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an online version of the magazine Fall 2004
Medical Rounds
Charles Gaskell
Charles Gaskell, limber again and back on the golf course.


For AS, at Last, a Workable Treatment

Charles Gaskell was never a great golfer—he just loved playing the game. Then at 28 he was hit by the crippling spine disease ankylosing spondylitis (AS). As is typical, the condition struck Gaskell in early adulthood, inflaming the spine and peripheral joints so severely that eventually he couldn’t perform standard activities, let alone golf. Over time, it causes the spine to grow rigid, severely limiting the range of motion in the back and neck. Walking turns into strenuous exercise; hip replacements are routine.

Today Gaskell is 45. In 17 years, AS had made his job in the construction industry too taxing and sitting for more than 10 minutes impossible. No medication provided ongoing relief. Then last summer, he met Johns Hopkins internist John Flynn, who put him on a new treatment: infusions of a tumor necrosis factor (TNF) inhibitor. And suddenly the crippling inflammation that had spread to Gaskell’s back and neck began to disappear. He could walk longer distances, even take up sports again.

To create that kind of response, TNF inhibitors block cytokines that play a critical role in inflammation. Several years ago, the drugs were found useful in treating rheumatoid arthritis, but it wasn’t until 2003 that the FDA gave the go-ahead for their use in AS patients. “What we’ve found,” Flynn says, “is that for the first time, we can help these people live normal lives. Their stiffness lessens remarkably, their mobility returns.”

Today, Charles Gaskell takes an occasional pain pill for residual discomfort and sees Flynn every eight weeks for a TNF treatment. Other than that, he is virtually pain-free. He’s also hitting his drives 40 yards farther on the golf course.

Michael Levin-Epstein

An Operation No One Else Would Tackle

> Maison after surgery with his mom.
There are some cases that can make even a surgeon take a deep breath. Eighteen-month-old Maison Jackson was like that. When Anthony Tufaro, who specializes in head and neck surgery, first took a look at Maison last summer, the tumor on the toddler’s face had ballooned to the size of a softball and inched dangerously close to his left eye. Tufaro couldn’t tell if the growth was cancerous or if Maison’s eye and socket would need to be removed to excise the growth. “What I did know, the moment I saw this little boy,” he says, “was that he needed an operation.”

Maison had what’s called an ossifying fibroma—a rare tumor that’s usually benign but very aggressive. It had grown so large that it had displaced his upper teeth and jaw. He couldn’t eat, he couldn’t breathe, he was snoring. “He was so dysfunctional from the tumor,” Tufaro remembers, “we had to do something.”

According to Maison’s mother, Tammie, the tumor had appeared around the time of his first birthday and then enlarged week by week, distorting his mouth, inflating his left cheek and closing his left nostril. At first, physicians had said it was simply part of the port wine stain Maison had been born with. The reddish facial birthmark, with its overabundance of capillaries just beneath the skin’s surface, typically signals the presence of Sturge-Weber syndrome, a congenital neurological disorder than can include excessive blood vessel growth on the surface of the brain. What Tufaro discovered, however, was that the tumor was sitting amid a bed of dilated blood vessels caused by the Sturge-Weber syndrome. Not only would he have to remove the boy’s upper jaw to excise the massive growth, he would have to perform that surgery with extreme adeptness to avoid the risk that the child could bleed to death.

For help, Tufaro turned to interventional radiologist Sally Mitchell. She used magnetic resonance imaging to make the tangle of blood vessels visible during surgery and then limited the blood flow throughout the four-hour procedure by remaining with Tufaro and floating coils in the vessels. Even so, says Tufaro, “I had to go slowly. One of the blood vessels feeding that tumor was the size of my finger.”

In the end, Tufaro removed virtually all of the toddler’s 5-centimeter mass. And to everyone’s relief, it proved noncancerous. “Maison will probably need further reconstructive surgery down the line,” Tufaro says, “but he bounced back one two three. He’s growing. He’s thriving.”

Mary Ann Ayd


Consultation with John Burton

John Burton

One of the founding fathers of modern geriatrics and the former chief of Hopkins’ now #1-ranked Division of Geriatric Medicine talks about the challenges and joys of treating older people.

Typically, geriatric patients have been cared for by adult medicine specialists, but you’ve made the point that physicians who treat older people need special training. Why?

Older patients have complicated, multiple illnesses and often minimal physiological reserves. Caring for them puts a premium on diagnostic and therapeutic judgment. You just can’t look in a textbook to find the answers. In geriatrics, you need above all to be an effective communicator, to possess deep compassion and exercise outstanding judgment. All these skills take particular training and focus. Serving as a primary care physician for older patients was both the most challenging and the most rewarding experience I’ve ever had.

The program you shaped here has been called a model. What’s different about it?

You can’t have a hospital, a doctor’s office and a nursing home as the only options when it comes to caring for frail older people. Older people need clinics that specialize in problems like osteoporosis and incontinence. We’ve got them. We also have geriatric fellows, residents and attending geriatricians making house calls all over the community around Johns Hopkins Bayview to visit older people, who would have a hard time coming into the hospital. We offer adult day care that has specialized activities and nursing for this population. All of these programs dovetail as a continuous, almost seamless system. Very few medical centers have anything like this.

Have you found any hurdles that seem particularly inherent to this specialty?

For one thing, practicing geriatric medicine is challenging from a financial point of view. Since it’s predominantly primary care, the specialty can be very labor-intensive. Yet, Medicare limits your reimbursement. Also, geriatricians are more dependent on developing partnerships with the medical school and hospital leaders to create and manage innovative care programs.

Where does the field go from here?

We are about to publish our study of the National Home Hospital initiative, in which we’ve examined the merits of taking care of acutely ill geriatric patients in a home setting rather than in the hospital. I believe that will be one of the models for the future. Patients want it.

Alternative to Angiography?

Joao Lima
> Joao Lima gets the clearest views yet of the heart with the 32-slice CT machine.

Each year, almost 6 million people come into an ER with chest pain. To determine if the patient has a heart-related ailment, physicians order an array of tests including angiograms, in which dyes are injected in the arteries. But, at the end of the day, “we often still don’t know whether the patient has coronary artery disease,” says cardiologist Joao Lima.

Now, Lima and other cardiologists here are using a new 32-slice CT scanner to get high-resolution, three-dimensional images of coronary arteries. The scanner gives them transparent views through different layers of the vessels, allowing them not only to detect obstructions, but also to evaluate the actual pathology of the arterial wall. They’ll be able to judge the density of the plaque and infer whether it’s a plaque that may rupture. And that’s something that even angiography can’t do.

“To our knowledge, it’s the only 32-slice machine in the United States,” says Mike Weisfeldt, the cardiologist who chairs Hopkins’ Department of Medicine. “More slices mean better quality. The pictures are just great.”

So, does that mean the multislice CT can replace angiography, the gold standard for diagnosing coronary artery disease? To begin to answer that question, over the coming months, internal studies using the scanner will focus on evaluating patients admitted with chest pain. Those studies then will be compared with angiograms done on the same patients.

“Eventually, the explosion of technology in CT will replace angiography,” Hopkins cardiologist Edward Shapiro says. “The only question is, Will this generation be the one that does it?”


Surgery can be the Solution to Too Much Pain

Kathy Gabrielson
> Betty Berlin's trigeminal neuralgia "came out of nowhere."

On Mother’s Day last year, Betty Berlin received a horrendous present—excruciating facial pain. Home alone, Berlin, 81, says she “danced and screamed for about 15 minutes,” until the anguish subsided. But the attack turned out to be no passing symptom. Berlin was diagnosed with a condition called trigeminal neuralgia (TN)

Classic TN like Berlin’s is characterized by overwhelming, unpredictable pain to areas served by the trigeminal nerve—the upper, middle and lower face. Patients liken what they feel to being struck with a 220-volt electrical wire for seconds to minutes at a time, making their previous heart attacks or kidney stones a walk in the park.

For Berlin and most others who develop the condition, the antiseizure drugs typically prescribed are effective at first, but eventually not enough. “The peaks of pain get higher, and the valleys aren’t as low and don’t last as long,” says Carol James, longtime physician assistant with neurosurgeon Benjamin Carson.

And so, to give patients a chance for lasting pain relief and also address the source of the pain—an overstimulated, hyper-reactive trigeminal nerve—three Hopkins neurosurgeons, Richard Clatterbuck, Benjamin Carson and Richard North, now offer treatments. And though surgery may sound like an extreme choice for facial pain, the suffering caused by the condition is “far more deleterious than the risks of the procedure,” James says. The oldest patient we did, at 100, “fared well.”

In one noninvasive approach, the neurosurgeons use the Leskell gamma knife to send a forced blast of radiation to the trigeminal nerve, which lies just outside the brain stem, and damage it just enough to reduce its sensitivity. In other cases, they actually perform a craniotomy and shift the abrasive blood vessels away from the nerve. Another treatment involves gently inserting a needle through the cheek and delivering nerve-toxic glycerol to the nerve. And finally, a small, carefully directed radiofrequency-emitting probe sometimes can be inserted that generates damaging heat to the nerve. The surgeons help patients choose the procedure that’s best for their case.

With Clatterbuck’s guidance, Berlin opted for the gamma knife approach. Answering a question this summer about how his patient was faring, the neurosurgeon responded, “Last I saw her she was pain-free and I believe off all medicines.” And in a final piece of advice, Clatterbuck added, “Patients with this problem should be referred to us early, before their pain becomes agonizing.”

Marjorie Centofanti

A Tough Female Procedure Gets Easier

Any woman who’s had the condition known as pelvic organ prolapse can testify that it causes an array of upsetting symptoms: urinary leakage, constipation and difficulties with intercourse among them. For years, though, women who wanted to correct the disturbing bulge of the pelvis that occurs when the support system for the vagina gives way had one choice: undergo a major abdominal operation with its lengthy recovery and risk of complications. Now, happily, laparoscopic surgery has also come to this urological condition.

In the last two years, at Johns Hopkins Bayview, James Wright, director of female urology, and Li-Ming Su, director of pelvic laparoscopy, have performed almost two dozen “laparoscopic colpopexies.” It takes between three and five hours to reconstruct the pelvic floor using the minimally invasive procedure. Recovery takes weeks rather than months.

“We make only four small, keyhole incisions across the abdomen, there’s reduced blood loss, and patients return to work and resume normal activities much sooner,” Wright says.

What makes it possible to do the complex procedure without opening the abdomen is the high-powered telescopic lens attached to a camera that surgeons use to gain excellent magnification of the pelvic organs. With this kind of clear view, they are able to resupport the vagina and pelvic organs internally through a combination of sutures and a mesh sling. If the prolapse involves the uterus, a hysterectomy may be necessary to repair all the damage, but that procedure can be done at the same time. So can a bladder suspension and rectocele repair. “In every case we’ve done, we’ve had no significant complications and very successful outcomes,” says Wright.


Long-Acting Ragweed Vaccine Nothing to Sneeze At

Peter Creticos
> Peter Creticos, searching for the solution to allergies.

In trying to find a better solution for allergy sufferers, Peter Creticos, medical director of the Johns Hopkins Asthma & Allergy Center, appears to have demonstrated that a long-acting ragweed vaccine in which patients receive just six weekly shots works as well as, if not better than, the current allergy injection regimen in which shots go on for four or five years. The vaccine induces counter-regulatory T-cells to produce specific “suppressor chemicals” that block the action of the harmful Th2 cells—the “bad guys” responsible for the inflammatory reaction in ragweed-allergic sufferers.

In an NIH clinical trial, Creticos and his team of researchers administered the vaccine only once a week for six weeks. Those receiving the long-term anti-allergen showed far more rapid improvement than patients receiving the conventional treatment. “With just six injections, patients showed the kind of improvement it usually takes at least three years for us to see,” the researcher says. “Since the long-lasting injections aren’t nearly as much of a nuisance, patients will be more likely to take them.”

As a result of this preliminary success, Creticos, in conjunction with the developing company, Dynavax Technologies Inc., has initiated a multi-center U.S. clinical trial to study the safety and benefits of the new vaccine in a larger group of ragweed-allergic patients. If those trials prove successful, the vaccine would move on to pivotal Phase III trials, the precursor to FDA approval. And if all goes well, there’s no reason, in theory, why a similar vaccine wouldn’t work for allergies to cats, dust mites or cockroaches, according to Creticos.



It’s Going to Be a Bumpy Ride

Mark Tso
> Mark Tso and his lycium barbarum

The idea seems utterly simple: If there’s any truth to the therapeutic value claimed for dietary supplements and other alternative treatments that Americans spend billions on every year, the best way to find out is to put these potions under the same microscope—double-blind, placebo-controlled trials—that U.S. researchers have been using for years to establish a therapy’s worth. And despite initial skepticism in some quarters here (why diddle with snake oil when there are real therapies to be tested?), Hopkins four years ago launched its Center for Complementary and Alternative Medicine to examine such seemingly far-out cancer remedies as red wine and bamboo grass leaves. With a $7.8 million, five-year grant from the National Institutes of Health, the center now has more than a dozen faculty affiliated with it. Among its first outcomes were two studies published this year by pain research director Srinivasa Raja showing that inflammation-induced pain in rats does respond—fasten your seatbelt—to both soy and tart cherries.

Any behind-the-back snickers about such research, however, have proven to be the least of some CAM investigators’ headaches. Center Director Adrian Dobs was all set to test the Chinese herb combination PC-SPES on the immune systems of prostate cancer patients when the FDA put her trial on hold. The world’s only manufacturer had just recalled batches laced with prescription drugs, then promptly folded. (Dobs now is evaluating fish oils as a remedy for extreme weight loss in pancreatic cancer patients.)

Pharmacology expert Charles Flexner had better luck but faced a mountain of work after the FDA insisted the ginseng he planned to study as a possible treatment for cancer drug side effects had to come from a manufacturer making reliable stock and also willing to share production details. To win the government’s imprimatur, which came in June, Flexner had to enlist the help of the American Ginseng Board to sort through the hundreds of producers of the pungent root.

Still, if anyone understands the tribulations of CAM research, it’s Mark Tso. As a young boy in China, the Wilmer professor ate bowl after bowl of orange-red berries that his grandmother cooked. The berries—lycium barbarum—contain a pigment believed to preserve vision. Tso has grown them in his Maryland backyard and adds a spoonful to his cereal every morning. But when he approached the FDA about formally testing the berries, the regulators were adamant that he needed a placebo. Try raisins, they suggested, or dates. There is no look-alike, Tso replied. Negotiations dragged on for months, and by the time both parties settled on dried dates as the placebo, the study had lost its funding priority.

The good news is, the lycium barbarum pigment is now available in a capsule. And Tso, who’s revised his protocol, is gearing up for round two.

Karen Blum

My Cousin Michael, Five Years After His Trip to Hell

Michael Billing after his stem cell transplant
> Michael Billig after his stem cell transplant.
In the autumn of 1999, a cancer patient named Michael Billig appeared on the cover of this magazine. Billig, a 43-year-old associate professor of anthropology at Franklin & Marshall College in Lancaster, Pa., had chronic lymphocytic leukemia (CLL) and had just come through a two-and-a-half-month stem cell transplant to try to halt the life-threatening disease. In an article called “To Hell and Back with My Cousin Michael,” Bill Glovin, senior editor at Rutgers Magazine, documented Billig’s experience in Hopkins’ special inpatient/outpatient (IPOP) unit during the hard days after his transplant.

Last spring, five years later, Michael Billig paid one more annual visit to his Hopkins oncologist, Ian Flinn, and went through his final bone marrow biopsy to check that he was still cancer-free. Glovin sent us this update on what had changed in his cousin’s life since last we heard from him:

“Deciding to do the transplant was one of the hardest decisions I’ve ever faced,” says the now 48-year-old full professor. “I was in remission after months of chemotherapy. People said, ‘Why run the risk of dying from the transplant when you may stay in remission for 10 years? If and when you relapse, a magic pill for CLL may exist by then.’”

By September 1999, just two months after completing his transplant, Michael felt elated to return to teaching. “But I was naive in thinking that I’d rolled the dice on the transplant, come out a winner and would only have to worry about a once-a-year bone marrow biopsy now. My red blood cell counts fluctuated wildly, and I had less energy and a weak immune system. Early on, after being absolutely convinced that I’d relapsed, Dr. Flinn assured me I hadn’t. I’ve been hospitalized for pneumonia the last two winters and always seem to have some lingering illness. All I wish for is two weeks of good health.”

Michael also went through a second divorce. Just four months before he was diagnosed with leukemia, he’d married Jane Rossetti, an economics professor at F&M. The marriage didn’t make it, even though Rossetti had put her squeamishness aside to meet IPOP’s requirement that patients have full-time caregivers. She was so moved, in fact, by what she saw in the special bone-marrow-transplant unit that she enrolled in nursing school and went on to become a cardiothoracic surgical nurse.

Billing today
> Billig today, on campus at Franklin & Marshall College, where he's on the faculty.

The magazine article proved useful to Michael. It helped family and friends—and complete strangers who might be considering a transplant—to understand the emotional and medical aspects of the procedure. Now, he recommends the story to people on a CLL Internet listserv and to others he counsels for the Leukemia and Lymphoma Society’s First Connection Program. “I talk about the ups, the downs,” Michael says. “I tell them that for me, there are some lingering difficulties, but that the sum total of my experience has been mostly positive. I’ve been able to complete a book, buy a house and see my children go off to college. I work hard and energetically, have a sex life, and I’m back in good physical shape. I rolled the dice—and for the most part, I’ve won.”


Not Just a Bag of Chromosomes

Kathy Wilson
> Cell nucleus expert Kathy Wilson sees new connections.
Walk into the office of cell biologist Kathy Wilson and her hand shoots up instantly for a toy perched on the shelf above her computer. “It’s not perfect,” she says, opening her Hoberman sphere (known among the cognoscenti as a trapezoidal icosatetrahedron ), “but it’s the closest thing to the cell nucleus I’ve been able to find.”

Wilson should know. Her lab is one of a handful worldwide that’s investigating links between a collection of proteins inside the nucleus and a group of diseases that affect specific combinations of tissues, such as heart, skeletal muscle and bone.

“The old view,” says the associate professor in Hopkins’ Institute for Basic Biomedical Sciences, “is that the cell nucleus is simply a chromosome warehouse.”

But that notion—still hanging around in virtually every college textbook—couldn’t be further from the reality that Wilson and others are just now beginning to explain. “There’s a whole world of structures and processes inside the nucleus,” she says. “It’s really the cell’s mothership.”

Two different membranes form the nuclear wall. The inner membrane, facing the chromosomes, contains a unique set of proteins that attach to chromosomes, other proteins named lamins, or both. The two membranes periodically join together to form pores that control what enters and exits the nucleus. In the nucleus, lamins assemble into filament networks on which many other proteins depend. Wilson is seeking clues to lamin mutations that give rise to at least 10 diseases now termed laminopathies. Among them are Emery-Dreifuss muscular dystrophy and a syndrome called Hutchinson-Gilford progeria that causes kids to look like 90-year-olds by the time they’re teenagers and die from heart disease or stroke. “Small mutations in one type of lamin,” says Wilson, “are enough to produce all these diseases.”

Wilson was just entering the University of Washington to major in geophysics—her stepfather was a polar ice expert— when she learned her mother had been diagnosed with a terminal illness. The news changed everything. Wilson went from being a straight A-er to getting two “major, face-slapping C’s.” And a word she remembered from grade school—catalyst—joined forces with her newfound realization that there was such a thing as medical research. “It’s good to be motivated by real problems,” she says of her mother’s death and her decision to shift her focus to biology. “But you have to think creatively and dive in playfully and let discoveries lead you in their own directions.”

In 1985, Wilson earned the University of California at San Francisco’s first Ph.D. in genetics (“that was the era after Genentech was founded”) yet quickly became restless. “I wanted something different,” says the 48-year-old, “and the missing part of the picture was cell biology. Science then was ignoring the nucleus, which is really difficult to study—it’s filled with chromosomes, you have to literally rip it apart, and then you’ve destroyed most of what you want to look at.”

The sheer difficulty alone makes this speaker of Chinese and maker of Seminole quilts start to grin. Yet always her eye is on the truly important prize.

Not long after her 1989 arrival at Hopkins as an assistant professor, Wilson was asked to testify before a Congressional committee on why the NIH, then in a budget crunch, should fund basic science research. Whether her arguments influenced the subsequent decision to double that agency’s budget is anyone’s guess. Wilson does know how her outlook affected one man.

“He has a Ph.D. in engineering, and his son has Emery-Dreifuss muscular dystrophy,” she says. “He contacted us and said, ‘I know you’re studying the basic science, but what are you doing to cure it.’ He ended up being a key donor to our lab.”

Mary Ann Ayd

Know Your Niche

Erica Matunis
To really understand stem cells, you have to understand the niche they live in. Erika Matunis, a researcher in the Department of Cell Biology, has one of the best systems available for doing just that. Matunis uses the highly structured environment in fruit fly testes to examine how stem cells are regulated in vivo, where they develop into sperm. What’s unique about her system is that it’s easy to distinguish the stem cells from the sperm cells they produce.

Matunis discovered that in the fly testis, stem cells are clustered around a hub of cells that regulate them. When the stem cell divides, one of the daughter cells remains a stem cell while the other daughter cell is pushed away from the hub, losing access to the signal, and then differentiating into a sperm precursor.

What would happen if the signal were turned off and on, Matunis began wondering. To find out, she used fruit flies with a temperature-sensitive mutation in their signaling gene that allowed her to turn off the insects’ signaling ability simply by moving them to a higher temperature. As she’d expected, when she took that step, the number of stem cells declined, but recovered when the signal was restored. What happened next, though, shocked even her. When she removed the signal long enough for all of the stem cells to disappear and then turned it back on, the whole population of stem cells still recovered.

“We thought getting rid of all the cells was going to be our negative experiment,” Matunis says, “so it was a real surprise to still see all those stem cells coming back.” In follow-up experiments, she and graduate student Christa Brawley determined that this happened because even the sperm precursors were reverting to stem cells when the signal from the hub was restored.

“We always thought that when a cell starts to differentiate, it doesn’t go backwards,” Matunis says. “It just goes to show that the niche is in charge.”

Daphne Monie

Mouse House Protector

Julie Watson
> Julie Watson can't do enough for her patients.
Nowhere in Julie Watson’s CV will you find the words asset manager. But for the researchers whose intellectual capital is literally tied up in the four-footed patients under her care, what this assistant professor of comparative medicine does to protect their investments can mean the difference between declaring a “profit” or going belly up.

Watson is one of eight laboratory veterinarians on call around the clock who maintain the health of tens of thousands of animals (most of them genetically modified mice) that help provide important breakthroughs in understanding human disease. A single infection could wipe out years of a researcher’s work, not to mention animals that can cost as much as $25,000 each. To ensure that all mice housed in the new Broadway Research Building move in clean and stay that way, Watson has been combining the latest high-tech—robotic delivery of fresh bedding, cage-by-cage ventilation, computerized environment control—with her own high vigilance. Among her tactics are carefully placed sentinels, ordinary mice that act as coal mine canaries, which she examines regularly for signs of disease. And she’s virtually perfected a method of disinfecting newborns and transferring them to foster mothers to prevent the spread of infection from mom to pup.

So, is Watson predicting a bull market? “Healthy mice,” she says dryly, “increase research success.”

Diane Bovenkamp


 The Research Brass Ring
 Incurable, Not Untreatable
 Circling the Dome
 Medical Rounds
 Annals of Hopkins
 Learning Curve
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