Sorry, I have not posted anything this weekend. I was out of town without a computer. Mother is doing about the same. She is still opening her eyes. All of her vital signs are good. She is showing marginal swelling of her ventricles in her head. The doctor still does not think that the shunt needs to go in. We have to keep praying that we do not need to put that in. She has been approved for the long term care facility at Trinity. We will be discussing her move soon. It will be at the same hospital but on a different floor.
God Bless,
Keith and Family
1 comment:
This is a study that might help brain trauma patients. You might want to have your MD check it out.
One Doctor's Lonely Quest To Heal Brain Injury - WSJ.com http://online.wsj.com/public/article_print/SB119076442562439330...
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Donald G. Stein, a medical researcher at Emory University, may be on
the path to treating traumatic brain injuries. The solution may be as
simple as providing head injury patients with high dosages of
progesterone.
September 26, 2007
PAGE ONE
MEDICAL MYSTERY
One Doctor's Lonely Quest
To Heal Brain Injury
After 40 Years, Skeptics
Back Hormone Therapy;
Experiments in a Trailer
By THOMAS M. BURTON
September 26, 2007; Page A1
ATLANTA -- As a young researcher in the 1960s, Donald G. Stein drilled through the skulls of
anesthetized rats and vacuumed out sections of their brains to see the effect on their behavior. But he
quickly became fascinated by something outside the scope of the research: Why did some female
rats promptly recover from their injuries, while males remained impaired?
His supervisors told him the difference was inconsequential and urged him to move on to more
important topics. But over his 40-year career as a brain researcher and university administrator, he
never let go of the question.
Decades of research -- often conducted in his
spare time and with piecemeal funding -- led him
to a surprising hypothesis: that progesterone, a
natural female hormone that protects fetuses in
the womb, may actually protect and heal injured
brains. His work slowly helped overturn medical
orthodoxy that states that brain tissue, once
injured, stays that way. Now he and colleagues
plan a large-scale human trial over the next
several years. While the outcome is far from
assured, the effort could produce a new treatment
for the estimated 10 million people world-wide
who suffer traumatic brain injuries each year.
Dr. Stein's journey shows just how difficult it is
to challenge the medical establishment, which
often begrudges ideas outside the mainstream. It
One Doctor's Lonely Quest To Heal Brain Injury - WSJ.com http://online.wsj.com/public/article_print/SB119076442562439330...
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DAMAGE CONTROL
• Brain Protection: Scientists are finding that
progesterone, a primarily female hormone, may play a
crucial role in fighting brain injury.
• Toiling in Private: Donald Stein has worked quietly in
animal labs for decades and finally may have the chance
to prove this concept.
• Pivotal Trial: He and Emory University colleagues
are about to embark on what they hope will be the
definitive study in human head-injury patients.
also underscores how difficult it is for a lone researcher to persevere without drug-company or other
major financial support: For many years, Dr. Stein held administrative jobs and had to moonlight to
continue his research. Drug companies tend to focus more on blockbuster drugs they design than on
naturally occurring ones with minimal profit potential.
"This is probably the most promising breakthrough in improving outcomes for traumatic brain
injury," says Gregory O'Shanick, national medical director of the Brain Injury Association of
America, which advocates for families of people disabled from brain injury. He first heard Dr. Stein
present his findings at an international medical meeting in 1992. "It's absolutely astonishing that it's
taken this long," he says.
Growing Up in the Bronx
Dr. Stein, an energetic and wise-cracking 68-year-old researcher at Emory University, was the only
member of his family to take up a career in science. "If you grow up in a tenement in the Bronx,"
Dr. Stein says, "the last thing you want is to work with rats."
As an undergraduate at Michigan State University in the
early 1960s, he helped pay some of his school costs by
working in a state mental hospital and the psychiatric
ward of a veterans' hospital.
He grew appalled by the ineffective treatments of the
day, such as blasting hopelessly psychotic patients with
water from a high-pressure hose to shock them out of
their condition and wrapping them in wet bedsheets.
Some of these patients had been given lobotomies, an operation that mimics a form of brain injury.
The therapies "seemed medieval to me and I was convinced there had to be a better way," he says.
A few years later, as a doctoral candidate at the University of Oregon in 1964, he stumbled onto
what would turn out to be his life's work. His job was to surgically injure rats' brains to help
determine which parts control memory and consciousness. But he was struck by an anomaly: Why
was it that about 30% of the injured rats didn't act impaired at all?
Medicine's prevailing view held that injured brain tissue would never heal, so his professors found
his data of little interest. "I was told, 'Don't waste your time on that. Stick to your topic.'" They
explained the differences as "natural variation," he said. But he was skeptical.
Dr. Stein took the question with him later that year to the Massachusetts Institute of Technology,
where he embarked on a prestigious postdoctoral fellowship. His supervisor, Steven Chorover, and
others at MIT urged him to stick with the memory work. "The work he wanted to pursue was not
something we were working on," recalls Dr. Chorover.
Dr. Stein still wanted to figure out why those brain-injured rats seemed to recover. But he says he
concluded that he wouldn't win tenure if he pursued the question.
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In 1966, with a wife and young child to support, he left MIT to take a job as a psychology professor
and director of the brain-research lab at Clark University in Worcester, Mass.
His growing interest in the possibility of recovery from brain injury put him in a tiny minority. Most
neurologists at the time still agreed with Nobel laureate Santiago Ramón y Cajal, who wrote in 1913,
"In the adult brain, nervous pathways are fixed and immutable. Everything may die, nothing may be
regenerated."
Starting in the late 1960s, Dr. Stein began publishing research that suggested the Nobel winner was
wrong.
His lab began methodically studying precisely why some rats stayed smart despite injury. The
researchers would place rats in a large vat of water. The rats had to swim to reach a safe platform in
a test called a "water maze." Then the scientists surgically damaged the animals' brains to study what
happened after injury: Would they still be able to maneuver through the maze? The rats that
recovered quickly were all female, although not all of the females recovered.
Dr. Stein considered whether the explanation might be something complex, like molecular or genetic
differences between males and females. But investigating that would take much more time and
money than seeing if a female hormone might yield some clues. First his team evaluated estrogen,
but didn't find a major correlation. Then they tried progesterone -- a female hormone that helps
protect fetuses from injury during pregnancy.
In these early experiments, Dr. Stein tested female rats to see if they would recover better or worse
at different times during their hormonal cycles that resemble human menstruation. Progesterone
levels rise and fall during these cycles, and these early studies did indeed show that female rats that
were high in progesterone recovered faster.
Dr. Stein thought he had a big part of the answer to the question that had been vexing him for years.
The medical establishment, however, largely shrugged off the results.
A naturally occurring hormone like progesterone, some forms of which have been available
generically for infertility, is of little interest to drug makers. That's because the substance probably
can't gain secure patent protection. That shut off a major avenue of potential funding for his research.
"Big pharma likes more of an airtight protection," says Todd Scherer, director of the Office of
Technology Transfer at Emory, Dr. Stein's current academic home.
Caroline Loew, senior vice president for science and regulatory affairs at Pharmaceutical Research
and Manufacturers of America, the main drug-industry trade group, says drug companies need
patent protection for their research investments. But she suggested the situation could benefit from a
government action along the lines of the federal Orphan Drug Act, which increased financial
incentives for companies researching rare diseases. A similar idea "may apply to this case," she
says.
Dr. Stein was turned down for half a dozen or more grants from the National Institutes of Health
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during the 1970s and 1980s. Zaven S. Khachaturian, a leading scientist and former NIH official,
says his ideas were "really creative but the NIH system never gave them the good scores they
deserved." At one point, he says, "I just told Don Stein that sometimes it doesn't pay to keep hitting
your head against the wall," Dr. Khachaturian says.
Dr. Stein recalls feeling "shaken" by the denials, while at the same time growing more determined to
prove his case. He kept up a steady drumbeat of research, published in a wide range of journals such
as Science, Brain Research, Experimental Neurology and others.
During his time at Clark, Dr. Stein was given to jeans, long hair and shooting his mouth off in
faculty meetings or challenging guest speakers, even eminent ones. "Eyebrows would go up
whenever Don's hand would go up," recalls Julio Ramirez, a former student, now a professor of
neuroscience at Davidson College.
But Dr. Stein also was developing into a powerful speaker himself. One
speech in Copenhagen in the late 1980s ended up offering a lifeline for his
research.
Diane Bistany, then a senior officer at reinsurance company General Re
Corp., heard the talk and was impressed. Dr. Stein spoke for 40 minutes
without notes, pacing the stage as he made an impassioned argument for the
notion that progesterone could be crucial to recovery for thousands of
people with traumatic brain injury.
There are five million patients in the U.S. alone disabled from brain injury.
"Not only was it his knowledge, but he had a passion for his research and
conveyed that this research was going to get somewhere and mean something," Ms. Bistany says.
Gen Re soon contributed grants of $50,000 a year for eight years, keeping his research going.
Around the same time, Dr. Stein grew frustrated at Clark, which was emphasizing clinical
psychology and less so the research he preferred. He applied for various positions at other
universities, but his ideas, while intriguing enough to win him speaking invitations, still seemed too
far out of the mainstream to win him a pure research job.
Finally, in 1988, he landed an administrative position, as dean of the graduate school and associate
provost for research at Rutgers University in Newark, N.J. He would work as dean until about 4
p.m., then return to the lab for several hours of work in the evening along with his research team.
Their work progressed step by step. First, did progesterone lower swelling in the brain? If so, did it
matter if the animals were females? What did estrogen do, if anything? When did the progesterone
have to be given? At what dose? Did progesterone affect animals' memories?
Maze Improvement
He found that female rats with much higher, pregnancy-level amounts of progesterone did far better
than other rats in following mazes. Even male rats also recovered far better from injury when given
One Doctor's Lonely Quest To Heal Brain Injury - WSJ.com http://online.wsj.com/public/article_print/SB119076442562439330...
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the hormone, performing just as well as the highest-performing females. The stuff worked when
given up to 24 hours after injury.
Then, in one crucial experiment in 1991, his team tested the amount of cerebral edema, or brain
swelling, in brain-injured rats with high progesterone levels versus others with none. Edema is
important because of its role in causing brain damage to proliferate.
Robin L. Roof, then a postdoctoral fellow in Dr. Stein's lab, was waiting for the results while
vacationing in a Michigan cottage. When a colleague left a message that there was "no difference,"
she thought the experiment had failed. But it turned out the colleague meant that
progesterone-protected, injured rats did just as well as rats with no injury at all. Immediately, says
Dr. Roof, now a researcher at Pfizer Inc., she realized "this was career-changing research."
Still, why would a hormone that rises and falls with menstrual cycles and enables fertility, protect
the brain? Unlike estrogen, progesterone doesn't produce visible female sex characteristics. It is
present in men at low levels. It rises sharply during pregnancy and helps protect the fetus. Through
multiple studies, Dr. Stein and colleagues concluded that it protects the brain in similar fashion.
In 1995, Dr. Stein joined Emory as dean of the graduate school and vice provost. University
administrators neglected to provide him lab space, thinking his brain-injury research was little more
than a hobby. So for six years his team worked in a moldy double-wide trailer between a parking lot
and an industrial-size trash bin. To complete the picture, they installed plastic flamingos in front.
But meanwhile NIH began to back his progesterone research, and the Centers for Disease Control
and Prevention also began giving him grants. His studies continued to show positive findings with
progesterone, and scientists elsewhere began to confirm them. Often, such confirming studies get
done because other scientists start out skeptical.
Dr. Robert Vink, chairman of neurosurgical research at the University of Adelaide in Australia, was
among the skeptics, but he grew intrigued by Dr. Stein's work. Dr. Vink has confirmed that
progesterone is beneficial in brain-injured animals in numerous ways, such as lowering brain
swelling and cell death, and improving animals' cognitive abilities. He says Dr. Stein is
"persevering. He's got data, 10 or 12 years now, showing that progesterone in animals is
neuroprotective. There's no doubt about it."
Still, others remain on the fence. David A. Hovda, a prominent University of California, Los
Angeles, neurosurgery professor, says he is still unconvinced that progesterone will prove to be an
effective human treatment. But he says he admires Dr. Stein's work. "Don Stein has a history of
stirring the pot," he says.
In the past decade, Dr. Stein says he and his team have repeatedly run into walls when trying to
discern the cellular and molecular mechanism through which progesterone works. But at other times,
they did have success on this "cellular pathway" research, and now are finding that there are at least
three or four such mechanisms.
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By 2000, the findings of Dr. Stein and other brain scientists were swaying the textbooks. One
leading neurology tome, "Principles of Neuroscience," said in its 2000 edition that functions such as
thought, language and memory "are all made possible by the serial and parallel interlinkages of
several brain regions, each with specific functions. As a result, damage to a single area need not
result in the loss of an entire faculty as many earlier neurologists predicted."
Still, as a practical matter, this was just nifty rat science. Dr. Stein's hypotheses wouldn't really
matter until they were borne out in humans.
After hearing Dr. Stein lecture a decade ago, Arthur Kellermann, then Emory's chief of emergency
medicine, resolved to get human studies going. He introduced Dr. Stein to David Wright, a young
Emory emergency doctor with research ambitions. Drs. Wright and Kellermann wrote an NIH grant
application in 1999 for the first phase of human study. Two years later, the federal agency approved
a grant of $2.2 million for the first stage of human research.
Progesterone Dosage
Over the next three years, the study focused on 100 head-injured patients who had been brought into
the emergency room at Grady Memorial Hospital in downtown Atlanta. Some patients received
standard treatment to control bleeding and fevers along with state-of-the-art head-injury treatment.
Others were also given intravenous progesterone, at triple the highest natural levels at the end of
pregnancy.
One Saturday morning in 2005, Dr. Stein was driving north of Atlanta on a shopping trip with his
wife when a stern-sounding Dr. Kellermann called him. Dr. Kellermann said he had just learned the
study's findings, adding, "Pull over to the side of the road."
Dr. Stein froze, fearing that decades of research with animals would prove useless, that progesterone
might have turned out to raise the death rate in humans for some unforeseen reason.
His heart was thumping as Dr. Kellermann told him the results: Patients on progesterone had a death
rate of just 13% from their head injuries, less than half the 30% death rate of those on standard
treatment. And progesterone showed no negative side effects. The 100-subject study was too small
to prove that progesterone caused the lowered death rate, but the findings were consistent with
animal research. Don Stein was so elated that he had to ask his wife to take over the driving.
In the respected journal "Annals of Emergency Medicine" this past April, Dr. Stein and his
researchers summarized the study: "Moderate traumatic brain injury survivors who received
progesterone were more likely to have a moderate to good outcome than those randomized to
placebo."
The story is still far from over. Before progesterone can be approved as a treatment, Dr. Stein's
findings must be proved in a larger study of humans. But as he and his team have persisted in
research, he has himself become the mainstream of neuroscience. His animal research now has been
replicated in dozens of studies at numerous research institutions.
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Dr. Stein and his Emory team have applied for NIH funds to do a 1,000-patient study, which will
give the definitive word. The NIH already has given an initial $229,000 grant to plan the study, but
Emory hasn't yet officially applied for the full grant. Such a trial could take five years or more.
Meanwhile, Emory's technology-transfer office is "optimistic" about developing and marketing
progesterone as a treatment for brain injury, says Dr. Scherer, director of that office.
For Dr. Stein, the results of the clinical study in emergency head-trauma patients were further reason
for enthusiasm -- "a tremendous culmination," as he puts it.
"Most bench scientists work for years to discover a truth about nature," he says. "Very few of us
ever get to have a major impact on people's lives. How can you not be excited?"
Write to Thomas M. Burton at tom.burton@wsj.com1
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