University Times

Researchers find enduring brain changes with bulimia

Brains of patients who have recovered from bulimia nervosa show persistent changes that may offer clues to understanding biological contributions, according to researchers at the University medical center.

The findings, published June 28 in the American Journal of Psychiatry, are evidence that scientists are making progress in localizing regions of the brain that may make people susceptible to developing bulimia nervosa and other eating disorders.

Walter H. Kaye, professor of psychiatry, and Guido Frank, visiting instructor in the Pitt medical school's Department of Psychiatry, used positron emission tomography (PET) to take pictures of brain activity in women who had been recovered from bulimia nervosa for at least a year. The images showed that alterations of part of the brain's serotonin system persisted after recovery.

The findings are significant for a number of reasons, according to Kaye, Frank and their colleagues, because the serotonin system directly affects the regulation of mood, appetite and impulse control.

The researchers compared women who were recovered from bulimia for at least a year with healthy volunteers who had never had an eating disorder. The women's brains were imaged by PET, and data from the individual images were averaged and compared against each other. The set of data from recovered bulimics showed that they did not experience a normal age-related decline in serotonin binding, but they had a reduction of serotonin binding in their orbital frontal cortex that was not evident in the images from the healthy women.

"The images support the possibility that these alterations may be related to the control of appetite, mood and impulse control and thus may make some women vulnerable for developing an eating disorder. Moreover, the fact that serotonin activity did not normally change with age offers important clues as to why bulimia nervosa may develop in teenage years," Kaye said.

In addition to the changes uncovered by imaging, the women who had recovered from bulimia nervosa had significantly higher scores on standard tests mental health professionals use to assess risk.

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Potential therapy for Fabry disease to be tested

Pitt will be one of 20 medical centers to take part in a major international study of a potential therapy for Fabry disease, a rare genetic disorder that affects about 1 in 40,000 males worldwide.

The goal of this trial is to determine the safety and efficacy of recombinant Human alpha-galactosidase A (Fabra-zymeTM) on the progression of the disease. Pitt is recruiting patients for the study, which will be a randomized, double-blind trial. This means that neither the investigators nor the participants will know who is receiving the treatment versus a placebo.

Last week's New England Journal of Medicine included a report on an earlier eight-center study that points to the potential of enzyme-replacement therapy to reverse many of the most severe health problems associated with Fabry such as kidney and heart failure and stroke.

"We will be working with families, Fabry patient organizations and medical centers throughout our area to identify patients for this very important clinical trial," said John Barranger, a professor in the human genetics department of Pitt's Graduate School of Public Health. "It is an excellent example of how genetics impacts public health leading to better diagnosis and treatment."

Fabry disease is an inherited condition known as lysomal storage disorder. It is caused by an enzyme deficiency that results in the body's inability to break down certain naturally occurring fatty substances called glycolipids — primarily GL-3.

In Fabry disease, these glycolipids accumulate in the body, principally in the lining of blood vessels in the kidney, heart and other organ systems. Symptoms include pain in the hands and feet, a spotted, dark red rash, kidney dysfunction, a decrease in the ability to perspire, stroke and heart attack. Because of such severe organ complications, Fabry is often fatal by age 40.

Linked to the X-chromosome, Fabry disease is a genetic disorder that is present at birth. Women can pass the trait for Fabry on to their male children. And, female carriers of the Fabry trait frequently have signs and symptoms of the disease.

In the Pitt study, participants will be treated for at least a year. To be eligible, patients must have clinical symptoms consistent with Fabry disease, be older than 16 and meet certain other criteria. Patients who have undergone or are currently scheduled for kidney transplantation or who are currently on dialysis are not eligible. Patients who have undergone previous enzyme therapy or who are pregnant or lactating also are not eligible.

For more information about the Fabry disease trial, call 1-800/334-7980.

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UPCI joins with Eli Lilly in clinical trials

The University of Pittsburgh Cancer Institute (UPCI) has announced a new collaboration with Eli Lilly and Company to more swiftly conduct clinical trials, the research that transforms laboratory breakthroughs into approved treatments.

"This collaboration represents a paradigm shift in the clinical trials process, and we are pleased that Lilly accepted our offer to be the first major pharmaceutical company to join our new initiative," said Ronald B. Herberman, UPCI director and Pitt associate vice chancellor for research, Health Sciences.

"Given Lilly's track record in oncology and its robust pipeline, the opportunity to build a broader and deeper relationship with the company could hardly be more attractive to our faculty and to our community-based oncologists."

While specific terms of the collaboration were not disclosed, UPCI, through the Pittsburgh Clinical Research Network, will provide project management oversight personnel for clinical trials involving anti-cancer compounds under development at Lilly.

Lilly, in turn, will sponsor both early and late phase clinical trials involving different types of cancer. The agreement is renewable on an annual basis.

Alan K. Hatfield, medical director of Lilly Oncology's U.S. affiliate, said Lilly was impressed with UPCI's ability to support clinical trials from many essential vantage points. These include a cadre of world-renowned physician-scientists, a network of eligible clinical trial participants and a project-management entity to oversee these trials.

UPCI has more than 60 faculty investigators, and its community-based network includes over 50 oncology practices spread throughout western Pennsylvania.

Herberman said: "UPCI is keenly aware of the need to continue to be responsive to other significant sponsors of oncology trials" and, in this light, "our intent is to establish only a handful of preferred partnerships with sponsors so that we are not encumbered by an unmanageable number of trials or by too many conflicts between or among sponsors."

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Study links stress with infertility

Increased levels of the stress hormone cortisol are clearly elevated in the bloodstream of child-bearing-aged women who have stopped menstruating, a senior researcher at the Magee-Womens Research Institute has found.

The study is significant because it also shows that a psychological intervention and stress-reduction therapy can have a positive impact on infertility associated with the cessation of menstruation.

Called functional hypothalamic amenorrhea (FHA), the condition affects some 5 percent of women in their reproductive years. It is characterized by wildly irregular or absent periods — often for as long as two years or more.

"FHA isn't caused by any real defects in the reproductive system," said Sarah Berga, a professor in the departments of obstetrics, gynecology and reproductive sciences and psychiatry at Pitt's School of Medicine. "We thought using stress-reduction techniques might reverse the process, and our results show we were right."

Berga presented the study findings last month at the 83rd annual meeting of the Endocrine Society, an organization made up of endocrine specialists in internal medicine, pediatrics and gynecology.

Now in its seventh year, the ongoing study has included both human volunteers and primates to link stress and infertility due to FHA. "We are finding out how stress causes infertility," said Berga, who also is director of the division of reproductive endocrinology and infertility at Magee-Womens Hospital of the UPMC Health System.

"This is something I've been working on for 15 years," she said. "Typically, these women are not aware they're under stress, or don't acknowledge it."

Women with FHA also share certain characteristics, such as a tendency toward perfectionism and poor nutritional or lifestyle choices. Many just try to get too much done in a day.

Fourteen women took part in the most recent phase of the study. Seven were treated with sessions of cognitive behavior therapy and dietary counseling, while seven were not. All were observed for a period of 20 weeks.

Of the treated women, six fully recovered normal menstrual cycles, and one partially recovered. Of those not treated, only one fully recovered. One partially recovered, and five continued to experience FHA.

"The endocrine system rewards moderation," Berga explained. "We try to teach balance and creative problem solving."

Long-term FHA affects more than fertility. It also can result in bone loss and affect brain function. If women with FHA take fertility drugs to get pregnant, the underlying stress process may lead to early delivery or poor fetal brain development.

Funding was provided by the National Institute of Mental Health, a component of the National Institutes of Health.

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Safe, effective treatment for overactive bladder in those with spinal cord injury

MS Extended release oxybutynin is a safe and effective treatment for overactive bladder in patients with spinal cord injury or multiple sclerosis, according to two studies that Pitt researchers presented at the World Health Organization Second International Consultation on Incontinence in Paris, France, July 1-3.

"The results of these studies should be encouraging to physicians treating multiple sclerosis and spinal cord injury patients. They can now treat overactive bladder as a secondary condition, effectively improving the patient's quality of life," said Michael B. Chancellor, a Pitt professor of urology, director of neuro-urology at the University medical center and lead investigator in the study.

Damage to the nervous system, as experienced in spinal cord injury and MS patients, can cause a condition referred to as neurogenic bladder. Patients with neurogenic bladder experience a malfunction of the autonomic nerves that control bladder function, resulting in overactive bladder.

Extended release oxybutynin is one of the leading treatments for overactive bladder, decreasing the frequency of urination with a minimal amount of side effects. Pitt's studies are the first to evaluate the drug's efficacy in MS and spinal cord injury patients.

In the first study, Chancellor and colleagues evaluated the effectiveness of extended release oxybutynin in patients who experienced detrusor hyperreflexia, commonly referred to as overactive bladder, and had some type of spinal cord injury.

Patients who received the drug greatly reduced their frequency of urination or catheterization by an average of two episodes a day with no serious side effects.

The second study evaluated the effectiveness of extended release oxybutynin in MS patients with neurogenic bladder. As in the study with spinal cord injury patients, oxybutynin reduced the number of voids or cathe-terizations by two a day with no serious side effects. Results also showed that oxybutynin did not increase residual urine volume. Increased urine volume could compromise overall bladder health, leading to urinary infections.

Overactive bladder affects approximately 17 million Americans, making it more prevalent than many commonly discussed conditions. With symptoms including involuntary loss of bladder control, the urgent need to urinate and frequent urination (more than eight times a day), overactive bladder is one of the more under-diagnosed and under-treated conditions in the United States, researchers say.

The studies were sponsored by ALZA Pharmaceuticals of Mountain View, Calif.