With thousands of asbestos workers demanding compensation
for lung disease,
a radiology researcher here finds that most cases lack merit.
Sometime in the mid-’90s, Joe Gitlin decided
enough was enough. For some 25 years, the radiology
researcher had watched uneasily as attorneys for asbestos
workers sought compensation for what they said was
the occupational lung disease, asbestosis. By then,
the cases—the longest-running mass tort litigation
in the United States—had cost some $70 billion.
Gitlin, who’s spent much of his professional
life trying to bring consistency to the reading of
images used to identify pneumoconioses—the class
of lung diseases caused by inhaling asbestos dust or
coal—suspected that many of these people didn’t
actually have asbestosis.
What stirred Gitlin was that the medical evidence
was often being glossed over in the legal tangles.
Even small quantities of asbestos can prompt the diaphragm
or body wall to make flat, fibrous plaques. But Hopkins’ studies
had shown that plaques don’t automatically signal
asbestosis and merit compensation, as some lawyers
and radiologists were claiming.
Around that time, Gitlin received a fateful phone
call from a group of attorneys. They wanted to know
if the researcher, with his reputation for measuring
image-reading accuracy and straight shooting, could
tell whether chest X-rays previously called positive
would hold up to scientific scrutiny.
“These lawyers were fed up with the status quo,” Gitlin
says. “They were genuinely interested in facts,
not merely defending corporations to save money.”
Gitlin was ready to go: He would put the cases to
the ultimate test—a rigorous review by reputable
radiologists with nothing to gain except truth itself.
That Joe Gitlin should be involved in dust policy
seems fitting. Growing up in the coal mining town of
Scranton, Pa., the epidemiologist says almost every
family he knew had deaths or sickness from inhaled
coal dust. “In ours, it was my uncle.” After
serving in World War II, Gitlin joined the U.S. Public
Health Service and earned a doctorate in public health
at Hopkins. “Otherwise,” he says, “I’d
have been digging coal.”
Today, Gitlin, who turned 80 this summer, has spent
almost four decades refining methods for interpreting
X-rays in clinical radiology. Many of those have related
to chest examinations that have served as a basis for
lawsuits, Since the late 1960s, federal and state governments
have required companies to screen workers for chronic
chest disease due to occupational exposure.
The system the government uses to identify these chest
ailments was actually devised at Hopkins in the 1970s
by Radiology’s first chair, Russell Morgan: Radiologists
who pass a nationally recognized course in dust-reading
become A readers. They then often move suspect images
on to B readers, who are skilled in detecting the pneumoconioses.
Gitlin and two of his Hopkins colleagues, Bob Gayler
and Paul Wheeler, helped Morgan develop the system.
Gayler and Wheeler maintain their qualifications as
But diagnosing asbestos-related lung ailments is no
clear-cut process. To demonstrate that point, Wheeler
displays the X-ray of a woman in her 80s who spent
years making asbestos mattresses for ships’ boilers.
Her plaque shows up as a shadow. But in her case, it
is all benign.
Still, plaques do signal asbestos exposure, and for
legal cases brought to Hopkins, the radiologists go
way beyond government criteria in making their diagnosis.
Instead of using only the required single posterior-anterior
chest X-ray, they take three or four X-rays at angles
and do CT scanning if they feel it’s necessary. “On
routine films, ribs and soft tissues overlie the lungs,
so they’re never crystal-clear,” Wheeler
says. “But high-res CT cuts right through that.”
To launch the “confirmatory” study requested
by the lawyers, Gitlin asked six of the country’s
best radiologists to go over 90 films of claimants
who had previously been diagnosed positive for asbestosis.
When it appeared clear that most of these asbestos
workers had been diagnosed incorrectly. Gitlin then
expanded his study to 492 cases. In August 2004, in
a paper published by Academic Radiology, the blue-ribbon
panel reported that compared to the 96 percent of images
called positive the first time, only 4.5 percent of
them actually read that way.
Last year, that study helped sway a federal judge
to hand down a decision against five B readers who
had churned out positive X-ray findings. The Gitlin
report, the judge made clear, made her more comfortable
with her decision. Since then, reporters in The Wall
Street Journal and The New York Times have used the
report to demonstrate corruption in the asbestos awards.
Next, Gitlin would like to study several thousand
X-rays in cases after awards were made—“to
tell us, really, how many are ill with something else.
A lot of those people are sick,” he says, “but
not with asbestosis, despite what they’re told,
and they need appropriate care.”
Kidney Swapping to Make a Match
It’s no secret that the number of people living with renal failure far
outstrips the supply of cadaver donor kidneys. Some 66,000 patients are on
the transplant waiting list, and more than 5,000 of them will die this year
for want of a suitable organ.
What especially bugs the Hospital’s transplantation
chief, Robert Montgomery, about these figures is that
in the last two decades, the number of people willing
to be live donors has tripled. Yet more than a third
of the time, their blood or tissue type doesn’t
match the person they want to give their kidney to.
Now, after five years of working with a program he
established here to deal specifically with this “mismatch” problem—the
first of its kind in the nation—Montgomery is
convinced he knows the best way to defang the incompatibility
issue. He has thrown his weight behind a method called
kidney Paired Donation that enables incompatible donor-recipient
pairs to find their matches among other mismatched
pairs like themselves. Of the 80 or so KPD transplants
performed in the United States, since the program began,
more than a third have been done here—including
the world’s first triple exchange (in which three
people simultaneously receive a kidney from another
patient’s living donor).
With Hopkins’ concentration on the mismatch
issue, it has now become the nation’s largest
referral center for incompatible kidney donors and
recipients. Furthermore, by analyzing their outcomes
data, Montgomery and the transplant team have shown
that KPD has the same survival and success rates as
compatible living donor kidney transplants. The next
step, Montgomery says, is creating a national program
that deals with the mismatch problem.
Andy Feinberg, Chief Explainer
Befuddling epigenetics has gone mainstream.
Not long ago, when Andy Feinberg would tell doctors
about a revolution he saw coming in cancer treatment,
he could barely get them to listen. Feinberg, a pioneer
in the field of epigenetics—information inherited
during cell division that doesn’t involve DNA
(even though it’s associated with it)—was
convinced that screening for certain epigenetic traits
would make it possible to identify patients at risk
for, say, colon cancer. Eventually, he suggested, drugs
might be able to ward off the cancer.
These days, Feinberg, who received an M.D. and an
M.P.H. from Hopkins and has been a professor here since
1994, heads a new division of the Department of Medicine
devoted entirely to epigenetics. And when he gave a
keynote address this year at the meeting of the American
Society of Clinical Oncology, he found himself speaking
to a standing-room-only ballroom and receiving a rock
“Oncologists were coming up to me saying, This
is what we’ve been waiting for,” he recalls
Epigenetics, however, is no straightforward discipline.
Even physicians with years of training can feel befuddled
by it. Put simply, it’s the information passed
on when a cell divides that isn’t written into
the DNA sequence itself—what reminds a gut cell
to divide into two gut cells, or a liver cell to spawn
a second liver cell. Scientists now know that several
factors can spur changes in this progression, and the
results can be disastrous. Methylation—the addition
of one carbon and three hydrogen atoms to a critical
section of DNA—for instance, can silence vital
genes. Modifications of proteins called histones—vital
in forming the structure of chromosomes—also
can close off (or open) certain genes.
“We really know a lot about DNA methylation
now,” Feinberg says. “We’re starting
also to learn a lot now about the histones and how
they are modified and how they control gene expression.
What we don’t know a lot about is how the marks
are recognized and preserved when the cell divides.”
One thing is clear: the potential impact of epigenetics
reaches far beyond cancer. The field could explain
the roots of ailments as disparate as bipolar disorder
and Alzheimer’s and play a major role in stem
cell research. For all those reasons, Hopkins Medicine
is getting behind it in a big way.
This past spring, the School of Medicine created an
Epigenetics Center at the Institute for Basic Biomedical
Sciences (IBBS), to be headed by Feinberg and Cynthia
Wolberger, a professor of biophysical chemistry and
an expert in the mechanisms that underlie epigenetic
Slated to be housed in the Rangos Building—due
for completion in 2008—the center will serve
as home for scientists from all over the University
as well as new recruits. Placing it with the basic
sciences confirms its importance at the most fundamental
areas of medicine, says molecular biologist Steve Desiderio,
director of the IBBS. “A cell in the retina of
the eye and a cell in the lining of the gut both have
the same genomic DNA sequence, but a rod cell and a
gut epithelial cell behave very differently. To understand
what makes a cell a cell, what makes us, us, it’s
essential to understand epigenetics.”
Such details may now be everyday fodder for Feinberg,
but he doesn’t forget his early days in the field.
The director of one of the organizations funding his
research, he says, even called epigenetics a dead end
and threatened to pull his money. Feinberg, who kept
plugging away, marvels at what’s happened since
then. “Epigenetics,” he says “has
Hunting and Gathering Sperm
Karen Boyle might be one of only a handful of women
nationwide who specialize in sperm harvesting. But
the men she treats are straightforward about what they
want—help in conceiving a child. Studies show
that 30 percent of the time when couples can’t
conceive, the sole problem is male infertility. Boyle,
a urologist who specializes in reproductive medicine,
often uses surgery to get around that.
When a man doesn’t ejaculate sperm, she explains,
the problem usually is either obstructive or productive.
But, even total absence of sperm in the ejaculate doesn’t
automatically mean that the swimmers don’t exist.
And if they do, she can choose from several extraction
In patients with a known obstruction, one option is
micro-epididymal sperm aspiration. This open-surgical
procedure requires putting the patient under general
anesthesia and using the operating microscope to search
for dilated portions of the epididymis—the coiled
tubule that stores sperm and carries it to the vas
deferens. The postoperative discomfort of this procedure
is slightly greater, Boyle says, but the sperm harvest
is usually better because she can see the dilated areas.
The extracted sperm are then used in a planned in-vitro
For men who prefer less-invasive surgery, Boyle can
potentially offer sperm aspiration—either
percutaneous epididymal or testicular. With these approaches,
she inserts a needle to retrieve the sperm, using only
a local anesthetic. But since she can’t directly
view the dilated areas, the sperm yield is generally
Finally, if the problem has to do with sperm production,
Boyle can excise a small piece of testicle to analyze
the seminiferous tubules where the sperm are produced.
She’s also one of a handful of specialists trained
to use a microdissection technique to locate the area
of the testicle most likely to have sperm. Microdissection
testicular sperm extraction, Boyle notes, has given
new hope to men with the chromosomal abnormality Klinefelter’s
Our sperm-retrieving approaches range from simple
to complex, Boyle acknowledges. But they sometimes
allow infertile men to conceive
Mary Ann Ayd
Big Hope for Marfan Patients
Dietz demonstrates that a common drug could prevent
a lethal complication.
|>"It was truly a jaw-dropping moment," Hal Dietz says.
Hal Dietz has spent his whole career figuring out
Marfan syndrome. And now, at 48, it looks like the
pediatric cardiologist may have come up with a way
to halt the disorder’s most lethal complication—a
potentially fatal rupture of the aorta. Last spring,
in one of the most exciting research breakthroughs
in a while, Dietz and his colleagues demonstrated in
mice that a common blood pressure medicine, losartan,
could prevent the deadly problem.
For the 30,000-plus Americans with the inherited disorder,
the news sent out ripples of elation. Caused by a defect
in the connective tissue protein fibrillin-1—which
gives organs their structure and strength—Marfan
wreaks havoc on the body’s blood vessels. Its
victims—characterized by their unusually long
legs, arms and fingers—develop dislocated lenses
in their eyes, damaged lungs and—most frighteningly—an
increasingly enlarging aorta. Without major surgery
to replace the aorta, it often ruptures.
To test their theory that the blood pressure drug
might halt this process, Dietz, a Howard Hughes investigator,
and his colleagues engineered a group of mice with
Marfan. When the mice were 2 months old and their aortas
had already begun to change, the researchers began
adding losartan to the drinking water for 15 of them.
Fifteen more mice were fed placebos and a final 15
received a beta blocker currently being used by physicians
to treat patients with the aortic abnormality.
When the Dietz group checked the mice after six months,
they found that those in the losartan group appeared
indistinguishable from the normal mice. Their aortas
no longer showed any damage. Meanwhile, the aortic
damage in the mice that had received placebos or beta
blockers had grown worse.
“It was truly a jaw-dropping moment—beyond
anything I could have anticipated or hoped,” Dietz
told Science magazine. So clear-cut, in fact, were
the study’s results that the National Institutes
of Health—in collaboration with the Pediatric
Heart Health Network— is quickly launching a
clinical trial of losartan in more than 700 young Marfan
“It’s a beautiful story,” Kenneth
Chien, the director of Massachusetts General Hospital’s
cardiovascular research center, told Science, “one
of the most classic examples of translational science
Reaming and Bolting in the Spinal Cord
Standard surgery with a signature twist
“It’s an easy operation, but very dangerous,” Don
Long says of the procedure that he and his fellow neurosurgeon
Ira Garonzik performed last spring on Judy Christmann’s
neck. “Perforate the trachea or the esophagus,
and the patient could die. Nick the vocal-cord nerve,
and she can’t speak. Injure the spinal cord,
she dies or is paralyzed.”
Christmann arrived at Hopkins with unrelenting pain
in her neck and shoulders, plus tingling and numbness
in her arms. Driving and typing were becoming impossible.
An MRI showed that arthritic degeneration in three
of her cervical discs was causing compression of the
vertebrae and pressure on the spinal cord. Worse, bone
spurs were pinching the nerves that branched off the
spinal cord, making the already small openings, “neural
foramen,” in her vertebrae even smaller. “My
family doctor said unless I had surgery, I’d
ultimately be paralyzed,” Christmann recalls. “One
of my co-workers steered me to Dr. Long.”
To relieve Christmann’s increasing discomfort,
Long and Garonzik did an operation called a Smith-Robinson
ACDF (for anterior cervical discectomy and fusion)
on her. Pioneered here in the 1950s, the procedure—literally,
yanking and scraping out spinal discs, reaming bigger
openings in vertebrae, perfectly hammering in pegs,
drilling and bolting bones—is now done worldwide,
but Hopkins-trained surgeons give it a signature twist.
“Everybody else does it from the right side
of the trachea and esophagus,” Long explains, “because
that’s easier for a right-handed surgeon. We
do it on the left side, because the vocal-cord nerve
is more protected there.”
In Christmann’s case, Long performed the decompression
half—removing the damaged discs. Garonzik then
handled the delicate instrumentation and reconstruction—fitting
pegs of cadaver bone between the vertebrae as spacers
and screwing on a titanium plate to immobilize the
neck while the vertebrae fuse with the cadaver bone.
Hopkins’ success rate with ACDFs is the highest
anywhere—the vertebrae fuse in nearly 100 percent
of patients. Those results, Long says, are achieved
by fitting the pegs of cadaver bone perfectly, like
dowels in fine furniture.
Three months post-op, Christmann reported her neck
pain had disappeared right after surgery. “The
numbness is mostly gone and getting better all the
time.” Her only complaint? “I’m wearing
this contraption around my neck until my six-month
checkup. It encourages the bones to fuse. But it makes
me look like a suicide bomber.”
Step by Step, Beating Back Paralysis
A new study demonstrates that severed nerves in a
limb can be persuaded to regrow.
Schnaar eyes a lab rat’s progress
When it comes right down to it, Ronald Schnaar notes,
lifelong paralysis is the fault of stubborn nerves.
And so this professor of pharmacology is on a mission
of persuasion—to convince nerves they should
The culprits that block nerve regrowth in our bodies,
Schnaar explains, are axon regeneration inhibitors
(ARIs). But scientists have learned that certain enzymes,
like sialidase, are able to block the blockers. Perhaps,
Schnaar conjectured, sialidase might also be able to
give injured nerves just the right push to grow. Not
all nerves are obstinate, he points out. Peripheral
nerves—those in our fingers, for instance—can
repair themselves when they’re severed and reattached.
“That’s because peripheral nerves are
laid out like railroad tracks,” Schnaar explains, “whereas
CNS [central nervous system] nerves in the brain and
spinal cord are more like a ton of spaghetti in a trash
compactor.” The result of this confusing
mess—the evolutionary price humans pay to cram
more information into a smaller space—is that
ARIs keep injured CNS nerves from regrowing. Their
higher density and complexity also make repair much
To get around this problem, surgeons have tried to
capitalize on the growth capabilities of peripheral
nerves by grafting pieces of peripheral nerves onto
damaged CNS nerve endings. But they’ve discovered
that ARIs can be so adept at inhibiting nerve growth
that CNS nerves can’t even make it into the graft.
Now, Schnaar’s lab has found out that sialidase
can thwart those ARIs and emancipate the nerves.
In a study spearheaded by University of Michigan scientist
Lynda Yang, who spent last year as a visiting scientist
with the Schnaar team, the researchers created a rodent
model that mimics a limb-paralyzing injury in humans.
They then surgically attached a peripheral nerve graft
to the rat’s severed nerve ending and continuously
pumped sialidase around the injury for 14 days. Finally,
by slicing open the peripheral nerve graft and dipping
the severed end into a tiny beaker of red dye, “we
were able to trace the nerves into the graft and count
them,” Schnaar says.
Remarkably, rats treated with sialidase had 2.6 times
more nerve growth than the control group. The study
appeared in the July 18 issue of the Proceedings
of the National Academy of Sciences.
As Schnaar recounted the details of this research,
he grinned with enthusiasm beneath his moustache . “This
is only a first step toward overcoming paralysis,” he
says. “But so
far, our results are looking very cool.”
Erika Gebel is a School of Medicine graduate student