| The latest medical advances from Johns Hopkins Medicine |
| HOPKINS STUDY REVEALS WHITE BLOOD CELLS CAN BOTH HURT AND HELP TRANSPLANTED KIDNEYS |
 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 study in 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, 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. In the Hopkins study, designed to try to find lymphocites 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. "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", says Rabb. 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, 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". |
| ANEMIA AFFECTS BODY -- AND MAYBE THE MIND |
 For older adults, anemia's trademark loss of oxygen-toting red blood cells has long been
linked to fatigue, muscle weakness and other physical ailments. Now researchers at Johns Hopkins have found a relationship between anemia and impaired thinking, too."Our work supports the notion that mild anemia may be an independent risk factor for so-called executive-function impairment in older adults," says Paulo Chaves, M.D., Ph.D., an assistant professor at The Johns Hopkins University School of Medicine. "If further studies confirm that's true, this could mean that correction of anemia in these patients might offer a chance to prevent such a cognitive decline." The Johns Hopkins investigators went looking for such an effect because previous studies showed that age-related declines in the brain's so-called executive function -- problem solving, planning, assessing dangers, following up on important activities -- lead to declines in self-sufficiency. "Executive function impairment, which happens often before memory loss occurs, may happen early on in the process of becoming unable to carry on with instrumental day-to-day living activities, such as shopping, cooking, taking medications, paying bills, walking, etc.," says Chaves. Chaves and his team gave three psychological tests commonly used to evaluate executive function to men and women between the ages of 70 and 80 years old. Approximately 10 percent had anemia, which was of mild intensity. Some 15 percent of those with the worst results on all three of the tests were anemic, compared to only 3 percent who scored best. Those with anemia were four to five times more likely to perform worst on the executive function tests, compared to those with normal blood hemoglobin, after taking into account the effect of other factors that affect cognition, such as age, education and existing diseases. "These preliminary results don't prove that anemia causes impaired executive function, nor indicate that treatment of anemia would necessarily lead to better executive function," says Chaves. "However, they are compelling enough to serve as a roadmap for continued research." How anemia could affect thinking remains to be determined. It could be that it chronically diminishes the supply of oxygen to the brain. Another view proposes that the fatigue accompanying anemia leads to inactivity and the loss of aerobic-fitness benefits to the prefrontal cortex. |
| HOPKINS-LED STUDY FINDS THAT CHRONIC FORM OF DEPRESSION RUNS IN FAMILIES |
 The odds are more than two to one that people whose close relatives developed chronic
severe unipolar depression when they were young will have it, too, according to results of a multicenter analysis of more than 600 people and their families.Results of the study show that siblings, parents or children of people diagnosed with chronic major depression before the age of 31 have a 2.52-to-1 chance of also having the disorder. Moreover, first-degree relatives of patients diagnosed with chronic major depression before the age of 13 have a 6.17-to-1 chance of having it. In this study, James B. Potash, M.D. and his team looked at 638 men and women diagnosed with early-onset major depression and 2,176 of their first-degree family members. The subjects were drawn from the Genetics of Recurrent Early-onset Depression (GenRED) project, a multicenter study of patients enrolled between 1999 and 2003 by Johns Hopkins and other researchers. "We have known for a long time that major depression runs in families, but we are still working on determining whether certain subtypes of the illness do so more strongly than others," says Potash. "Our large study allows us the numbers to examine these questions in subgroups." Potash credits lead author Francis Mondimore, M.D., of the Department of Psychiatry at Johns Hopkins, with observing that many of the study participants reported having been depressed "as long as [they] can remember." This led Mondimore to focus on chronic -- or persistent -- depression over time. An estimated 30 percent of those with major depressive disorder have symptoms most or all of the time, with only incomplete remissions, over many years, according to Potash. Mondimore says a similar technique, examining a subtype of illness, was used to discover a familial relationship in breast cancer in women -- a finding that paved the way to discovering a link between the BRCA1 gene and that disease. GenRED II, a larger study now under way at Johns Hopkins and five other sites, is recruiting 2,700 people to identify genes for major depression. Data also is being collected on other potential contributing factors, such as early childhood trauma. |
| HOPKINS SCIENTISTS LINK IMMUNE RESPONSE TO "GHOST" PARASITES AND SEVERELY CONGESTED SINUSES |
 Although it's unclear why it's so, scientists at Johns Hopkins have linked a gene that
allows for the chemical breakdown of the tough, protective casing that houses insects and worms to the severe congestion and polyp formation typical of chronic sinusitis.A team of Johns Hopkins sinus experts has found that the gene for the enzyme, acidic mammalian chitinase (AMCase) is up to 250 times more active in people with severe sinus inflammation that persists even after surgery when compared to patients in whom surgery is successful. Sinus surgery is usually the treatment of last resort for those who do not respond to drug therapy. The Johns Hopkins report is believed to be the first to identify the enzyme's presence in the nose and confirm its link to sinusitis. "This finding does not mean that there are actually parasites in the nose causing sinusitis, but our study does lend support to the concept that really severe and persistent sinusitis may be a case of a misplaced immune response directed against parasites that are not really there," says study lead author Andrew Lane, M.D., an associate professor at the Johns Hopkins University School of Medicine and director of its rhinology and sinus surgery center. The theory, Lane says, is that allergies and asthma result from genes that control the body's defenses against parasites, but these genes are dormant in healthy people. When turned on by so-called "ghost parasites", however, the potent inflammatory response is medically very difficult to control. Researchers say that although chitin, a rigid chemical compound common to fungi, insects and roundworms, is not naturally found in the human body, the presence of its corresponding enzyme and its role in the buildup of mucus and fluids, and polyp formation makes the enzyme a legitimate target for drug therapies to block its production and action. "If we can selectively shut down the antiparasite immune response, we could potentially have new treatments for these airway diseases of the lung and nose," says Lane. New therapies are needed, he says, as an alternative to long-term steroids, which block the inflammatory chemical pathway but also have debilitating side effects, including loss of bone density, cataracts in the eye and weight gain. An estimated 32 million Americans suffer from persistent inflammation of the tissue that lines the nasal and sinus cavities, according to the United States Centers for Disease Control and Prevention. All patients that participated in the study were monitored for a minimum of nine months to see if polyps and their resulting symptoms returned. Ten in the surgery group had their polyps return within six months, while 12 remained symptom free. When researchers initially compared all the nasal tissue amples, they found that half had the gene for AMCase turned on, or expressed, to make the chitinase protein. During follow up, they found that the 10 patients who had their polyps return had exceedingly higher levels of AMCase expression than the other sinusitis patients and controls. Lane adds that future research will have to determine if high genetic expression of AMCase is an underlying cause of inflammation or if AMCase is simply one of many chemicals produced by cells in the nose in response to chronic inflammation. The next phase of their research, he says, is to look for what triggers the anti-parasite response. However, Lane cautions that this reaction against parasites may come at the expense of the nose's ability to ward off other invaders, such as bacteria, viruses or fungi. "The epithelial cells lining the nasal and sinus cavities play an important role as first responders of the immune system," he says. "But when they are distracted fighting non-existent parasites, they cannot deal well with the very real microbes continuously coming into the nose." This, Lane notes, may promote growth of bacteria and fungi in the nose, which is a common finding in those with chronic sinusitis with polyps. |
| CLOSING IN ON LETHAL HEART RHYTHM IN YOUNG ATHLETES |
 Their new findings should increase the accuracy of tests to identify those at risk for arrhythmogenic right ventricular dysplasia (ARVD), which is among the top causes of sudden cardiac death in the young and fit. In February, the same team linked one third of ARVD cases in their large database of patients to a dozen abnormal changes in a gene called plakophilin 2 (PKP2), which makes proteins involved in heart cell stickiness. In the new study, the Hopkins team found four mutations in another sticky protein gene, Desmoglein 2 (DSG2), in five of 33 patients tested. "This gene is highly expressed in the heart, where muscle tissue expands and contracts with the heartbeat," says senior study author and cardiac geneticist Daniel P. Judge, M.D. "Our results confirm that altered genes are responsible for ARVD. And now that we know the genetic roots of this disease, we can also create better blood tests for their proteins to predict who is at risk for developing this condition." ARVD is characterized by weakness in the desmosome, or cell to cell binding structure. The inherited condition leads to the buildup of excess fatty and scar tissue in the heart's right ventricle, causing irregular beats and - unless diagnosed and treated with drugs or implanted defibrillators - triggering a fatal heart rhythm disturbance. "We expect a test for DSG2 mutations to be available to those with a family history of the condition before the end of the year," he says. The same Hopkins team developed a blood test to screen for PKP2 mutations. That test became available in May and is currently the only one available for detecting those at greater risk of the disease. All patients in the study were part of a patient database created at Hopkins in 1998. The researchers focused on cell adhesion proteins because they had already been linked to Naxos syndrome, which produced symptoms in the right ventricle similar to those documented in ARVD. According to the researchers, not everyone with a genetic mutation develops ARVD. Further analysis of the condition's genetic roots will help researchers to calculate the precise increased risk from each mutation for developing symptoms and dying. |
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| 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 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. 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. "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. |
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