University Times

Pitt researcher heads team searching for genetic basis of bulimia nervosa

Researchers at Western Psychiatric Institute and Clinic are leading an international effort to locate the genes responsible for the eating disorder bulimia nervosa.

Walter Kaye, professor of psychiatry and director of the Eating Disorders Module, is principal investigator of the multi-center study that may help solve the mystery of why some people seem to be predisposed to the disease and why it may run in families.

Bulimia nervosa is characterized by binge eating, the consumption of large amounts of food in a short time, followed by purging, either by vomiting or using laxatives. It frequently causes serious medical complications and psychological conditions. Unlike anorexia nervosa, in which patients lose much of their body weight, people with bulimia usually maintain normal weight. Both conditions commonly begin in adolescence and affect more women than men.

"The amount of evidence that eating disorders have a biological basis has been growing steadily," Kaye said. "By locating the gene or genes that contribute to eating disturbances or excessive concerns about body shape and size, we may be able to provide preventive counseling for those at risk and help identify new treatments," he said.

Research sites in four U.S. cities — Pittsburgh, Philadelphia, New York and Los Angeles — and in Canada, Germany and Italy will recruit 400 women or men with bulimia nervosa who also have a biological relative with similar eating concerns or problems. These relative pairs will provide blood samples for genetic analysis and will be interviewed about their disorder.

Because these procedures can be performed where a patient lives, no traveling is required. According to Kaye, comparing the genes from this large group of relatives may identify the gene or genes underlying the disorder.

To learn more, call toll-free, 1-888-895-3886 or e-mail to info@cope.wpic.pitt.edu. All communication is confidential.

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Enzyme that detoxifies cancer drug linked to Alzheimer's risk

A naturally produced enzyme, bleomycin hydrolase, whose only known function is to detoxify a widely used cancer agent, has now been linked to a four-fold increased risk of developing Alzheimer's disease (AD), according to an article by Pitt researchers in the March issue of Nature Genetics.

Bleomycin hydrolase breaks down bleomycin, a potent cancer drug used to treat testicular and other cancers. Investigators at Pitt and elsewhere have long researched ways to selectively activate bleomycin hydrolase in healthy tissues that are damaged by bleomycin. This agent can cause life-threatening lung fibrosis in patients treated with the drug.

"Our research discovery is significant because it provides the first susceptibility gene for sporadic, or non-familial, cases of Alzheimer's disease in people who lack the only other known inherited risk factor, APOE*4, for sporadic disease," noted Susana Montoya, co-author of the study and a Pitt graduate student. "The bleomycin hydrolase risk factor also is greater than any known environmental risk factor for Alzheimer's disease." More than 90 percent of AD cases are sporadic and of late onset. Previous research has shown that individuals with the APOE*4 form of the apolipoprotein gene are at higher-than-expected risk of developing sporadic AD.

Apoplipoprotein E is thought to facilitate the deposition of amyloid plaques within the brains of AD patients. Investigators have long sought risk factors for members of the population who do not carry APOE*4 (about 40 percent) yet still develop sporadic AD. Four million Americans are affected by AD, according to the National Alzheimer's Association.

"This discovery gives us another significant opportunity to identify people at risk for Alzheimer's disease. With this information, we can explore potential mechanisms to intervene early to prevent disease development or significantly delay its course," noted Steven DeKosky, co-author, professor of psychiatry, neurology and human genetics, and director of Pitt's Alzheimer's Disease Research Center (ADRC). DeKosky also is chairperson of the Alzheimer's Association's Medical and Scientific Advisory Committee.

"It's obvious that the bleomycin hydrolase protein did not evolve to counter the effects of a single cancer agent," said Robert Ferrell, professor of human genetics and senior author of the paper. "Our research finding suggests a plausible role for this enzyme in processing the amyloid precursor proteins that give rise to the plaques characteristic of Alzheimer's disease." "This research could be the first step toward designing a therapy in which we would selectively alter bleomycin hydrolase activity in brain cells to prevent the generation of disease plaques," added John S. Lazo, co-author, professor and chairperson of Pitt's pharmacology department, and co-director of Molecular Therapeutics/Drug Discovery at the University of Pittsburgh Cancer Institute.

In their research, Pitt investigators studied the bleomycin gene in 357 Alzheimer's disease patients and 320 controls obtained through the ADRC and the Indiana Alzheimer's Disease Center Cell Repository. The bleomycin gene has two forms, or alleles, called A and G. The investigators found that individuals with two copies of the G bleomycin hydrolase allele (G/G) and without APOE*4 are four times more likely to have AD. About 6 percent of the population would be expected to fit this genetic profile (G/G, -APOE*4).

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Operation can relieve crippling hip condition

Each year, more than 15,000 people in the United States ages 20 to 40 develop a painful, crippling and hard-to-diagnose hip condition called osteonecrosis, in which the bone and surrounding veins and arteries of the ball-and-socket joint lose blood supply and die. This leads to painful cartilage collapse, joint dysfunction and, in some cases, the need for total hip replacement.

A seven-year study by UPMC Health System orthopaedic surgeons shows that a unique, microscopic bone and tissue transfer technique can provide relief by restoring living bone and vascular tissue and allowing less-painful mobility in the hip joint. The UPMC team, led by Dean Sotereanos, a Pitt associate professor of orthopaedic surgery, reported its findings in a recent issue of the journal Clinical Orthopaedics and Related Research. Sotereanos also will report on the technique at the American Academy of Orthopaedic Surgery annual meeting March 19.

"This procedure can save young patients from needing total hip replacements," Sotereanos said. "It is well-known that total hip replacements in young patients do not fare well because the implant often loosens with wear and tear and lasts up to only 10 years before requiring re-implantation." Necrosis of the hip can be difficult to diagnose. Often, it is accompanied by, and confused with, back and knee pain, stiffness and immobility of the hip joint and groin pain with weight bearing. It can occur in one or both hips. While most cases are caused by systemic steroid drug use (such as in organ transplant recipients) or chronic alcohol consumption, it also can result from traumatic injuries and connective tissue diseases as well as a number of other conditions.

The bone and tissue transfer procedure involves removing the portion of dead bone from the femoral head (tip of the thigh bone which is the ball of the hip's ball-and-socket joint) and drilling into the ball a four-to-five-inch piece of the fibula (outer bone of the lower leg). Surgeons also restore blood flow by transferring veins and arteries with the fibula. The surgery typically takes six hours.

Only a few surgeons nationwide perform the procedure. UPMC, whose surgeons have performed more than 260, boasts the second-largest number of cases in the world.

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Mathematical brain wave research published

A mathematical model of the mechanisms by which brain waves change based on humans' activity levels, from fully alert to sleeping, is the subject of new research by Pitt mathematician Bard Ermentrout published in the Feb. 27 issue of the journal Science.

This computational neuroscience modeling looks directly at the origins of certain brain waves in the thalamus, the portion of the human brain that relays information from our senses to the cerebral cortex, the main part of the brain where humans do most of their thinking. The brain has a certain set of rhythms that vary according to consciousness level. These rhythms originate in the thalamus and have a lower frequency, or occur less often, when a person is sleeping and have higher frequencies when a person is alert.

Ermentrout and his colleagues discovered that certain waves originating in the thalamus are not the kind of smooth continuous waves that might be expected, but instead "jump" as if interrupted along their way.