| The latest medical advances from Johns Hopkins Medicine |
| "SHAPELY" GERMS SHAPE UP THE IMMUNE SYSTEM |
 Like shoppers in search of the perfect pair of jeans, the body's special immune system
cells apparently have assistants that help them rapidly "try on" different pieces of a microbe to find one piece that's shaped just right to fit their cellular skins, Johns Hopkins scientists report.Working with flu viruses to see how these sentinel cells work, the Hopkins team discovered that they first feel out a microbe's chemical "shape" until they find a section that fits tightly into grooves on their surfaces. "It turns out that these immune cells do this very well with a bit of help from a protein assistant that gets rid of ill-fitting microbe parts to speed up the trying-on process," says Scheherazade Sadegh-Nasseri, Ph.D., associate professor of pathology, biophysics and biophysical chemistry. A report on the work appears in the January edition of Nature Immunology. Researchers long have known that the immune system needs the "assistant" protein DM to set up the infectious, recognizable part of a germ-the antigen-so that the anti-infectious attack can begin. Cells missing DM can't do this at all. The new Hopkins work shows that they actually oversee the selection of the best-fitting antigen, too. In experiments measuring the length of time an antigen stays stuck, DM makes sure an infected cell holds onto a microbe long enough to catch the attention of immune cells in the first place, Sadegh-Nasseri says. To uncover DM's expanded job, Sadegh-Nasseri isolated a protein antigen from the flu virus as a test case and found that cells with DM normally hold on for about six days, long enough for symptoms like sniffles and fever, as signs of immune battle, to develop. When they removed DM from normal cells, the cells did not bind the flu antigen at all. Later, when they mutated the antigen-binding part of the cell, the flu antigen "fell off" after only 10 minutes. When the scientists studied the 3-D shape of the part of the cell that tries on the antigen, they discovered that the antigen fell off after 10 minutes whether DM was there or not, but only when one specific chemical bond was disrupted. "DM somehow alters this chemical bond to make antigens fall off a thousand times faster than usual," says Sadegh-Nasseri. "We couldn't believe our eyes when we saw it." Ill-fitting antigens were kicked off in 10 minutes and replaced. Better fitting antigens, like the flu antigen, held on for days. "We think that as the cell tries each of the thousands of different antigens found on an invading microbe, DM monitors how well each antigen fits by somehow disrupting this special chemical bond," says Sadegh-Nasseri. "Somehow, the better fitting ones are resistant to DM's assault and stay stuck-these antigens ultimately are presented to immune cells to start the infection-fighting battle." "Just like trying on those designer jeans, if the jeans feel better with the top button undone, it's probably not the best fit," she added. The research was funded by the National Institutes of Health. Authors on the paper are Kedar Narayan, Chih-Ling Chou, AeRyon Kim, Isamu Hartman, Sarat Dalai, Stanislav Khoruzhenko and Sadegh-Nasseri, all of Hopkins. |
| DRUG TREATMENT SLOWS MACULAR VISION LOSS IN DIABETICS |
 A drug commonly used to slow the loss of central vision has shown promise in stemming a
common precursor of blindness in diabetics, which involves the same central light-sensitive area of retina, Johns Hopkins Wilmer Eye Institute scientists report.Encouraged by the effect of ranibizumab in people with macular degeneration, the Hopkins researchers injected the drug into the eyes of 10 people losing their sight from macular edema, one of many complications of diabetes and a first stage of diabetic retinopathy. Over the course of several months of therapy, every patient in the preliminary Hopkins study could read at least two more lines on the standard eye chart, the researchers said. Moreover, the thickness of the patients' maculae, the central part of the retina responsible for seeing fine details, decreased an average of 85 percent. "The results are impressive," says Quan Dong Nguyen, M.D., M.Sc., an assistant professor of ophthalmology at the Wilmer Eye Institute at Johns Hopkins, "although we will not know until we begin a larger clinical trial what the long-term benefits of the drug might be." The Hopkins group believes that ranibizumab interferes with a protein that spurs the growth of unwanted blood vessels in the back of the eye. Vascular endothelial growth factor, or VEGF, is released when the oxygen supply in the eye is restricted by blood vessel damage related to diabetes. In a self-preserving attempt to acquire more oxygen, the VEGF signals for the creation of new blood vessels, which almost always damage, rather than improve, vision by blocking light's entry onto the retina. "We've suspected for awhile that ranibizumab's ability to shut down VEGF's signaling would do the trick because it's highly likely that VEGF is the culprit when it comes to diabetic macular edema," says Nguyen. More than 4 million diabetics in the United States have diabetic retinopathy and, according to the National Eye Institute, one in 12 of those experience at least some vision loss. Macular edema, a first stage of retinopathy, occurs when, over time, excess uncontrolled blood sugar damages the tiny blood vessels in the eye, causing fluid and fat to leak onto the retina at the back of the eye. The swelling interferes with focus and blurs vision. Making matters worse, a lack of oxygen often then triggers VEGF's production cycle. All 10 subjects in the study had some vision loss at the start of the clinical trial, in which ranibizumab was administered at the one, two, four and six month marks. The thickness of each patient's macula was also measured at each point in the study using an advanced digital imaging technique. "Within a week, several patients experienced dramatic reductions in the thickness of their maculas, and there were further improvements with each injection," says Peter Campochiaro, M.D., the Dolores and George Eccles Professor of Ophthalmology at The Johns Hopkins University School of Medicine, who is also an investigator in the study. Ranibizumab is marketed for treatment of neovascular macular degeneration by Genentech Inc. under the brand name of Lucentis. |
| NATURAL PROTEIN STOPS DEADLY HUMAN BRAIN CANCER IN MICE |
 Scientists from Johns Hopkins and from the University of Milan have effectively proven
that they can inhibit lethal human brain cancers in mice using a protein that selectively induces positive changes in the activity of cells that behave like cancer stem cells.The most common type of brain cancer - glioblastoma - is marked by the presence of these stem-cell-like brain cells, which, instead of triggering the replacement of damaged cells, form cancer tissue. Stem cells, unlike all other cells in the body, are capable of forming almost any kind of cell when the right "signals" trigger their development. For their treatment experiment, the researchers relied on a class of proteins, bone morphogenic proteins, that cause neural stem-cell-like clusters to lose their stem cell properties, which in turn stops their ability to divide. First they pretreated human glioblastoma cells with bone morphogenic protein 4 (BMP4), then injected these treated cells into mouse brains. In mice injected with cells that were not pretreated, large, invasive cancers grew. In the mice with BMP4-treated cells, no cancers grew at all. Three to four months after injection, all mice that got untreated cells died, and nearly all mice with BMP4-treated cells were alive. Next, the scientists delivered slow-release BMP4-containing "beads" directly into mouse brains with implanted glioblastoma cells. Mice that got empty beads developed large malignant tumors and died. Mice with BMP4 beads survived much longer, and 80 percent survived four months after cancer cell implants. "Our idea is to treat patients with BMP4 or something like it right after surgery to remove glioblastoma in hopes of preventing the regrowth of the cancer and improving survival time," says Alessandro Olivi, M.D., director of the Division of Neurosurgical Oncology at Hopkins and a contributor to the study. Olivi says clinical studies using BMP4 could begin within a year and, if successful, drug therapies could be available to the public within three to four years. "This was proof of the idea that BMPs could stop glioblastoma by depleting the stem-cell-like population that feeds it," says Henry Brem, M.D., chairman of the Department of Neurosurgery at Hopkins and a collaborator in the study. "This opens exciting doors to future research into treatments and therapies for such a devastating disease." |
| "ERECTILE DYSFUNCTION" DRUGS HEIGHTEN NATURAL ANTI-CANCER ACTIVITY |
 Sildenafil and other "impotence drugs" that boost the production of a gassy chemical
messenger to dilate blood vessels and produce an erection now also show promise in unmasking cancer cells so that the immune system can recognize and attack them, say scientists at the Johns Hopkins Kimmel Cancer Center.Tests at Hopkins on mice with implanted colon and breast tumors showed that tumor size decreased two- and threefold in sildenafil-treated animals, compared to mice that did not get the drug. In mice engineered to lack an immune system, tumors were unaffected, proof of principle, the scientists say, that the drug is abetting the immune system's own cellular response to cancer. The Hopkins team says boosted levels of the chemical messenger nitric oxide appear to dampen the effects of a specialized cell that diverts the immune system away from tumors, allowing swarms of cancer-attacking T-cells to migrate to tumor sites in the rodents. Lab-grown cancer cells treated with sildenafil showed similar results, as did tissue samples taken from 14 head and neck cancer and multiple myeloma patients. Sildenafil, marketed under the trade name Viagra, is one of a class of drugs used to treat erectile dysfunction in millions of men, and in recent years, its ability to stimulate the production of NO has been investigated by experts in diseases linked to the activity of blood vessels and blood components. The new Hopkins study homes in on a tactic used by cancers to avoid detection by the immune system by turning elements of that system to its own advantage, says Ivan Borrello, M.D., assistant professor at the Johns Hopkins Kimmel Cancer Center. Borrello and his colleagues found that tumors exploit nitric oxide-producing immune cells to create a sort of "fog" that keeps them hidden from white blood cells (T-cells) that mount attacks on tumors. These NO-producing cells, a.k.a. myeloid-derived suppressor cells (MDSCs), normally use nitric oxide to help bring the immune system back down to surveillance levels after an "attack mode" response to foreign material. The impotence drugs seem to reverse this process, stopping the production of nitric oxide by MDSCs thereby allowing other immune cells to "see" the cancer and attack it, says Paolo Serafini, Ph.D., a research fellow in Borrello's laboratory and lead author on the paper. Nitric oxide is infamous among city dwellers as a component of air-polluting smog, but is gaining importance in medical research for its cell-signaling duties and its ability to divert soldiering T-cells that patrol and protect. The Hopkins team also analyzed gene expression patterns of the myeloid-derived suppressor cells and found that sildenafil blocked two genes regulating enzymes -- arginase and nitric oxide synthase -- which are key to triggering immune suppression via MDSCs. Borrello's team found that the arginase enzyme, which metabolizes a dietary supplement called L-arginine, also contributes to dampening the immune system through MDSCs much like nitric oxide, and its production can be reversed by sildenafil. "Impotence drugs won't cure cancer," Borello cautioned, "but could be used in addition to standard chemotherapy or immunotherapy treatments." The investigators are planning human studies to begin in the next year. Funding for the study was provided by the Italian Association for Cancer Research. Coauthors include Kristin Meckel, Michael Kelso, Kimberly Noonan, Joseph Califano, and Wayne Koch from Johns Hopkins; and Luigi Dolcetti and Vincenzo Bronte from the Istituto Oncologico Veneto in Padua, Italy. |
| KIDNEY STONES OCCURRING MORE OFTEN IN CHILDREN |
 Kidney stones in children - considered all but a medical aberration until recently - are now becoming a fairly common condition. It's a growing and disturbing trend that has pediatricians at the Johns Hopkins Children's Center, and around the country, sounding the alarm. While doctors have yet to quantify the precise increase and tease out the factors behind it-better detection devices probably play some role-pediatricians agree that too much salt and too little drinking water in children's diets are probably the main culprits. "More and more children with kidney stones are coming to us," says kidney specialist Alicia Neu, M.D., co-director of the kidney stone clinic at the Children's Center. "While this is somewhat unexpected, it is not totally surprising given that so many other conditions are on the rise in children due to poor diet, such as high blood pressure, type 2 diabetes and obesity to name a few." Kidney stones are rarely a serious condition, but can be extremely painful and can cause urinary tract infections. Limiting salt in the diet and drinking plenty of water are the best ways to prevent the most common types of kidney stones or slow their growth. Here are several simple tips to keep in mind: • Doctors recommend consuming no more than 2.4 grams of sodium a day, or 6 grams (1 teaspoon) of table salt a day. • Stay away from salty snacks, such as chips and pretzels, which are loaded with sodium. • Processed foods, including smoked and cured meats, as well as sodas and canned products have the highest sodium content. • Look for "no salt added" or "low sodium" labels when buying food. • Rinse canned foods under water to remove some of the sodium. • Tea, coffee, dark chocolate, spinach, nuts and wheat bran can also increase the risk of certain types of kidney stones. • A child needs to drink two liters (64 ounces) of water a day. • Sugar-laden juices and sodas don't count as proper hydration. "Clearly, when it comes to water consumption, what is needed is a cultural change, and schools have to play a role in making bottled water available and limiting soft drinks, as well as allowing children to visit the restroom as needed," says urologist Yegappan Lakshmanan, M. D., co-director of the Center's pediatric stone clinic. A good way for a child to tell if he or she is drinking enough water is the urge to urinate every three hours. If a child urinates less frequently than that, it might be a sign of dehydration, Lakshmanan says. Signs and symptoms of kidney stones include: • Intense pain in the lower-back and/or in the sides • Frequent and painful urination • Blood in the urine and/or cloudy urine • Urinary tract infections, secondary to kidney stones, accompanied by fever The pediatric kidney stone clinic at the Children's Center is a one-stop shop that consolidates under one roof imaging technology, treatment, management and nutrition and lifestyle counseling. |
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| SAFER ICU'S: CHEAP, SIMPLE, "LOW-TECH" STEPS WORK |
 Hospitals will quickly slash the rate of common, costly and potentially lethal catheter-related bloodstream infections in their intensive care units (ICUs) by using cheap, low-tech, common-sense measures like hand washing, timely removal of unneeded catheters, and use of sites other than the groin to place lines when possible, according to a report from safety experts at Johns Hopkins in the Dec. 28 issue of the New England Journal of Medicine. "There's just no reason any more not to do these relatively simple things," says Peter Pronovost, M.D., professor of medicine and medical director of Hopkins' Center for Innovation in Quality Patient Care, who led researchers in their review of 103 Michigan ICUs, before, during and after implementing a variety of measures designed to reduce such infections. "A common misperception among hospital-based clinicians is that it often costs much too much money and time to significantly improve patient safety," says Pronovost. "Our data destroys this myth by showing that profound improvements can be made with minimum cost and effort, as long as clinical teams are committed to improving safety and willing to diligently observe relatively simple safety measures." Nationwide, an estimated 80,000 bloodstream infections occur each year as a result of central venous catheters, which are tubes inserted through a blood vessel that ends near or in the heart to deliver treatments and monitor care. Bloodstream infections are involved in up to 28,000 deaths in the United States alone among these ICU patients. Economically, the toll is enormous, Pronovost says, with an average cost to the health care system of $45,000 per patient for treatment and billions each year nationwide, "far more than it costs to implement steps to prevent the infections in the first place." In the Michigan hospital system, which served as a pioneering pilot site for infection prevention measures, efforts included training physicians and nurses about infection control; using special, standardized central-line supply carts that are controlled for one-time use; requiring use of a cockpit-style "checklist" to ensure adherence to infection-control practices such as hand washing; avoiding catheter placement through the femoral artery in the groin, an area notoriously difficult to keep sterile; using and changing gloves, gowns and masks for each procedure; cleaning patients' skin with chlorhexidine; and removing catheters as soon as possible, even if there's a chance they might be needed again at some point. The safety plan also requires immediate "stop now" orders by any member of the health care team when a checklist is not followed to the letter and feedback to each member of the care team about the number and rates of catheter-related bloodstream infections at weekly and quarterly meetings. Pronovost said the study team gathered information in Michigan representing 375,757 ICU catheter-days, collected quarterly for up to 18 months after implementation of the safety measures. The results were dramatic, he says, when the steps were implemented. The median rate of catheter-related bloodstream infections per 1,000 catheter-days decreased from 2.7 at baseline to 0 after implementation of the safety measures, and the mean rate decreased from 7.7 at baseline to 1.4 at 16 to 18 months of follow-up. The study was funded by a grant from the Agency for Healthcare Research and Quality. |
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