News From Harvard Medical, Dental, & Public Health Schools--May 2, 1997
CONTENTS
Experimental Therapeutics
Biological
Chemistry
Health Care
Research Briefs
Awards
Bulletin
Forum
Humans have exploited nature's medicine chest of healing plants and herbs for thousands of years, but they hit a real vein of gold when they stumbled on the bark of the willow tree. So versatile is this plant--the bark has been used to reduce pain, fever, and inflammation--that in 1853, a German pharmacist named Hoffman sought and found a way to synthesize and amplify its main compound, salicylate, creating one of the first designer drugs, aspirin.
Nearly a century and a half later, HMS scientists appear to have
improved upon Hoffman's design. They have created a pair of molecules that
exceed aspirin's anti-inflammatory powers. The first molecule builds upon
a natural substance, lipoxin A4, that is released in the body during the
normal course of inflammation. The second molecule is modeled after a substance,
15-epi-lipoxin A4, that is actually triggered in the body by aspirin.
Charles Serhan and colleagues (Tamoko Takano, research fellow in medicine, and Jane Maddox, instructor in anaesthesia) are developing superior drugs to control inflammation.
When applied topically to mouse ears, the molecules reduced
acute inflammation by 95 percent, making them more potent than aspirin and
even more potent than one of the most powerful known anti-inflammatory agents,
dexamethasone. The researchers' findings appear in the May 5 Journal
of Experimental Medicine.
"It's gangbusters," says Charles Serhan, professor of anaesthesia (biochemistry and molecular pharmacology) and director of the Center for Experimental Therapeutics and Reperfusion Injury at Brigham and Women's Hospital.
High Hopes for Patient Care
He and his colleagues are currently working with Shearing AG, a German-based pharmaceutical company, to develop even more effective forms of the drug that might be taken orally and intravenously. If successful, they could provide powerful tools for controlling the inflammation that accompanies many pathological conditions, including reperfusion injury, arthritis, and heart disease.
During inflammation, leukocytes (dark gray spots--see
arrows) rush from the blood
vessels
to the site of inflammation (top). Topical application of analogs of lipoxin
A4 and aspirin-triggered 15-epi-lipoxin
A4 inhibits this process (bottom).
Aspirin may be a medical miracle--it has additionally been shown to reduce one's risk for colon cancer and Alzheimer's disease--but it has been a medical mystery, as well. Scientists had little clue as to how it worked for much of this century. Part of the mystery was revealed in the 1970s and '80s when aspirin was shown to inhibit the production of two natural compounds--prostaglandins and thromboxanes--that control pain and clotting, respectively. Yet it was unclear how aspirin reduced inflammation.
About ten years ago, Serhan, in collaboration with colleagues at the Karolinska Institute in Sweden, noticed that the body reduces its own inflammation in a curious way. Normally, inflammation occurs when leukocytes-- members of the immune army--and platelets flock to the scene of an injury or infection. At some point, though, these soldier immune cells stop migrating: How do they know when to stop? Serhan and his colleagues discovered that when white blood cells and platelets start crowding one another, lipoxin A4 (LXA4) is produced. LXA4 acts as a natural anti-inflammatory agent by signaling leukocytes to stop migrating.
Lipoxins are structurally related to prostaglandins and thromboxanes and, in fact, are created from the same precursor, arachidonic acid, though through different enzymatic intermediaries. Prostaglandins and thromboxanes are produced through an enzyme cyclooxygenase (COX). It is by targeting COX that aspirin prevents prostaglandins and thromboxanes from being formed.
Although lipoxins are produced via a different enzyme intermediate--lipoxygenase (LO)--Serhan and his colleagues thought initially that they might also be inhibited by aspirin via their enzymatic middleman. "We were accustomed to thinking of aspirin as an inhibitor," Serhan says. Yet when he and his colleagues mixed human leukocytes and endothelial cells in the presence of aspirin, they found that aspirin triggered an array of products, including a cousin of LXA4, called 15-epi-lipoxin A4.
"This was a big change in our thinking--aspirin actually triggers and stimulates the formation of something. This was heresy," says Serhan. Even more surprising, 15-epi-LXA4 appeared to be twice as effective at reducing inflammation as LXA4.
At first, it was unclear how aspirin could be exerting its triggering effect. What the researchers discovered--after considerable biochemical sleuthing--is that aspirin targets COX, thus preventing the prostaglandins and thromboxanes from being formed. But the COX enzyme is not completely inactivated. In fact, it appears to convert arachidonic acid into another product, 15-RHETE, which is then picked up by white blood cells and rapidly transformed to the anti-inflammatory 15-epi-lipoxin A4.
While 15-epi-lipoxin A4 is rapidly formed, the researchers observed that it is also rapidly inactivated by enzymes. Thinking it might be possible to improve upon nature's design, Serhan and his colleagues developed a series of analogs to 15-epi-LXA4 and also to LXA4. They had two goals in mind: "Can we sustain the biological action by avoiding inactivation and can we increase bioavailability?" says Serhan.
To address the first, the researchers put a bulky chemical--a methyl group--onto the tail of the molecule in the hope that it might block enzymes from attacking and inactivating the molecule. They also added two other structures to improve bioavailability. When they were done they had created molecular analogs that when tested in cultured human cells turned out to be even more powerful anti-inflammatory agents than either the native or aspirin-triggered compounds.
To test the analogs in vivo, the researchers cloned the mouse lipoxin A4 receptor--which turned out to be highly homologous to the human receptor. They then applied the analogs topically to mouse ears, which they then inflamed (using a proinflammatory agent, leukotriene B4). As they report in this month's JEM, inflammation was almost completely eliminated in the analog-treated animals compared with controls (see photos).
The researchers believe they can make their analogs even more powerful. "What kinds of things can we do to the molecule to tweak it, to make it more bioavailable and have a longer half-life? We're doing those studies now," says Serhan.
--Misia Landau
Some Americans grow nostalgic about the "good old days" when doctors made house calls and the quality of care was assumed to be uniformly high. The fact is, we did not always know how good the care was that we received. There were no broad-based clinical-performance standards to define quality and to serve as a basis for evaluation. In any particular case, there was no widespread acceptance of which clinical criteria were key to diagnosis and treatment, which treatments were appropriate, and which outcomes could be expected.
"The ultimate goal is to produce measures
that become national standards and that
are easily modified to reflect changing
clinical practice."
--Barbara McNeil
Eight national studies, funded by the federal Agency for Health Care Policy and Research, now are under way that aim at developing and implementing measures of quality in large-scale settings. Collectively, the projects are called QSPAN, a shorthand for "Expansion of Quality Measures." Two of them were awarded to Harvard Medical School. One involves evaluating HEDIS (Health Employer Data and Information Set), the most common system in use for gauging health-care performance. The other is a project called Expansion of Quality Measures for Cardiovascular Diseases, or QSPAN-CD.
A two-phase, five-year program begun last fall, QSPAN-CD is developing and testing a set of performance measures for a group of interrelated cardiovascular diseases, including acute myocardial infarction (AMI), congestive heart failure (CHF), and hypertension. These conditions affect millions of Americans--particularly the elderly, poor, and members of minority groups--at a cost that in 1996 alone exceeded $150 billion.
This spring the QSPAN-CD project team reached its first milestone in identifying an initial list of performance measures. The list is a distillation of existing practice guidelines--volumes of them, in fact--and clinical-trial data. "We had to abstract something from the guidelines that is quantifiable, a set of key variables," says principal investigator Barbara McNeil, Ridley Watts Professor of Health Care Policy and head of the department.
The resulting collection of measures, 92 in all, then went through another filter. The research team asked four panels of stakeholders to rate the measures in importance. The four were physicians, consumers, health-plan administrators, and purchasers/regulators (from businesses, Medicare and Medicaid programs, and state quality improvement organizations). "This was one of the first times researchers have tried to get information on what is important for quality from these four perspectives," says McNeil. Though there was variation among the measures deemed important, there also was overlap. In fact, the researchers ended up with 95 consensus measures since there was at least some support for all, plus a few additions.
One such measure in cases of AMI is this: If a patient's left ventricular ejection fraction (LVEF), which reflects the heart's capacity to pump blood, is less than 40 percent, a prescription should be given, within one month, for an angiotensin-converting enzyme (ACE) inhibitor, a kind of vasodilator. The researchers now are gathering data on which patients who fit this profile received a prescription. A quality-of-care indicator for a given health-care provider is formed by dividing the number of applicable patients given a prescription by the number of all applicable patients.
The researchers identified the data source in this case to be in- and outpatient medical records from the provider. Sources of data for other quality measures are pharmacy records or patient surveys. Deciding which source is best in terms of cost and accuracy for each quality measure is one of the demands of the project.
"Once we get data, then the variability of adherence to these measures can be determined, for example, 20 to 90 percent," McNeil says. "Then we have to determine at what level of analysis it is possible to measure quality." That is, can quality be determined at the level of the health plan, the branch office of the health plan, or the individual doctor? The critical factors are the number of appropriate patient observations that can be associated with each level of specificity and the cost of gathering the data. The researchers also are asking: At what level of distinction do consumers expect to have quality-of-care indicators? Is it enough for them to compare HMOs or do they need to compare doctors?
Among the other project researchers are coprincipal investigator Heather Palmer, lecturer on health services at the Harvard School of Public Health; Edward Guadagnoli, associate professor of health care policy; Sharon-Lise Normand, assistant professor of biostatistics in the Department of Health Care Policy; Paul Hauptman, instructor in medicine at Brigham and Women's Hospital; Laura Peterson, senior clinical research specialist; and Raymond Hyatt, project director.
By the summer of 1998, the QSPAN-CD team will have collected their data from the four health plans involved in the project: Allina in Minneapolis, Minn.; PacifiCare in Portland Ore.; United HealthCare in Atlanta, Ga.; and Prudential in Baltimore, Md. Two of the plans, United and Prudential, are each expanding to a second city.
"The ultimate goal," McNeil says, "is to produce measures that become national standards and that are easily modified to reflect changing clinical practice."
--Robert Neal
Gene expression is to DNA what the act of sculpting is to a block of marble. Until the cell "decides" which genes to transcribe into functioning proteins, DNA is nothing more than raw material. Some of the greatest finds in modern biology involve the discovery of the molecular hammers and chisels, that is, the mechanisms by which the expression of particular genes is switched on and off.
Stuart Schreiber (left) and Chris Hassig bring the perspective of chemistry to the study of histones, which now appear to play a role in regulating gene expression.
For the last two decades, most research on gene expression has focused on the enzymes that manipulate stretches of DNA. But this research has mostly ignored the fact that DNA does not come in stiff, orderly strands, like uncooked spaghetti, all ready to use. Instead, coils of DNA in the nucleus come packaged in a protein-rich goop of chromatin, whose bulk comes mostly from proteins called histones. Histones have been looked upon as scaffolding at best by scientists eager to get at the precious DNA draped around them. For most of the modern explorers of gene expression, says Harvard University graduate student Chris Hassig, "histones just got in the way."
At the same time, a small cadre of histone and chromatin experts have put forward the view--and some supporting, if circumstantial, evidence--that histones actually play a role in regulating gene expression. Already by 1965, some enterprising biochemists had shown that histones attached to DNA that was actively being transcribed were chemically different from histones attached to transcriptionally silent DNA. Specifically, the histones associated with active DNA were covered with acetyl groups--acetylated--whereas silent DNA clung to nonacetylated histones. But until about two years ago, there was never a clear demonstration that the unwrapping of DNA from histones via acetylation could start gene transcription, or that the tightening of the histones to the DNA via deacetylation could stop it.
Now chromatin modification is finally coming into its own as a way for genes to be switched on and off, thanks in large part to the laboratory of Hassig's adviser, Stuart Schreiber, in the Harvard University Chemistry Department, as well as the HMS laboratory of Kevin Struhl, the David Wesley Gaiser Professor of Biological Chemistry and Molecular Pharmacology. Each group is publishing a paper in the May 2 Cell.
Kevin Struhl (right) and David Kadosh have arrived at the study of histones via experience in investigating gene transcription. Struhl says the field is expanding rapidly.
What these labs--and several other labs around the world--have done is "to make a direct link between chromatin-modifying agents and a mechanism regulating transcription," says geneticist Bob Kingston of Massachusetts General Hospital.
That two laboratories in different parts of the University would converge on the same molecules illustrates the interdisciplinary approach that uncovered this mechanism. Working in collaboration with Don Ayer at the University of Utah, Schreiber's laboratory brought a chemist's-eye view to understanding fundamental biological processes; Struhl's lab brought a long track record in the study of the regulation of gene transcription in yeast.
The Schreiber work began with the curiosity of graduate student Jack Taunton, says Hassig, who sought the mechanism of an obscure anticancer agent, trapoxin. "All that was known about trapoxin was that it arrests the growth of certain tumor cells," Hassig says. Soon, a Japanese group had identified a potential molecular target for trapoxin: the enzyme histone deacetylase, which could remove acetyl groups from histones.
Taunton and Hassig first had to confirm that trapoxin's target was, indeed, histone deacetylase, which they did. The next step was to discover the milieu in which the enzyme was acting. Perhaps the ability to strip acetyl groups from histones was incidental or irrelevant. So the researchers looked in the genome database for other proteins with a sequence analogous to that of the target they had identified.
One analogous protein popped up immediately: the yeast protein Rpd3. The sequence similarity suggested that Rpd3, too, would be able to remove acetyl groups from histones--that "histone deacetylation" might be its main function.
This was a tremendous coup. Based on the work of Struhl and others, Rpd3 had been known to be involved in transcriptional regulation. But what it was doing was unknown. Hassig's and Taunton's data strongly suggested that trapoxin was stopping cell division by affecting histones. Schreiber and his students had unwittingly stumbled on a whole new mechanism, in which, says Hassig, "the unpacking of DNA is itself a form of transcriptional regulation."
With no knowledge of what was going on in Schreiber's lab, Struhl and his graduate student David Kadosh had for about two years been moving in the same direction. Two years earlier, Struhl had uncovered a new type of regulatory mechanism in yeast, a mechanism which was later found in higher organisms as well. This mechanism involved a "corepressor," a protein that takes part in stopping transcription of DNA without itself binding to the DNA. That task is delegated to a DNA-binding protein, which at that time had not yet been identified. But how corepressors worked was unknown, says Struhl. "Either the corepressor affects the transcription machinery, or it affects the chromatin structure in some way."
Trying to get to the heart of how corepressors work, Kadosh looked at a yeast molecule that was a suspected corepressor, Sin3. Kadosh and Struhl noticed right away that a second yeast protein--Rpd3--seemed to be Sin3's constant companion. But Rpd3's role--and for that matter, Sin3's--was unclear. In the Cell paper, Kadosh and Struhl identified a DNA sequence and its corresponding binding protein that respond to Sin3 and Rpd3. In effect, they showed how Sin3 and Rpd3 could be recruited to DNA to turn off transcription.
It was at that point that Struhl heard about Schreiber's finding: Rpd3 was a histone deacetylase. And suddenly all the pieces fell into place, a moment that both Struhl and Hassig say was enormously exciting. "It led to a very obvious model," says Struhl, "that a biologically relevant mechanism for the regulation of gene transcription was targeting histones. This was unprecedented."
As the evidence has begun to mount that the acetylation and deacetylation of histones really does play a role in the management of DNA transcription, the number of scientists working in the field has "exploded," says Struhl. And now, of course, the real work begins. "How exactly are these molecules acting on chromatin?" Hassig asks. "What are the functional consequences of that?" It may take 10 years or more, says Kingston, to understand the new mechanism and see how it interacts with previously known forms of gene regulation. Scaffolding no more, histones have finally entered the scientific limelight.
--Steven Dickman
People who do not graduate from high school are twice as likely to suffer an anger-induced heart attack as people with at least some college experience, according to an article in the April 14 issue of the American Medical Association's Archives of Internal Medicine.
Murray A. Mittleman, HMS assistant professor of medicine at Beth Israel Deaconess Medical Center, and colleagues interviewed 1,623 patients an average of four days following myocardial infarction (MI) to determine their emotional state of anger two hours prior to their MI. Feelings categorized as "very angry, furious, or enraged" were reported by 3.9 percent of patients with less than a high school diploma, 2.2 percent of patients who had finished high school, and 1.7 percent of patients with at least some college education.
"The risk of having an MI triggered by isolated episodes of anger declined consistently and significantly with increasing levels of educational attainment," write Mittleman and his colleagues. Patients with less than a high school education were 3.3 times more likely to suffer an anger-induced heart attack, and those with at least some college education were 1.6 times more likely to suffer an anger-induced heart attack than people not experiencing episodes of anger.
"Further research is required to better elucidate the exact mechanisms of the partial protection against the triggering of MI that people with higher educational attainment experience," write the authors.
Two commonly available drugs appear to slow the progress of Alzheimer's disease by about 7 months, according to a report by scientists at 23 sites of the Alzheimer's Disease Cooperative Study. The drugs--selegiline (Eldepryl) and alpha tocopherol (vitamin E)--delayed important milestones, such as entry into nursing homes. They decreased by about 25 percent the loss of ability to perform daily activities in people with moderately severe disease.
The clinical trial examined the effects of the two drugs in 341 patients at the study sites, including one located at Massachusetts General Hospital that is directed by John H. Growdon, professor of neurology. Patients were divided into four groups, each with a different treatment regimen: selegiline alone, vitamin E alone, a combination of the two drugs, and placebo. Patients were assessed every 3 months for 2 years with regard to four important milestones of progression of the disease--institutionalization, loss of ability to perform basic daily activities, progression to severe dementia, and death.
In an analysis that combined all four milestones, the researchers found that patients taking selegiline took 215 days longer to reach any one of the four milestones than did patients on placebo. With vitamin E, the delay was about 230 days. The combination of the drugs showed less of an effect, with a delay of only 145 days. The findings are reported in the April 24 New England Journal of Medicine.
Beyond their significance for patients, the findings are important in understanding the factors involved in the symptoms of Alzheimer's disease. Researchers exploring the idea that oxidative damage may play a role in the disease theorize that drugs such as selegiline and alpha tocopherol keep oxidative damage of brain cells at bay and, in this manner, may reduce disease symptoms.
Academic researchers in the life sciences who are involved with commercialization of their research or who participate in academic-industry research relationships are more likely to withhold the results of their research from the scientific community, according to a study by HMS researchers in collaboration with scientists at the University of Minnesota. Withholding of information is also high among scientists involved in genetic research and those who publish many research articles. The study appears in the April 16 Journal of the American Medical Association.
The researchers surveyed a random sample of 3,400 life-science faculty members at medical and graduate schools across the country. Almost 20 percent of the more than 2,000 who responded reported delaying publication of research for more than six months at least once. The most frequently cited reasons were the need for time to prepare a patent application, protection of the proprietary value of research, and protection of scientific lead. Nine percent admitted refusing to share research results or materials with other scientists, citing protection of a scientific lead, the limited supply or costs of requested material, or informal agreements with companies as primary reasons for their refusals.
Although the overall numbers of scientists who admitted behaviors associated with research secrecy was relatively low, the researchers note that such behavior is contrary to the ideals of science, which encourage free exchange of information, and to the policies of the National Institutes of Health and most research universities. "The fact that we can document this kind of behavior--and we believe the rates seen in this survey probably reflect minimum levels--is cause for concern and further investigation," says lead author David Blumenthal, associate professor of health care policy at MGH. Other MGH authors on the study are Eric Campbell and Nancyanne Causino.
Homosexual and bisexual men who were sexually abused during childhood or adolescence are twice as likely to engage in unsafe sexual practices as homosexual and bisexual men who have not been abused, according to a study in the April Journal of General Internal Medicine. The study was conducted by researchers at Massachusetts General Hospital in conjunction with researchers at other institutions.
The research team surveyed several hundred homosexual and bisexual men about their past and present sexual experiences. The men were participating in two long-term studies of factors related to HIV infection at the Fenway Community Health Center in Boston. Of the men who reported being abused before age 16, 21 percent had engaged in unprotected receptive anal intercourse, compared with 11 percent of those who did not report abuse.
"In general populations, there has been clinical evidence that childhood sexual abuse increases the incidence of such problems as depression, substance abuse, low self-esteem, and promiscuous sexual behavior," says lead author William Lenderking, HMS instructor in psychology in the Department of Psychiatry at MGH. "But there has been little research specifically directed to studying the effects of sexual abuse among homosexual and bisexual men." Lenderking was a research associate in biostatistics at the Harvard School of Public Health at the time of the study.
The donor and recipients of the ninth annual Alpert Prize gather at the April 17 ceremony. From left, they are Warren Alpert, whose foundation gave the prize; Pnina Sachs; Leo Sachs and Donald Metcalf, the two recipients; and Josephine Metcalf.Bachrach
The Warren Alpert Foundation presented its ninth annual Alpert Prize to Leo Sachs and Donald Metcalf for their discovery of protein molecules that regulate the growth of bone-marrow cells. Their research has led to the worldwide use of a protein, called granulocyte colony-stimulating factor, as a major support drug in cancer treatment.
Sachs, of the Weizmann Institute of Science in Rehovot, Israel, has provided insight into the molecular basis of normal and abnormal cell development in blood-forming tissues. His findings illuminate the molecular controls that regulate blood-cell viability, growth, and maturation into distinct cell types. Metcalf, of the Walter and Eliza Hall Institute of Medical Research at the University of Melbourne in Australia, is recognized for his research of cell colony-stimulating factors. This research led to the current understanding of individual molecules that control blood-cell development and has facilitated the therapeutic regulation of bone-marrow growth.
The pair are sharing the $100,000 award, which was established by Medical School benefactor Warren Alpert and recognizes scientists who have cultivated their basic-science discoveries into clinical applications.
Faculty Council
At the sixth meeting of the Faculty Council for 1996-97, members heard about changes in the Veterans Health Care System and the implications for patient care, research, and teaching. Over the next several years the 11 veterans hospitals in New England will face substantial budget cuts by the federal government, in part, due to government efforts to redirect funding to areas where the most veterans now reside. In the past 15 years, Massachusetts has lost more than 20 percent of its total veteran population while Arizona has seen an almost twenty-five percent growth in veteran numbers. Additionally, with more veterans over age 65, many are now accessing other health-care options, including managed care, via their Medicare benefits. The result is a move away from the priority medical center structure that has been utilized in the past and a move toward outpatient care. New England will retain one tertiary-care facility, to be located in Boston. The newly formed Veterans Integrated Service Network 1 (VISN1), the New England health-delivery system for veterans, is moving to an integrated delivery system designed to retain services to veterans while reducing costs as necessitated by budget cuts.
In order to arrive at the best system possible, the Deloitte & Touche Consulting Group has worked with VISN1, under the Direction of Denis FitzGerald, on an analysis of the possible options for cost-saving measures. FitzGerald and VISN1 are committed to keeping both the Jamaica Plain and the West Roxbury VA Hospitals open with changes occurring at both facilities. A plan for the changes has been outlined and will be presented to the undersecretary for health, Kenneth Kizer, with a decision to follow in 1998. Dean Tosteson and the council expressed a commitment to keeping the VA a strong entity for teaching, research, and patient care. Many council members asserted that the VA setting provides one of the best arenas for student and resident learning. The point was made that attempting to replicate programs such as those already existing in cardiac surgery and spinal-cord injury at the West Roxbury facility would come at a large cost. In integrating services, important issues will include managing staff cuts and maintaining the working relationship between VA centers and HMS faculty and students, among others. Dean Tosteson made clear that both he and Dean-Elect Joseph Martin strongly support the continuation of Harvard Medical School's long-standing involvement with VA patient care, teaching, and research efforts.
Council members then heard part four of a discussion of opportunities for incorporating computer technology with medical education. Judith Messerle, Countway librarian for the Harvard Medical and Boston Medical Libraries, and members of her staff discussed the Countway's "Library Without Walls," which through the Internet (http://www.med.harvard.edu/ countway) allows HMS community members to renew books, request an interlibrary loan, ask reference questions on line, sign up for a library workshop, and request a literature search. Information on line includes new library acquisition lists, electronic journals, library exhibit listings, and library position openings. Efforts have been made to provide access to as many electronic journals as possible and to offer both faculty and students new technologies in biomedical information such as the Whole Brain Atlas (showing detailed computer images of brains), an interactive protein database, and the Geographical Information System (which allows gathering a range of statistical data). Messerle said the Countway Campaign and renovation plans were going quite well and that nearly three quarters of the amount needed to pay for a major renovation of the library has already been raised.
A proposal for the creation of the Harvard Division of Sleep Medicine and Circadian Biology was postponed for consideration at a future council meeting.
The Women's Health Initiative, a major national study that will involve
164,500 participants across the U.S., is the first clinical trial of its
size and scope to address critical health issues of postmenopausal women.
Three clinical trials will focus on whether a low-fat diet can reduce the
risk of breast or colorectal cancer; how hormone-replacement therapy affects
the risk of heart disease, osteoporosis, breast cancer, and Alzheimer's
disease; and whether calcium and vitamin D supplementation reduces the incidence
of hip fractures and colorectal cancer. In addition, an observational study
will examine how the lifestyles and risk factors of women affect health
outcomes and quality of life.
Brigham and Women's Hospital, one of 16 Vanguard Centers for the WHI, is actively recruiting women over age 55 who are interested in taking part. "This landmark study addresses the major public-health issues that concern postmenopausal women," says JoAnn Manson, associate professor at HMS and HSPH and principal investigator of the initiative at BWH.
Unlike the well-known Nurses' Health Study, which is an observational study examining associations between women's health habits, medications, and diets and their subsequent state of health, the WHI is a randomized clinical trial that will assess the role of several interventions in the prevention of heart disease, cancer, osteoporosis, and other major health problems.
Women faculty and staff in the Harvard medical community are now being invited to join the WHI. Recruitment will continue until January 1998. To be eligible to participate, women must be between age 55 and 79, past menopause, and planning to stay in the greater Boston area for at least three years. For more information, please call 617-278-0782.
Dean Tosteson surveys Yvonne Chan's and Richard Gallo's poster as Chan explains their project.
The 57th annual Soma Weiss Medical and Dental Student Research Day took place on April 24 with nearly 100 student poster presentations. There was a rich variety of topics: gene expression, periodontitis, angiogenesis and tumor growth, children's health, and "suicide by cop," to name a few. The four student speakers (Jennifer Brown, '98; Melinda Fan, '98; Ajeya Joshi, '97; and Alice Tsang, '99) used the limelight to share their research in greater depth. In his keynote speech, Dean Daniel Tosteson reflected on the future of biomedical science. Among his observations was that in the coming years some of the most dramatic research will focus on the relationship between genes and the nature of the brain-mind. Turning to the students near the end of his talk, he asked with a deference he had shown all afternoon, "Where are we going? Your guess is certainly as good and probably better than mine."
* The Bristol-Myers Squibb Foundation has selected the Harvard School of Public Health to share in $800,000 awarded to four academic institutions over a two-year period to support research and community-based prevention and intervention programs designed to improve women's health. The funds will support a collaborative project with HSPH and the Roxbury Comprehensive Community Health Center to reduce mortality from cardiovascular disease among women in Roxbury through assessment of risk factors and intervention efforts.
* Walter C. Guralnick, professor emeritus of oral and maxillofacial surgery at Harvard School of Dental Medicine, was awarded a grant by the W.K. Kellogg Foundation to study the delivery of oral health care in the context of the changing health-care climate. Guralnick has established the Woodshole Group, comprised of 17 professionals from around the country who will meet several times a year to work on the study.
In 1985 Harvard Medical School created a new sequence of courses called Patient-Doctor I, II, and III to teach students the fundamentals of interacting with patients and to introduce the finer points of listening, observing, and physical examination. A natural outgrowth of the design and implementation of these courses was the adoption of a method of evaluating these skills, called the Objective Structured Clinical Examination (OSCE). OSCE, which was first introduced in Scotland in 1975, is a method of measuring medical-student ability with an emphasis on a range of patient-care skills. At HMS, all second-year students are now evaluated this way.
Introduced to HMS in 1994 by Suzanne Fletcher, director of Patient-Doctor II, in collaboration with the Office of Educational Development, OSCE is an answer to problems seen in the more traditional oral examination. Oral examination is problematic in that the cases presented and the preceptors involved vary from student to student, opening the possibility for unwanted biases. "It's the student variability we want to measure," says Claus Hamann, medical director of OSCE, "so in order to measure that, it is necessary to create a system in which the other variables remain constant."
The idea behind OSCE is to test the students' performance in the areas of history-taking, physical examination, interpretation, differential diagnosis, verbal presentation, and patient interaction. Hamann and the Patient-Doctor II site directors compile a uniform set of criteria based on course goals and create vignettes to test students' ability with respect to the criteria. Collaboration involves site directors from all nine sites where Patient-Doctor II is taught--Mt. Auburn, the Brigham, HPHC, Beth Israel Deaconess East and West campuses, the Lahey Clinic, Mass. General, N.E. Baptist, and the West Roxbury VA, where Hamann was originally a site director.
Another benefit of this type of evaluation is that it allows each student to see a variety of different cases presented in a range of ways. An example is a station where the student is presented with a real, live patient to examine. In this case the proctor is able to evaluate not only the accuracy of the diagnosis, but also the skill with which the student conducts a physical exam and the student's interaction style. At another station a proctor can observe how a student performs in a role-play or makes a diagnosis based on a slide or video tape.
The logistics of OSCE are hair-raising. This year the Offices of Educational Development and Educational Resources coordinated 163 second-year students with 160 faculty proctors over three days, April 7, 9, and 11. Students have two-and-a-half hours to complete a total of 16 stations plus two rest stations. Each station is proctored by one faculty member and each offers a different scenario to test student skills. Hamann says that to ensure objectivity the proctors are given standard evaluation checklists.
A crucial element of the OSCE process is feedback that each proctor gives the student in the last several minutes the student is at the station. In fact, while the students are "graded" on their performance at OSCE, the grade does not factor into their grade for the course. The result is that OSCE is learning-driven, and students say that the feedback is the most meaningful part of the process.
This year the administration of OSCE was moved to earlier in the course, allowing it to be a valuable tool for students, faculty, and site directors to measure progress and spot areas where improvement is needed. Then the remainder of the course can be used to work further on those skills. "If students tend to excel in a particular area, then we know that that skill is being taught effectively and we should continue teaching it that way," says Hamann. "Similarly, if we see an area where there is a consistent need for improvement, we can try to make the necessary adjustments in our method of teaching and hopefully teach that skill in a more effective manner."
--Molly Walker
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