Contents:
Public Health
One of the most vexing questions about women's health is what, if anything, can be done to reduce the risk of breast cancer.
Uncertainties and controversies abound: At what age should women begin mammography screening, and how often? What role does dietary fat play? Do pesticides and other environmental toxins increase risk? Does tamoxifen's apparent protective effect against breast cancer outweigh the increased risk of endometrial cancer?
And what about physical activity? Women and their physicians surely would welcome solid evidence that something as inexpensive and nontoxic as exercise could help lower breast cancer risk.
Unfortunately, that evidence remains elusive. In a study of more than 100,000 nurses, Beverly Rockhill, instructor in medicine at Brigham and Women's Hospital and HMS, and co-authors at BWH, HMS, and the Harvard School of Public Health, found that physical activity, either during late adolescence or in the more recent past, does not seem to affect breast cancer risk in young women. The study was published in the August 5 Journal of the National Cancer Institute.
A Missing Link
Researchers have pursued the exercise-breast cancer link because it is both scientifically plausible and appealing as a prevention strategy, Rockhill says.
"The underlying hypothesis is that more active women seem to have lower levels of circulating estrogen," she explains. "Extremely active women may even shut down their menstrual cycles, but women who are only moderately active also seem to have lower levels of ovarian hormones. And we know from research that higher levels of these hormones are correlated with breast cancer risk." In addition, fat cells produce estrogen, and greater body fat appears to be associated with a higher risk of breast cancer in postmenopausal women, so exercise might also protect against postmenopausal breast cancer by keeping body fat low.
| A study by Beverly Rockhill and colleagues at HMS and HSPH suggests that exercise has little or no effect on breast cancer risk in young women. |
"People are interested in this because physical activity is modifiable--something you could tell women that they could do themselves to change their breast cancer risk," she adds, in contrast to known risk factors such as genetics and age at menarche, first childbirth, and menopause.
The new study does not rule out the possibility of a benefit. But it further muddies an already murky picture. Several earlier studies uncovered evidence that exercise does reduce risk. Most striking was a 1994 report by Leslie Bernstein and colleagues at the University of Southern California who found, in a case-control study of women under age 40, that the most physically active women--who averaged at least 3.8 hours of exercise per week beginning at menarche--had a 60 percent reduction in risk compared with those who did not exercise. Similarly, a 1997 cohort study in Norway found a 37 percent reduction in risk among women who ranked themselves as highly active. However, other studies have shown either a very modest reduction in risk or none at all.
In their analysis, Rockhill and colleagues used questionnaire data from the Nurses Health Study II, a prospective cohort study of women who were 25 to 42 years old in 1989. Participants were asked to recall how many months per year they had participated in strenuous physical activity at least twice a week at ages 18 to 22, and to estimate the number of hours per week they currently spent in at least moderately vigorous exercise (walking at an easy pace, for example, was not included).
During the six years the group was followed, 372 women were diagnosed with breast cancer. Women who reported high levels of physical activity during either period of life were about 10 percent more likely to get breast cancer than less active women. But these findings were not statistically significant, so the researchers could infer neither risk nor benefit.
Compounding the problem of interpreting the data from various studies are differences in the specific questions women were asked about their activity levels. Rockhill acknowledges that the questions asked in the Nurses Health Study II about adolescent physical activity were posed in a way that might not optimally reflect important variations in exercise patterns. Nevertheless, responses to these questions do correlate with objective measures such as body mass index, suggesting they are capturing some real variation.
"One thing that's still unclear is the period of life during which physical activity might have the most influence on breast cancer risk," she adds. "If a woman is very active between, say, the ages of 12 and 18, is that the most important period? If she then gives it up for the rest of her life, is that enough? Conversely, if a middle-aged woman takes up exercise on the advice of her doctor, is that going to be too late to influence her lifetime risk? Nobody knows the answers."
Future research, the authors write, should focus on improving assessment of lifetime physical activity as well as clarifying whether there is an optimal time period, frequency, or intensity of physical activity associated with decreased breast cancer risk.
Essentially, Rockhill says, two possibilities could explain the negative results of hers and others' studies: "Either the amount of activity required to affect breast cancer risk is very high, and our measures are not doing well at identifying the most active women. Or, there's really nothing there--physical activity is not a protective factor against breast cancer.
"If it is a protective factor, it's going to be a fairly weak one," she adds.
Even if no link to breast cancer can be firmly established, Rockhill says, there are still plenty of reasons to exercise. Its benefits for cardiovascular and musculoskeletal health, for example, are unquestioned.
--Tom Reynolds
Variety is called the spice of life, but it is more like the main ingredient when it comes to the underlying biology. Proteins, for example, often appear in different forms that seem to have similar function but reveal key differences when circumstances change. By selecting from this store of variations, or polymorphisms, evolution arrives at many of its adaptations.
Polymorphisms are central to understanding the origins not just of beneficial traits but of many diseases, most recently late-onset Alzheimer's, according to a new study by HMS and HSPH researchers. Rudolph Tanzi, Deborah Blacker, and their colleagues have found that people carrying a common variant of a protein, called alpha2 macroglobulin (A2M), are three times more likely to develop Alzheimer's disease than those with the standard form of the protein.
A More Potent Risk Factor
Until recently, the only established genetic risk factor for late-onset Alzheimer's was a variant of apolipoproteinE called ApoE4. Risk was seen to increase in people carrying two copies of the gene for this variant. Yet a single copy of the gene for the newly discovered A2M variant increases risk to the same degree, report the researchers in the August 1 Nature Genetics, suggesting that this gene variant, called A2M-2, may be an even more powerful late-onset Alzheimer's risk factor than ApoE4.
| Marilyn Albert, Deborah Blacker, Linda Rodes, and Rudy Tanzi collaborated with others to find the A2M-2 gene. |
Tanzi speculates that while the A2M-2 variant may be able to carry out its main task of degrading amyloid-beta protein (A-beta), the main constituent of Alzheimer's plaques in the brain, it may perform less efficiently than the normal version. "So A2M-2 might allow more A-beta to collect at the synapse," says Tanzi, an associate professor of neurology at Massachusetts General Hospital. As a person ages, the disadvantage could show up in the form of more accumulated A-beta in the brain.
Still, people carrying the gene for A2M-2 do not necessarily develop Alzheimer's. "You can be 90 and carry the A2M-2 allele and not get the disease," says Tanzi. He believes that A2M-2 may work in combination with other genetic variations to bring about the disease. "I think we're going to see that late-onset Alzheimer's involves a combination of effects, all modest, of a large set of genes. So we have to start rethinking the whole paradigm of late-onset Alzheimer's," he says.
The new paradigm--a mixture of genetic polymorphisms that are only revealed to be harmful under conditions of advanced age--could explain why so many older people suffer from Alzheimer's. More than 30 percent of Americans over the age of 85 have the disease. As people live longer, additional harmful polymorphisms could be exposed. "As life spans are extended more and more, how many so-called benign common polymorphisms are just lying in wait and are going to spring up to challenge whether you're going to be able to live past a hundred without getting some form of cancer, diabetes, or stroke?" says Tanzi.
Recognizing Ethnic Variation
When Tanzi and his colleagues began their quest for a new late-onset Alzheimer's gene, the field was littered with unsuccessful candidates. Many were doomed to fail because they were isolated by a faulty technique. Typically, researchers would compare the genes of Alzheimer's patients to those of age-matched unaffected people without paying attention to the ethnic composition of the two samples. Yet ethnic groups vary notoriously in the frequency of certain genetic variants. "What researchers didn't realize is if you see an allele frequency difference, it was most likely because the ethnicity of the cases and controls was not the same," says Tanzi.
| Normally, the A2M protein protects against Alzheimer's by delivering A-beta into the neuron where it is degraded. However, to enter the neuron by the LRP receptor, the A2MA-beta complex must first bind a protease. Tanzi speculates that while the A2M-2 gene is capable of making normal protein, it might produce some fraction that is unable to bind protease. With entry into the neuron impeded, A-beta could accumulate in the extracellular spaces, eventually forming destructive Alzheimer's plaques. ApoE may hasten the disease process by competing with A2M-2 for LRP and A-beta. |
Using family data from the National Institute of Mental Health, he and his colleagues compared Alzheimer's patients with unaffected siblings. Scanning the entire genome for possible areas of difference, they hit upon a region on chromosome 12 that held the gene for A2M. The A2M protein was known to share the LRP receptor with ApoE and also with APP, a protein associated with early-onset Alzheimer's. A2M was also known to play an important role in the brain, regulating the activity of several proteins, including proteases, which degrade damaged or unneeded proteins.
Intrigued, the researchers began looking for polymorphic versions of the A2M gene in the general population. "We found this weird deletion in the database," says Tanzi, referring to the A2M-2 gene, which has five fewer bases than the standard version. To the researchers' surprise, 30 percent of the population carried the A2M-2 variant.
Meanwhile, researchers were uncovering more about the protein. Professor of neurology Dennis Selkoe (at HMS and BWH) and his colleagues found that A2M, when bound by a serine protease, was able to degrade A-beta in vitro. Other researchers were reporting that the A-betaprotease complex could bind LRP. "So all these biological scenarios just all fell out. It was an amazing convergence," says Tanzi.
Focusing on Families
The linchpin turned out to be a powerful new statistical technique developed by Nan Laird, the Henry Pickering Walcott professor of biostatistics at HSPH, with help from Blacker, an assistant professor of psychiatry at HMS and MGH and an assistant professor in the Department of Epidemiology at HSPH. Previously, to compare two siblings required also having data from parents--a rarity among late-onset Alzheimer's patients. Laird and Blacker invented a version of the method that eliminated this need--and, in fact, required only two family members, an affected and unaffected sibling. "That's what changed the world for us," says Tanzi.
He and his colleagues ran the family-based program, and other tests including an odds ratio. "By association and odds ratio, A2M-2 was at least as strong a risk factor as ApoE4 for Alzheimer's disease," says Tanzi. He and others believe that A2M-2 and ApoE4 may interact, the first deciding whether a person will develop Alzheimer's disease and the second when it occurs (see figure).
Much remains to be learned about the latest Alzheimer's gene before it can be used to predict risk for the disease. "We don't know even 5 percent of what we need to know before we begin thinking of using it for that purpose," says Tanzi. "But we do know something new and valid and very useful, which is a healthy functioning A2M is probably protective against age-related changes leading to Alzheimer's."
--Misia Landau
Developmental biologists have long wondered how Hedgehog proteins manage to broadcast long-distance signals. Now Norbert Perrimon, professor of genetics at HMS, and his colleagues have found a gene for a "hairy" associate that helps escort the signals from cell to cell.
Named tout-velu (French for "all hairy"), the new gene is among those responsible for patterning of the embryonic cuticle in Drosophila. Without it, the embryo "looks like a ball of hair," says Perrimon. Humans lacking the equivalent genes, EXT1 and EXT2, sprout bony growths near the joints of their legs and arms, a hereditary condition called exostoses.
"At the molecular level, the mechanisms between Drosophila and human proteins are highly conserved. Both homologues usually have the same biochemical activities, although the outcome of their functions can be different," says Perrimon.
In the July 2 Nature, Perrimon and his colleagues report that the tout-velu protein helps developmental signals sent by the Hedgehog family of proteins travel long distances in Drosophila embryos.
Hairy Moment in the Lab
The researchers began to figure out the gene's role last year after Yohanns Bellaiche, the paper's lead author and a former graduate student in Perrimon's lab, was first to clone tout-velu. Bellaiche then worked with Inge The, a postdoctoral fellow in Perrimon's lab, to uncover the role of the protein.
| Norbert Perrimon and Inge The found that Hedgehog proteins require assistance from the tout-velu protein to transmit long-distance developmental signals. |
The embryos' hairy appearance had tipped off the researchers that the gene might be expressing a molecule involved in Hedgehog signaling, which, in vertebrate development, controls the fate of cells and tissues as diverse as neurons and bone. Of the six proteins known to be involved in Hedgehog signaling in Drosophila, three have human matches that are either oncogenes or tumor suppressors in the skin and nervous system. Tout-velu turned out to be the seventh member of the Hedgehog signaling pathway.
A major question in Hedgehog signaling has been how the proteins communicate with faraway cells. Hedgehog proteins are tethered to a bulky cholesterol anchor in the cell membrane, which limits their ability to travel.
When they first looked at the development of Drosophila wing disks lacking the tout-velu gene, the researchers found that the Hedgehog system still managed to send out signals. However, those signals stopped at neighboring cells. This suggested that tout-velu does not alter the signal, just the way the signal spreads.
"Tout-velu helps relay messages, but is not absolutely necessary. It's not as if Hedgehog signaling is abolished, but only nearby cells pick it up," says The. "We now think there is an active mechanism to move it farther."
Sketching the Protein's Part
To demonstrate tout-velu's role in that active signaling mechanism, they grew Drosophila with mutations for tout-velu and the gene for Patched, a receptor protein that binds Hedgehog. They looked at two indicators for tout-velu, the Patched protein, and another protein called Cubitus interruptus. During normal development, Hedgehog can activate Patched from five cells away within the embryo and Cubitus interruptus from up to ten cells away.
"We took away the genes to show what they normally contribute to and took snapshots during development," says The.
The researchers found that with Patched missing, the Hedgehog signal still spread from cell to cell. The same held true for cells missing tout-velu, although the signal did not travel long distances. When both tout-velu and Patched were missing, the signal stopped at the first cells it encountered.
"Without Patched to hold Hedgehog and tout-velu to help it move, Hedgehog doesn't go very far," says The.
The next step, she says, is to find out tout-velu's exact function in signaling, whether it helps in sending, carrying, or receiving the cell-to-cell signal. So far, the researchers have found that tout-velu can be seen in a vesiclelike structure inside the cell, hinting that it might be involved in endocytosis.
The work demonstrates that the Hedgehog genes have several levels of regulation, says Perrimon. Not only is expression regulated, but diffusion and movement as well.
They also found that the regulation of the movement of Hedgehog has a human match. The tout-velu gene turned out be a counterpart for the human genes, with about 60 percent of the amino acid sequences matching EXT-1 and 25 percent matching EXT-2.
Earlier research had established that during human bone growth, a protein called Indian Hedgehog acts in a growth plate at the tip of the long bones of the legs and arms. During bone development, one of the roles of Indian Hedgehog is to regulate the role of cartilage cell differentiation.
As part of that regulation process, somehow the cells producing Indian Hedgehog communicate with another group of cells that produce a hormone-related protein. However, since the two groups of cells lie far away from each other, Indian Hedgehog needs help with long-distance signaling.
The lack of a protein similar to tout-velu might dampen or prevent that signaling, causing abnormal growth.
"There's a fine balance for proper development," says The. "Without the proper regulation of Hedgehog's signaling and diffusion, you have different cell fates in both humans and Drosophila."
--Cassie Ferguson
One of the severe complications of metastatic prostate cancer is spinal nerve root pain. This distressing sensation--often intense and unremitting--may be caused by a peptide released in high concentrations by prostate tumor cells, according to a new study by HMS researchers.
Endothelin-1 (ET-1) is a powerful constrictor of blood vessels that has been observed to produce signs of pain when administered intraperitoneally in animals, and intra-arterially in humans. To further examine its pain-producing properties, Gudarz Davar and his colleagues applied the peptide to the surface of sciatic nerves in rats. The animals exhibited marked unilateral hind paw flinching that lasted at least 60 minutes, the authors write in the September NeuroReport.
The behavioral effect was not due to muscle irritation. When Gudarz, an assistant professor of anaesthesia at HMS and Brigham and Women's, and his colleagues applied ET-1 to muscles surrounding the sciatic nerves, they observed no flinching, though the animals showed signs of generalized distress. To establish that ET-1 acts on pain receptors, morphine, which blocks certain pain receptors, was applied to the sciatic nerves prior to ET-1 application. The researchers saw no sign of hind paw flinching.
"This model could . . . prove useful for the preclinical evaluation of compounds that block the actions of ET-1 and that might treat cancer-associated pain in humans," write the authors.
In 1993, the National Cancer Institute withdrew its recommendation of mammography screening for women in their 40s. Though it has since reversed its decision, the utility of mammograms for women under 50 continues to be a controversial issue. A report appearing in the May-June issue of The Breast Journal by Daniel Kopans and his colleagues suggests that studies showing mammography is significantly more useful once a woman reaches 50 are based on improperly organized data.
Kopans, an associate professor of radiology at HMS and Massachusetts General Hospital, and his colleagues found that when women were grouped by year of birth, the rate of cancer detection by mammogram showed a steady increase in women ages 40 to 79. Some earlier studies that grouped women by larger age ranges--for example, comparing all women in their 40s with all women in their 50s--gave an erroneous impression of abrupt change in the effectiveness of mammography at age 50.
Some studies have used larger ranges, comparing women in their 30s and 40s with women in their 50s and 60s. Because breast cancer incidence increases with age, comparing results of such large combined age groups skews the results toward the extremes.
Kopans and his colleagues reviewed data from more than 72,000 mammogram screenings performed at MGH between October 1990 and October 1995. They calculated percentages of women recalled for an additional exam, those referred for a biopsy, biopsies that resulted in a detected cancer, and overall cancers.
When grouped by decades, the proportion of cancers detected by mammogram-initiated biopsy was 16.7 percent among women in their 40s and 28.9 percent among women aged 50 to 79. But year-by-year analysis showed cancer detection in 20 percent of biopsies among 49-year-old women and 20.5 percent of biopsies in 50-year-old women.
The authors conclude that the age of 50 has no biological significance in determining when regular mammographic screening should begin.
In vitro, thrombospondin-1 (TSP-1) regulates the attachment, migration, differentiation, and proliferation of a wide variety of cells, but the in vivo functions of this protein, which is found in extracellular spaces throughout the body, have been a mystery.
Several months ago, Jack Lawler, an associate professor of pathology at HMS and Beth Israel Deaconess, and his colleagues knocked the TSP-1 gene out of a strain of mice. Within four weeks of birth, the mice had developed severe lung problems, including epithelial abnormalities and chronic pneumonia. The abnormalities resembled those seen in mice lacking another protein, transforming growth factor-beta1 (TGF-beta1).
Knowing that TSP-1 binds, and possibly activates, TGF-beta1 in cell-free systems, Lawler and his colleagues gave the TSP-1 knockouts a daily dose of a peptide that activates TGF-beta1. The daily elixir corrected the mice's lung abnormalities, Lawler and his colleagues report in the June 26 Cell. "These studies show that TSP-1 is an important activator of TGF-beta in vivo," he says.
TGF-beta is known to suppress inflammation and tumor growth as well as play an important role in growth and development. Modulating TGF-beta is a priority for the body. "TSP-1 is the first activator of this important cytokine shown to function in natural, untreated, nondiseased tissues in vivo, though it is probably not the only activator," the authors write. Nor is TGF-beta activation the only function of TSP-1. The protein also appears to inhibit new blood vessel growth, or angiogenesis, as evidenced by the increased density of blood vessels in the skin and pancreas of the knockout mice.
Intriguingly, the mice exhibited lung abnormalities similar to those seen in certain human diseases, including asthma and cystic fibrosis. The discoveries that TSP-1 activates TGF-beta1 and that small peptides can modify its effects in vivo "suggest new routes that might be considered to interfere with the progression of such diseases," write the authors.
Women with normal cholesterol levels who have had a heart attack may benefit from taking the cholesterol lowering drug Pravastatin. A study by Brigham and Women's researchers found that the drug decreased risk of heart attack, stroke, and other adverse cardiovascular events by nearly one half in a group of 576 such women.
The study, which was published in the August 1 Cardiology, found that the benefits began in the first year of drug use, showing that the drug reduced the risk of stroke in these women by 56 percent. It also reduced the risk of adverse coronary events, including recurrent heart attack, death from coronary disease, and the need for revascularization procedures, including angioplasty and bypass surgery, by 46 percent. In fact, researchers found that for every 1,000 women treated, 228 cardiovascular events were avoided.
"This study represents a major advance for treating women for cardiovascular disease, which is by far the leading cause of death in women in the U.S. and worldwide," said principal investigator Frank Sacks, associate professor of medicine at HMS, BWH, and HSPH.
A class of drugs currently undergoing phase III clinical trials for certain types of human cancer appears to improve the condition of mice with a multiple sclerosislike disease, according to a study by Kai Wucherpfennig, an assistant professor of neurology at HMS and Dana-Farber, and colleagues from other institutions. The study, which appears in the July Annals of Neurology suggests the drugs, called matrix metalloproteinase inhibitors (MMPI), may have potential benefit for the treatment of MS.
In the study, MMPI treatment was given to mice with a disease called chronic-relapsing EAE, which has many similarities to MS, including recurring inflammatory destruction of myelin in the optic nerves, brain, and spinal cord. MMPI, when given to mice with chronic-relapsing EAE, significantly ameliorated the disease course and decreased the number of relapses. Analysis of spinal cord tissue from treated mice showed a striking reduction of scarring and a strong inhibition of myelin destruction.
In addition, Wucherpfennig and his colleagues found that MMPI decreased the expression of two proteins, tumor necrosis factor-alpha and FasLigand, which play a role in the autoimmune process damaging the central nervous system in MS. Surprisingly, it increased the expression of a third protein, interleukin-4, on glial cells in the brain.
More than 250,000 people in the U.S. are affected by MS. Clinical trials using MMPIs to treat the disease have already been initiated, according to the study's lead author Wolfgang Liedtke, a Rockefeller University researcher.
People with chronic fatigue syndrome (CFS) may lose their jobs as a direct result of their condition, according to a study by an HMS researcher.
Their symptoms, such as persistent fatigue, headaches, joint and muscle pain, fever, cognitive difficulty, and depression prevent a high proportion of CFS sufferers from working, the study indicates. The findings appear in the July/August issue of Psychosomatic Medicine. A 1997 four-city study by the Centers for Disease Control estimated that the prevalence of CFS ranges from 4.0 to 8.7 per 100,000.
"People's impairments may keep them from getting to work. And once they get there, their symptoms may compromise their ability to work," says Norma Ware, the study author and assistant professor of medical anthropology in the Department of Social Medicine. Getting to work in the morning can be a challenge because joint pains may prohibit those with CFS from grasping a steering wheel, or they might fall asleep en route. Once they reach the workplace, their symptoms may compromise their ability to think, listen, speak, write, and perform physical tasks.
| According to Ware, some CFS sufferers cannot perform everyday tasks while others can work around the condition. |
The study examines the "role constriction" caused by CFS in 66 New Englanders from ages 27 to 72, most of whom had been ill for more than five years. Of the 66 subjects, 50 had held jobs at the onset of their illness, but when Ware interviewed them, 25 had become unemployed. "Role constriction works to push chronically ill persons out of the work force and away from the social mainstream," she writes.
All 25 who had lost their jobs attributed the loss to CFS, which has no known cause, though past studies have pointed to immune deficiency, viral infection, and psychiatric linkages.
The 25 subjects who were still employed had devised ways to resist role constriction by hiding or working around their condition. "They find different strategies to compensate for their deficiencies, for example, a nurse might move into a desk job," says Ware.
Some of these working subjects strive to appear well by dressing up and wearing extra makeup. They might avoid office events that could reveal their impairments. Some conserve energy for their jobs by using free time to rest, time that otherwise would be dedicated to family and friends. Others, like the nurse, work less, doing easier tasks and eliminating business travel.
The best solution to balancing work and CFS, suggests Ware, is for businesses to create a flexible schedule that allows people to take breaks, arrange the order of their tasks, and work from home when necessary.
"A big problem is being able to say, 'I'll be functional from 9 to 5.' Instead, they need a more flexible schedule so they can work when they feel able," says Ware.
The study was funded by the National Institute of Allergy and Infectious Diseases.
--Cassie Ferguson
Social Medicine
Psychiatrists in Japan have defined a disorder in which people think they have AIDS despite negative HIV test results. Their description is based, in part, on Japanese views of their own culture, suggests a study by a Harvard Medical School researcher, but it may mask serious social problems associated with AIDS in that country.
In a year of observational work at a Japanese AIDS hotline, Elizabeth Miller, a resident in medicine and pediatrics at Massachusetts General Hospital, found that some callers were under the illusion that they had AIDS despite having tested negative several times. In the July/August issue of Psychosomatic Medicine, she reports how the phenomenon, called AIDS neurosis, was viewed by AIDS activists, psychiatrists, and health officials.
| Cultural influences may cause Japanese people who test negative for HIV to still think they are positive, says Elizabeth Miller. |
AIDS neurosis is characterized by depressive symptoms, phobic tendencies, and hypochondriacal thoughts.
"It's a category created by psychiatrists, but reflects a number of psychiatric illnesses," says Miller, who notes that only a handful of psychiatrists have actually treated cases of AIDS neurosis. "I was interested in why a diagnostic category gets created."
She encountered people with AIDS neurosis while answering phones at an AIDS hotline in 1992 and 1993. Miller describes the typical caller as a young to middle-aged Japanese male with no evidence of previous neurotic tendencies who had a single sexual encounter with a foreign prostitute.
"So many of the symptoms were similar," says Miller. "They'll feel sick or tired and think that is evidence that they have AIDS.
"There isn't any single cultural explanation, but aspects of Japanese society, including the hesitation to talk about sexual issues, a fear of foreigners, and an obsession with purity are used as explanations for this illness," she adds.
AIDS neurosis was first described by Japanese psychiatrists in 1987, following a series of AIDS panics nicknamed the "Three Big Commotions."
In her research, Miller found that people described AIDS neurosis as a distinctly Japanese "culture bound" syndrome, with greater severity and numbers than are found in other societies.
AIDS neurosis has four categories of severity, ranging from simple fears to delusional states and suicidal tendencies.
"The cultural explanation for AIDS neurosis should be critically examined," says Miller. "The emphasis on the illness as a culture specific disorder tends to hide other problems associated with AIDS in Japan, including discrimination, violence in the sex industry, and government corruption."
The study was funded by a National Science Foundation Graduate Fellowship and a Fellowship through the Department of Social Medicine at HMS.
--Cassie Ferguson
erbert Kressel, chief medical officer and head of the Department of Radiology, was named president of Beth Israel Deaconess Medical Center on July 23. Kressel will assume his new post later this year when outgoing president David Dolins officially steps down. Kressel is a radiologist who is known for patenting an externally movable probe used to project magnetic resonance images from inside the body. The selection of Kressel marks the first executive appointment made by James Reinertsen, the new chief executive of BID's parent company, CareGroup.
* Raul Ruiz, HMS '99, has been named a 1998 Fellow for the Program in Violence and Prevention for Minority Medical Students by the National Medical Fellowships Inc. Recognized for their potential as leaders in violence prevention and education, Ruiz and other minority medical students will train to understand and address violence from a public health perspective.
* Andrew Brotman, senior vice president for Physician Integration of CareGroup and head of the Department of Psychiatry at BID, was appointed interim president of Mount Auburn Hospital on July 1 by the hospital's board of trustees in concert with Mitchell Rabkin and James Reinertsen, who succeeded Rabkin as CEO of CareGroup in July.
* Richard Blumberg, associate professor of medicine, has been named chief of the Gastroenterology Division at Brigham and Women's Hospital. Blumberg has been acting chief of the division since January 1998. He directs research in mucosal immunology focusing on mucosal lymphocyte-epithelial cell interactions with a special interest in inflammatory bowel disease and mucosal immunoregulation.
* Chinweike Ukomadu, instructor in medicine, has been named the 1998 recipient of the BWH Minority Faculty Development Award. The honor includes a $150,000 grant distributed over several years. The award was designed to increase the likelihood that more minority and women physicians will choose to remain at BWH and advance through faculty training programs. The grant was made possible through the efforts of Partners board of trustees chair Jack Connors, vice chair Marshall Wolf, the BWH diversity committee, administration, and clinical departments.
* Lawrence Friedman, associate professor of medicine and director of the Gastrointestinal Clinic at MGH, has been named treasurer of the American Society for Gastrointestinal Endoscopy. The ASGE is a 7,000 member professional society of digestive disease physicians in the U.S. and 50 foreign countries working to advance knowledge of gastrointestinal disease through the use of endoscopy in clinical practice and research.
* Michele Gougeon, executive vice president and chief operating officer of McLean Hospital, has been named chief operating officer of Partners Psychiatry and Mental Health. While continuing her role at McLean, Gougeon will now devote one third of her time to Partners Psychiatry. In this role, she will manage current activities at Partners institutions and implement mental health service strategy through the community-based psychiatric network.
* Seven Harvard affiliates ranked among the top hospitals in the country, according to the July 27 U.S. News & World Report "America's Best Hospitals" issue. Massachusetts General Hospital and Brigham and Women's Hospital ranked third and eighth on the Honor Roll. Beth Israel Deaconess Medical Center ranked eighth in geriatrics; Children's Hospital was first in pediatrics; Dana-Farber Cancer Institute ranked fifth in cancer; McLean Hospital ranked third in psychiatry; and Spaulding Rehabilitation Hospital ranked 13th in rehabilitation.
* The American College of Cardiology gave a first place Young Investigators Award to Ulrich Laufs, research fellow in medicine, for his work in physiology; a second place Young Investigators Award to Umer Sayeed-Shah, former research fellow in surgery, for his work in molecular cardiology; and a Young Teacher Award to James Kirshenbaum, assistant professor of medicine.
* BWH President Jeffrey Otten was named chairman-elect of the board of trustees for the Massachusetts Hospital Association at the society's annual meeting in June.
* George Thibault, professor of medicine and chief medical officer at BWH, was elected president of the Harvard Medical School Alumni Association in June.
* Lisa Najavits, assistant professor of psychology in the Department of Psychiatry at McLean Hospital, received the Early Career Contribution to Research Award from the International Society for Psychotherapy Research at the annual conference in June.
* Santa Ono, associate professor of ophthalmology at the Schepens Eye Research Institute, received the 1998 Pharmacia International Award in Allergy Research from the Pharmacia Allergy Research Foundation on June 22. He will share a $50,000 award, given for his research group's studies on the molecular basis of allergic disease.
* Recipients of the first annual Henry K. Beecher Prize in Medical Ethics for the best essay in medical ethics were announced on June 3. Sonia Batra, '00, won $1,000 for "The Role of Health Care Within a Rawlsian Framework of Justice." Honorable mentions went to Warren Kinghorn, '01, for "Decompartmentalizing Ethics" and Wesley Ulm, '00, for "Confronting Our Souls in the Mirror: Human Cloning and Germline Manipulation of Complex Traits."
* Russell Nauta has been named chair of the Department of Surgery at Mount Auburn Hospital. He will also serve as vice chair of the Department of Surgery at BID. Formerly chief of the Division of General Surgery and professor of surgery at Georgetown University, Nauta completed his internship and residency in general surgery at Peter Bent Brigham/Brigham and Women's Hospital. He also served as chief resident in surgery and clinical fellow in surgical oncology at BWH. His clinical interests include abdominal and breast cancers, surgery of hernia, and acute surgical illness.
* Moritz Ziegler became surgeon in chief and chief of the Department of Surgery at Children's Hospital on July 1. He was surgeon in chief and director of the Division of Pediatric Surgery at Children's Hospital Medical Center in Cincinnati and professor of pediatrics and surgery at the University of Cincinnati College of Medicine. A pediatric surgeon who trained under former U.S. Surgeon General C. Everett Koop at The Children's Hospital of Philadelphia, Ziegler is interested in transplantation and oncologic surgery, as well as nutritional support for surgical patients.
* Paul Howard was honored at McLean Hospital's Symposium on Medical Ethics on June 15 for his 60-year tenure at McLean, the longest recorded service in the history of the hospital. Beginning as a resident in 1938, Howard held many important clinical positions over the years, such as chief of both Men's and Women's Service and acting clinical director. He continues his commitment to McLean even at the age of 93, serving as chair of the Institutional Review Board, a position he has held for 26 years. McLean president and psychiatrist in chief Bruce Cohen said, "Throughout many of these years it can be said, without exaggeration, that Paul was the heart of the clinical service, the focal point for education programs, and a key player in research."
* Marsha Moses, assistant professor of surgery at Children's Hospital, was named a Biomedical Research Fellow by the Mary Ingraham Bunting Institute of Radcliffe College for her work on "The Characterization of Two Novel Genes Associated with Breast Cancer Progression." Bunting Awards are designed to "support women of exceptional promise and demonstrated accomplishment who wish to pursue independent work in academic and professional fields."
* Lois Lampson, associate professor of neuroscience in the Department of Neurology, and Lynnette Phillips, research fellow in neurology, both at BWH, along with five Harvard undergraduates have received a $1 million grant to study how to manipulate the immune system to destroy cancer that has spread throughout the brain.
* The Longwood Symphony Orchestra will perform a free concert in the Hatch Shell on the Esplanade on Wednesday, August 26 at 7:30 p.m. All are invited to hear medical colleagues perform works of Haydn, Bartok, and St. Saens. Caroline Choi, HMS '00, will be featured on violin. If you have questions, please call Lisa Wong, president of The Longwood Symphony Orchestra at 332-7011 or e-mail her at: wong.lisam@mgh.harvard.edu.
* The Harvard Medical School White Pages can now be accessed on-line from any computer, including non-Harvard machines, at http://whitepages.med.harvard.edu. If you have requested that your e-mail address remain hidden, it will not be available through the public version of the White Pages.
* The Center for the Prevention of Cardiovascular Disease at Harvard School of Public Health and Hoechst-ARIAD Genomics Center have signed an agreement to collaborate on the identification of novel genes involved in atherosclerosis and to exclusively license drug discoveries from the collaboration. Under the direction of Arthur Lee, acting director of CPCD, associate professor of molecular biology, and attending cardiologist at BWH, scientists from the Genomics Center and the CPCD will attempt to identify the genes that cause heart disease. A grant of $1.4 million spread over three years will make the research possible.
* Spaulding Rehabilitation Hospital and Fleet Bank have created an assistive technology loan program designed for citizens with disabilities who are unable to afford the technology they need to maximize physical or cognitive functioning. Currently offered in 11 other states, this is the first program of its kind in Massachusetts that offers an interest rate below the prime rate (as designated by Fleet Bank). Loans for qualified applicants will cover devices denied by an insurance company--such as self feeding trays, hand-pedaled bicycles, page turners, and home modifications--because they are not considered medically necessary. All applicants must be referred by Spaulding to the One Federal Street, Boston, branch of Fleet Bank.
* McLean Hospital has signed an affiliation agreement with Fundacion Clinica Medica Sur in Mexico City to share clinical talents and cultural perspectives. This summer, McLean will provide six weeks of intensive clinical training to a young Medica Sur psychiatrist who specializes in eating disorders. This psychiatrist, along with other Medica Sur clinicians, will gain experience working in McLean's acute psychiatric setting. Lloyd Sederer, McLean's medical director, said, "We are hopeful that this new relationship will offer educational, patient referrer, and health services research opportunities for Medica Sur and McLean."
Joseph Barron, former lecturer on prosthetic dentistry at HSDM, died on July 5 at the age of 81.
For fifty years, Barron was a staff member at Beth Israel Hospital and was affiliated with the Dana-Farber Cancer Institute, Massachusetts Eye and Ear Infirmary, the New England Medical Center, and Brigham and Women's Hospital.
Barron graduated from Harvard College in 1938 and from HSDM with honors. He received a Distinguished Alumnus Award from the Dental School.
He was a founder and two-time president of the American Academy of Maxillo-Facial Prosthetics and taught at the Medical and Dental Schools and Boston University.
Barron was a major in the U.S. Army in Europe during WWII. From 1946 on, he researched maxillofacial prosthetics and their use to reconstruct facial damage by disease and accidents.
He leaves his wife, Beatrice (Homonoff); three sons, James H. of Newton, Fred of Los Angeles, and Thomas of Brookline; five grandchildren and one great-grandchild.
Gareth Green, HSPH professor emeritus of environmental health and associate dean for professional education until his July 1 retirement, died on July 18 at the age of 67.
Born in Brookline, Green graduated from Harvard College and Harvard Medical School. He joined the faculty at the University of Vermont after graduating and was a professor at Johns Hopkins University from 1976 to 1990.
Green joined HSPH in 1990 where he directed the Master of Public Health program and led the Office for Professional Education. In 1994 he chaired the National Institutes of Health Technology Assessment Panel study of Gulf War syndrome.
He leaves his wife, Joanna (Erskine); a daughter, Jennifer Joy Green Wesley of Rhode Island; two sons, Geoffrey of Vermont and Alan of Pennsylvania; his mother, Dorothy Bradford Summers Green of Lexington; three brothers and five sisters; and six grandchildren.
Donald Breslin, assistant clinical professor of medicine at Beth Israel Deaconess, died on July 3 at the age of 69.
Breslin was a specialist in vascular medicine and worked at the Lahey Clinic in Burlington for thirty years. He was born in Toronto and graduated from Yale College and McGill University's School of Medicine.
He was the author of many articles in professional journals and edited several texts, including "Renovascular Hypertension," published in 1982.
He leaves his wife, Evalynne (Wood); a daughter, Lisa Karen of Boston; and a son, Paul Andrew of Philadelphia.
The Harvard Mahoney Neuroscience Institute at HMS has named Roone Arledge, chairman of ABC News, the 1998 recipient of the David Mahoney Prize. The award was presented on July 26 in Lausanne, Switzerland.
Arledge was honored for his commitment to use TV news programs to educate the public about advances in neuroscience research. "During his years at the helm, ABC News has detailed the tremendous benefits of neuroscience in its evening news, its news magazines, and its news specials," says David Mahoney who, with his wife Hildegarde, helped found the institute in 1990.
The David Mahoney Prize was established in 1995 to recognize individuals who have contributed to public awareness of neuroscience and neurodegenerative diseases.
There was a time when Michelle Johnson thought she might be
about the only African American woman graduate student in the Harvard medical
area. Given the hermetic nature of lab work plus the decentralized nature
of the medical area's various institutions, the chances of meeting other
scientists with the same background were very low.
Then, when Harold Amos, the Maude and Lillian Presley professor emeritus of microbiology and molecular genetics at HMS, and Jocelyn Spragg, the faculty director of minority programs in the Division of Medical Sciences, held a reception for minority graduate students and postdoctoral fellows in March 1994, Johnson, a DMS graduate student in the Department of Pediatric Surgery at MGH, realized she was not alone. Kenneth Maynard (left), then a postdoctoral fellow and now an assistant professor in surgery at MGH, who had similar feelings, came to the same realization.
"Most of the graduate students and postdoctoral fellows thought they were the only [minority] people around," says Spragg. "The ones who came to that meeting were so energized they decided to form a group."
Following the reception, about five people met in a small room in the MEC basement. They decided to call their group the Minority Biomedical Scientists of Harvard (MBSH) and named Maynard the chairperson. They drafted a mission: to offer a place for minority graduate students and postdoctoral research fellows to meet and to build ties between those students and faculty.
The new group would play a different role than the Hinton-Wright Society and the Third World Caucus, minority student organizations whose members tend to focus on health care and clinical research rather than basic science.
The group would not be all science, though. It would also be social--an informal place to talk about everything from research to the problems faced by minorities.
For example, says Spragg, "One of the issues of being part of a minority group, whether real or self-imposed, is a sense of being a representative of your group rather than an individual."
Johnson, who was last year's chairperson, says, "It's a wonderful feeling to have a place where you're comfortable talking about anything from science to social issues."
In the intervening years since that first meeting, the membership has grown to over 100 people. Membership is open to all science graduate students and postdocs at Harvard University. The only requirement is having the desire to advance underrepresented minorities in science, says the current chairperson, Chad Womack, a research associate in the Department of Immunology and Infectious Diseases at the School of Public Health.
With funding and administrative support from DMS, the group helps its members develop professionally through workshops and networking. Last year, they held a series of how-to seminars on grant writing, preparing journal papers, teaching, and thesis survival. The group also hopes to create outreach programs to introduce and encourage elementary through high school students to explore biomedical sciences.
Once a month, about 20 members of the group hold a journal club. Johnson says the club turned out to be the perfect preparation for a thesis seminar.
"They didn't hold back at all. The people in the journal club grilled me," she says.
"By the time professors were asking the same questions during my thesis committee meeting, it was a piece of cake."
Once a year the group invites a guest lecturer, a distinguished minority scientist, to speak to the entire Harvard science community. This year John Watson, professor of biochemistry at the University of California at San Francisco, gave a lecture titled "Regulation of Mevalonic Acid Synthesis: In Search of the Sterol and Non-Sterol Regulatory Signal Molecules." Following the presentation, they also held a dinner in Watson's honor where they could talk more informally, asking more personal questions such as, "What is it like to be a tenured minority professor in academia?"
Current president Womack says he expects the group to continue growing, and hopes that more graduate students and postdocs in Cambridge will join.
"MBSH fills a need for a sense of community among minority scientists," he says.
--Cassie Ferguson
Dear Editor:
In her Forum article, Robin Lucas does a good job documenting the dilemmas and difficulties faced by all graduate students today as they begin to think about life outside the laboratory. However, I feel she is incorrect to refer to nonacademic career choices as "alternative" or "nontraditional." From the perspective of the millions of people gainfully employed outside the ivory tower, academia is considered to be the alternative and nontraditional career path. The scientific establishment harbors a common sentiment that those in careers outside of the academic laboratory must be those who were unable to find success in the lab, and either from lack of publications, grant money, or tenure were driven out of science. Clearly a newer and younger generation of graduate students and postdocs thinks differently, willfully choosing to explore options away from the benchtop. If we are to successfully challenge the perceptions of the establishment, we must first change our own perceptions. A career in business, industry, journalism, or law is anything but alternative.
Donny Wong
Graduate Student in the Division of Biological
Sciences
Department of Cancer Cell Biology
Division
of Toxicology
Harvard School of Public Health
Calendar Deadlines: Focus normally appears every other Friday, with some variation for holidays and summer. The calendar in each standard issue includes events in the two-week period beginning the Wednesday after the Friday issue date. The deadline for calendar submissions is Wednesday of the week before the issue date. This means that the deadline for submission is two to four weeks before the event. Sorry, we cannot accept any submissions that come in after the deadline. If you would like to receive submission information, leave your request and fax number at 432-1592. The next Focus deadline is July 8.
Key to Institutions:
BBRI-Boston Biomed. Rsrch. Inst.
BIDE-Beth Israel Deaconess/East
Campus
BIDW-Beth Israel Deaconess/West Campus
BWH-Brigham
& Women's Hosp.
BVA-Brockton Veterans Administration
CBR-Center for Blood Research
CAM-Cambridge Hosp.
CH-Children's Hosp.
DFCI-Dana-Farber Cancer Inst.
FDC-Forsyth Dental Ctr.
HMS-Harvard Medical School
HIM-Harvard Insts. of Medicine
HSDM-Harvard School
of Dental Medicine
HSPH-Harvard School of Public Health
HU-Harvard University
JBCC-Judge Baker Children's
Ctr.
JDC-Joslin Diabetes Ctr.
MTA-Mt. Auburn
Hosp.
MEEI-Mass. Eye & Ear Infirmary
MGH-Mass.
General Hosp.
MGHE-Mass. General Hosp. East
MH-McLean
Hosp.
MMHC-Mass. Mental Health Ctr.
SBI-Shriners
Burns Inst.
SERI-Schepens Eye Research Inst.
SRH-Spaulding
Rehab. Hosp.
WRVA-West Roxbury VA
Wednesday, August 19
Anesthesiology Grand Rounds Gary Strichartz, BWH Local Anesthetic Pharmacology 7:00 am, CWN L1 Lect. Hall, BWH
Anesthesiology Grand Rounds Lynne Uhl, BID Massive Transfusion 7:00-8:45 am, Sherman Aud., BIDE
Oral and Maxillofacial Surgery Grand Rounds Bart Blaeser, MGH Controversies in Treatment of Facial Fractures 7:00 -8:00 am, Ether Dome, Bulfinch Bldg., MGH
Anesthesiology Conference Robert Study, BWH Succinylcholine 8:00 am, CWN L1 Lect. Hall, BWH
Oral and Maxillofacial Surgery Grand Rounds Thomas Dodson, MGH Complications of Facial Fractures 6:00-7:00 pm, Ether Dome, Bulfinch Bldg., MGH
Thursday, August 20
Anesthesiology Grand Rounds Marc Semigran, MGH Cardiovascular Applications of Inhaled Nitric Oxide 8:00-9:00 am, Clinics 3, Upper Amp., MGH
Anesthesiology Lecture Series Lorraine Foley, BID Difficult Airway Medic Alert Registry: Where is it Going? 4:00-5:00 pm, Kirstein Bldg., Grossman Conf. Ctr., BIDE
Wednesday, August 26
Anesthesiology Grand Rounds Stephen Pratt, BID Safety Training 7:00-8:45 am, Sherman Aud., BIDE
Anesthesiology Grand Rounds Paul Allen, BWH Malignant Hyperthermia 7:00 am, CWN L1 Lect. Hall, BWH
Anesthesiology Grand Rounds Richard Teplick, BWH Rational Selection of Cardiovascular Drugs 8:00 am, CWN L1 Lect. Hall, BWH
Thursday, August 27
Anesthesiology Grand Rounds Sharyn Lenhart, Univ. of Mass. Med. School Gender Issues in Medicine 8:00-9:00 am, Clinics 3, Upper Amp., MGH
Anesthesiology Lecture Series Mark Poulin, BID Obstructive Sleep Apnea 4:00-5:00 pm, Kirstein Bldg., Grossman Conf. Ctr., BIDE
Wednesday, September 2
Anesthesiology Conference George Toupulos, BWH Case Potpourri 7:00 am, CWN L1 Lect. Hall, BWH
Anesthesiology Grand Rounds Hassan Ali, MGH New Muscle Relaxants: An Update 8:00 am, CWN L1 Lect. Hall, BWH
Oral and Maxillofacial Surgery Grand Rounds Members of the Dept. of Oral and Max. Surgery Abstract Presentations for the AAOMS Meeting 6:00-7:30 pm, Ether Dome, Bulfinch Bldg., MGH
Thursday, September 3
Anesthesiology Grand Rounds Henry Mankin, MGH My Heroes and Their Deeds: How Orthopedic Surgery Changed in the Last Century 8:00-9:00 am, Clinics 3, Upper Amp., MGH
Tuesday, September 8
Pathology & Combined Pathology Lecture Ehud Skutelsky, Tel Aviv Univ. School of Med. The Dr. Monroe Schlesinger Memorial Lecture: Histochemical Characterization of Polyanionic Constituents in Normal and Pathological Cells and Tissues 2:00-3:00 pm, Rabb Bldg., Rm. 242, Riesman Conf. Rm., BIDE
Focus
A Publication
of HMS Office of Public Affairs
Harvard Medical School, Office of Public Affairs
25 Shattuck Street, Room 001, Boston, MA 02115
Tel: 617/432-1589, Fax: 617/432-0089
E-mail: Focus@hms.harvard.edu
Editor
Robert Neal
Senior Science Writer
Misia Landau
Science Writer
Gabrielle Strobel
Production Manager
Suzanne Clifford
Assistant Editor
Tiffany Doyle
Copy Editor
Tom Reynolds
Photography:
Graham Ramsay (all photos except Maynard (from MGH Photo Lab) and Tanzi)
Illustration:
Advanced Medical Graphics