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Widening the Window

Strategies to buy time in treating ischemic stroke

BLOCKED BLOOD

BLOCKED BLOOD: Brain images, such as this one made by a CT scan, can reveal tissue killed by an ischemic stroke (orange), thereby letting physicians know if there?s still time to treat a patient.

Nine years ago the Food and Drug Administration approved tissue plasminogen activator (tPA) as the first, and still only, drug for treating ischemic strokes, which are caused by blood clots in the brain that starve neurons of oxygen. Yet only 3 percent of stroke victims receive this clot-busting thrombolytic, largely because they enter the emergency room within three hours of the onset of symptoms. After that, tPA's effectiveness in reducing death and disability sinks, while the relative risk of dangerous hemorrhaging rises. Recently scientists have discovered ways that could extend tPA's window of time, at least for some patients, and have found alternatives that may be both effective and safe beyond three hours.

A key to a bigger tPA window was the realization among researchers that not all neurons deprived of oxygen died after three hours, as was previously assumed. Restoring blood flow can revive enough neurons to significantly improve recovery. The trick is figuring out which patients can still benefit from treatment.

From the beginning, doctors used CT scans to triage patients, separating the many with ischemic stroke, who are candidates for tPA, from the few with hemorrhaging stroke, who are not. (About 80 percent of all strokes are ischemic.) But the images could not show how much of the ischemic tissue was already dead and how much was still salvageable. "We were treating patients blindly," remarks Steven Warach of the National Institutes of Health's Stroke Center. "We didn't know what was going on in the brain."

Today's MRI scans can distinguish between dead and dying cells, and newer CT scans seem able to as well. "It's been a big advance," says Warach, who described MRI's diagnostic effectiveness in the March 2005 American Journal of Neuroradiology. "We can push the time window for tPA to eight hours." Selecting patients for treatment on the basis of a "tissue clock" rather than the "ticking clock" gives many more patients a chance for a fuller recovery. As important, MRI and CT imaging may also identify those at risk for bleeding if given thrombolytics, a concern that keeps some physicians from administering tPA even within three hours.

Simple, nondrug measures may keep endangered neurons alive until they can be rescued with tPA, says Aneesh B. Singhal of Massachusetts General Hospital, where a small pilot study gave participants high-flow oxygen through a face mask. "It buys time," explains Singhal, who co-authored the paper on it in the April 2005 Stroke. "We can delay the progression of ischemic stroke by several hours. Because oxygen therapy is readily available in ambulances and the ER, it could make logical combination therapy" with tPA.

Meanwhile potentially safer drugs have entered late-stage clinical testing. Desmoteplase, which derives from the saliva of a vampire bat, chews up the fibrin holding a clot in place just as tPA does, but it is more potent and selective. "Even at nine hours, patients had significant long-term clinical benefits, in terms of better recovery after 90 days," says Warach of phase II results. The drug recently entered phase III trials.

Another drug in phase III testing protects neurons by way of a different method. Cerovive (NXY-059) works by scavenging up free radicals that break down the blood-brain barrier and worsen stroke outcome. Preliminary results from a global trial, known as SAINT I, suggest the chemical reduces the amount of disability after a stroke.

Even with the good news, many patients will not qualify for these therapies, because they may still arrive too late or have contraindications. A therapy that encourages brain cells to step up their own repair mechanisms might be the best solution, but that is still a long way off. 

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Oxygen Meant to Resuscitate May Damage Brain

Imaging study finds that pure oxygen feeds routinely administered to revive stroke victims and others may do more harm than good 

man oxygen mask

DILUTION MAY BE NECESSARY: Researchers performed a brain-imaging study that revealed feeds of pure oxygen, administered to resuscitate patients, may actually do harm to the brain.

A new study suggests that pumping pure oxygen into patients' noses and mouths during a stroke or other medical emergency may exacerbate rather than reduce potential brain damage.

Medical personnel routinely slap an oxygen mask on people struggling to breathe as well as on stroke victims left oxygen-deficient in some parts of their brains. Until recently, doctors believed this was the fastest and most effective way to deliver oxygen to needy lung or brain tissue.

But pure oxygen causes rapid breathing, meaning that as it is pumped into the lungs, more carbon dioxide is exhaled, "and that makes the blood vessels much smaller," says Ronald Harper, a neurobiology professor at the University of California, Los Angeles, and senior author of the study published today in PLoS Medicine. The shrunken vessels "cannot deliver as much blood—or the oxygen that's in the blood—to the brain" or the heart.

Harper and his colleagues used functional magnetic resonance imaging (fMRI) to trace the effects of pure oxygen on the brains of 14 healthy children, ages eight to 15 years. In addition to constricting blood flow, administering pure oxygen caused some areas of the subjects' brains to go haywire: the hippocampus (buried deep in the midbrain), the insula (located in the brain's center), and the cingulate cortex, part of the its outermost surface. Harper says that these regions are generally linked to learning, memory and emotions, but also regulate pain, stress and blood pressure. In addition, he says, they signal the hypothalamus to kick into action. The hypothalamus is the brain's master gland, regulating everything from the body's temperature and heart rate to its internal clock (by serving as a link between the nervous system and various glands throughout the body).

"Those brain areas which influence the hypothalamus, when you give 100 percent oxygen, they turn on like crazy," Harper says. "They begin driving the hypothalamus very hard." The action triggers the gland to flood the blood with catecholamines: hormones (such as adrenaline and norepinephrine) and neurotransmitters, like dopamine, all of which feed into the pathway that controls contraction of the heart muscle. This chemical dump disrupts the heart rate, causing a reduction in blood flow and, hence, less oxygen being delivered to cells.

The good news: researchers discovered that the negative effects can be avoided if the oxygen is mixed with as little as 5 percent carbon dioxide before being administered. The combo neither triggered significant changes in any of the aforementioned brain regions nor disturbed the hypothalamus.

"The downsides of continuing to overlook the dangers of this [type of treatment] may [result in] a considerable amount of harm to patients," says researcher Joe Fisher, a professor of medicine at the University of Toronto, who in 2002 suggested that giving pure oxygen to patients poisoned by carbon monoxide might exacerbate rather than limit or reverse damage. "You would think it's like chicken soup to the soul," he says about the traditional wisdom of administering oxygen. "[But], we saw a mechanism that could lead to additional damage."

Based on the brain-imaging findings, "It's hard to imagine a situation where you would want to give oxygen without carbon dioxide," says the study's lead author, Paul Macey, an assistant neurobiology researcher at U.C.L.A. Harper adds that concentrated feeds of room air, containing only 21 percent oxygen, have proved effective in resuscitating newborns who have trouble breathing and turn blue (from a lack of oxygen). "I think that any administration of high levels of oxygen should be reviewed," he cautions, "to determine whether it is necessary," given the dangers.

The march of the ants holds clues for humans

Americans spend a total of 3.7 billion hours a year in congested traffic. But you will never see ants stuck in gridlock.

Army ants, which Dr. Couzin has spent much time observing in Panama, are particularly good at moving in swarms. If they have to travel over a depression in the ground, they erect bridges so that they can proceed as quickly as possible.

"They build the bridges with their living bodies," said Dr. Couzin, a mathematical biologist at Princeton University and the University of Oxford. "They build them up if they're required, and they dissolve if they're not being used."

The reason may be that the ants have had a lot more time to adapt to living in big groups. "We haven't evolved in the societies we currently live in," Dr. Couzin said.

By studying army ants - as well as birds, fish, locusts and other swarming animals - Dr. Couzin and his colleagues are starting to discover simple rules that allow swarms to work so well. Those rules allow thousands of relatively simple animals to form a collective brain able to make decisions and move as if they were a single organism.

Deciphering those rules is a big challenge, however, because the behavior of swarms emerges unpredictably from the actions of thousands or millions of individuals.

"No matter how much you look at an individual army ant," Dr. Couzin said, "you will never get a sense that when you put 1.5 million of them together, they form these bridges and columns. You just cannot know that."

To get a sense of swarms, Dr. Couzin builds virtual models as computer programs. Each model contains thousands of individual agents, which he can program to follow a few simple rules. To decide what those rules ought to be, he and his colleagues head out to jungles, deserts or oceans to observe animals in action.

In the case of army ants, Dr. Couzin was intrigued by their highways. Army ants returning to their nest with food travel in a dense column. This incoming lane is flanked by two lanes of outgoing traffic. A three-lane highway of army ants can stretch for as far as 450 feet, or 140 meters, from the ant nest, comprising hundreds of thousands of insects.

What Dr. Couzin wanted to know was why army ants do not move to and from their colony in a mad, disorganized scramble. To find out, he built a computer model based on some basic ant biology. Each simulated ant laid down a chemical marker that attracted other ants while the marker was still fresh. Each ant could also sweep the air with its antennas; if it made contact with another ant, it turned away and slowed down to avoid a collision.

Dr. Couzin analyzed how the ants behaved when he tweaked their behavior. If the ants turned away too quickly from oncoming insects, they lost the scent of their trail. If they did not turn fast enough, they ground to a halt and forced ants behind them to slow down. Dr. Couzin found that a narrow range of behavior allowed ants to move as a group as quickly as possible.

It turned out that these optimal ants also spontaneously formed highways. If the ants going in one direction happened to become dense, their chemical trails attracted more ants headed the same way. This feedback caused the ants to form a single packed column. The ants going the other direction turned away from the oncoming traffic and formed flanking lanes.

To test this model, Dr. Couzin and Nigel Franks, an ant expert at the University of Bristol in England, filmed a trail of army ants in Panama. Back in England, they went through the film frame by frame, analyzing the movements of 226 ants.

Eventually they found that the real ants were moving in the way that Dr. Couzin had predicted would allow the entire swarm to go as fast as possible. They also found that the ants behaved differently if they were leaving the nest or heading back. When two ants encountered each other, the outgoing ant turned away further than the incoming one. As a result, the ants headed to the nest end up clustered in a central lane, while the outgoing ants form two outer lanes.

Dr. Couzin has been extending his model for ants to other animals that move in giant crowds, like fish and birds. And instead of tracking individual animals himself, he has developed programs to let computers do the work.

To study humans, Dr. Couzin teamed up with researchers at the University of Leeds. They recruited eight people at a time to play a game. Players stood in the middle of a circle, and along the edge of the circle were 16 cards, each labeled with a number. The scientists handed each person a slip of paper and instructed the players to follow the instructions printed on it while not saying anything to the others. Those rules correspond to the ones in Dr. Couzin's models. And just as in his models, each person had no idea what the others had been instructed to do.

In one version of the experiment, each person was instructed simply to stay with the group. As Dr. Couzin's model predicted, they tended to circle around in a doughnut-shaped flock. In another version, one person was instructed to head for a particular card at the edge of the circle without leaving the group. The players quickly formed little swarms with their leader at the head, moving together to the target.

The scientists then sowed discord by telling two or more people to move to opposite sides of the circle. The other people had to try to stay with the group even as leaders tried to pull it apart.

As Dr. Couzin's model predicted, the human swarm made a quick, unconscious decision about which way to go. People tended to follow the largest group of leaders, even if it contained only one additional person.

Dr. Couzin and his colleagues describe the results of these experiments in a paper to be published in the journal Animal Behavior.

Remnant of Yellowstone volcano rising: study

A big blob of molten rock appears to be pushing up remnants of an ancient volcano in Yellowstone National Park in Wyoming, scientists reported on Friday.

They say no volcanic explosion is imminent -- that already happened 642,000 years ago, creating the volcanic crater known as a caldera where part of Yellowstone Lake sits.

But satellite readings show just how volcanically active the area remains, the researchers reported in the journal Science.

From the middle of 2004 through 2006, the floor of the caldera rose 7 inches at a rate of 2.8 inches a year -- the biggest rise ever measured, they reported.

"There is no evidence of an imminent volcanic eruption or hydrothermal explosion. That's the bottom line," University of Utah seismologist Robert Smith said in a statement.

"A lot of calderas worldwide go up and down over decades without erupting."

Yellowstone is North America's largest volcanic field, produced by what is known as a hotspot, a plume of hot and molten rock squirting up from 400 miles beneath the planet's surface.

Monstrous eruptions took place there starting 2 million years ago but activity bubbles along much more calmly now -- akin to similar volcanic fields such as the Campi Flegrei just outside Naples in Italy.

Beneath the field lies what is known as a magma chamber, which is actually similar to a wet sponge in structure.

"Our best evidence is that the crustal magma chamber is filling with molten rock," Smith said. "But we have no idea how long this process goes on before there either is an eruption or the inflow of molten rock stops and the caldera deflates again."

Heat from the chamber warms the park's hundreds of hot springs and geysers, including "Old Faithful," perhaps the world's best-known geyser.

Established in 1872 as the first U.S. national park, Yellowstone also stretches to parts of Montana and Idaho.

The Old Faithful geyser is seen in Yellowstone National Park in a 2002 handout photo from the National Park Service. A big blob of molten rock appears to pushing up remnants of an ancient volcano in Yellowstone National Park in Wyoming, scientists reported on Friday. (NPS/Handout/Reuters)

The Old Faithful geyser is seen in Yellowstone National Park in a 2002 handout photo...
The DNA Age
In DNA Era, New Worries About Prejudice

When scientists first decoded the human genome in 2000, they were quick to portray it as proof of humankind’s remarkable similarity. The DNA of any two people, they emphasized, is at least 99 percent identical.

The DNA Age

A Delicate Discussion

Articles in this series explore the impact of new genetic technology on American life.

Multimedia

Minute Genetic Differences Can Mean a Lot
Minute Genetic Differences Can Mean a Lot

But new research is exploring the remaining fraction to explain differences between people of different continental origins.

Scientists, for instance, have recently identified small changes in DNA that account for the pale skin of Europeans, the tendency of Asians to sweat less and West Africans’ resistance to certain diseases.

At the same time, genetic information is slipping out of the laboratory and into everyday life, carrying with it the inescapable message that people of different races have different DNA. Ancestry tests tell customers what percentage of their genes are from Asia, Europe, Africa and the Americas. The heart-disease drug BiDil is marketed exclusively to African-Americans, who seem genetically predisposed to respond to it. Jews are offered prenatal tests for genetic disorders rarely found in other ethnic groups.

Such developments are providing some of the first tangible benefits of the genetic revolution. Yet some social critics fear they may also be giving long-discredited racial prejudices a new potency. The notion that race is more than skin deep, they fear, could undermine principles of equal treatment and opportunity that have relied on the presumption that we are all fundamentally equal.

“We are living through an era of the ascendance of biology, and we have to be very careful,” said Henry Louis Gates Jr., director of the W. E. B. Du Bois Institute for African and African American Research at Harvard University. “We will all be walking a fine line between using biology and allowing it to be abused.”

Certain superficial traits like skin pigmentation have long been presumed to be genetic. But the ability to pinpoint their DNA source makes the link between genes and race more palpable. And on mainstream blogs, in college classrooms and among the growing community of ancestry test-takers, it is prompting the question of whether more profound differences may also be attributed to DNA.

Nonscientists are already beginning to stitch together highly speculative conclusions about the historically charged subject of race and intelligence from the new biological data. Last month, a blogger in Manhattan described a recently published study that linked several snippets of DNA to high I.Q. An online genetic database used by medical researchers, he told readers, showed that two of the snippets were found more often in Europeans and Asians than in Africans.

No matter that the link between I.Q. and those particular bits of DNA was unconfirmed, or that other high I.Q. snippets are more common in Africans, or that hundreds or thousands of others may also affect intelligence, or that their combined influence might be dwarfed by environmental factors. Just the existence of such genetic differences between races, proclaimed the author of the Half Sigma blog, a 40-year-old software developer, means “the egalitarian theory,” that all races are equal, “is proven false.”

Though few of the bits of human genetic code that vary between individuals have yet to be tied to physical or behavioral traits, scientists have found that roughly 10 percent of them are more common in certain continental groups and can be used to distinguish people of different races. They say that studying the differences, which arose during the tens of thousands of years that human populations evolved on separate continents after their ancestors dispersed from humanity’s birthplace in East Africa, is crucial to mapping the genetic basis for disease.

But many geneticists, wary of fueling discrimination and worried that speaking openly about race could endanger support for their research, are loath to discuss the social implications of their findings. Still, some acknowledge that as their data and methods are extended to nonmedical traits, the field is at what one leading researcher recently called “a very delicate time, and a dangerous time.”

“There are clear differences between people of different continental ancestries,” said Marcus W. Feldman, a professor of biological sciences at Stanford University. “It’s not there yet for things like I.Q., but I can see it coming. And it has the potential to spark a new era of racism if we do not start explaining it better.”

Dr. Feldman said any finding on intelligence was likely to be exceedingly hard to pin down. But given that some may emerge, he said he wanted to create “ready response teams” of geneticists to put such socially fraught discoveries in perspective.

The authority that DNA has earned through its use in freeing falsely convicted inmates, preventing disease and reconstructing family ties leads people to wrongly elevate genetics over other explanations for differences between groups.

“I’ve spent the last 10 years of my life researching how much genetic variability there is between populations,” said Dr. David Altshuler, director of the Program in Medical and Population Genetics at the Broad Institute in Cambridge, Mass. “But living in America, it is so clear that the economic and social and educational differences have so much more influence than genes. People just somehow fixate on genetics, even if the influence is very small.”

But on the Half Sigma blog and elsewhere, the conversation is already flashing forward to what might happen if genetically encoded racial differences in socially desirable — or undesirable — traits are identified. 

“If I were to believe the ‘facts’ in this post, what should I do?” one reader responded on Half Sigma. “Should I advocate discrimination against blacks because they are less smart? Should I not hire them to my company because odds are I could find a smarter white person? Stop trying to prove that one group of people are genetically inferior to your group. Just stop.” 

Renata McGriff, 52, a health care consultant who had been encouraging black clients to volunteer genetic information to scientists, said she and other African-Americans have lately been discussing “opting out of genetic research until it’s clear we’re not going to use science to validate prejudices.”

“I don’t want the children in my family to be born thinking they are less than someone else based on their DNA,” added Ms. McGriff, of Manhattan.

Such discussions are among thousands that followed the geneticist James D. Watson’s assertion last month that Africans are innately less intelligent than other races. Dr. Watson, a Nobel Prize winner, subsequently apologized and quit his post at the Cold Spring Harbor Laboratory on Long Island.

But the incident has added to uneasiness about whether society is prepared to handle the consequences of science that may eventually reveal appreciable differences between races in the genes that influence socially important traits.

New genetic information, some liberal critics say, could become the latest rallying point for a conservative political camp that objects to social policies like affirmative action, as happened with “The Bell Curve,” the controversial 1994 book that examined the relationship between race and I.Q.

Yet even some self-described liberals argue that accepting that there may be genetic differences between races is important in preparing to address them politically.

“Let’s say the genetic data says we’ll have to spend two times as much for every black child to close the achievement gap,” said Jason Malloy, 28, an artist in Madison, Wis., who wrote a defense of Dr. Watson for the widely read science blog Gene Expression. Society, he said, would need to consider how individuals “can be given educational and occupational opportunities that work best for their unique talents and limitations.”

Others hope that the genetic data may overturn preconceived notions of racial superiority by, for example, showing that Africans are innately more intelligent than other groups. But either way, the increased outpouring of conversation on the normally taboo subject of race and genetics has prompted some to suggest that innate differences should be accepted but, at some level, ignored.

“Regardless of any such genetic variation, it is our moral duty to treat all as equal before God and before the law,” Perry Clark, 44, wrote on a New York Times blog. It is not necessary, argued Dr. Clark, a retired neonatologist in Leawood, Kan., who is white, to maintain the pretense that inborn racial differences do not exist.

“When was the last time a nonblack sprinter won the Olympic 100 meters?” he asked.

“To say that such differences aren’t real,” Dr. Clark later said in an interview, “is to stick your head in the sand and go blah blah blah blah blah until the band marches by.”

Race, many sociologists and anthropologists have argued for decades, is a social invention historically used to justify prejudice and persecution. But when Samuel M. Richards gave his students at Pennsylvania State University genetic ancestry tests to establish the imprecision of socially constructed racial categories, he found the exercise reinforced them instead.

One white-skinned student, told she was 9 percent West African, went to a Kwanzaa celebration, for instance, but would not dream of going to an Asian cultural event because her DNA did not match, Dr. Richards said. Preconceived notions of race seemed all the more authentic when quantified by DNA.

“Before, it was, ‘I’m white because I have white skin and grew up in white culture,’ ” Dr. Richards said. “Now it’s, ‘I really know I’m white, so white is this big neon sign hanging over my head.’ It’s like, oh, no, come on. That wasn’t the point.”

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