University Times

Quality care study may reduce pneumonia hospitalizations

A carefully implemented system of pneumonia care can lead to better outcomes and fewer unnecessary hospitalizations, according to a School of Medicine study published in the Annals of Internal Medicine.

An estimated 5 million pneumonia cases are diagnosed each year in physicians’ offices and hospital emergency rooms, accounting for 86 million days of restricted activity for those affected and more than $9 billion in health care costs nationwide. Despite its prevalence, physicians frequently overestimate the probability of death in many pneumonia patients, leading to potentially unnecessary and costly hospitalizations.

“Pneumonia is common, costly and serious, but for patients at lower risk it often can be treated successfully at home, at 1/20th the cost of hospitalization,” said professor of medicine Michael Fine, author of the study.

The year-long, multi-center randomized trial conducted by investigators from the School of Medicine and the Pittsburgh VA Healthcare System involved more than 3,200 patients in 32 hospital emergency departments in Connecticut and southwestern Pennsylvania.

“A unique aspect to this study was the use of one of three different interventions at sites, each of varying intensity, allowing us not only to alter care, but also to determine the amount of effort needed to create change,” noted lead author Donald M. Yealy, professor and vice chair of emergency medicine at Pitt.

Participating emergency departments were randomly assigned as low-, moderate- or high-intensity sites — designations reflecting the level of feedback, reinforcement and continuous quality improvement activities that each emergency department would carry out relevant to its pneumonia patients. All emergency departments agreed to follow uniform practice guidelines.

In the low-intensity sites, practitioners also were asked to voluntarily develop quality improvement strategies for pneumonia care and received supportive literature. Moderate-intensity sites received the supportive literature and reminders and were mandated to develop quality improvement strategies for pneumonia care. Additionally, the moderate-intensity sites received on-site educational training sessions, which reinforced practice guidelines and offered in-depth training in pneumonia assessment. High-intensity sites received all low-intensity and moderate-intensity strategies plus real-time reminders, medical provider audits and feedback, and participated in site-specific ongoing quality improvement activities.

Study results showed that the moderate- and high-intensity strategies safely increased the proportion of low-risk patients who were treated successfully as outpatients. Additionally, the high-intensity strategy effectively increased the proportion of practitioners who implemented guideline recommendations in clinical practice.

The study was funded by the Agency for Healthcare Research and Quality, U.S. Department of Health and Human Services.

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DNA repair enzyme may suppress tumors

Certain enzymes detect and repair damage to DNA, but when they fail to do their work, it can lead to mutations that can cause cell death and cancer.

Pitt researchers are finding that the work of some DNA repair enzymes appears to be more critical than others, particularly in developing embryos. The enzyme DNA polymeraze zeta (pol zeta) can give cells with damaged DNA a new lease on life, but the absence of this enzyme in cells that have growth control problems can lead to cancer.

“Pol zeta appears to be the only one of a group of specialized DNA polymerases that is critical for development in animals,” said John P. Wittschieben, pharmacology research instructor at the School of Medicine. “Moreover, its loss in animal cells plays a significant role in the development of chromosomal instability, which is a hallmark of cancer. Therefore, we believe its function may be to suppress the development of tumors,” he said.

First discovered in budding yeast cells, and later in plants and animals, pol zeta has the ability to save cells with damaged DNA from dying off. Other research has shown that inactivation of this enzyme in yeast leads to a dramatic decrease in the frequency of mutations induced by DNA-damaging agents.

In a study reported in Cancer Research, Wittschieben — working in the laboratory of Richard D. Wood, the Richard M. Cyert Chair in Molecular Oncology and director of the molecular and cellular oncology program at the University of Pittsburgh Cancer Institute — sought to determine pol zeta’s key role in mice cells.

The researchers disabled the Rev3L gene that controls pol zeta’s lesion-replicating capabilities. However, knocking out the gene proved lethal to the mice embryos. The investigators isolated fibroblasts from these embryos to see if they could be kept alive in culture. After repeated attempts, the mouse embryonic fibroblasts (MEFs) failed to divide and died within a few weeks or months.

Suspecting that the MEFs were dying because they were self-destructing, or undergoing apoptosis, the investigators then knocked out the gene for a protein known as p53, which is a cell-suicide-signaling molecule.

After matings between the p53 knockout mice and Rev3L knockout mice, the investigators isolated and cultured MEFs from all the offspring of the matings to see if any would grow. The cells all failed to divide, but three months later, some cells began to grow and at a surprisingly robust rate.

“Once the cells in which Rev3L and p53 had been knocked out began to divide, they did so very rapidly,” said Wittschieben. “Because the only Rev3L-deficient cells that began dividing also were p53 deficient, we believe that knocking out their apoptotic mechanism was key to this viability. However, they didn’t begin dividing right away, so something else must have happened. We are still not sure what that something else is,” he said.

The researchers found a dramatic difference between these cells and normal ones. The cells’ chromosomes showed a 10-fold increase in the incidence of swapping and fusing of genes and other genetic material between chromosomes and an increase in the number of chromosomes compared to normal cells.

The high frequency of DNA rearrangements in Rev3L/p53-deficient cells suggests that pol zeta in normal cells is responsible for preventing double-stranded breaks from occurring in chromosomes. When pol zeta is absent, it leads to a massive amount of double stranded breaks, some of which are repaired correctly and others that are repaired incorrectly by being fused to other genes or chromosomes.

Wood said these findings have significant implications for human cancer research because cancer cells show high degrees of chromosomal instability.

And, the human Rev3L gene is in a segment of chromosome 6 where multiple tumor suppressor genes are believed to reside. Many human cancers, including some leukemias and lymphomas, are associated with chromosomal instabilities in this particular area.

This work was supported by a grant from the National Cancer Institute. Contributing to the study were Shalini C. Reshmi and Susan M. Gollin of the Graduate School of Public Health.

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Fox grant will support Parkinson’s gene therapy

An innovative gene therapy approach pioneered by RheoGene Inc. will be refined and tested in preliminary clinical trials within four years, thanks to a $4.2 million grant from the Michael J. Fox Foundation for Parkinson’s Research (MJFF).

A wholly owned affiliate of UPMC, RheoGene Inc. has developed technology to manage gene expression, a key component of gene-based therapies. RheoGene’s therapeutic system uses a patented small-molecule mediator that can turn genes on or off as well as adjust the level of gene activity similar to the way a rheostat regulates electric current.

“This project has the potential to revolutionize the clinical application of gene therapy,” said MJFF President and CEO Deborah W. Brooks.

Parkinson’s disease gradually destroys brain cells that produce dopamine, a chemical messenger crucial for the cellular communication that controls muscle movement. As dopamine levels drop, symptoms — including tremors, stiff or frozen limbs, slow movement and impaired balance or coordination — increase.

Current treatments focus on replacing lost dopamine with the drug levodopa (L-dopa), which converts to dopamine in the brain, or brain surgery to control tremors. Both are temporary fixes.

While research on gene-based treatments continues, there are risks associated with failure to regulate gene expression or turn it off entirely if there are worrisome side effects. A RheoGene-led team will work to further the technology, called the RheoSwitch Therapeutic System (RTS), for safe and effective use to control the intensity and timing of gene expression.

The therapy involves a drug, taken orally, to act as an “on switch.” When the drug is no longer taken, gene expression stops. Testing in animal models has indicated that RTS can work as envisioned by researchers.

The MJFF-funded project will begin with a dual focus. One gene target that researchers will evaluate produces glial cell derived neurotrophic factor (GDNF), a naturally occurring protein that protects and stimulates regeneration of brain cells that secrete dopamine. The other gene target of interest produces aromatic L-amino acid decarboxylase (AADC), an enzyme involved in dopamine synthesis.

The team is led by coordinating principal investigator Dean Cress, a biochemist and co-founder of RheoGene, and J. Mark Braughler, head of RheoGene’s clinical applications office and lab in Pittsburgh. The team includes experts in gene therapy for Parkinson’s disease: Krystof Bankiewicz of the University of California-San Francisco and Martha C. Bohn at Northwestern University.

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Search for missing galaxies yields no results

Pitt astronomers, in conjunction with the Universitäts-Sternwarte München in Munich, Germany, announced at a meeting of the American Astronomical Society Jan. 6 that their search for dwarf galaxies in fast-moving clouds of gas has yielded no results. The researchers are suggesting alternative avenues of research to find the supposedly “missing” galaxies.

The team, which includes Regina Schulte-Ladbeck, associate dean for undergraduate studies and professor of physics and astronomy in the School of Arts and Sciences, and Ulrich Hopp of the Universitäts-Sternwarte München, has been searching for stars in high-velocity clouds. However, said Schulte-Ladbeck, “Our searches have come up empty.”

The mathematical simulations that astronomers use to establish how galaxies were formed predict that every giant galaxy should have a few hundred “dwarf” galaxy companions. But in our own neighborhood, the Milky Way Galaxy, there are only 50 or so such dwarves.

Some astronomers had suggested a simple way to explain the difference would be if the missing dwarf galaxies were located in high-velocity clouds. Schulte-Ladbeck and Hopp hoped to measure the distances between the clouds and the Milky Way to obtain proof that the clouds indeed held additional satellite galaxies of the Milky Way.

To search for stars in the clouds, the researchers took a two-pronged approach. They used the Two Micron All Sky Survey to look for bright stars in circular patches of sky 2 degrees across, the area typically covered by the gas clouds that make the most promising dwarf galaxy candidates.

Then, using accurate positions of where most of the hydrogen gas in several clouds is located, the researchers trained one of the 8-meter (315-inch) telescopes of the European Southern Observatory’s Very Large Telescope, located in northern Chile’s Atacama Desert, on small regions within the clouds to see if any faint stars had formed there. Neither method turned up any stars.

Schulte-Ladbeck and Hopp conclude that it is unlikely that hundreds of additional dwarf satellites of the Milky Way have been somehow “hiding” from observers, and they encourage astronomers to pursue other solutions to the discrepancy.

Funding for this study was provided by NASA and Pitt’s School of Arts and Sciences.

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Study finds 2 forms of mild cognitive impairment

A study by researchers from Pitt’s School of Medicine and the University of California-Los Angeles have found two forms of mild cognitive impairment (MCI), a transitional stage between normal cognition and Alzheimer’s disease. The work, published in the Archives of Neurology, could lead to better diagnosis and treatment of MCI patients, perhaps delaying or preventing the onset of dementia.

MCI is categorized into two sub-types. Those with MCI, amnesic subtype (MCI-A) have memory impairments only, while those with MCI, multiple cognitive domain subtype (MCI-MCD) have other types of mild impairments, such as in judgment or language, but with either mild or no memory loss. Both sub-types progress to Alzheimer’s disease at the same rate. Until now it was not known if the pathologies of the two types of MCI were different, or if MCI-MCD was simply a more advanced form of MCI-A.

Using a new imaging procedure that creates 3-D maps of the brain, researchers determined specific areas that had degenerated in people with MCI.

Researchers found that the hippocampus of the patients with MCI-A was 14 percent smaller than that of the healthy subjects, nearly as great as the 23 percent shrinkage seen in Alzheimer’s disease. But, the hippocampus of those with MCI-MCD most resembled that of those in the control group, showing only 5 percent shrinkage. The hippocampus is a brain area critical for memory and one of the earliest to change in Alzheimer’s patients.

Using magnetic resonance imaging data from six patients with MCI-A, 20 with MCI-MCD, 20 with Alzheimer’s disease and 20 healthy controls, researchers created 3-D mesh reconstructions of each participant’s hippocampus that allowed them to see where the hippocampus had deteriorated.

This study is the first to use such modeling technology to visualize changes in the brains of people with MCI. Prior studies have been able to measure only the volume of the hippocampus and estimate atrophy through noticeable volume loss.

“These vibrant images produced by 3-D modeling have proven what we suspected — there are at least two transitional states that lead to Alzheimer’s disease,” said James T. Becker, a neuropsychologist and professor of psychiatry, neurology and psychology at the School of Medicine and lead author of the study. “Now we can investigate these pathways and develop treatments that, we hope, may slow or stop the progression of Alzheimer’s.”

Co-authors from Pitt are Simon W. Davis, psychiatry; Carolyn Cidis Meltzer, radiology and psychiatry, and Oscar L. Lopez, neurology.

The study was funded by grants from the National Institute on Aging, National Library of Medicine, National Center for Research Resources and National Institute of General Medical Sciences.

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New football helmet design may reduce concussions

Phase I of a three-year study by the UPMC Sports Medicine concussion program indicates that new football helmet designs may reduce the incidence of concussions in high school football players, but has no impact on recovery time for concussion victims. Published in the February issue of Neurosurgery, the UPMC study of more than 2,000 high school football players in western Pennsylvania is the first on-the-field investigation to compare concussion rates and recovery times for high school football players wearing the Riddell Revolution helmet, with its newer technology and design, to concussion rates and recovery times for players wearing traditional helmets.

The annual concussion rate was 5.4 percent in athletes wearing the Revolution helmet, compared to a 7.6 annual percent rate in athletes wearing standard helmets, representing a 2.3 percent decreased absolute risk of concussion for high school football players.

In terms of relative risk, Revolution wearers were 31 percent less likely to sustain a concussion compared to athletes who wore standard football helmets.

No statistical differences were found when examining the recovery rates for concussion victims wearing the Revolution and traditional helmet samples.

Results also revealed that the two helmet groups did not differ significantly regarding mechanism of injury, region of helmet struck or presence of on-field signs and symptoms of concussion.

“These findings reaffirm numerous previously published studies indicating that careful concussion evaluation and management is absolutely essential for safe return to play,” said principal investigator Micky Collins, assistant director of the UPMC Sports Medicine concussion program.

The Revolution helmet, introduced in 2002, was developed with the intent of reducing the incidence and severity of concussion. The design features and engineering specifications of the helmet were formulated after several years of biomechanical laboratory testing. The current study compared the new Revolution helmet with models of traditional design from Riddell and other manufacturers that were on the market prior to 2002.

“By continuing this type of study long term, we will be able to obtain essential real-life data and increase our knowledge and understanding of how sports helmet technology and design may be effective in reducing the incidence of concussions in athletes,” said Mark Lovell, director of the UPMC program and co-author of the study.

The UPMC Sports Medicine concussion program conducted the study with funding support from Riddell.

Other authors of the study are Joseph Maroon of neurological surgery and Grant L. Iverson of psychiatry.

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Research may improve diagnosis, treatment of interstitial lung disease

Pitt researchers reported in the Jan. 15 American Journal of Respiratory Critical Care Medicine that anti-inflammatory drugs may be unnecessary for lung patients with idiopathic pulmonary fibrosis (IPF). In a related study, they identified a protein found in excess amounts in the lung tissue of IPF patients that could be a better target for therapy.

IPF, a form of interstitial lung disease, is characterized by scarring of the interstitium, or tissue between the lungs’ air sacs. The condition causes the tissue to thicken and become stiff, or fibrotic, making breathing difficult. A number of chronic lung conditions, including IPF, are categorized as interstitial lung diseases, which have similar symptoms but different clinical courses.

IPF has a high death rate due to respiratory failure. Definitively diagnosing the condition often requires a lung biopsy, which can complicate treatment.

“Unfortunately, many patients do not receive lung biopsies. As a result, about one-third of patients who come to our clinic have previously been misdiagnosed, and many have been treated with the wrong medications,” said James Dauber, medical director of Pitt’s Dorothy P. and Richard P. Simmons Center for Interstitial Lung Disease and professor of medicine.

To improve the diagnosis and treatment of interstitial lung diseases, Naftali Kaminski, director of the Simmons Center and associate professor of pathology and human genetics, Dauber and their co-workers studied the gene expression patterns of several types of interstitial lung diseases.

Using biopsy samples from 15 IPF patients; 12 with hypersensitivity pneumonitis, another form of pulmonary fibrosis, and eight patients with the less-understood nonspecific interstitial pneumonia, researchers found that although all the patients had similar X-ray and laboratory test results, their gene expression patterns were radically different.

Those with hypersensitivity pneumonitis showed significantly increased expression of genes associated with inflammation, immune cell activation and immune response. In contrast, there was almost no genetic evidence of inflammation in the idiopathic pulmonary fibrosis samples.

“Our results show that interstitial pulmonary fibrosis and hypersensitivity pneumonitis, which clinically often look quite similar, are really two vastly different conditions,” said Kaminski.

“Idiopathic pulmonary fibrosis is characterized by the increased expression of genes involved in the re-growth of lung tissue. So, it is not really an inflammatory condition per se. On the other hand, hypersensitivity pneumonitis does exhibit all of the hallmarks of inflammation, with increased expression of genes that control T-cell activation and immune responses.”

Another surprising finding came when the investigators compared these gene expression patterns to from the eight patients diagnosed with nonspecific interstitial pneumonia. Two of the eight cases exhibited interstitial pulmonary fibrosis-like gene expression patterns, one closely resembled the gene expression pattern of hypersensitivity pneumonitis, while the other five expression patterns resembled neither. Thus, the investigators were able to reclassify some of the cases of nonspecific interstitial pneumonia.

If the findings hold up in larger studies, the diagnosis and management of interstitial lung disease may change radically. “Until now, the treatment of idiopathic pulmonary fibrosis has been primarily focused on its inflammatory component. However, our findings indicate that lung tissue from these patients does not exhibit a typical inflammatory pattern. So, these patients need to be managed in an entirely new way,” said Kaminski.

Although there is no effective treatment for IPF, results of another study by Kaminski and his colleagues suggest help may be on the way. In an on-line edition of PLoS Medicine, Kaminski’s team reported that idiopathic pulmonary fibrosis lung tissue samples display an overabundance of the protein osteopontin, which other studies have implicated in the growth and progression of tumors.

In further examining the potential role of osteopontin in IPF, the researchers found that it directly increases the proliferation and movement of fibroblasts — the cells centrally involved in lung fibrosis.

“Taken together, these findings are very exciting, because we now have a basis for designing drugs that are specifically directed against osteopontin. By manipulating osteopontin levels, we may be able to slow or stop the course of this deadly disease. In addition, the level of osteopontin may be used as a diagnostic marker for this disease,” said Kaminski.

Other Pitt investigators involved in this research are Kevin Gibson, Thomas Richards and Samuel Yousem.

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Stimulation of brain may help survivors of stroke improve movement of arms, hands

UPMC physicians are participating in a multi-center study that may help stroke survivors gain greater use of their arms and hands by electrically stimulating the brain during physical rehabilitation. Pilot studies have shown that such a combination is safe and enhances motor function to a greater degree than rehabilitation alone. The electrical stimulation is provided by the temporary surgical placement of an electrode on the covering of the brain to stimulate the cerebral cortex.

“The most common neurological deficit among stroke survivors, and a substantial contributor to post-stroke disability, is motor weakness on one side of the body. The only treatment available for patients with such deficits is rehabilitative therapy. However, many patients are not responsive to standard therapy or they achieve a less than satisfactory improvement in function,” said Douglas Kondziolka, Peter J. Jannetta Professor of Neurological Surgery and Radiation Oncology and vice chairman of education in the School of Medicine’s Department of Neurological Surgery.

Following a stroke, many patients show some spontaneous neurologic improvement. Restoration of function may be the consequence of neuroplasticity — the brain’s ability to make new areas of the brain take over the function of stroke-damaged areas. The brain’s cerebral cortex, with its extensive network of interconnected neurons, is thought to be an important site for neuroplasticity.

Participants in the study will have an electrode surgically placed on the dura, the membrane covering the brain. A wire from the electrode will be tunneled under the skin to a stimulating device, about the size of a pacemaker, that will be placed under the skin. During six weeks of daily rehab sessions, the stimulator will be turned on just before the start and will be turned off when the rehab session is over.

The electrode and stimulator will be removed about eight weeks after the completion of the rehab period. Participants will be followed closely for improvements for six months and will be compared to a control group, which will undergo rehabilitation only.

The study is sponsored by Northstar Neuroscience, which developed the technology.

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Revisiting report errors is educational tool for residents

Pitt researchers have identified areas in which radiology residents most often misinterpret test results and say the data can be used as a tool to prompt residents to more carefully examine those areas in which most errors tend to occur.

“Overnight emergency department radiology coverage results in preliminary readings that occasionally differ from final interpretations,” said Barton Branstetter IV and colleagues in their 2005 Radiological Society of North America poster presentation in Chicago.

From 612,890 radiology reports reviewed, researchers pinpointed 3,194 instances (0.52 percent error rate) of discrepancy significant enough to change patient management. The error types were classified as overcalled, undercalled or misinterpreted, then categorized by organ system: neuroradiology (0.35 percent error rate), musculoskeletal (0.77 percent error rate), thoracic (0.62 percent error rate) and abdominal (0.43 percent error rate).

In neuroradiology, stroke was most often misinterpreted or undercalled (22 percent of cases). In musculoskeletal imaging, leg fractures were misinterpreted or undercalled (51 percent). In abdominal imaging, leaks and inflammation were missed or undercalled most often (25 percent). In thoracic imaging, confusion between congestive heart failure and pneumonia predominated, with 28 percent of pneumonia cases missed.

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UPB center gets grants

The Center for Rural Health Practice at Pitt-Bradford has received grants totaling $62,000 to investigate how federal and state funds for selected chronic disease prevention and health promotion activities are applied at the local level.

The grants from the Walsh Center for Rural Health Research and the National Association of County and City Health Officials will fund “Financing Rural Public Health Activities in Chronic Disease Prevention and Health Promotion.”

Michael Meit, director of the Center for Rural Health Practice, and Lorraine Ettaro, visiting assistant professor of public health, will work with researchers from the Walsh Center in Bethesda.

“Although public health funding for rural areas comes from a multitude of federal, state and local sources,” Meit said, “very little is known about how federal and state funds for particular public health objectives are being used at the local level.”

In order to better understand the federal-state funding for local public health activities, researchers will examine funds for selected chronic disease prevention areas from the Centers for Disease Control and Prevention.

The project aims to describe how CDC funds are used by states and identify infrastructure-related barriers that rural communities may face in securing and using funds for such purposes.

Researchers will develop a descriptive analysis of the distribution of prevention funds across the 50 states and a more in-depth approach through case studies of six states, including Pennsylvania.

The Center for Rural Health Practice includes the Pitt-Bradford campus, the six Pitt Schools for the Health Sciences and the UPMC Health System.

The center’s purpose is to connect the health resources and expertise from throughout the University system to the realities of rural health practice.