| The latest medical advances from Johns Hopkins Medicine |
| HOPKINS PERFORMS HISTORIC "DOMINO DONOR" "QUINTUPLE" KIDNEY TRANSPLANT |
 Surgical teams at Johns Hopkins have successfully completed the first five-way donor
kidney swap among 10 individuals. All five organ recipients -- three men and two women -- are fine, as are the five donors, all of whom are women. The marathon, 10-hour surgeries that began at 7 a.m. Nov. 14 occupied six operating rooms
staffed by twelve surgeons, eleven anesthesiologists and eighteen nurses at The Johns Hopkins Hospital.
Four transplant candidates had come to Johns Hopkins separately for evaluation, each with a willing donor whose blood and tissue types were incompatible with the intended recipient and who therefore could not donate to their loved one. Using a previously developed living donor matching system, the Johns Hopkins transplant team included a so-called altruistic donor in the mix and were able to arrange a five-way swap, in which all four original candidates received compatible kidneys from someone they had never met, and the remaining kidney went to a patient who was next on the United Network for Organ Sharing (UNOS) organ recipient list. An altruistic donor is a person who, for personal reasons, has a generous desire to donate a kidney to no particular recipient. The Johns Hopkins transplant team is a pioneer in the exchange of kidneys between incompatible donor-recipient pairs. Johns Hopkins performed the first non-domino KPD transplant in the United States in 2001, the first non-domino KPD triple transplant in 2003 and the first triple domino transplant in 2005. To date, its surgeons have transplanted 41 patients in KPD operations. In Tuesday's operations, surgical teams took kidneys from five unrelated female donors and transplanted them into the five unrelated recipients, whose ages range from 40 to 77 years. The one "altruistic" donor is a healthy 48-year-old computer programmer who says she was motivated to donate a kidney after losing both her husband and her daughter in separate accidents or illnesses. "It has been a privilege to help this person fully realize her altruism by placing her into a domino transplant where her gift has made five transplants possible that would not have occurred," says Robert Montgomery, director of the Incompatible Kidney Transplant Program, chief of the Division of Transplantation, and director of the Comprehensive Transplant Center at Hopkins. In a paper published last August in the British journal Lancet, Montgomery laid out the blueprint for a wider system of pairing altruistic donors and incompatible recipient pairs to greatly increase the number of available organs and better serve the interests of both transplant donors and recipients. Without a universal system of this kind in place, Montgomery says altruistic donors often end up on an Internet donation site or are subject to inconsistent allocation systems in which only a single patient benefits. "With domino paired donation, all three of these ethical tenets are satisfied," says Montgomery. "The likelihood of a good outcome is increased by spreading the risk of recipient graft loss across more people. The neediest are served, since in many cases incompatible donor-recipient pools have a high proportion of patients who are hard to match. And fairness is served because the last paired donor's kidney in the chain is allocated to the next compatible patient on the deceased donor waiting list." Each of the donors will be monitored for the remainder of their lives to make sure their remaining kidney continues to function properly. The recipients have been placed on medications that will help ensure that they won't reject the kidney. They will be evaluated weekly for the first six weeks, then monthly, with the frequency of hospital visits slowly tapering off over time. The average expected life of a live donor kidney is 18 to 20 years. The recipients had lost the use of their kidneys for a variety of reasons, including blood clots, end-stage renal disease and a motor vehicle accident. Nearly 100 medical professionals were instrumental in making this complex series of transplants possible, including immunogeneticists, anesthesiologists, operating room nurses, nephrologists, transfusion medicine physicians, critical care doctors, nurse coordinators, technicians, social workers, psychologists, pharmacists, financial coordinators and administrative support people. |
| MILLIONS WITH ARTHRITIS MAY BENEFIT FROM BONE LOSS DRUG |
 People taking a widely used medication to strengthen fragile, aging bones may also be
protecting their joints, according to a recent study led by Johns Hopkins rheumatologist Clifton Bingham, M.D.
Researchers began to wonder if risedronate might be used to treat osteoarthritis after noticing that the drug, and other compounds in the same class of drugs, not only slowed joint damage in animals, but also reduced cartilage-irritating bone lesions in humans. For two years, an international team of investigators studied 2,483 arthritic men and women, from both the United States and Europe. All of those enrolled in the study had a loss in the cartilage that cushions the knee joint, a hallmark symptom of osteoarthritis. Bingham and his team said study participants were given either a placebo or risedronate at a range of doses, including the standard doses normally prescribed to treat bone loss. The amount of cartilage detected in their knees was measured by X-ray analysis at the one- and two-year marks. Blood tests were also used to check for a marker of cartilage breakdown known as CTX-II. CTX-II is released in the bloodstreams of people with osteoarthritis when cartilage begins to fray. How fast and to what degree cartilage breaks down can be approximated by levels of CTX-II. "The blood tests revealed not only that risedronate stabilized bone loss, but also that it was most likely slowing the breakdown of cartilage, too" says Bingham. Bingham emphasizes that X-rays failed to show any dramatic visible changes in the structure of the joints with risedronate compared to a placebo: however, the numbers of patients exhibiting significant progression of the disease were few in all treatment groups. A great challenge now is identifying the risk factors for joint deterioration in osteoarthritis, adds Bingham. In the United States, where an estimated 25 million people have osteoarthritis and 44 million have osteoporosis, participants in the study group taking risedronate experienced a noticeable drop in their CTX-II levels. Patients taking the drug at normal levels and at higher than usual doses given for comparison experienced similar slowdowns in cartilage decline, without significant adverse side effects. Those in the placebo group, however, experienced increases in CTX-II levels, suggesting that their cartilage was deteriorating faster than that in those taking the drug. "We are not recommending that everyone with arthritis run out and get a prescription for these kinds of drugs, nor are we suggesting at this time that doctors use risedronate as an arthritis treatment," cautions Bingham. "But what we can say now is that drugs affecting bone turnover need to be further evaluated for their potential effects as arthritis therapies." The blood test changes seen in the study would suggest that people already taking bone strengthening drugs may be simultaneously helping their joints, concludes Bingham. NOTE: Dr. Bingham has received consulting fees from Proctor & Gamble Pharmaceuticals, the makers of Actonel, the brand name for risedronate. Additionally, several other members of his research team have received consulting fees from other pharmaceutical companies. |
| 'MUSCLE' PROTEIN DRIVES PROSTATE CANCER |
 Researchers at the Johns Hopkins Kimmel Cancer Center have for the first time implicated
the muscle protein myosin VI in the development of prostate cancer and its spread.
In a series of lab studies with human prostate cancer cells, the Johns Hopkins scientists were surprised to find overproduction of myosin VI in both prostate tumor cells and precancerous lesions. When the scientists genetically altered the cells to "silence" myosin VI, they discovered the cells were less able to invade in a test tube. "Our results suggest that myosin VI may be critical in starting and maintaining the malignant properties of the majority of human prostate cancers diagnosed today," says Angelo M. De Marzo, M.D., Ph.D., a study coauthor and associate professor of pathology, urology and oncology. The Johns Hopkins work, published in the November issue of the American Journal of Pathology, has potential value for better ways to diagnose the disease, treat and track the effects of drugs and surgery. "Targeting myosin VI represents a promising new approach that could lead eventually new approaches to treating the disease," says Jun Luo, Ph.D., senior author of the paper and assistant professor of urology. Myosins are a class of 40 motor proteins that power cell movement and muscle contractions. Normally, as they work, myosins slide in a single direction along the threads of a protein called actin. But myosin VI moves against the grain, and it does not function as a classical "muscle" protein. Using a DNA microarray to study all of the genes in 59 samples of benign or cancerous prostate tissue from patients at Johns Hopkins, the researchers found the malignant samples showed a 3.7-fold higher expression of myosin VI as compared to normal samples, and a 4.6-fold increase as compared to the samples from patients with enlarged prostate. Next, the researchers hunted for myosin VI in 240 prostate tissue samples, discovering overproduction early in the development of prostate cancer in such pre-tumor conditions as high-grade prostatic intraepithelial neoplasia (PIN) and proliferative inflammatory atrophy. Finally, when they altered some cancerous cells by knocking down their myosin VI protein, the cancer cells not only were less able to spread around, but also showed 10 times the amount of a tumor suppressor called thioredoxin-interacting protein (TXNIP). Prostate cancer, which affects one in nine American men over the course of their lives, is mainly diagnosed by needle biopsy of the prostate gland after a blood test shows an increased level of prostate-specific antigen (PSA). While the PSA test is now widespread and provides many men with early diagnosis and better chance of a cure, says Luo, it may not be sensitive or specific enough to pinpoint the existence of cancer. Using myosin VI or other factors, it may be possible, Luo says, to create a laboratory test to identify high or low levels in urine or blood samples, and this might aid in the detection of prostate cancer. Myosin VI also has been shown to be associated with ovarian cancer. |
| RESEARCHERS FIND GENE LINKED TO CROHN'S DISEASE |
 An international team of researchers has identified another gene mutation linked to the
inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis.
The team, including Johns Hopkins gastroenterologists and geneticists, says the novel mutation is in the interleukin-23 (IL-23) gene receptor present in healthy people without Crohn's disease but rare in those with the disease. IL-23 is a protein that regulates chronic inflammation and helps the body fight bacterial infections. Its receptor, IL23R, is present on lymphocytes and macrophages, white blood cells responsible for mounting immune response to infections. IL-23 has long been linked to IBD and autoimmune psoriasis, but this new genetic variation in the protein's receptor offers a novel pathway for tracking the disease process and for potential drug treatments. "The IL-23 receptor variation we discovered appears to affect the IL-23 pathway, altering the body's response to chronic inflammation, which may trigger autoimmune disease," says study co-author Steven R. Brant, M.D., associate professor of medicine and director of research and the genetics laboratories of Johns Hopkins' Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center. "The fact that this gene has already been implicated in other autoimmune disease like psoriasis offers strong evidence that we are on the right track. In the Crohn's study, researchers located the IL23R disease-associated protein variant by scanning nearly all of the 22,000 genes that make up the human genome. The study looked at 547 test subjects with Crohn's disease and 548 healthy controls. Patients were recruited from six of the seven centers in the consortium. Researchers examined more than 300,000 variations in the genetic code, known as single nucleotide polymorphisms or SNPs, to identify which of the variations among these 22,000 genes can explain the genetic predisposition to developing Crohn's disease. SNPs are commonly occurring variations in our DNA code that are routinely used as a method for finding genetic links to diseases. Researchers scanned the genomes using a relatively new technology that allows researchers to study variations found in nearly all human genes for association with diseases. More than 1 million Americans have Crohn's disease or ulcerative colitis. Because IBD tends to run in families and is more prevalent in certain ethnic populations, scientists have long suspected that there is a significant genetic component. Brant says the team has identified additional gene variations potentially related to Crohn's disease, and the consortium will investigate these as well. "As more genes associated with Crohn's disease are discovered, we envision a time when gene testing may provide important guidance regarding the prognosis and treatment of each patient," says co-author Themistocles Dassopoulos, M.D., an assistant professor of medicine at the Meyerhoff Inflammatory Bowel Disease Center. |
| DIABETES NOT THE SAME FOR ALL AGES |
The study found that these two age groups have different disease burdens and may require different treatment goals. "The number of individuals aged 65 or older in the U.S. is increasing markedly and diabetes is a growing problem in this population. In addition, people are living to much older ages with high quality of life, which speaks to the need for more aggressive treatment among elderly persons with diabetes," said Elizabeth Selvin, PhD, MPH, lead author of the study and a postdoctoral fellow in the Bloomberg School of Public Health's Department of Epidemiology. The study authors analyzed 1999-2002 data for 2,809 elderly persons in order to present a nationally representative estimate of the prevalence of diabetes among elderly persons in the general U.S. population. The data were taken from the National Health and Nutrition Examination Survey (NHANES), an on-going cross-sectional survey of the civilian, non-institutionalized U.S. population. The authors report that 15 percent of the U.S. population aged 65 years or older, had been diagnosed with diabetes, a figure that represents approximately 5.4 million individuals. In addition, 6.9 percent of the U.S. population aged 65 years or older (2.4 million individuals) have undiagnosed diabetes and are unaware of their condition. Elderly persons with middle-age-onset diabetes were more likely to have retinopathy, reflecting the cumulative damage of high glucose levels over the course of many years. They also had much worse glycemic control. In contrast, elderly persons with newly diagnosed diabetes had a comparable burden of cardiovascular disease but required less aggressive treatment to reach blood pressure and cholesterol treatment goals. "The two types of elderly persons with diabetes have distinct characteristics, including different burdens of disease," said Selvin. "Elderly people with diabetes are a heterogeneous group and doctors may need to consider different treatment goals for these two groups in clinical practice." |
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| CHOCOLATE "OFFENDERS" TEACH SCIENCE A SWEET LESSON |
Some "chocoholics" who just couldn't give up their favorite treat to comply with a study to test blood stickiness have inadvertently done their fellow chocolate lovers - and science - a big favor. Their "offense," say researchers at Johns Hopkins led to what is believed to be the first biochemical analysis to explain why just a few squares of chocolate a day can almost halve the risk of heart attack death in some men and women by decreasing the tendency of platelets to clot in narrow blood vessels. "What these chocolate 'offenders' taught us is that the chemical in cocoa beans has a biochemical effect similar to aspirin in reducing platelet clumping, which can be fatal if a clot forms and blocks a blood vessel, causing a heart attack," says Diane Becker, M.P.H., Sc.D., a professor at the Johns Hopkins University's School of Medicine and Bloomberg School of Public Health. Becker cautions that her work is not intended as a prescription to gobble up large amounts of chocolate candy, which often contains diet-busting amounts of sugar, butter and cream. But as little as 2 tablespoons a day of dark chocolate - the purest form of the candy, made from the dried extract of roasted cocoa beans - may be just what the doctor ordered. "Eating a little bit of chocolate or having a drink of hot cocoa as part of a regular diet is probably good for personal health, so long as people don't eat too much of it, and too much of the kind with lots of butter and sugar," says Becker. In the study, 139 people were disqualified from a much larger study looking at the effects of aspirin on blood platelets. The Genetic Study of Aspirin Responsiveness (GeneSTAR) was conducted at johnd Hopkins from June 2004 to November 2005 and enrolled more than 500 men and 700 women participants nationwide. Shortly before aspirin dosing began for the subjects, they were told to stay on a strict regimen of exercise and to refrain from smoking or using foods and drinks known to affect platelet activity. These included caffeinated drinks, wine, grapefruit juice - and chocolate. The non-compliers - who admitted to eating chocolate - were a diverse group who got their flavonoid "fix" from a variety of sources, including chocolate bars, cups of hot cocoa, grapes, black or green tea, and strawberries. And while they were excluded from the aspirin study, Becker and her team scoured their blood results for chocolate's effect on blood platelets, which the body recycles on a daily basis. When platelet samples from both groups were run through a mechanical blood vessel system designed to time how long it takes for the platelets to clump together in a hair-thin plastic tube, the chocolate lovers were found to be less reactive. Platelets from those who stayed away from chocolate as instructed clotted faster. In another key test of urine for waste products of platelet activity, primarily urinary thromboxane, scientists found that chocolate eaters showed less activity and waste products on average, at 177 nanograms per millimol of creatinine, versus an average of 287 nanograms per millimol of creatinine in the group that abstained. Participants ranged in age from 21 to 80; 31 percent were black and the rest were white. In total, more than 200 different tests of platelet reactivity were performed and analyzed in the study. Because whole blood contains other cells that affect platelet aggregation, testing was repeated using a purified version of test samples made up of strictly platelet-rich plasma. None of the "offenders" had previous histories of heart problems, such as a heart attack, but all were considered to be at slightly increased risk of heart disease because of family history. Fifty percent of women participants were postmenopausal. "These results really bring home the point that a modest dietary practice can have a huge impact on blood and potentially on the health of people at a mildly elevated risk of heart disease," says study co-author Nauder Faraday, M.D., an associate professor at Johns Hopkins. "But we have to careful to emphasize that one single healthy dietary practice cannot be taken alone, but must be balanced with exercise and other healthy lifestyle practices that impact the heart." |
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