News From Harvard Medical, Dental, & Public Health Schools--February 21, 1997
CONTENTS
Neurobiology
Much like a complex society, the human body relies on different communication systems, such as nerve transmission, hormones, and gap junctions.
Gap junctions? While the basic function of the former two systems are familiar even to the casual observer, gap junctions for decades have not revealed their raison d'être. Consequently, these ubiquitous channels linking neighboring cells have long remained obscure.
Not any longer. In one of the first glimpses at what gap junctions actually do--and how they may cause disease--researchers led by David Paul, associate professor of neurobiology at HMS, demonstrate that they are crucial to female fertility, at least in mice. In the February 6 Nature, the scientists report that mice engineered to lack the gene for one such channel never produce mature eggs because the nurturing cells in the ovarian follicles cannot communicate properly with the oocytes they shelter.
Filling in the Gaps
Co-author Daniel Goodenough, Takeda Professor of Cell Biology at HMS, first isolated gap junctions biochemically and named their protein subunits connexins. These proteins assemble into tiny tubes in the cell membrane, connect to a similar tube in a neighbor's membrane, and so create a pore through which small molecules can pass from cell to cell.
Gap junctions are everywhere, occurring in all multicellular organisms from sponges on up. In mammals, cells of almost every tissue make them at some point during development.
Researchers suspect that gap junctions are the Baby Bells of the body's communication systems, serving as local distributors of information coming in via long-distance carriers like hormones. In the ovaries, for example, hormones convey messages from the brain, but not all ovarian cells have the necessary receptors. Those that do may use gap junctions to forward the information to their neighbors, says Paul.
At the same time, gap junctions are thought to create private communication networks. If only certain cells are supposed to hear an incoming message, gap junctions linking only the targeted recipients would enable limited distribution, says first author Alexander Simon, a research fellow in Paul's lab.
But solid experimental proof for these scenarios is missing, in part because it is difficult to identify individual signals passing through the pores. Indeed, Paul says a 30-year-old hypothesis, namely that gap junctions somehow control the development and size of an organism, still awaits testing. "That is what we hoped the knockout mice would do--give us better answers about what the specific functions are," says Paul.
The mice obliged. Females unable to form certain types of gap junctions--those made from connexin37--turned out infertile because communication between the oocyte and its surrounding cells is jammed. During each normal menstrual cycle, an immature follicle, consisting of an oocyte embedded in a single layer of nurturing cells, begins to mature. Spurred by hormones, the oocyte grows larger, and the nurturing cells divide to form a multilayered coat. After ovulation, the remaining follicle turns into the corpus luteum, a gland that secretes progesterone to support a possible pregnancy.
In the knockout mice all this goes awry. The follicle never reaches its proper size because the nurturing cells do not divide enough. The egg never matures, either, and ultimately dies. In another instance of poor communication between nurturing cells and oocyte, the follicle behaves as if nothing is amiss, proceeding to become a corpus luteum even though the egg has not ovulated.
| Another Discrepancy: A question on a telephone survey found that for 30 percent of respondents, there were no health-care decisions they wanted to take part in. The corresponding mail survey found this portion to be a dramatically lower 5 percent. The problem was identified: The phone-screening technique put the "No Decisions" option first while the mail survey presented it last. Apparently, some people who would have chosen "No Decisions" if given this option first over the phone went ahead and checked a different option on the mail survey. The current solution is to rearrange the mail survey so "No Decisions" comes first. |
Paul suspects that a back-and-forth of different signals coordinates the sequential steps that eventually yield a mature egg, but the nature of these signals is still mysterious. Moreover, gap junctions are not the only means of communication at play in the follicle's development. Growth factors and hormones are also known to be involved, and sorting out the respective roles of each will require more research, Simon adds.
Trapped in the Wrap:
Connexins and Nervous System DiseaseOne of the few known examples of what connexins (see main story) do come from studies of genetic diseases in humans.
Charcot-Marie-Tooth (CMT) syndrome is a common, disabling disease of the peripheral nervous system. People with CMT suffer muscle wasting and gradually lose sensation in their extremities.
When David Paul, who had cloned the gene for connexin32, mapped its location to an area of the X chromosome, clinicians who were hunting for the gene causing an inherited, X-linked form of the disease took note. Later, Paul and others showed connexin32 was indeed the culprit.
Connexin32 appears to enable communication between axons, the neuron's extensions, and Schwann cells, which produce the insulating myelin . To speed up nerve transmission, Schwann cells wrap their own membrane so tightly around axons that there is no space left between the wraps, except for several tiny pockets. Somehow, however, the Schwann cell must exchange nutrients and signaling molecules between its cell body and the trapped cytoplasm surrounding the axon.
That is where connexins come in, Paul believes. By creating a conduit through the wraps, they probably help maintain the isolated cytoplasm. In patients with mutated connexin32, the myelin degenerates and the axon eventually dies, he says.
The finding may have implications for female infertility in humans, possibly helping to explain the pathophysiology of certain cases. In some women suffering from a syndrome called spontaneous premature ovarian failure, the follicles turn into corpora lutea before the oocyte is ready, similar to what happens in the knockout mice. "That rings a bell," says Paul, but he adds that more research is needed to explore this link, and systematic studies of the underlying causes of human infertility are difficult to carry out.
As often happens in science, Paul and Simon started this work expecting to study something completely different. The researchers had reason to believe that depriving mice of connexin37 would cause major defects in the cardiovascular system. It didn't. "Doing knockouts is like riding a wild horse," Paul says. "You never know where you'll get dumped off."
--Gabrielle Strobel
O happiness! Our being's end and aim!" exclaimed the great poet Alexander Pope--with telling irony. Stunted and deformed as a child by tuberculosis of the spine, and haunted in later life by violent headaches, Pope was living proof that humans may strive for happiness but do not always reach that end.
There is a group of people who lead extremely difficult lives and yet appear unusually cheerful. Children who suffer from a rare disease called Angelman syndrome struggle with a whole panoply of disabilities--mental retardation, severe speech impairment, seizures, abnormal gait.
"Yet they seem to really enjoy a lot of things, and they're just much more easily stimulated to laugh and to smile," says Joseph Wagstaff, assistant professor of pediatrics at Children's Hospital. Wagstaff and Marc Lalande, associate professor of pediatrics, have been searching for the genetic defect that causes Angelman, or "happy puppet," syndrome. In the January 15 Nature Genetics, the colleagues, together with Tatsuya Kishino, research fellow in pediatrics, report that the mutation occurs in a gene called E6-AP, on chromosome 15. It is one that few would have suspected.
Since Angelman syndrome primarily affects behaviors controlled by the nervous system, most researchers expected the mutation would occur in a gene coding for a protein expressed mostly in the brain. E6-AP, which was discovered in 1993 in the lab of Peter Howley, George Fabyan Professor of Comparative Pathology, codes for a protein found in every tissue.
The discovery is unexpected for another reason. In most genetic diseases, it does not matter which parent donates the mutant gene. But Angelman syndrome affects only those who inherit the mutation from their mother. The reason is that the paternal gene, through a mysterious process called genetic imprinting, is always "turned off" whether mutated or not, so defects cannot show up.
Genetic imprinting affects only a tiny fraction--about 1 percent--of genes. Nobody thought E6-AP belonged to this exclusive group. "Everyone said it wasn't imprinted. So we were surprised," says Lalande.
Cause and Defect
He and Wagstaff are currently trying to figure out how the E6-AP defect actually causes Angelman disease. Meanwhile, they are envisioning ways to prevent or alleviate the syndrome. For example, it may be possible to activate the father's gene to make up for the mutation in the mother's, Wagstaff says.
Angelman syndrome was first recognized over three decades ago. During a holiday in Italy in 1965, an English physician named Harry Angelman happened to see a painting called "Boy with a Puppet." The boy's laughing face and the marionette in his lap reminded Angelman of three children in his practice who exhibited an unusual set of traits: mental retardation, jerky movements and gait and, most curious, frequent smiling and laughter. Angelman immediately wrote a paper with the title "puppet children"--which elicited some attention in Europe but languished in most American medical libraries.
Then, in 1987, a group of HMS researchers, along with an Oregon team, discovered that many Angelman children had a little piece missing from chromosome 15. "So there was something concrete to deal with," Wagstaff says. What struck researchers is that the deletion appeared to be in the exact same region of chromosome 15 that is missing in another disease, Prader-Willi syndrome. Prader-Willi was known to be genetically imprinted--only deletions inherited from the father cause disease.
A year later, Joan Knoll, assistant professor of pathology, discovered that the missing chunk in Angelman patients was always on the maternal chromosome, leading some to think that the mutant gene for Angelman and Prader-Willi might be identical. But in 1992, Wagstaff and Lalande, by narrowing down the region of the deletions, showed that the genes causing Angelman's and Prader-Willi were not the same. Still, the actual location of the Angelman defect remained a mystery.
Cornering the Culprit Gene
About a year ago, Wagstaff came across a report of a patient with an unusually small deletion in chromosome 15. Comparing that patient to several others, he was able to link the common genetic defect to a tiny region on chromosome 15. Kishino, using a technique for identifying genes called exon trapping, was able to pinpoint the actual mutation to the E6-AP gene.
"We then went back and found mutations in some of the patients where we'd never been able to find them before--which proved that E6-AP was, essentially, the Angelman gene," Wagstaff says.
E6-AP appears to play a role in ubiquitin transfer, a process in which proteins are targeted for destruction inside the cell. While this process occurs in all tissues, E6-AP may perform its role differently in the brain. The researchers are planning to collaborate with Howley to look at the effects of the Angelman mutation on ubiquitin transfer. They are also hoping to find which brain proteins interact with the E6-AP protein. Although therapies designed to activate the paternal Angelman gene may be many years away, the researchers believe that patients and their families may benefit immediately from the discovery. "You can now tell parents it's a specific gene that's involved--so they won't blame what they ingested as teenagers or all the other things that come with it," says Lalande. "So it's a very important finding from a human perspective."
--Misia Landau
If a man says he has trouble getting the health care he needs, this might reflect poorly on his health-care plan. It might, that is, until it is known that the reason for his trouble is the distance he lives from the nearest bus stop.
This kind of background information--important for the individual but irrelevant to the health plan and to other health-care consumers--is data researchers want to screen out when evaluating health plans. A unique aspect of an ongoing federally funded study called CAHPS, the Consumer Assessments of Health Plans Study, is the emphasis it places on gathering and presenting solid data. The study focuses on the very foundation of assessment: constructing survey questions that accurately probe for a specific range of information and developing "report cards" that effectively present the resulting evaluation.
When completed, the health-plan reports not only will describe and rate health plans but guide consumers through the process of choosing which plan is best for them. The study seeks to create the first national standard for assessing health plans, based on data gathered from consumers across the country. The initial consumer survey is due to be released at the end of March for review by the government. The survey's projected time of release for public review is May.
Paul Cleary, professor of medical sociology in the HMS Departments of Health Care Policy and Social Medicine, is one of the leaders in the study, being carried out by three consortia headed by the Medical School, RAND, and Research Triangle Institute. "There is a lot of evaluation," Cleary says of the emphasis on developing questions and report formats, "more than anyone has ever done."
A technique being used is "cognitive testing," which involves interviewing survey respondents to find out their understanding of the survey questions and the rationale for their answers. These efforts have uncovered discrepancies like the one above in which access to care was interpreted by some to include personal issues like proximity to a bus stop or availability of a baby-sitter. This particular question had to be rephrased to ask people about their ability to get needed tests and treatment instead of needed health care, narrowing the scope of responses.
The rise of competition within the U.S. health-care system has made medical care a major issue for the nation. Several organizations have developed report cards, but most of these are based on surveys designed to obtain information for health-plan administrators; the data helps identify areas for quality improvement or marketing. Cleary says not only is this information not geared primarily toward consumers, but "there is a lack of standardization. It is hard to compare among plans."
The CAHPS initiative, sponsored by the federal Agency for Health Care Policy and Research, extends current survey practices by asking consumers about their experiences with their health care and health-care plans. CAHPS also explores related topics such as access to health care, use of plan services or lack of use, quality of care received, and outcomes of treatment. The study has gathered data from a variety of consumer segments.
Underlying these activities are the fundamental components of CAHPS: developing better questionnaires for consumers to evaluate their health-care plans; creating a variety of report formats that encourage consumers to use the information given; producing manuals enabling organizations to gather data themselves; and evaluating the efficacy of these systems.
The study is a five-year project that was begun in October 1995. During phase 1, which lasted about a year, researchers worked collaboratively to develop and test a consumer survey kit, user manual, and reports for use by consumers. Phase 2, now in its early stages, involves demonstration and evaluation and is due to be completed in September of the year 2000.
--Robert Neal
Eating too many refined carbohydrates such as white bread, mashed potatoes, and French fries while skimping on high-fiber foods such as whole-grain bread, beans, and peanut butter may increase a woman's risk of developing diabetes. A team of HSPH researchers found that women who consumed a diet with a high glycemic load--carbohydrates that increase blood glucose levels--and low intake of cereal fiber were two and a half times more likely to develop adult-onset diabetes than women with a low glycemic load and high cereal intake. Data came from the Nurses' Health Study, funded through Brigham and Women's Hospital. The study is published in the February 12 Journal of the American Medical Association.
Adult-onset, or Type II, diabetes affects 16 million Americans. It increases the risk of heart disease and stroke six-fold in women and is the leading cause of new adult cases of blindness, kidney failure, and nerve damage.
"Because these results are so strong and consistent with previous evidence about the protective benefits of a high fiber diet, we suggest that grains be consumed in a minimally refined form to reduce the risk of diabetes," comments co-author JoAnn Manson, HMS associate professor of medicine and HSPH associate professor of epidemiology. Other authors are Jorge Salmerón, research fellow in the Department of Nutrition at HSPH; Walter Willett, Fredrick Stare Professor of Epidemiology and Nutrition at HSPH and professor of medicine at HMS; Meir Stampfer, HSPH professor of epidemiology and nutrition and HMS associate professor of medicine; Graham Colditz, associate professor of epidemiology at HSPH; and Alvin Wing, senior programmer analyst in the department of epidemiology at HSPH.
Type 2 T helper cells (TH2) develop from naive T cells with the aid of interleukin-4, a chemical signal produced by other immune cells. Because natural killer-like T cells, a particular kind of lymphocyte, secrete large amounts of interleukin-4, they were thought to be important for the initiation of a helper T cell response. Natural killer-like (NK-like) T cells, for their part, are believed to rely on CD1 molecules for development.
A team of HSPH researchers created a strain of mice lacking the CD1 molecule. They report in the February 14 Science that while the mice lacked NK-like T cells, they could still mount an immune response. "Although dependent on CD1 for their development, IL-4-secreting NK-like T cells are not required for TH2 responses," write the HSPH authors. They are Stephen T. Smiley, research associate in cancer biology; Mark H. Kaplan, research associate in cancer biology; and Michael Grusby, assistant professor of molecular immunology and HMS assistant professor of medicine.
Varying when you sleep can significantly affect your mood, researchers at Brigham and Women's Hospital report in the February issue of the American Medical Association's Archives of General Psychiatry. Twenty-four healthy young subjects (16 men and eight women) were put on either a 30-hour sleep-wake schedule for approximately three weeks, or a 28-hour schedule for approximately five weeks. Both schedules led to a mismatch between the subjects' sleep-wake cycle and their circadian timing system, which is based on a cycle of about 24 hours.
"Mood improved, deteriorated, or remained stable when subjects remained awake at different times of their internal clock," says Diane Boivin, HMS research fellow in medicine, and lead author of the study. On average, the subjects' mood was lowest when the middle of the first 16 hours of wakefulness occurred around 6 a.m. Mood scores were highest when the middle of the 16-hour wakefulness episode occurred between 2 p.m. and 10 p.m.
Education
What do the Washington Redskins offensive line and Harvard Medical School have in common? Mark Adickes, a proud member of the HMS Class of 2000. Adickes came to HMS with a Super Bowl ring and a growing family. And in spite of his atypical background, he is fitting in nicely and having the time of his life.
Adickes was urged to participate in athletics by his father, an army chaplain and ex-college basketball player. He chose to play football in high school because he was "so much bigger than everybody else." Adickes did not have aspirations to play in the NFL until he was recruited by Baylor and played well against a first-round draft pick during one of his college games. In part because he was never passionate about his business major, in his last two years he focused on preparing to play football professionally. By the time he was a senior, Adickes was an all-American.
Upon graduating, he was drafted into the USFL--a now-defunct league--and played with the L.A. Express, whose quarterback was Steve Young (currently of the 49ers). In his first year playing professionally, he injured his knee for the second time (he had torn knee ligaments as a sophomore at Baylor). This time the injury "completely destroyed" his anterior cruciate and tore his posterior cruciate. By the end of the second year, however, he had recovered sufficiently to be drafted in the first round by the Kansas City Chiefs.
Years before, as a fledgling football player in fourth grade, he had attended the first game ever played at Arrow Head Stadium, home of the Chiefs. Upon "entering the stadium again as a member of the Kansas City Chiefs, the stadium seemed so much smaller," Adickes says.
He left the Chiefs and went to the Redskins when he was told by coach Marty Schottenheimer that at 290 pounds he was too small. He played three seasons with Washington and coach Joe Gibbs. In his second year, the team went to the Super Bowl and won it, an experience Adickes calls surreal. "The buildup was incredible, and, of course, the adrenaline was flowing. But I had been playing for 21 years. During that time, I had played in games that were more personally meaningful." Still, he admits, it was a thrill to be a part of that team where "the chemistry was extraordinary."
The last year he played he was 32 years old and, by that time, he had "one foot out the door." He had become interested in sports medicine through his personal experience with knee injuries. Rather than mourning the end of his football career, he was eager to move on, calling the shift a "perfect transition." Initially, Adickes thought he would simply get training in physical rehabilitation. Without his wife's encouragement, he would never have decided to go to medical school and would not have applied to Harvard. But she convinced him to shoot for the stars, so fresh from the NFL, he enrolled at George Mason University in northern Virginia and took two years of science courses to prepare for medical training.
With respect to where he is now, Adickes says, "I look at my athletic career as a gift because there was a lot of luck involved. I worked to get where I got as a football player, but at the same time, I take more pride in the work I did to get into medical school. Walking into the atrium in the MEC for the first time was the most thrilling experience of my life--more thrilling even than walking into the stadium to play in the Super Bowl."
--Molly Walker
Charlene Brown, Myrtha Cesar, and Victoria McGhee Smith have been selected by the W.K. Kellogg Foundation to receive its Community Based Training Fellowship for 1997. Each fellowship award is $10,000, plus a $1,000 travel stipend. Fifteen second- and third-year minority medical students were selected nationwide to receive fellowships.
The program offers supervised, elective rotations at community primary-care health centers in urban and rural areas across the country, and concentrates on serving those who lack access to health services because of geographic isolation, lack of providers, or financial barriers. The program consists of two, eight- to ten-week rotations at a designated Kellogg site, where each fellow will work with her academic adviser in a community-based primary-care facility, assisting in health-care delivery, community epidemiology, and health education.
This March will mark the one-year anniversary of the establishment of the Walter S. Kerr Professorship in Urology at Massachusetts General Hospital. Scott McDougal, chief of Urology at MGH, was the first to be appointed to the professorship. It is the first and only chair in the Department of Urology at MGH.
Kerr graduated from Harvard College and received his medical degree from the University of Pennsylvania Medical School. He received urologic training at MGH before becoming a member of the staff. He also joined the faculty at HMS, where he currently is clinical professor emeritus of surgery. Kerr has spent more than 50 years in the Harvard community and at MGH. He is also past president of the American Urological Association.
McDougal, in addition to his appointments at HMS and MGH, served as president of the American Board of Urology and was recently awarded the Russell & Mary Hugh Scott Award for Teaching and Education, presented by the American Foundation for Urologic Disease, Inc. McDougal's recent research interests include predictors of prostate cancer and mechanisms of ammonium transport.
Charlene Brown, Myrtha Cesar, and Victoria McGhee Smith (l to r) will get training at community primary-care health centers through Kellogg fellowships.
* The new senior vice president for science and technology at HMS Beth Israel Deaconess Mount Auburn Institute for Education and Research is Barry I. Eisenstein. Eisenstein comes to the institute from Indiana, where he was vice president of Infectious Disease and Clinical Development at Lilly Research Laboratories. Eisentein also sits on the advisory council of the Howard Hughes Medical Institute.
* George Thorn, professor emeritus of medicine at HMS has been awarded the 1997 Public Welfare Medal by the National Academy of Sciences. Thorn's 40-year commitment to public welfare includes leadership of the Howard Hughes Medical Institute, the country's largest nonprofit organization dedicated to supporting medical education and research. Thorn served as physician in chief of the Peter Bent Brigham (now Brigham and Women's) Hospital from 1942 to 1972.
* John Mannick, Moseley Distinguished Professor of Surgery at HMS and surgeon in chief emeritus at Brigham and Women's Hospital, was elected president of the Lifeline Foundation. The foundation is an educational and research arm of the Joint Council of the Society for Vascular Surgery and the North American Chapter of the International Society for Cardiovascular Surgery. Mannick's term began on January 1.
* At the 1996 meeting of the American Society of Tropical Medicine and Hygiene, Thomas H. Weller was awarded the Walter Reed Medal in recognition of his accomplishments in the field of tropical medicine. Weller, Richard Pearson Strong Professor Emeritus of Tropical Public Health, was head of the Department of Tropical Public Health from 1954 to 1981.
* The Wellman Laboratories of Photomedicine at Massachusetts General Hospital have received an $8 million grant from the U.S. Department of Defense (DoD) for continuing research into the medical use of lasers. The grant will fund a project that has already received $42 million from DoD over the past 12 years and involves finding medical applications for high-intensity, pulsed lasers, particularly free-electron lasers.
* James F. Gusella, the Bullard Professor of Neurogenetics at HMS, shared the 1997 King Faisal International Prize in Medicine. The prize, awarded for innovative research on degenerative diseases, recognizes Gusella's work on Huntington's disease. In 1983, Gusella succeeded in mapping the gene locus for the disease and, later, unraveled the structure of the gene responsible for Huntington's.
* Last month, Massachusetts General Hospital and McLean Hospital celebrated the opening of the new MGH Obsessive Compulsive Disorders Institute (OCD). The program, representing the first collaboration between the Psychiatry Departments of MGH and McLean, will be housed in McLean's Hill Center and will offer partial hospitalization and residential treatment.
* In January a memorandum of understanding was signed by South Cove Community Health Center (SCCHC) and Beth Israel Deaconess Medical Center outlining a partnership involving expanded community-based care and hospital services for the Greater Boston Asian Community. The agreement makes BID the principal hospital and network affiliate for SCCHC's health center for adult care (medicine, obstetrics, and gynecology). SCCHC is currently the primary community health center through which BID serves the Greater Boston Asian population.
* Lowell General Hospital recently joined the Dana-Farber/Partners CancerCare network (DFPCC), making available DFPCC's cancer care and research resources to a population outside Boston for the first time. Lowell General is in the process of constructing a $12 million, 20,000-square-foot cancer center, which will operate in collaboration with DFPCC. The center is due to open in the spring of 1998.
Americans and Russians may sit side-by-side in space, but they still do not always see eye-to-eye. When the Russians insisted that American astronauts who had just returned from the Mir space station remain lying down, many Americans were frankly puzzled.
"It caused quite a bit of head scratching for a little while," said Jim Pawelczyk, assistant professor of physiology at Penn State University, at a Castle Society event on January 17. As it turns out, the Russians were on to something. In experiments, Pawelczyk found that most newly returned astronauts could not maintain a standing position for even ten minutes.
Why they could not stand--the problem of orthostatic intolerance--is just one of the many questions Pawelczyk will be trying to answer as one of four payload specialists assigned to the Neurolab U.S. Space Shuttle mission. Neurolab, which is a 16-day mission scheduled for March 1998, is devoted to conducting experiments in a wide range of scientific fields, from neural plasticity and mammalian development to sleep and sensorimotor performance.
The mission represents the combined effort of 26 principal investigators, including Charles Czeisler, HMS associate professor of medicine, and Ken Kosik, associate professor of neurobiology. It has the financial support of five American agencies--NASA, NIH, NSF, and the Office of Naval Research (ONR)--as well as the space agencies of Canada, France, Germany, Japan, and Europe.
Only two payload specialists will actually fly on the shuttle. The other two specialists will serve in a ground capacity, said Pawelczyk. The decision about who will fly will be made over the next several weeks.
Meanwhile, Pawelczyk has been designing specific experiments to investigate the problem of orthostatic intolerance. He is also undergoing Space Shuttle training. "So in two weeks, I'll go off and go parasailing and jump in the ocean and learn how to deploy life rafts," he said.
--Misia Landau
On Becoming a Doctor
It was Jennifer's eighth birthday. She had been hoping to get home before the day arrived and was very unhappy to be celebrating in the hospital. "So, everyone remember, we have to sing for her on walk rounds today. But we've really got to get her home for her party on Saturday. Even if we just let her go home for the afternoon, we have to do everything we can to make it happen," our senior resident told us at work rounds.
Jennifer had end-stage AIDS. Her mother had died several years ago, and she was being raised by her aunt. We found her that morning in the playroom. She was standing in the middle of the room holding onto her IV pole, contemplating the arts and crafts project set up on the far table. A Hispanic little girl, she had shoulder-length, unbrushed, brown hair, puffy cheeks, and glowing brown eyes. She was wearing red-and-white striped leggings, and her belly bulged slightly beneath the blue hospital johnny top. She broke into a shy smile as we sang.
"Happy birthday, Jennifer!" Her intern handed her a present with a blue bow. Jennifer ripped off the paper and found a white box inside. She probed further in the box and finally pulled out a golden heart charm. "Will that fit on your necklace, do you think?" the senior asked her. Jennifer nodded and started to finger a gold chain around her neck.
During my month on the school-age children's service, there was always at least one HIV-positive patient and often two or three. All of the patients that I saw had acquired HIV congenitally. There was a wide range of disease; some of the children were sick and dying while others were only mildly affected as yet. But with the new protease inhibitors, there was a refreshing sense of hope for the healthiest of these children.
Annie also had AIDS, but she didn't know it. Or at least, no one had told her. Although she had been healthy for much of her life, her list of medications had rapidly expanded as her CD4 count plummeted. This time, she was in for pancreatitis. Her primary physician had been trying for years to get her mother to tell her the diagnosis.
Annie was a quiet, thin child. She had pale brown skin and deep black eyes. Her hair was always pulled neatly into two fluffy pigtails. She had a slight overbite and crooked white teeth, and her chronically inflamed parotid salivary glands gave her face the appearance of a chubby child. She was on infection precautions and unable to leave her room during this admission. A Clostridium difficile infection in her bowel gave her bloody diarrhea that terrified her and made her an infection risk to the other children.
"This is horrible. I can't take care of this child who doesn't know her diagnosis!" Her intern was appalled. "How could her mother not tell her? What am I going to do if she asks me what is wrong with her?"
"That's a good question. What are you going to say if she asks?" the senior resident returned.
"Well, I guess I would just tell her that one of her medications made her tummy sick, and we are going to help her get better," the intern said.
But during her entire week in the hospital, Annie never asked.
One night, the nurse came in to tell us that Annie had just had a large, bloody bowel movement and was terrified. She wanted one of the doctors to come in and tell her she was OK. We found Annie with her mother. She was trying to squeeze her long, ten-year-old body into the small sanctuary of her mother's lap. Her mother looked at us with anxious eyes. Her taught skin had been sculpted into pronounced ridges and valleys by worry. We reassured Annie and then left the room. I never saw her mother again.
I was frustrated with Annie's mother for handling the situation badly. I understood her mother's fear of the stigma associated with AIDS and her desire to protect Annie from it. Yet how could she rob her child of an explanation? I knew that we as acute-care givers did not have sufficient depth in our relationship either with Annie or with her mother to address this issue. We could only watch and hope that her mother eventually would make the decision to release Annie from the confines of the dark secret she was keeping.
--Ellen Rothman, HMS '98
All patient names in this column are pseudonyms.
To the Editor:
I want to make everyone at HMS aware of the controversy over the annual Norman E. Zinberg Memorial Award to be given to the U.S. drug czar, Gen. Barry McCaffrey, at the March 7 continuing education course offered by the Department of Psychiatry at Cambridge Hospital and the Division on Addictions. This controversy has led Dr. Lester Grinspoon, an eminent drug researcher, to resign from the faculty of the Zinberg Center for Addiction Studies. Those of us who support Dr. Grinspoon's position respect Gen. McCaffrey's right to speak and be heard at Harvard, or to receive an award from a military academy. But McCaffrey is undeserving of an award from a medical institution--an award whose previous recipients had made significant contributions to knowledge about the addictions.
A career military man, Gen. McCaffrey has no record of achievement as a researcher or clinician. (Nor does his corecipient, former Senator George McGovern.) He will not engage in open scholarly debate with people of differing views. He advocates cracking down on physicians who recommend the medicinal use of marijuana--a policy New England Journal of Medicine editor Jerome Kassirer calls "misguided, heavy-handed, and inhumane." While asking the Institute of Medicine to study the therapeutic efficacy of marijuana, McCaffrey ignores the institute's finding that needle-exchange programs for drug users save lives and slow the spread of AIDS.
Finally, it dishonors the memory of Norman Zinberg to give an award in his name to a knee-jerk antidrug enforcer. Dr. Zinberg argued eloquently for flexible, pragmatic drug policies based on scientific knowledge, not the cultural prejudices that McCaffrey perpetuates. If the conference organizers really value controversy and debate, they should invite a speaker qualified to reassert Dr. Zinberg's viewpoint in Gen. McCaffrey's presence.
Archie Brodsky
Research Associate,
Program in Psychiatry and the Law,
Dept. of Psychiatry, Massachusetts Mental Health Center
Editor
Robert Neal
Senior Science Writer
Misia Landau
Science Writer
Gabrielle Strobel
Production Manager
Suzanne Clifford
Assistant Editor
Molly Walker
Harvard Medical School
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