University Times

Neuroscientists uncover mechanism for neuron death

An influx of calcium specifically into mitochondria appears to trigger the death of neurons exposed to glutamate, a neurotransmitter that proves toxic when it's overproduced in traumatic brain injury and stroke.

This finding, described by Pitt investigators in the September issue of Nature Neuroscience, derails a long-held assumption that high concentrations of calcium within a cell's cytoplasm — and not in the mitochondria — causes cells to die.

"In our research, we found that neurons can accumulate high amounts of calcium inside the cytoplasm without breaking down. It's only when large amounts of calcium flow into mitochondria that neurons die," said Ian Reynolds, associate professor of pharmacology at Pitt's School of Medicine.

"This information clearly shows that we should consider designing drugs to target mitochondria to prevent or intervene in glutamate-induced neuronal damage," Reynolds said. Specific calcium channels on the surface of mitochondria may prove one important target for drug design, he added.

As with all living cells, a neuron consists of a cell membrane enclosing fluid cytoplasm. Within the cytoplasm are intracellular organelles, including mitochondria. Mitochondria are kidney-shaped organelles that have their own DNA and which produce energy for cells to function. Glutamate works by binding to receptors on the surface of a neuron. This binding activates an influx of calcium that triggers the neuron to release additional glutamate, which stimulates other neurons, resulting in neurotransmission. Sometimes, however, injured or diseased nerves release too much glutamate. Excess glutamate overstimulates neurons. The resultant neurotoxicity causes cell death.

Traditionally, neuroscientists have thought that too much calcium would perturb calcium-sensitive enzymes within the cytoplasm. These enzymes are critical to the function of a neuron. Several research teams have suggested that the disturbance of these enzymes, rather than any problems with mitochondria, mediate cell death. "We discovered that neurons can tolerate 20 times more calcium than what was formerly believed to be lethal, as long as this calcium doesn't get inside mitochondria," said Amy Stout, first author on the paper and a post-doctoral student investigator in Reynolds's lab.

Calcium influx into mitochondria appears to trip a death switch for neurons, whereas changes in calcium-sensitive enzymes within the cytoplasm are like dimmer switches that change the health of a neuron by degrees, according to Reynolds.

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World's first combined PET/CT scanner in trial at UPMC

Doctors' ability to see into the body for diagnosis and planning treatment may take a big step forward based on technology now under study at UPMC Health System.

By performing both PET (Positron Emission Tomography) and CT (Computer-assisted X-ray Tomography) studies sequentially on the same unit, anatomical and functional information is combined in a single image. A small pilot series of patients is being evaluated using a prototype of the new technology. "Combining PET and CT scanning is a revolutionary breakthrough," said Richard L. Baron, a Pitt professor of radiology and chairperson of UPMC's radiology department. "This new technology not only provides far more information about the state of disease processes, but also reduces the need for invasive diagnostic procedures, such as biopsies, and improves the accuracy of needed procedures by pinpointing precise sites for testing." Advances in radiology over the past quarter century have provided doctors with alternative methods of seeing inside the body. CT scanning, a system of multiple X-ray data assembled by computer, that was developed in 1972, provides much more accurate and precise images of internal anatomy than even the most advanced single-image X-rays. PET imaging provides detailed information on biochemical processes that physicians use as markers of disease.

Until now, correlating these sets of data — showing exactly where in the body diseases exist — has been frustrated by technical difficulty of superimposing these images. Many times the systems in use are incompatible. Additional problems have been the lack of precise points of reference and shifting of the internal organs during the time lapse between images. The PET/CT scanner will not be available elsewhere for at least a year to a year and a half, said David Townsend, UPMC senior PET physicist, associate professor of radiology, and chief investigator of this study. Townsend proposed development of the PET/CT scanner in 1995, after working with colleagues in Europe to develop the lower-cost rotating PET scanner. His collaboration with CTI PET Systems, Inc., Knoxville, TN (which pioneered every major commercial advance in PET imaging technology), yielded the prototype now in trial at UPMC.

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Study results may promote delivery of services for abused kids & their families

The results of two new studies completed at Western Psychiatric Institute and Clinic may help community organizations that provide services to abused children and their families reevaluate the types of therapy they provide, said David J. Kolko, associate professor of child psychiatry and psychology and a nationally recognized expert on child abuse.

The Pittsburgh Service Delivery Study was designed to document the service delivery experiences and outcomes of 90 families referred to Child Protective Services (CPS) following an allegation of child physical or sexual abuse. Measures included CPS risk assessments, interviews with child victims and their parents to evaluate client outcomes and family satisfaction with services, and community service provider reports. In his initial report from this study published in the latest issue of Child Maltreatment, Kolko found that risk assessment and related evaluations were generally conducted on time, but they were occasionally completed well beyond suggested deadlines. Reports based on the caseworkers' risk assessment were not found to be related to clinical measures of individual or family functioning based on child and parent reports. Compared to physically abused children, sexually abused children had higher rates of nonparent perpetrators, police reports, official substantiation, and ratings of the severity of their incidents.

In the second report from that study, Kolko and his colleagues examined the services received by abused children and their families. They found that less than 20 percent of the children received individual treatment, while more than 50 percent of the parents or families received treatment. Some of these services were more common depending upon the type of abuse. For example, sexually abused children more often received individual services, whereas physically abused children more often participated in family services.

"These findings will hopefully contribute to our understanding of some of the operations of CPS agencies and suggestions for enhancing their role in the service delivery system developed for abused children and their families," Kolko said.

One recent advance in helping the abusive family is the development and evaluation of specialized treatments. In one of the few federally funded outcome studies with school-aged physically abused children and their offending caregivers, Kolko and his colleagues found that structured, treatment protocols conducted at UPMC were effective in reducing parental anger and use of physical force. The results, published in Child Maltreatment with a sample of 55 families, indicated that individual skills-based therapy or family therapy showed better improvement on several outcomes, such as parental abuse risk and family conflict, than families who received routine services elsewhere in the community. These individual and family treatments were designed to be similar in several ways. Both interventions followed treatment manuals that included content for use in the clinic and during follow-up home visits; were administered in at least 12, one-hour weekly clinic sessions within a 16-week period, for a total of about 18 hours of service; and included structured supervision meetings and ongoing ratings of client involvement and performance.

"Studies like this one are needed because there have been relatively few rigorous evaluations of short-term treatments directed towards physically abused children and their offending parents or families," Kolko explained. "Because abused children can suffer long-term emotional and behavioral problems, we need to have an understanding of the types of therapies that work best to reduce the after-effects of an abusive experience and to try to prevent future episodes of family violence. Our data show that some therapies may work better than others in limiting additional violence and improving family adjustment."

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Researchers to study urinary incontinence

B. Joan McDowell and Sandra Engberg recently received a five-year, $2 million grant from the National Institute of Nursing Research, an arm of the National Institutes of Health, for their research on urinary incontinence in homebound older adults.

This study will examine the effectiveness of a prevention intervention in maintaining improved continence achieved at the end of a short-term treatment program for urinary incontinence.

"Many patients who are successfully treated for incontinence by a health care provider have difficulty continuing treatment on their own," McDowell explained.

McDowell and Engberg will study the effectiveness of a relapse prevention intervention program. This is the first such continence study to examine the effectiveness of an intervention designed to encourage adherence to an exercise program over the long term. The program will target homebound older adults receiving home care.

Urinary incontinence affects an estimated 13 to 53 percent of the homebound elderly. Urinary incontinence not only is a costly issue, but it also has severe effects on patients' quality of life. Despite these facts, research on urinary incontinence in the homebound elderly has been limited.

For their study, registered nurses specializing in the care of urinary incontinence will go into patients' homes to provide treatment. Using biofeedback, the nurses will teach patients how to use their pelvic floor muscles to prevent incontinence episodes. During these sessions, skin patches similar to electrocardiogram patches will be placed on the skin overlying the pelvic floor and abdominal muscles. Patients will be able to observe the results of their efforts on a computer screen as they learn to contract their pelvic muscles while keeping their abdominal muscles relaxed.

"Many patients mistakenly use their abdominal muscles instead of their pelvic muscles," McDowell said. "By using biofeedback, we can teach patients how to strengthen and use their pelvic floor muscles to decrease the number of incontinence episodes." In addition, McDowell and Engberg will study cost-effectiveness of this type of prevention therapy when compared to the costs associated with urinary incontinence.

McDowell and Engberg recently completed a similar study and found that after eight weeks of treatment, homebound older adults decreased their incontinence by an average of 74 percent.

For more information about these studies, call 412/ 624-1210.

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Women who hide anger may have higher risk for cardiovascular disease

Middle-aged women who hide their anger, have hostile attitudes or feel self-conscious in public may have a greater risk of developing cardiovascular disease, according to research from Pitt's School of Medicine.

The 10-year Pitt study is the first to associate psychosocial characteristics of middle-aged women to intima-media thickness (IMT), an early marker of atherosclerosis or high blood pressure. The study appeared in the journal Psychosomatic Medicine.

According to study author Karen A. Matthews, a professor of psychiatry, epidemiology and psychology, earlier studies suggested a relationship between hostile feelings and cardiovascular disease, but didn't provide a coherent picture of the characteristics of women at risk. Matthews evaluated the ability of measures of hostile attitudes, anger, anxiety and related characteristics to predict the extent of IMT and plaque in the carotid arteries of healthy middle-aged women.

In a randomly selected group of 200 healthy premenopausal women between the ages of 42 and 50, those who reported hostile attitudes, holding in anger and feeling self-aware in public situations were at risk of higher IMT scores 10 years later, as seen using ultrasound.

"This study provides compelling evidence that attitudes and style of expression have an effect on cardiovascular health in women," Matthews said. "It may be best to express negative feelings in a constructive fashion rather than hold them in."

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Injury center gets $4 million grant for study

The Center for Injury Research and Control (CIRCL) at UPMC Health System has received a $4 million award from the Centers for Disease Control (CDC) for the study of injury surveillance and interventions designed to reduce the incidence of injury in Pennsylvania and the tri-state region.

CIRCL is one of nine such programs with the official CDC designation as an injury control research center. These centers are responsible for the relevant and innovative methods for injury surveillance and prevention that can then be used by state and local government agencies.

CIRCL director Donald W. Marion said there is an urgent need for improvement in injury prevention, and better methods for surveillance of injury.

"Statistics released by the CDC indicate that since 1985, there has been a nearly two-fold increase in the incidence of intentional violence leading to death in the United States," Marion said. "Incidence of intentional and fatal violence among young African-American men is approximately 2.5 times higher than it was 10 years ago. In Pennsylvania, there are an estimated 120 non-fatal head injuries per 100,000 people and seven spinal cord injuries per 100,000 people. Children suffer from injuries at the highest rates. In 1995, there were 10,762 cases of child abuse reported to Harrisburg." n