The research sheds light on the biochemical mechanisms involved in the disease and suggests new avenues of study for preventing brain-cell death in at-risk people before symptoms appear. The drug can actually prevent brain cells from dying, said Dr. Ilya Bezprozvanny, associate professor of physiology at UT Southwestern. It's much more important than people thought.

The study, of which Dr. Bezprozvanny is senior author, appears in the July 25 issue of The Journal of Neuroscience . The drug, called tetrabenazine (TBZ), is commercially distributed as Xenazine or Nitoman and blocks the action of dopamine, a compound that some nerve cells use to signal others. TBZis approved for use in several countries, but not the U.S., to treat uncontrollable muscle movements in Huntington's and other neurological conditions. Huntington's is a fatal genetic condition that usually manifests around ages 30 to 45, according to the Huntington's Disease Society of America. About one in 10,000 people in America have the disease, with another 200,000 at risk. One of the most famous people with Huntington's was folk singer Woody Guthrie, who died in 1967. Huntington's is caused by a dominant gene, meaning that a person carrying the gene is certain to develop the disease and has a 50 percent chance of passing it on to his or her children. Symptoms include jerky, uncontrollable movements called chorea and deterioration of reasoning abilities and personality. Symptoms begin after many brain cells have already died. Although a genetic test exists, some people with a family history of Huntington's choose not to be tested because there is no cure and because they fear loss of health insurance. There are treatments to lessen the symptoms, but there is currently no way to slow or halt the progression of the disease. In the current study, the UT Southwestern researchers used mice that were genetically engineered to carry the mutant human gene for Huntington's, causing symptoms and death of brain cells similar to those seen in the disease. The study focused on an area of the brain called the striatum, which plays a critical role in relaying signals concerning motion and higher thought and receives signals from several brain regions. The striatum is primarily made up of nerve cells called medium spiny neurons, which undergo widespread death in Huntington's. One major input to the striatum comes from an area called the substantia nigra, which controls voluntary movements and sends signals to the striatum via nerve cells that release dopamine. The researchers conducted various coordination tests on both normal and genetically manipulated mice. Engineered mice given a drug that increased brain dopamine levels performed worse on these tasks, while TBZ protected against this effect. Most importantly, TBZ appears to reduce significantly cell loss in the striatum of the engineered mice, the scientists report. More research is needed to determine whether this protective effect might also be present in humans, and also whether at-risk people would benefit from the drug, Dr. Bezprozvanny said. Clinical trials in humans would be very difficult, however, because trials require many participants and there is no easy way to score effectiveness of a presymptomatic drug, Dr. Bezprozvanny said. Thus, his future studies in animals will look at the effectiveness of TBZ given just after initial symptoms have developed. This situation simulates what would probably happen in a human trial, he said. Other UT Southwestern researchers involved in the study were Dr. Tie-Shan Tang, instructor in physiology; and Dr. Xi Chen and Dr. Jing Liu, postdoctoral researchers in physiology. The work was supported by the Robert A. Welch Foundation, the Huntington's Disease Society of America, the Hereditary Disease Foundation, the HighQ Foundation and the National Institute of Neurological Disorders and Stroke.

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The study found that increases in the rate of breast cancer occurred almost entirely among ER+ cancers (breast cancers sensitive to hormones, such as estrogen receptor-positive), which made up more than 80 percent of the breast cancers diagnosed in women over the age of 45. Recent laboratory and epidemiological evidence suggests that such changes may also particularly increase the development of receptor-positive breast cancer. This study confirms that the increased use of hormones led to more receptor-positive breast cancers and that declines in hormone use led to parallel declines in receptor-positive cancers. On the other hand, the pattern for ER- cancers was quite different and is enigmatic. The rate of ER- cancers decreased from 1980 to 1995, increased from 1995 to 1999, then decreased sharply from 2000 to 2006. This pattern does not coincide with the time periods of increased mammography screening and hormone therapy use and the drop in hormone therapy use that began around 2000. The drop in hormone therapy began around 2000, confirming the suspicion that ER- cancers are not sensitive to the rise and fall in hormone therapy.

This work was funded by the National Cancer Institute, part of the National Institutes of Health. James V. Lacey Jr., Ph.D.; J. Daniel Carreon, M.S.; and Robert N. Hoover, M.D., Sc.D., of NCI's Division of Cancer Epidemiology and Genetics actively collaborated in all aspects of the study.

Kaiser Permanente's Center for Health Research, founded in 1964, is a non-profit research institution dedicated to advancing knowledge to improve health. Kaiser Permanente is America's leading integrated health plan. Founded in 1945, it is a not-for-profit, group practice program headquartered in Oakland, Calif. Kaiser Permanente serves more than 8.7 million members in nine states and the District of Columbia. Today it encompasses the not-for-profit Kaiser Foundation Health Plan, Inc., Kaiser Foundation Hospitals and their subsidiaries, and the for-profit Permanente Medical Groups. Nationwide, Kaiser Permanente includes approximately 156,000 technical, administrative and clerical employees and caregivers, and 13,000 physicians representing all specialties. For more Kaiser Permanente news, visit the KP News Center at: xnet.kp/newscenter.

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