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January 11, 2007


Hospital choice impacts end-of-life care

Although dying minority patients are more likely to use intensive care services than their white counterparts, the difference is due mostly to the particular hospitals that treat them rather than racial and ethnic disparities, according to a recent Pitt study published in the December 2006 issue of Health Services Research.

One in five Americans die using intensive care services, consuming more than 80 percent of all terminal hospitalization costs. The study, which measured the ethnic and racial disparities of patients specifically in end-of-life intensive care, followed a different pattern than previous studies that compared patients who were in intensive care for non-terminal reasons. It found that although minorities, specifically African Americans, receive less intensive care treatment than Caucasians for most medical services, African-American patients receive more intensive care treatment than Caucasian patients at the end of their lives.

Additionally, the study revealed that minorities often access different health care providers than Caucasians because of residential segregation, and these hospitals were found to have higher rates of intensive care use with dying patients than the predominantly Caucasian hospitals. Thus, the heavier use of intensive care treatment by minorities was related to the specific physicians and hospitals that the patients used rather than variations of race and ethnicity in the same hospital.

“We found that the higher rate of ICU use among minorities who die in the hospital was mostly attributable to their use of hospitals with higher end-of-life intensive care for all dying patients, including white patients,” said Amber Barnato, an assistant professor in the School of Medicine and the Graduate School of Public Health.

“It could be that these higher intensity hospitals have a more intensive practice style, irrespective of patients’ wishes, or that these hospitals are responding to some community preferences for more intensive treatment that are shared across racial and ethnic groups, which seems much less likely,” Barnato said.

After comparing 1999 hospital discharge data for approximately 200,000 adults from non-federal hospitals in Florida, Massachusetts, New Jersey, New York and Virginia, researchers found that end-of-life ICU use was highest among minorities, varying from 64.4 percent among Hispanics, 64 percent among African Americans and 57.5 percent among Caucasians. Statistically, racial and ethnic gaps among patients in end-of-life intensive care were much smaller when the particular hospitals that treated the patients were accounted for.

Other Pitt authors of this study were Derek Angus, vice chair of research in the Department of Critical Care Medicine; Chung Chou H. Chang, a research assistant professor in the Department of Medicine and Department of Biostatistics, and Lisa A. Weissfeld, a professor in the Department of Biostatistics.

This study was supported by the Robert Wood Johnson Foundation and the National Institute on Aging.


UCSUR names award winners

The University Center for Social and Urban Research (UCSUR) has named two research projects winners of the sixth annual Steven D. Manners Faculty Development Awards, established in memory of the center’s assistant director.

The awards, according to UCSUR Director Richard Schulz, are intended to “continue the trend begun by Steve Manners, which was to support faculty members and their research and to improve the research infrastructure at the University.”

Larissa Myaskovsky, a faculty member at the Center for Health Equity Research and Promotion at the VA Pittsburgh Healthcare System, has received the award for her project, “Understanding and Reducing Racial Depression Stigma, Race and Treatment-Seeking Behavior and Attitudes.”

Shanti Gamper-Rabindran and Aaron Swoboda, both assistant professors at Pitt’s Graduate School of Public and International Affairs, received the award for their project, “Does the U.S. Public Disclosure Program on Factories’ Emissions Truly Cause Emissions Reductions in Poor and Minority Urban Neighborhoods?”

Myaskovsky’s project seeks to determine whether culturally based patient characteristics can explain race disparities in kidney transplantation.

Culturally based patient characteristics — including differences in health care attitudes and perceived racism in the health care system — already have been shown to play significant roles in African-Americans’ health behaviors and outcomes in other diseases such as HIV and heart disease, as well as infant health.

African Americans are disproportionately affected by end-stage renal disease (ESRD). The major causes of ESRD include diabetes and hypertension, two diseases that are more prevalent among African Americans than among whites. These diseases are related to a combination of differences including access to health care, socioeconomic status and health behaviors. While the best treatment for ESRD is a living donor kidney transplant, African Americans are much less likely to identify a living donor, or receive a living donor kidney transplant than whites. Although this disparity has been recognized for several years, relatively little is known about its causes.

In the study, ESRD patients from both UPMC and the VA Pittsburgh Healthcare System will be asked to participate in two telephone interviews during the time that they are being evaluated for a transplant. The interviews will focus on their experiences with health care and their social and health background. A long-term goal of this project is to translate research findings into successful educational interventions that reduce racial disparities in kidney transplantation.

Gamper-Rabindran and Swoboda will study the impact of the public dissemination of information on plants’ state-level Toxic Release Inventory (TRI) rankings.

The TRI is a nationwide public disclosure program that has made plant-level emissions available to the public since 1987 and has been perceived as a major innovation in U.S. environmental policy. Advocates of the Right-to-Know movement argue that this information disclosure program has enabled the public to exert pressure on plants to reduce their emissions.

The researchers will ask whether plants reduced their pounds of emissions as a result of public pressure and also assess whether these changes translate into reductions in health-indexed emissions and whether plant emissions are correlated with neighborhood socioeconomic variables.

Results from this study will assist the EPA, policymakers, activists and members of the public in understanding whether the TRI program has been effective at reducing health-indexed emissions.


DNA damage adds to aging, study finds

The accumulation of genetic damage in our cells is a major contributor to how we age, according to a study recently published in the journal Nature by an international group of researchers that included several from Pitt.

The study found that mice completely lacking a critical gene for repairing damaged DNA grow old rapidly and have physical, genetic and hormonal profiles very similar to aged mice that had grown old naturally. Furthermore, the premature aging symptoms of the mice led to the discovery of a new type of human progeria, a rare inherited disease in which affected individuals age rapidly and die prematurely.

“These progeroid mice, even though they do not live very long, have remarkably similar characteristics to normal old mice, from their physical symptoms, to their metabolic and hormonal changes and pathology, right down to the level of similar changes in gene expression,” said corresponding author Jan Hoeijmakers, head of genetics at the Erasmus Medical Center in Rotterdam. “This provides strong evidence that failure to repair DNA damage promotes aging — a finding that was not entirely unexpected since DNA damage was already known to cause cancer. However, it shows how important it is to repair damage that is constantly inflicted upon our genes, even through the simple act of breathing.”

The study found that a key similarity between the progeria-like, or progeroid, mice and naturally old mice is the suppression of genes that control metabolic pathways promoting growth, including those controlled by growth hormone. How growth hormone pathways are suppressed is not known, but this response appears to have evolved to protect against stress caused by DNA damage or the wear-and-tear of normal living. The authors speculate that this stress response allows each of us to live as long and as healthy a life as possible despite the accumulation of genetic damage as we age.

Findings from this study help to reconcile two conflicting hypotheses currently favored in the field of aging research about why we get old, according to the authors. The first is that the genes inherited from parents determine lifespan and how well people age. The second is that lifespan and fitness in old age are determined by how much damage is incurred over a lifetime.

Laura Niedernhofer, assistant professor of molecular genetics and biochemistry in Pitt’s School of Medicine and first author of the study, said: “Our study suggests that both of these hypotheses are correct. Damage, including DNA damage, drives the functional decline we all experience as we age. But how we respond to that damage is determined genetically, in particular by genes that regulate the growth hormone and insulin pathways.”

The investigators compared the expression pattern of all of the genes (approximately 30,000) in the liver of 15-day-old mice that had been generated in the laboratory to harbor a defect in their XPF-ERCC1 enzyme (an enzyme necessary for removing DNA damage) and that had symptoms of rapidly accelerated aging to the genes expressed by normal mice of the same age.

This comparison revealed a profound suppression of genes in several important metabolic pathways in the progeroid mice. Most notably, the progeroid mice had a profoundly suppressed somatotroph (growth hormone) axis — a key pathway involved in the promotion of growth and development-compared to normal mice.

The investigators also found low levels of growth hormones in the progeroid mice and ruled out the possibility that this suppression was due to problems with their hypothalamus or pituitary glands, which regulate growth hormone secretion. Furthermore, they demonstrated that if normal adult mice were exposed to a drug that causes DNA damage, such as a cancer chemotherapy agent, the growth hormone axis similarly was suppressed. In other words, DNA damage somehow triggered hormonal changes that halted growth, while also boosting maintenance and repair.

Because growth hormone levels go down as people get older, contributing to loss of muscle mass and bone density, the investigators systematically compared the gene expression pattern of their progeroid mice to normal old mice to look for other similarities. What they found was a striking similarity pattern between the progeroid and normal-aged mice in several key pathways.

Indeed, for genes that influence the growth hormone pathway, there was a greater than 95 percent correlation in changes in gene expression between the DNA repair-deficient mice and old mice. Remarkably, there was a near 90 percent correlation between all other pathways affected in the progeroid mice and the older mice.

“Because there were such high correlations between these pathways in progeroid and normal older mice, we are quite confident that DNA damage plays a significant role in promoting the aging process. The bottom line is that avoiding or reducing DNA damage caused by sources such as sunlight and cigarette smoke, as well as by our own metabolism, also could delay aging,” said Niedernhofer.

Other Pitt researchers involved in this study were Andria Rasile Robinson and Anwaar Ahmad of the University of Pittsburgh Cancer Institute.


Breast cancer research funds donated

Magee-Womens Research Institute (MWRI) has received $100,000 from The Glimmer of Hope Foundation to support breast cancer research.

In partnership with the University of Pittsburgh Cancer Institute and the Magee-Womens Hospital, MWRI is involved in basic and clinical investigations to assess a full range of issues related to breast cancer.

MWRI has attracted some $185 million in project grant funding focusing on research in women’s and infants’ health.


Researcher to explore recovery from kidney failure

John A. Kellum, associate professor of critical care medicine in the School of Medicine, has received a grant from the National Institutes of Health to explore the mechanism responsible for recovery from kidney failure. The grant is a five-year, $1.8 million award from the National Institute of Diabetes and Digestive and Kidney Diseases for research that will shed light on the role of inflammation, as well as other factors in recovery from acute renal failure (ARF).

The project, called Biological Markers of Recovery for the Kidney, or BioMaRK, will examine how such factors influence survival as well as recovery of kidney function. The researchers plan to assess how certain inflammation markers relate to clinical outcomes and build a risk-prediction model based on clinical variables and those biomarkers. The results of this study could lay the foundation for the development of ARF treatment therapies, particularly those designed to enhance organ recovery.


Heart cell proteins to be studied

Yong Tae Kwon, assistant professor of pharmaceutical sciences in the School of Pharmacy, has received a five-year, $1.8 million grant from the National Institutes of Health to identify and characterize proteins that regulate cardiovascular growth.

Recent research has suggested that the proteins play a critical role in cardiac development, signaling and the thickening of the heart’s walls, by regulating the activation of other proteins that direct the generation of new cardiac cells. The research could lead to new pharmaceutical therapies.


Teen anti-smoking approaches to be studied

The National Cancer Institute has awarded a $660,000 grant to Brian Primack, assistant professor in the School of Medicine’s Division of General Internal Medicine, for his project “Media Literacy to Prevent Adolescent Smoking Initiation.” Prior research suggests that adolescents who are “media literate,” or wise to some of the tricks of the advertising trade, are less likely to take up smoking.

With this funding, Primack will work to develop ways to measure smoking literacy and assess the relationship between smoking media literacy and smoking initiation. A third project aim is to pilot test an anti-tobacco media literacy curriculum among a group of teenagers.


Dengue fever study funded

Derek Cummings, a visiting assistant professor in epidemiology at the Graduate School of Public Health, has received a Burroughs Wellcome Career Award at the Scientific Interface for his research on dengue fever, which results from a mosquito-borne virus and leads to serious illness and death in many parts of the world.

The award, which provides five years of support for a total of $500,000, will fund Cummings’s work to develop a population data-based model that may help predict the virus’s transmission mechanism to its human host.

The awards are given to early-career scientists who have a background in the physical sciences and are pursuing research projects on biological issues. Cummings is one of 12 scientists throughout the country who received this award for 2007.


Simulation aims to aid melanoma diagnosis

Dana Grzybicki, a research assistant professor in the School of Medicine’s Department of Pathology, was awarded more than $270,000 from the Department of Health and Human Services Agency for Healthcare Research and Quality as part of an initiative to study the safe delivery of health care through medical simulation.

Grzybicki’s study aims to improve the diagnostic accuracy of community generalist pathologists in the identification of malignant melanoma through the use of a cognitive simulation system.


Impulsive? Maybe it’s just an overactive ventral striatum

A new Pitt study published in the Journal of Neuroscience has found that the preferences for delayed or immediate gratification may lie in the brain’s ventral striatum, which mediates the responses and physiological states associated with reward and pleasure.

The study, which provides new insight about reward-based decision making, may have implications for understanding and treating addiction disorders.

In the study, 45 normal adult volunteers were presented with the choice of getting between 10 cents and $105 at that very moment or waiting one week to five years for a sure $100.

Brain imaging showed those volunteers who were classified as the more impulsive decision makers who tended to seek more immediate rewards had significantly more activity in the ventral striatum.

“The ventral striatum appears to be a nexus where we balance acting impulsively to achieve instant gratification and making prudent choices that may delay rewards,” explained lead author Ahmad R. Hariri, assistant professor of psychiatry and director of the developmental imaging genetics program at the School of Medicine and Western Psychiatric Institute and Clinic.

“Understanding what drives individual differences in ventral striatal sensitivity could aid efforts to treat people who have difficulty controlling impulsive behavior, by adjusting the circuitry.”

The preference for immediate over delayed rewards of larger value, which researchers term “delay discounting,” has already been linked to impulse-control problems such as substance abuse, addiction and pathological gambling. And separate studies have shown that people with addiction disorders have a more active ventral striatum.

Based on their findings, Hariri and his colleagues now are looking at whether ventral striatum activity can help predict substance abuse disorders in those at risk. Since the activity of the ventral striatum is modulated by dopamine, a brain chemical also associated with reward, they plan to explore the role that variations in dopamine-related genes may play in determining differences in ventral striatum reactivity.

Pitt co-authors of the paper were Stephen Manuck, School of Arts and Sciences, and Sarah M. Brown and Douglas E. Williamson, School of Medicine.


Gateway theory may not accurately predict progression of drug abuse

A 12-year Pitt study suggests that marijuana is not necessarily a “gateway” drug that predicts or eventually leads to substance abuse.

While the gateway theory posits that each type of drug is associated with certain specific risk factors that cause the use of subsequent drugs, such as cigarettes or alcohol leading to marijuana, this study’s findings indicate that environmental aspects have stronger influence on which type of substance is used. That is, if it’s easier for a male teen to obtain marijuana than beer, then he’ll be more likely to smoke pot.

This evidence supports what’s known as the common liability model, an emerging theory that states the likelihood that someone will transition to the use of illegal drugs is determined not by the preceding use of a particular drug but instead by the user’s individual tendencies and environmental circumstances.

Ralph E. Tarter, a professor of pharmaceutical sciences at the School of Pharmacy and lead author of the study, said: “The emphasis on the drugs themselves, rather than other, more important factors that shape a person’s behavior, has been detrimental to drug policy and prevention programs.

“To become more effective in our efforts to fight drug abuse, we should devote more attention to interventions that address these issues, particularly to parenting skills that shape the child’s behavior as well as peer and neighborhood environments.”

The Pitt researchers tracked 214 boys beginning at ages 10-12, all of whom eventually used either legal or illegal drugs. When the boys reached age 22, they were categorized into three groups: those who used only alcohol or tobacco, those who started with alcohol and tobacco and then used marijuana (gateway sequence) and those who used marijuana prior to alcohol or tobacco (reverse sequence).

Nearly a quarter of the study population who used both legal and illegal drugs at some point — 28 boys — exhibited the reverse pattern of using marijuana prior to alcohol or tobacco, and those individuals were no more likely to develop a substance use disorder than those who followed the traditional succession of alcohol and tobacco before illegal drugs, according to the study, which appears in the December issue of the American Journal of Psychiatry.

“The gateway progression may be the most common pattern, but it’s certainly not the only order of drug use,” said Tarter. “In fact, the reverse pattern is just as accurate for predicting who might be at risk for developing a drug dependence disorder.”

In addition to determining whether the gateway hypothesis was a better predictor of substance abuse than competing theories, the investigators sought to identify characteristics that distinguished users in the gateway sequence from those who took the reverse path. Out of the 35 variables they examined, only three emerged to be differentiating factors: Reverse pattern users were more likely to have lived in poor physical neighborhood environments, had more exposure to drugs in their neighborhoods and had less parental involvement as young children. Most importantly, a general inclination for deviance from sanctioned behaviors, which can become evident early in childhood, was associated strongly with all illicit drug use, whether it came in the gateway sequence or the reverse.

According to the study, interventions focusing on behavior modification may be more effective prevention tactics than current anti-drug initiatives. For example, providing guidance to parents — particularly those in high-risk neighborhoods — on how to boost their caregiving skills and foster bonding with their children could have a measurable effect on a child’s likelihood to smoke marijuana. Also, early identification of children who exhibit antisocial tendencies could allow for interventions before drug use even begins.

Although this research has significant implications for drug abuse prevention approaches, Tarter notes that further investigation should explore if the results apply to females as well. Also, the examination of behaviors in phases beyond alcohol and marijuana consumption in the gateway series will be necessary, he said.

Other Pitt authors of the study were Michael Vanyukov, Maureen Reynolds and Levent Kirisci, also of the School of Pharmacy, and Duncan Clark, School of Medicine.

The research was funded by the National Institute on Drug Abuse.


RheoGene licenses gene technology

RheoGene Inc., a wholly owned affiliate of UPMC, has granted a nonexclusive license to Centocor Research and Development Inc. of Radnor, Pa., to use the biotech company’s gene-targeting AttSite recombinase, an enzyme-based technology designed to guide gene insertion into specific “hot spots” within the genome to ease the exchange of DNA and development of new genetic sequences and cell lines. Financial terms were not disclosed.

“We are very excited that one of the world’s pioneers and leaders in the development and manufacturing of monoclonal antibodies for immune-related diseases has recognized the value of our AttSite technology for use in cell-line development,” said RheoGene president and CEO Tom Tillett.

This is the second significant AttSite licensing agreement announced this year. In July, RheoGene completed a similar licensing agreement with Symphogen A/S of Copenhagen, Denmark.

UPMC acquired RheoGene in 2004 for further development of its gene regulation technology with funding from Rohm and Haas Co. RheoGene has operations based in Pittsburgh and Norristown.

Centocor is a wholly owned subsidiary of Johnson & Johnson.


Grant funds study of tablet PCs in doctor-patient communication

The Robert Wood Johnson Foundation has awarded the School of Medicine’s Center for Primary Care Community-Based Research a $75,000 grant to investigate the use of tablet personal computers as a patient activation tool.

This study is designed to increase physician-patient communication, patient and physician satisfaction, and clinical outcomes for underserved patients. Principal investigator Janine E. Janosky said the use of tablet PCs is an innovative way to educate and prepare patients for their appointment. Through the assessment of risk factors for chronic disease such as diabetes and heart disease, an individualized report of family history and current conditions, patients then can feel more confident in their interaction with the physician. Physicians also will receive a copy of the patient’s self-reported risk factors, family history and conditions during the visit, thus increasing the probability that the patient’s concerns will be addressed, prevention measures may be instituted earlier, and self-management of chronic diseases will be increased.


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