UW School of Medicine Online News 4-18-08

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University of Washington School of Medicine

Online News

Vol. 12, No. 16
April 18, 2008
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To view an archived version of Online News on the UW
Medicine Web site, visit:
http://www.uwmedicine.org/Global/NewsAndEvents/somnews/index.htm

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This week’s news:

* Case study by UW researchers Bruce Psaty and Richard Kronmal finds that data submitted to FDA by study sponsor Merck minimized the appearance of mortality risk from Vioxx in some trials

* Laura Moore Cunningham Foundation establishes scholarship for Idaho medical students

* UW scientists uncover details about how dietary restriction slows down aging

* UWMC scores highest in patient satisfaction among hospitals in King County, according to survey data published online by Washington State Hospital Association

* Adam Drewnowski selected for Astor Visiting Lectureship at Oxford University

* Gustavo Matute-Bello in Division of Pulmonary and Critical Care Medicine recently elected to Western Society for Clinical Investigation

* Carlos Pellegrini, chair of surgery, knighted by the French Republic in recognition of outstanding accomplishments and service


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APPEARANCE OF MORTALITY RISK FROM VIOXX IN SOME TRIALS MAY HAVE BEEN MINIMIZED

A new case study by UW researchers found that data submitted to the FDA by Merck minimized the appearance of mortality risk from taking rofecoxib, also known as Vioxx, in some clinical trials. The UW case study appears in the April 16 issue of JAMA.

UW faculty members Bruce M. Psaty, professor of medicine and epidemiology, and Richard A. Kronmal, professor of biostatistics, conducted a review of documents to describe how the study sponsor represented findings regarding the risk of death associated with Vioxx in clinical trials of patients with Alzheimer disease or cognitive impairment. The documents became available during litigation related to Vioxx involving Merck, including internal company analyses and information provided by the sponsor to the Food and Drug Administration (FDA). The authors also evaluated information in two published articles that reported results of these trials.

The trials enrolling Alzheimer disease patients started in 1998, but the published articles, which simply listed counts of deaths in the text, were not published until 2004 and 2005. However, the UW researchers said, the published articles did not include analyses or statistical tests of the mortality data, and the two articles concluded that regarding safety, rofecoxib was “generally well tolerated.” Vioxx was withdrawn from the market in September 2004.

In contrast, in April 2001, the company’s internal intention-to-treat analyses of pooled data from two trials identified a significant three-fold increase in total mortality. These mortality analyses were neither provided to the FDA nor made public in a timely fashion, according to the UW researchers. Even though the data submitted to the FDA minimized the appearance of a mortality risk, the FDA raised questions about the “ethics” of continuing one of the studies in light of the increased risk of death. Merck characterized the mortality findings as “small numeric differences… most consistent with chance fluctuations.” Merck did “not believe that a safety issue had been identified.” There was no data and safety monitoring board in place to protect the patients in this trial.

The UW researchers point out that study sponsors have a direct financial interest in their products and a duty to provide a return on shareholders' investments, and that it is difficult to ensure transparency in research results if sponsors choose to present their products in the best possible light. The findings from the study suggest that greater protections are needed for research participants, the authors argue, and that new approaches are needed for the conduct, oversight, and reporting of industry-sponsored trials.

As disclosed in their JAMA article, Psaty has testified before a U.S. Senate Finance Committee hearing in 2004 entitled "FDA, Merck, and Vioxx: Putting patients first," and Kronmal has been retained by plaintiffs' attorneys as an expert witness in cases related to rofecoxib and cardiovascular events.


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IDAHO FOUNDATION ESTABLISHES SUPPORT FOR MEDICAL STUDENTS

The cost of medical education continues to rise, with medical students often amassing a staggering amount of debt in the process. A young couple recently profiled in The New York Times amassed some $330,000 in education loans over the course of their four-year study at Harvard Medical School. At the UW, 87 percent of medical students graduate with debt, and the median debt owed by a graduating student has risen past $100,000.

One UW medical student from Idaho each year will soon have some extra financial help, thanks to the Laura Moore Cunningham Foundation (LMCF) of Boise. LMCF recently established the Laura Moore Cunningham Endowed Scholarship for Idaho Medical Students. The foundation’s gift of $250,000 is being matched 50 percent by the UW under its Students First initiative. Students First provides need-based scholarships for undergraduate, graduate, and professional students.

The aim of the scholarship, foundation leaders said, is to support and promote Idaho students coming back to the state to practice in high-need areas, specifically in rural areas and in family medicine. Paul Ramsey, dean of the UW School of Medicine, added that the endowment addresses two of the top priorities of the school: alleviating debt for medical students and encouraging students to consider practicing in underserved areas.

Starting in 2009, income from the $375,000 endowment will be used each year to fund the tuition of a second-year medical student from Idaho. Students will be selected based on academic merit and financial need, with preference given to rural first-generation college students who hope to return to Idaho to practice medicine.

Laura Belle Moore Cunningham, daughter of the Idaho pioneer family that founded Idaho First National, was born in 1869 and raised in Boise. Dedicated to her community, she was an active leader, donor and volunteer. The foundation was started upon Cunningham's death in 1963, and is sustained through volunteer leadership of her family. The foundation provides more than 450 scholarships to Idaho students at community colleges and universities every year.


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RESEARCHERS UNCOVER DETAILS ABOUT HOW DIETARY RESTRICTION SLOWS AGING

UW scientists have uncovered details about the mechanisms through which dietary restriction slows the aging process. Working in yeast cells, the researchers have linked ribosomes, the protein-making factories in living cells, and Gcn4, a specialized protein that aids in the expression of genetic information, to the pathways related to dietary response and aging. The study, which was led by UW faculty members Brian Kennedy and Matt Kaeberlein, appears in the April 18 issue of the journal Cell.

Previous research has shown that the life-span-extending properties of dietary restriction are mediated in part by reduced signaling through TOR, an enzyme involved in many vital operations in a cell. When an organism has less TOR signaling in response to dietary restriction, one side effect is that the organism also decreases the rate at which it makes new proteins, a process called translation.

In this project, the UW researchers studied many different strains of yeast cells that had lower protein production. They found that mutations to the ribosome, the cell's protein factory, sometimes led to increased life span. Ribosomes are made up of two parts -- the large and small subunits -- and the researchers tried to isolate the life-span-related mutation to one of those parts. They found that the long-lived strains had mutations that disrupted the large ribosomal subunit, but never had mutations in the small subunit.

The researchers also tested a drug called diazaborine, which specifically interferes with synthesis of the ribosomes' large subunits, but not small subunits, and found that treating cells with the drug made them live about 50 percent longer than untreated cells. Using a series of genetic tests, the scientists then showed that depletion of the ribosomes' large subunits was likely to be increasing life span by a mechanism related to dietary restriction -- the TOR signaling pathway.

Scientists have known that dietary restriction decreased TOR signaling, and that decreased TOR signaling reduced translation or protein production, but this was the first direct evidence that all three were acting in the same genetic pathway, explained Kennedy, an associate professor of biochemistry.

Further research on what was happening in those cells with reduced protein production showed that Gcn4 was playing a role in the process. Gcn4 is a specialized protein called a transcription factor, which helps transfer genetic information during cell growth. When ribosomes aren't working at 100 percent, most proteins are made less efficiently -- but Gcn4 production can sometimes go up in those situations.

The researchers found that in the long-lived strains, the cells were indeed producing more Gcn4. When they blocked that increase in Gcn4, the yeast cells did not have a longer life span. The results suggest that Gcn4 is an important player in this longevity pathway, said Kaeberlein, an assistant professor of pathology. Although they don't know if Gcn4 plays a similar role in other organisms, there are Gcn4-like proteins in worms, flies, mice, and humans that appear to be regulated in a similar way.

The researchers hope that this work will help them learn the details of how TOR regulates aging, allowing them to identify better targets for treating age-related diseases in people.

The study's lead author is Kristan Steffen, a graduate student in the UW Department of Biochemistry. Vivian MacKay, a research professor of biochemistry, was also a co-author on the study.


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UWMC RANKED HIGHEST FOR PATIENT SATISFACTION AMONG HOSPITALS IN KING COUNTY

UW Medical Center has earned highest marks for patient satisfaction among all hospitals in King County, according to information from the Washington State Hospital Association (WSHA) and the Centers for Medicare and Medicaid (CMS).

The association recently added a new feature to its Web site, which already provides Centers for Medicare & Medicaid (CMS) information on quality and pricing. WSHA has repackaged hospital comparison data based on patient satisfaction surveys CMS released in late March. The surveys included questions regarding cleanliness of the facility, noisiness, and communication and courtesy of health care professionals. This latest addition of information is based on surveys conducted between October 2006 and June 2007.

Last week, the Seattle Times reported on the WSHA satisfaction survey and noted that UWMC was the hospital earning highest marks for satisfaction among all hospitals in King County. The hospital garnered an overall score of 71 percent, which is above the national average of 63 percent and the state average of 64 percent. Lorie Wild, chief nursing officer for UWMC, noted in the Seattle Times article that while UWMC scored well, the results also show that the medical center has room to grow.

Surveys and care-quality and pricing data can be helpful benchmarks for consumers, added UWMC Executive Director Stephen Zieniewicz, and can also provide important information for health care professionals striving to improve performance at a facility. Academic medical centers often struggle with such data comparisons, Zieniewicz said, since our teaching mission can often lead to higher costs of care. Academic centers are also often the last resort for patients with very complicated health problems, so measures of length of stay and outcomes reflect that fact.

Data from the WSHA satisfaction survey and other CMS information is available online at:
http://www.wahospitalquality.org/index.php


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DREWNOWSKI SPEAKING AT UNIVERSITY OF OXFORD IN LECTURE SERIES FOR DISTINGUISHED ACADEMICS

Adam Drewnowski, UW professor of epidemiology and medicine and director of the Center for Public Health Nutrition, is speaking about diets, obesity, and economics in a series of lectures next week at the University of Oxford. Drewnowski has been invited by the university as part of its Astor Lecture Series, which brings distinguished academics from the United States to lecture at Oxford for one week.

Drewnowski will speak in four events, from April 22 to 24, and will address several topics, including the effects of sweet taste on feeling sated, the cost of healthy diets, the geographical mapping of obesity, and the links between income and health. Drewnowski is a leader in the field of obesity prevention and treatment, and his current work is focused on poverty and access to healthy foods. Drewnowski's visit is being sponsored by Oxford's Unit for Biocultural Variation and Obesity.


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MATUTE-BELLO RECENTLY ELECTED TO WESTERN SOCIETY FOR CLINICAL INVESTIGATION

An item in last week's issue of the Online News listed several UW faculty who had recently joined the American Society for Clinical Investigation and the Western Society for Clinical Investigation. That list inadvertently omitted one UW faculty member: Gustavo Matute-Bello, assistant professor of medicine in the Division of Pulmonary and Critical Care Medicine, was recently elected to the Western Society for Clinical Investigation.

Matute-Bello is a physician at the VA Puget Sound Health Care System in Seattle. He studies the mechanisms leading to epithelial damage in acute lung injuries and the interactions of those mechanisms with lung host defenses.


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PELLEGRINI NAMED KNIGHT IN FRENCH LEGION OF HONOR

Carlos Pellegrini, the Henry N. Harkins Professor and Chair of Surgery at the UW, was made a knight in the French Legion of Honor this month in recognition of his outstanding accomplishments and service. Appointment to the Legion of Honor, which was established in 1802 by Napoleon Bonaparte, is the highest recognition given by the French Republic. Members are appointed for life.

Pellegrini was also recently named an honorary fellow of the Royal College of Surgeons in Ireland, in recognition of his outstanding contributions to surgery and surgical education. The fellowship is the highest honor that the Royal College bestows and is reserved for those who make significant contributions to surgery and to the betterment of humanity.

Pellegrini is the immediate past-president of the American Surgical Association, current president of the Society of Surgical Chairs, a regent of the American College of Surgeons, and a director of the American Board of Surgery. He was profiled in a recent Q&A feature in University Week, which can be found here:
http://uwnews.org/uweek/uweekarticle.asp?articleID=40889


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Justin Reedy, editor:
206-685-0382, jreedy@u.washington.edu

Online News is copyright 2008. All rights, including electronic
redistribution, are reserved.

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