cancer confined to the prostate, men with prostate cancer that had invaded outside of the gland at the time of surgery, and a diverse group of patients with benign conditions of other organs as well as individuals with other cancer types. Patients with an EPCA-2 cutoff level of 30 nanograms per milliliter or higher were considered to be at risk for prostate cancer. This cutoff value was established in a pilot study of 30 blood samples and was then applied throughout the larger study. Results showed that the EPCA-2 test was negative in 97 percent of the patients who did not have prostate cancer. Men with no evidence of disease (regardless of their PSA levels), as well as the control group of patients with other cancer types and benign conditions, all had EPCA-2 levels below the cutoff. In contrast, in a multi-institutional study published in 2003 in the Journal of Urology, PSA levels between 4 and 10 nanograms per milliliter were shown to be accurate in identifying patients without prostate cancer only 19 percent of the time. In addition, 77 percent of the BPH patients had a level of EPCA-2 lower than the cutoff point. Getzenberg says this is well within the likely percentage range of BPH patients who are prostate-cancer free. He says this result was encouraging since BPH is often associated with elevated PSA levels, leading to misdiagnosis and unnecessary biopsies. When it came to correctly identifying patients with prostate cancer, EPCA-2 levels at or above the cutoff were detected in 90 percent of the men with organ-confined prostate cancer and 98 percent of the men with disease outside of the prostate. Overall, in this study, the EPCA-2 test detected 94 percent of the men with prostate cancer. The 2003 study showed that PSA levels between 4 and 10 nanograms per milliliter detected 85 percent of the patients with prostate cancer. Results of the study also revealed that EPCA-2 levels were significantly higher in patients whose cancers had spread outside of the prostate compared to those with disease confined to the gland. EPCA-2 was dramatically better at separating these groups than were PSA levels, according to Getzenberg. "This is important since cancer that has spread outside of the prostate is more deadly, which makes it even more crucial to have a tool that detects it early," says Getzenberg. Finally, the EPCA-2 test identified 78 percent of the men with prostate cancer in the group with PSA levels below the accepted cutoff level of 2.5 nanograms per milliliter. EPCA-2 is the second prostate-cancer marker identified by Getzenberg and his team that has outperformed PSA. Last year, they discovered an unrelated tissue-based test, EPCA-1, that also proved effective at identifying prostate cancer. The only commonality between these markers is that they were discovered using the same approach. Getzenberg says the efficacy of EPCA-1 as a test of biopsy samples is currently being evaluated. Prostate cancer is the most common type of cancer found in American men. The American Cancer Society estimates that there will be approximately 234,460 new cases of prostate cancer in the United States in 2006, and 27,350 men will die of this disease. Getzenberg says larger clinical trials for EPCA-2 are planned that could make this test available to the public in approximately 18 months. Funding for the study was provided by the National Cancer Institute of the National Institutes of Health and Onconome Inc. Licensing agreements exist between Onconome Inc. and both the University of Pittsburgh and Johns Hopkins University. Getzenberg is a paid consultant to Onconome Inc. and is entitled to a share of royalty received by both universities on sales of products described in this manuscript and related technologies. The terms of this arrangement are being managed by the Johns Hopkins University in accordance with its conflict of interest policies. Other researchers from the Brady Urology Institute at Johns Hopkins who contributed to this study are Eddy S. Leman, Ph.D.; Department of Urology Chairman Alan W. Partin, M.D., Ph.D.; Daniel W. Chan, Ph.D.; Bruce J. Trock, Ph.D.; Lori J. Sokoll, Ph.D.; Leslie Mangold and Grant W. Cannon.   CHILDHOOD SLEEP APNEA LINKED TO BRAIN DAMAGE, LOWER IQ   In what is believed to be the first study showing neural changes in the brains of children with serious, untreated sleep apnea, Johns Hopkins researchers conclude that children with the disorder appear to suffer damage in two brain structures tied to learning ability. Writing in the Aug. 22 issue of the global online journal Public Library of Science Medicine, the Johns Hopkins investigators say they compared 19 children with severe obstructive sleep apnea (OSA) to 12 children without the disorder. Using a special type of MRI, researchers identified changes to the hippocampus and the right frontal cortex. Next, using IQ tests and other standardized performance tests that measure verbal performance, memory and executive function, researchers were able to link the changes in the two brain structures to deficits in neuropsychological performance. The hippocampus, a structure in the temporal lobe, is vital to learning and memory storage, while the right frontal cortex governs higher-level thinking, such as accessing old memories and using them in new situations. "This should be a wake-up call to both parents and doctors that undiagnosed or untreated sleep apnea might hurt children's brains," says lead author Ann Halbower, M.D., a lung specialist at the Johns Hopkins Children's Center. "This is truly concerning because we saw changes that suggest brain injury in areas of the brain that house critical cognitive functions, such as attention, learning and working memory." While researchers have known for years that fragmented sleep, interrupted breathing and oxygen deprivation -- all hallmarks of sleep apnea -- harm children's learning ability and school performance, this is the first time they have linked changes in the brain's chemistry to the syndrome in children, Halbower believes. "We cannot say with absolute certainty that sleep apnea caused the injury, but what we found is a very strong association between changes in the neurons of the hippocampus and the right frontal cortex and IQ and other cognitive functions in which children with OSA score poorly," Halbower says. Children with OSA had lower mean IQ test scores (85) than children without OSA (101). Children with OSA also performed worse on standardized tests measuring executive functions, such as verbal working memory (8 versus 15) and word fluency (9.7 versus 12). Using magnetic resonance spectroscopic imaging, which plots peak levels of brain chemicals in the form of graphs, researchers compared the ratios between each two of three chemicals - N-acetyl aspartate (NAA), creatine and choline - in children with apnea and in those without. The hippocampus and the right frontal cortex of children with sleep apnea showed altered ratios of these neurochemicals that are not specific to any one disease but indicate injury to brain cells. Next, researchers plan to study whether the ratios will return to normal once the sleep apnea is treated. In both children and adults, untreated sleep apnea has been linked to cardiovascular problems and learning and memory deficits. However, the cognitive effects of untreated apnea might be far more damaging in children than in adults, researchers point out, because they occur during critical developmental periods. The frontal cortex matures throughout the teen years and continues well into the 30s, and researchers fear that childhood injury to this area might lead to long-term cognitive deficits. Obstructive sleep apnea affects 2 percent of children in the United States, but it is unclear how many of these suffer from severe apnea. Halbower estimates that up to 17 percent of sleep apnea patients seen at the Children Center's sleep clinic have the severe form. Sleep apnea occurs because of partial or complete obstruction of the airways during sleep due to anatomic and/or neuromotor factors. In children, the leading cause of sleep apnea is enlarged tonsils and adenoids, and the first line of treatment is surgical removal. Another treatment is wearing a special mask at night to ensure smooth airflow and uninterrupted breathing during sleep. Researchers from the Kennedy Krieger Institute in Baltimore and the University of Pennsylvania participated in the study. Co-authors from Johns Hopkins include Mahaveer Degaonkar, M.D., Peter Barker, M.D., Christopher Earley, M.D., Philip Smith, M.D., and Mark Mahone, M.D. Researchers from other institutions include Cristine Prahme, M.D., of the Kennedy Krieger Institute, and Carole Marcus, M.D., of the University of Pennsylvania School of Medicine. The research was funded in part by the Thomas Wilson Sanitarium for the Children of Baltimore City and the General Clinical Research Center at The Johns Hopkins University School of Medicine. Founded in 1912 as the children's hospital of the Johns Hopkins Medical Institutions, the Johns Hopkins Children's Center offers one of the most comprehensive pediatric medical programs in the country, from performing emergency trauma surgery, to finding causes and treatments for childhood cancers, to delivering a child's good bill of health. The Johns Hopkins Children Center's Pediatric Trauma Service is Maryland's only state-designated trauma center for children. With recognized Centers of Excellence in 20 pediatric subspecialties including cardiology, transplant, psychiatric illnesses and genetic disorders, Children's Center physicians, nurses and staff provide compassionate care to more than 90,000 children each year.   MODEL PREDICTS COLON CANCER INHERITABLE GENETIC DEFECTS   Researchers from the Johns Hopkins Bloomberg School of Public Health and other institutions have developed a new prediction model for colorectal cancer. The model, called MMRpro, is based on an individual's detailed family history of colorectal and endometrial cancer, as well as knowledge of how genetic mutations manifest themselves--in the form of tumors. It can assess a person's probability of carrying a particular defect within so-called mismatch repair genes. The study was published in the September 27, 2006, issue of the Journal of the American Medical Association (JAMA). "Genetic defects can be passed from parents to their children; as a result, colon cancer runs in families. Our model will help identify individuals likely to have particular genetic defects. The results will give them useful information about their colon cancer risk before they decide whether to undergo invasive screenings or expensive genetic testing," said Sining Chen, PhD, lead author of the study and an assistant professor in the Johns Hopkins Bloomberg School of Public Health's Department of Environmental Health Sciences. Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer, is characterized by the inheritance of defects in the MLH1, MSH2 and MSH6 genes. These three genes help repair mismatches that can occur during the duplication of the genetic code when new cells are made, and are known as mismatch repair (MMR) genes. Of the projected 600,000 MMR mutation carriers in the United States, each has approximately a 50 percent chance of being diagnosed with colorectal cancer by age 70, explained Giovanni Parmigiani, PhD, senior author of the study and a professor of oncology, biostatistics and pathology at Johns Hopkins University. The researchers applied MMRpro software to 279 individuals' family histories. The study participants were tested with sensitive laboratory mutation-detection techniques. MMRpro predictions were compared to the laboratory test results, as well as predictions made with widely used assessment guidelines. The researchers found that MMRpro more accurately predicted mutation carriers than two other assessment tools--the Bethesda guidelines and the Amsterdam criteria-- that are currently available to families faced with the possibility that they have inherited the genetic defects related to colon cancer. MMRpro can identify more mutation carriers and fewer non-carriers than other assessment tools. MMRpro was able to access individuals who already have cancer as well as those who do not. Existing assessment tools can only be applied to individuals with cancer. In addition, certain MMR genetic mutations are hard to detect in laboratory tests. MMRpro was able to provide a useful risk assessment when conventional laboratory tests did not find a genetic mutation. "In the United States this year, over 146,000 people will be diagnosed with colorectal cancer and 56,000 will die. Colorectal cancer is one of the most preventable forms of cancer. We expect that MMRpro will contribute significantly to controlling the disease and helping prioritize individuals for early detection interventions," said Chen. "We also expect that it will be a tool for investigators interested in understanding inherited colorectal cancer, allowing them to select families to more efficiently study these genetic defects." The study authors warn that MMRpro results should be interpreted by physicians and cancer counselors. The model software is available at http://astor.som.jhmi.edu/BayesMendel and at www4.utsouthwestern.edu/breasthealth/cagene/. "Prediction of Germline Mutations and Cancer Risk in the Lynch Syndrome" was written by Sining Chen, Wenyi Wang and Giovanni Parmigiani, with the Johns Hopkins Bloomberg School of Public Health. Additional co-authors are Shing Lee, Khedoudja Nafa, Johanna Lee, Kathy Romans, Patrice Watson, Stephen B. Gruber, David Euhus, Kenneth W. Kinzler, Jeremy Jass, Steven Gallinger, Noralane Lindor, Graham Casey, Nathan Ellis, Francis M. Giardiello, the Colon Cancer Family Registry and Kenneth Offit. Funding was provided by grants from the Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancer at the Johns Hopkins Medical Institutions, the National Cancer Institute, the Cancer Research and Prevention Foundation, the John G. Rangos Sr. Family Charitable Foundation, the Clayton Fund, the Niehaus-Southworth-Weissenbach Research Fund and the Evan Frankel Fellowship.