Finding May Solve Riddle of Fatigue in Muscles

By GINA KOLATA
One of the great unanswered questions in physiology is why muscles get tired. The experience is universal, common to creatures that have muscles, but the answer has been elusive until now.
Scientists at Columbia say they have not only come up with an answer, but have also devised, for mice, an experimental drug that can revive the animals and let them keep running long after they would normally flop down in exhaustion.
For decades, muscle fatigue had been largely ignored or misunderstood. Leading physiology textbooks did not even try to offer a mechanism, said Dr. Andrew Marks, principal investigator of the new study. A popular theory, that muscles become tired because they release lactic acid, was discredited not long ago.
In a report published Monday in an early online edition of Proceedings of the National Academy of Sciences, Dr. Marks says the problem is calcium flow inside muscle cells. Ordinarily, ebbs and flows of calcium in cells control muscle contractions. But when muscles grow tired, the investigators report, tiny channels in them start leaking calcium, and that weakens contractions. At the same time, the leaked calcium stimulates an enzyme that eats into muscle fibers, contributing to the muscle exhaustion.
In recent years, says George Brooks of the University of California, Berkeley, muscle researchers have had more or less continuous discussions about why muscles fatigue. It was his work that largely discredited the lactic-acid hypothesis, but that left a void.
What did make muscles tired?
The new work in mice, Dr. Brooks said, “is exciting and provocative.” It is a finding that came unexpectedly from a very different line of research. Dr. Marks, a cardiologist, wanted to discover better ways to treat people with congestive heart failure, a chronic and debilitating condition that affects an estimated 4.8 million Americans.
Its hallmark is a damaged heart, usually from a heart attack or high blood pressure. Struggling to pump blood, the heart grows, sometimes becoming so large that it fills a patient’s chest. As the disease progresses, the lungs fill with fluid. Eventually, with congested lungs and a heart that can barely pump, patients become so short of breath that they cannot walk across a room. Half die within five years.
In his efforts to understand why the heart muscle weakened, Dr. Marks focused on the molecular events in the heart. He knew the sequence of events. As the damaged heart tries to deal with the body’s demands for blood, the nervous system floods the heart with the fight or flight hormones, epinephrine and norepinephrine, that make the heart muscle cells contract harder.
The intensified contractions, Dr. Marks and his colleagues discovered, occurred because the hormones caused calcium to be released into the heart muscle cells’ channels.
But eventually the epinephrine and norepinephrine cannot stimulate the heart enough to meet the demands for blood. The brain responds by releasing more and more of those fight or flight hormones until it is releasing them all the time. At that point, the calcium channels in heart muscle are overstimulated and start to leak.
When they understood the mechanisms, the researchers developed a class of experimental drugs that block the leaks in calcium channels in the heart muscle. The drugs were originally created to block cells’ calcium channels, a way of lowering blood pressure.
Dr. Marks and his colleagues altered the drugs to make them less toxic and to rid them of their ability to block calcium channels. They were left with drugs that stopped calcium leaks. The investigators called the drugs rycals, because they attach to the ryanodine receptor/calcium release channel in heart muscle cells. The investigators tested rycals in mice and found that they could prevent heart failure and arrhythmias in the animals. Columbia obtained a patent for the drugs and licensed them to a start-up company, Armgo Pharma of New York. Dr. Marks is a consultant to the company.
It hopes to start testing one of the drugs for safety in patients in the spring, but the tests will not be at Columbia because of the university and investigators’ conflicts of interest. In the meantime, Dr. Marks wondered whether the mechanism he discovered might apply to skeletal muscle as well as heart muscle. Skeletal muscle is similar to heart muscle, he noted, and has the same calcium channel system. And heart failure patients complain that their muscles are extremely weak.
“If you go to the hospital and ask heart failure patients what is bothering them, they don’t say their heart is weak,” Dr. Marks said. “They say they are weak.”
So he and his colleagues looked at making mice exercise to exhaustion, swimming and then running on a treadmill. The calcium channels in their skeletal muscles became leaky, the investigators found. And when they gave the mice their experimental drug, the animals could run 10 to 20 percent longer.
Then, collaborating with David Nieman, an exercise scientist at Appalachian State University in Boone, N.C., the investigators asked whether the human skeletal muscles grew tired for the same reason, calcium leaks.
Highly trained bicyclists rode stationary bikes at intense levels of exertion for three hours a day three days in a row. For comparison, other cyclists sat in the room but did not exercise.
Dr. Nieman removed snips of thigh muscle from all the athletes after the third day and sent them to Columbia, where Dr. Marks’s group analyzed them without knowing which samples were from the exercisers and which were not.The results, Dr. Marks said, were clear. The calcium channels in the exercisers leaked. A few days later, the channels had repaired themselves. The athletes were back to normal.
Of course, even though Dr. Marks wants to develop the drug to help people with congestive heart failure, hoping to alleviate their fatigue and improve their heart functions, athletes might also be tempted to use it if it eventually goes to the market.
The odds are against this particular drug being approved, though, cautions Dr. W. Robb McClellan, a heart disease researcher at U.C.L.A.
“In heart failure, there are three medications that improve mortality, but there have probably been 10 times that many tested,” he said.
Even if the first drug that prevents calcium leaks does not work in patients, Dr. McClellan added, the important advance is to understand the molecular events underlying fatigue. “Then,” he said, “you can design therapies.”
So the day may come when there is an antifatigue drug.
That idea, “is sort of amazing,” said Dr. Steven Liggett, a heart-failure researcher at the University of Maryland. Yet, Dr. Liggett said, for athletes “we have to ask whether it would be prudent to be circumventing this mechanism.”
“Maybe this is a protective mechanism,” he said. “Maybe fatigue is saying that you are getting ready to go into a danger zone. So it is cutting you off. If you could will yourself to run as fast and as long as you could, some people would run until they keeled over and died.”

Sticky molecule may hold key to nerve disorders

Thu Nov 29, 2007 2:42 PM ET
By Ben Hirschler
LONDON (Reuters) – A sticky molecule previously linked to inflammation also helps seal vital insulation around peripheral nerves, making it a potential target for new drugs against nerve disorders, scientists said on Thursday.
The latest research suggests the molecule, known as JAM-C, could be a key player in regulating the way nerves work.
In genetically modified mice without the adhesion molecule, the myelin insulation sheath protecting nerves deteriorates and the animals experience faulty nerve firing, muscle weakness and a shortened stride, researchers reported in the journal Science.
The team also found that nerves of patients with certain peripheral nerve disorders had defective JAM-C.
Taken together, the findings suggest the molecule is a key player in regulating the structure and function of peripheral nerves and its malfunction may cause a number of illnesses.
JAM-C, which was discovered only recently, is already being studied as a target for new medicines involved in inflammation and as a possible route to fight cancer, since it seems to help tumors form new blood vessels.
“This finding opens up yet another area that this molecule should be investigated in — but it’s very early days,” Sussan Nourshargh, professor of microvascular pharmacology at Barts and The London School of Medicine, said in an interview.
Nourshargh made the discovery of the molecule’s role in peripheral nerves by accident, while investigating blood vessels. Her team then collaborated with scientists at Imperial College London, University College London, Cancer Research UK and the University of Geneva to advance the work further.
There are more than 100 kinds of peripheral nerve disorders affecting approximately one in 20 people. They often afflict people with existing diseases like diabetes and lupus, a chronic autoimmune disease.
Symptoms include numbness, pain, tingling, muscle weakness and sensitivity to touch. Problems often start gradually and steadily get worse.
Nourshargh said the new molecule was not found in the central nervous system and was therefore unlikely to play a role multiple sclerosis.
JAM-C seems to work by sealing off the insulation in the critical gaps between so-called Schwann cells, which produce the myelin layers that wrap around nerve cells.
(Reporting by Ben Hirschler, editing by Paul Casciato)

Back From the Dead

Doctors are reinventing how they treat sudden cardiac arrest, which is fatal 95 percent of the time. A report from the border between life and death.
By Jerry Adler
Newsweek
July 23, 2007 issue – Bill Bondar knows exactly where he died: on the sidewalk outside his house in a retirement community in southern New Jersey. It was 10:30 on the night of May 23, a Wednesday, and Bondar was 61—a retired computer programmer with a cherry red Gibson bass guitar, an instrument he had first picked up around the same time as Chuck Berry. He was 6 feet 1 and 208 pounds, down about 50 pounds over the last several years. On that night he had driven home from a jam session with two friends and, as he was unloading his car, his heart stopped. That is the definition of “clinical death,” one of several definitions doctors use, not always with precision. He wasn’t yet “brain dead,” implying a permanent cessation of cerebral function, or “legally dead,” i.e., fit to be buried. But he was dead enough to terrify his wife, Monica, who found him moments later, unconscious, not breathing, with no pulse. His eyes were open, but glassy—”like marbles,” Monica says, “with no life in them. They were the eyes of a dead man.”
In a general sense, we know what happened to Bondar. His doctor at the University of Pennsylvania Hospital, Dr. Edward Gerstenfeld, later determined that Bondar’s left anterior descending artery was 99 percent blocked by a coating of plaque, leaving a passage “the width of a hair.” A blockage in that vessel, the largest artery feeding the heart, is known to cardiologists as the widowmaker. A tiny clot lodging there would have sent his heart into a brief burst of the ineffectual rhythm known as fibrillation, before it stopped altogether. Within 20 seconds the hundred billion neurons in Bondar’s brain would have used up their residual oxygen, shutting down the ceaseless exchange of electrical charges that we experience as consciousness. His breathing stopped as he entered a quiescence beyond sleep.

One of the best books written on near death experiences “Eyes of an Angel”

About 250,000 times a year in the United States, someone’s heart stops beating on the street, or at home or at work. This can be the result of a heart attack, when a clot chokes off a coronary artery, or a host of other conditions including congenital defects, abnormal blood chemistry, emotional stress and physical exertion. Without CPR, their window for survival starts to close in about five minutes. Life or death is mostly a matter of luck; response time to a 911 call varies greatly by location, but can exceed 10 minutes in many parts of the country. In rough numbers, they have a 95 percent chance of dying.
How long has it been since you’ve read an article about heart attacks that didn’t mention saturated fats? Our age is obsessed with “health,” but when health fails, the last line of defense is in the emergency room, where doctors patrol the border between life and death—a boundary that they have come to see as increasingly uncertain, even porous. This is a story about what happens when your heart stops: about new research into how brain cells die and how something as simple as lowering body temperature may keep them alive—research that could ultimately save as many as 100,000 lives a year. And it’s about the mind as well, the visions people report from their deathbeds and the age-old questions about what, if anything, outlives the body. It begins with a challenge to something doctors have always been taught in medical school: that after about five minutes without a pulse, the brain starts dying, followed by heart muscle—the two most voracious consumers of oxygen in the body, victims of their own appetites. The emerging view is that oxygen deprivation is merely the start of a cascade of reactions within and outside the cells that can play out over the succeeding hours, or even days. Dying turns out to be almost as complicated a process as living, and somehow, among its labyrinthine pathways, Bondar found a way out.
Monica tried to recall what she had learned in a CPR class decades earlier. She bent over Bondar and began pushing down on his chest, then rushed back to the kitchen to dial 911. “My husband is dying!” she gasped to the operator.
Compressing Bondar’s chest would have sent a trickle of blood to his brain, supplying a fraction of its normal oxygen consumption, not enough to bring him back to consciousness. But the West Deptford police station was only three blocks away, and within two minutes of Monica’s call three officers arrived with a defibrillator. They placed the pads on Bondar’s chest, delivered two jolts of electricity to his heart, and got a pulse back. Soon paramedics arrived with oxygen and rushed him to a nearby community hospital. The report Monica received there after an hour was equivocal: Bondar was “stable”—his heart rate and blood pressure back to near normal—but he was still in a coma. It was then that Monica made a decision that may have saved his life. She asked that her husband be moved the 15 miles to Penn, the region’s leading university hospital.
Dr. Lance Becker, director of Penn’s year-old Center for Resuscitation Science, frequently dreams about mitochondria: tubular structures within cells, encasing convoluted membranes where oxygen and glucose combine to produce the energy the body uses in moving everything from molecules across cell membranes to barbells. Recently mitochondria have been in the news because they have their own DNA, which is inherited exclusively down the female line of descent, making them a useful tool for geneticists and anthropologists.
But Becker is interested in mitochondria for another reason: he believes they are the key to his audacious goal of tripling the time during which a human being can go without a heartbeat and still be revived. That the five-minute rule is not absolute has been known for a long time, and the exceptions seem to involve low temperatures. Children who fall through ice may survive unexpectedly long immersions in cold water. On Napoleon’s Russian campaign, his surgeon general noticed that wounded infantrymen, left on the snowy ground to recover, had better survival rates than officers who stayed warm near the campfire. Becker is hoping to harness this effect to save lives today.
Becker is 53, slender and boyish in a way that belies his thinning hair; his typical greeting to colleagues is a jaunty “What’s up, guys?” For his lab he has assembled a high-powered team from a wide range of specialties, including a brilliant young neuroscientist, Dr. Robert Neumar; an emergency-medicine specialist, Dr. Ben Abella; plus cardiologists, biochemists, bioengineers and a mouse-heart surgeon. His associate director, Dr. Vinay Nadkarni, comes from pediatrics. Becker has in effect re-created at Penn, on a more ambitious scale, the laboratory he founded in 1995 at the University of Chicago, with a grant of $50,000 from the philanthropist Jay Pritzker. Ten years earlier Pritzker had walked into the emergency room at Chicago’s Michael Reese Hospital complaining of chest pains, and crumpled to the floor. Becker resuscitated him, the beginning of both a rewarding friendship (Pritzker lived for 14 more years) and a new direction for Becker’s career. “Every day since then,” he says, “I would go home and wonder why Jay Pritzker got a second chance and so many other people didn’t.”
Becker’s interest in mitochondria reflects a new understanding about how cells die from loss of circulation, or ischemia. Five minutes without oxygen is indeed fatal to brain cells, but the actual dying may take hours, or even days. Doctors have known for a long time that the consequences of ischemia play out over time. “Half the time in cardiac arrest, we get the heart going again, blood pressure is good, everything is going along,” says Dr. Terry Vanden Hoek, director of the Emergency Resuscitation Center at the University of Chicago, “and within a few hours everything crashes and the patient is dead.” It took some time, though, for basic research to supply an explanation. Neumar, working with rats, simulates cardiac arrest and resuscitation, and then examines the neurons at intervals afterward. Up to 24 hours later they appear normal, but then in the next 24 hours, something kicks in and they begin to deteriorate. And Dr. James R. Brorson of the University of Chicago has seen something similar in neural cells grown in culture; deprive them of oxygen and watch for five minutes, or even much longer, and not much happens. “If your car runs out of gas, your engine isn’t destroyed, it just needs fuel,” he says.
Cell death isn’t an event; it’s a process. And in principle, a process can be interrupted. The process appears to begin in the mitochondria, which control the cell’s self-destruct mechanism, known as apoptosis, and a related process, necrosis. Apoptosis is a natural function, destroying cells that are no longer needed or have been damaged in some way. Cancer cells, which might otherwise be killed by apoptosis, survive by shutting down their mitochondria; cancer researchers are looking for ways to turn them back on. Becker is trying to do the opposite, preventing cells that have been injured by lack of oxygen from, in effect, committing suicide.
It’s a daunting problem. “We’re asking the questions,” says one leading researcher, Dr. Norm Abramson of the University of Pittsburgh. “We just haven’t found the answers.” Until recently, the conventional wisdom was that apoptosis couldn’t be stopped once it was underway. It proceeds by a complex sequence of reactions—including inflammation, oxidation and cell-membrane breakdown—none of which seems to respond to traditional therapies. Becker views cell death in cardiac arrest as a two-step process, beginning with oxygen deprivation, which sets up the cell for apoptosis; then the heart starts up again and the patient gets a lungful of oxygen, triggering what is called reperfusion injury. The very substance required to save the patient’s life ends up injuring or killing him.

One of the best books written on near death experiences “Eyes of an Angel”

Researchers have ransacked their arsenal of drugs looking for ways to interrupt this sequence. Over the years they have tried various techniques on nearly 100,000 patients around the world. None has shown any benefits, according to Dr. A. Michael Lincoff, director of cardiovascular research at the Cleveland Clinic. But one thing does seem to work, something so obvious and low-tech that doctors have a hard time accepting it. It’s hypothermia, the intentional lowering of body temperature, down to about 92 degrees Fahrenheit, or 33 Celsius. Research by a European team in 2002 reported favorable results from a controlled study of several hundred cardiac-arrest patients; subjects who were cooled both had better survival rates and less brain damage than a control group. The first big international conference on cooling took place in Colorado this February. Despite favorable studies and the endorsement of the American Heart Association, “we were concerned that [hypothermia] still wasn’t catching on,” says the conference organizer, Dr. Daniel Herr of Washington Hospital Center in Washington, D.C. The two leading manufacturers of cooling equipment—Medivance, Inc., and Gaymar Industries—say only about 225 hospitals, out of more than 5,700 in the United States, have installed machines for inducing hypothermia. Herr says the treatment requires a “paradigm shift” by doctors. “People have a hard time believing that something as simple as cooling can make such a big difference.” Perhaps that’s because no one quite understands how cooling works. It appears to work globally on apoptosis, rather than on any of the individual biochemical pathways involved in it. “The short answer is, we don’t know,” says Neumar.
Researchers have also been looking into the way patients get oxygen during resuscitation, and afterward. The treatment goal in cardiac arrest has been to rush oxygen to the heart and brain at maximum concentration; the mask the paramedic pops on your mouth supplies it at 100 percent. “The problem with that,” says Dr. Ronald Harper of UCLA, “is it does some very nasty things to the brain.” Harper believes a mixture containing 5 percent carbon dioxide would buffer those negative effects, but the idea is still controversial. At the University of Maryland, Dr. Robert Rosenthal and Dr. Gary Fiskum have been looking into whether oxygen concentrations should be dialed down much more aggressively. In their lab, dogs with induced cardiac arrest recovered better when they were taken off full oxygen after just 12 minutes, compared with an hour in the control group. Rosenthal says in practice patients sometimes are left on pure oxygen for much longer than an hour—in one hospital he studied, for as much as 121 hours.
At Penn, Becker’s Resuscitation Center coordinates with the Emergency Department on a protocol for cooling patients in cardiac arrest. “We look at their prior mental state,” says Dr. Dave Gaieski. “If someone was in a coma in a nursing home, we’re not going to cool them.” The same goes for patients whose hearts stopped for longer than an hour. Since 2005 just 14 patients have met Penn’s criteria for hypothermia. Eight survived, six of them with complete recovery. No one knows how many others were saved by cooling around the country.
Bondar arrived at Penn at about 1:30 a.m., still comatose, minutes ticking away while he was evaluated for cooling. Once the decision was made, the team sprang into action, injecting him with an infusion of chilled saline—two liters at about 40 degrees—then wrapping him in plastic tubes filled with chilled, circulating water. Becker believes, based on animal work, that cooling patients even sooner—ideally, on their way to the hospital—would be even more effective, and part of the work of his lab involves perfecting an injectable slurry of saline and ice that could be administered by a paramedic. Bondar was kept at about 92 degrees for about a day, then allowed to gradually return to normal temperature. He remained stable, but unresponsive, over the next three days, while Monica stayed at his bedside. She finally went home Sunday evening, and was awakened Monday by a call from the hospital that she was sure meant bad news.
“Guess what?” said the voice on the other end. “Bill’s awake.”
Bondar’s first words were, “How did I get here?” He had lost track of a full week, from about two days before his heart attack until he woke up. That’s not unusual; short-term memory is often the first casualty of cardiac arrest. Neumar says certain cells in the hippocampus, the part of the brain that forms new memories, are for unknown reasons especially sensitive to ischemia. Another Penn patient, Sean Quinn, was 20 and a student at Drexel University when he went into unexplained cardiac arrest in 2005. He was one of the earliest patients cooled at Penn, and there’s reason to believe that it saved his life, but the continuing memory deficit has prevented him from returning to college.
Certainly, people do not form memories while they’re in a coma. Exactly one year before Bondar had his heart attack, Brian Duffield, then 40, a salesman in Tucson, collapsed in the shower after a swim. Luckily for him, he was on the campus of the University of Arizona, whose hospital uses a cooling protocol similar to Penn’s. “I was there one minute and the next thing I know, it’s a few days later and people are telling me I was dead and came back,” says Duffield. But Duffield’s memory and intellect and personality all returned intact from his brush with death, as did Bondar’s. This is, on some level, deeply mysterious. We experience consciousness embedded in time, a succession of mental states continually re-created in our brains, even during sleep. But when the brain shuts down, where does the mind go?
That is the crux of one of the oldest debates in philosophy. The materialist view is that Bondar’s memories resided in the physical state of the cells and synapses of his brain, a state that is preserved for some period after the heart stops beating. Becker has pronounced perhaps a thousand deaths in his career, but often with the feeling that—despite the lack of pulse, breathing or discernible brain function—something vital remains in the body on the bed. He felt it most strongly when his own father died of cardiac arrest at the very hospital where Becker was working in 1993. When Becker saw him, he was already dead, but something seemed preserved. “I just had the sense he wasn’t really dead yet,” Becker says. “He was dead. He had been pronounced. But he hadn’t left.”

One of the best books written on near death experiences “Eyes of an Angel”

This is the belief motivating people who pay to have their bodies frozen in liquid nitrogen after their deaths, in the hope that they can someday be thawed and restored to life. The Alcor Foundation, in Scottsdale, Ariz., has signed up about 825 prospective patients, and has preserved 76 of them, including Ted Williams. These aren’t all whole bodies; some people opt for just their heads, which, apart from being cheaper, freeze faster than an entire body, reducing the danger of frost damage to the cells. Of course, we are a long way from knowing how to reanimate a frozen body, let alone just a head. One possibility, according to Tanya Jones, chief operating officer of Alcor, is to take a cell from the head and clone a new body to attach it to. The other is to scan the entire three-dimensional molecular array of the brain into a computer which could hypothetically reconstitute the mind, either as a physical entity or a disembodied intelligence in cyberspace. This, obviously, is not for the impatient. The physicist Ralph Merkle, an Alcor board member, has used this idea to popularize a fourth definition of death: “information-theoretic” death, the point at which the brain has succumbed to the pull of entropy and the mind can no longer be reconstituted. Only then, he says, are you really and truly dead.
But there’s another answer to the question of where Bondar’s mind was during the last week of May. This is the view that the mind is more than the sum of the parts of the brain, and can exist outside it. “We still have no idea how brain cells generate something as abstract as a thought,” says Dr. Sam Parnia, a British pulmonologist and a fellow at Weill Cornell Medical College. “If you look at a brain cell under a microscope, it can’t think. Why should two brain cells think? Or 2 million?” The evidence that the mind transcends the brain is said to come from near-death experiences, the powerful sensation of well-being that has been described by people like Anthony Kimbrough, a Tennessee real-estate agent who suffered a massive coronary in 2005 at the age of 44. Dying on the table in the cath lab during angioplasty, he sensed the room going dark, then lighter, and “all of a sudden I could breathe. I wasn’t in pain. I felt the best I ever felt in my life. I remember looking at the nurses’ faces and thinking, ‘Folks, if you knew how great this is, you wouldn’t be worried about dying’.” Kimbrough had the odd sensation of being able to see everything in his room at once, and even into the next room. He is one of about 1,200 people who have registered their experiences with a radiation oncologist named Dr. Jeffrey Long, who established the Near Death Experience Research Foundation in 1998 to investigate the mystery of how unconscious people can form conscious memories.
That’s also what motivates Parnia, who has begun a study of near-death experiences in four hospitals in Britain, aiming for 30 by the year-end. The study will test the frequently reported sensation of looking down on one’s body from above, by putting random objects on high shelves above the beds of patients who are likely to die. If they later claim to have been floating near the ceiling, he plans to ask them what they saw. Parnia insists he’s not interested in validating anyone’s religious beliefs; his idea is that death can be studied by scientists, as well as theologians.

One of the best books written on near death experiences “Eyes of an Angel”

As for Bondar, his mind stayed put during his ordeal, which ended when he went home with Monica on June 1, nine days after he died. Gerstenfeld had given him an implantable defibrillator, cleared his blocked artery and inserted a stent to keep it open. “He came back fully intact,” says Gerstenfeld. “He was dead, if only for a few minutes. But it could have been much worse. He could have been dead-dead.”
We are, Becker believes, at the forefront of a revolution in emergency medicine destined to save millions of lives in the years ahead. This is doctoring at its most basic, wresting people back from death. “I have been fighting with death for 20 years,” he says. “And I’ll keep doing it, I think, until I meet him in person.”
With Matthew Philips, Joan Raymond and Julie Scelfo
© 2007 Newsweek, Inc. | Subscribe to Newsweek

One of the best books written on near death experiences “Eyes of an Angel”

Deadly twist at the chiropractor’s office

Chiropractor’s move can trigger strokes in healthy patients
By Jennifer Wolff
Self
Updated: 1:51 p.m. ET June 17, 2007
Christa Heck lay crumpled on her right side in the front seat of her SUV, staring helplessly at the dashboard. She tried to right herself, but her body wouldn’t obey her brain: One arm was limp, the other floundering uncontrollably. Ten minutes earlier, she’d been at her chiropractor’s office for a routine follow-up. But something had obviously gone wrong. Lying virtually paralyzed across her passenger seat, “all I could do was pray someone would help me,” she recalls. “I thought I was going to die.”
Heck, a 43-year-old mother of four from Mahopac, New York, had been seeing a chiropractor on and off for 20 years to treat headaches and lower-back pain. A pharmaceutical representative, she spent her days driving to sales calls and her nights working long hours at the computer. A few visits to adjust her back and cervical spine — the bones that run up through the neck — always relieved the strain. “I had the impression that it was good for health maintenance,” she says. “Not once had I been told there were risks involved.”
In November 2003, she’d had her first visit with a new chiropractor recommended by a friend. He snapped her neck to one side, then to the other, and she felt the same pop she had many times before. But 24 hours later, her head still hurt. Then, while cooking dinner, “I turned my head to the left, and the room started spinning and I felt nauseous. It lasted only a second,” she says. “I thought it was an inner ear infection.”
The next day, Heck returned to the chiropractor and told him about her vertigo, nausea and hurting head. “Let me see if I can get rid of that headache,” Heck says he told her, twisting her head to one side until it popped. When he twisted to the other side, however, it didn’t crack. He told her to take a deep breath and relax, then massaged her neck briefly before placing his hands on both sides of her head to try again. Once more, her neck didn’t pop. “I felt this wave of nausea,” Heck recalls. “I left the office a little dazed.”
Minutes later, Heck pulled her car up to a convenience store to get some ginger ale to settle her stomach. But when she shifted her SUV into park, she collapsed, the motor still running. She tried grabbing her cell phone, but her hands flailed. Eventually, she inched it between her fingers and after several tries managed to press the keys to speed-dial her husband, Ed. “All he says he heard was me crying and slurring my words, but he couldn’t make out any of them,” she says. Finally, Ed recognized two words: Red Mills, the name of the convenience mart. “He was 45 minutes away,” Heck says. “I was terrified.”
By the time her husband arrived, Heck felt a little better. She was weak but could sit up and talk. They considered dialing 911 but knew an ambulance would take her to a hospital where Ed once had a bad experience. So instead, he drove her home.
The next day, Heck awoke feeling numb on the right side of her body. Her left eyelid drooped, and the right side of her face was frozen. When she walked, both feet dragged. Ed called family friend M. Mehdi Kazmi, M.D., assistant clinical professor of neurology at Albert Einstein College of Medicine in the Bronx. As the doctor quizzed her over the phone, Heck mentioned she’d just visited a chiropractor.
“Oh, Christa,” he said. “I need to see you right away.”
Dr. Kazmi examined her only a few minutes before he escorted her across the street to Montefiore Medical Center, where doctors took scans of her neck and brain. “Christa is lucky to be alive,” he says. “I knew the moment I saw her that she had had a stroke.” And he is convinced that the stroke was caused by Heck’s neck adjustment, which tore a critical artery that keeps blood flowing to the brain. “I see at least two cases like this or worse a year,” Dr. Kazmi says. “Cervical manipulation is a preposterous thing to do, and it should be banned.”
Americans make some 250 million visits to a chiropractor each year, and 105 million of those appointments include neck manipulations, according to the American Chiropractic Association in Arlington, Virginia. In addition to being used for neck, back and headache pain, the treatment is purported by some chiropractors to ease ailments as diverse as asthma, PMS and attention deficit disorder.
Chiropractic theory holds that when vertebrae become misaligned, they may put pressure on nerves along the spine, interrupting the nerves’ signals to the rest of the body. “Through improving the functioning of the joints, you are at the very least improving overall health,” says ACA spokesman William J. Lauretti, assistant professor at New York Chiropractic College in Seneca Falls. “When a spinal joint is not functioning properly, it’s a chronic irritant to the nervous system.”
Introduced in the late 19th century by the founder of chiropractic medicine, Daniel David Palmer — a Canadian schoolteacher who became famous for his healing touch — neck adjustments are given routinely and repeatedly by U.S. chiropractors, as well as some physicians, physical therapists and massage therapists. But despite patients’ enthusiasm for the neck adjustment — 45 percent of respondents to a Self.com poll said they had seen a chiropractor — researchers have not produced definitive proof of its medical value.
In 1996, several chiropractic groups commissioned a study from the Rand Corporation, an independent research company in Santa Monica, California; Rand reported that there have not been enough studies to show long-term benefits from cervical manipulations for neck, head and shoulder pain and only sparse evidence of short-term relief. A 2005 study in the Journal of Manipulative and Physiological Therapeutics reached a similar conclusion. Earlier this year, an evaluation of chiropractic visits and other complementary treatments for lower-back pain conducted by Harvard Medical School in Boston found the therapies “did not result in clinically significant improvements in symptom relief or functional restoration.” (The researchers did not track whether patients were getting neck adjustments specifically, but the ACA estimates 42 percent of appointments include them.)
What neck adjustments can do
In Self’s online poll, more than 20 percent of women who visited the chiropractor said they felt no better afterward. Eight percent said they felt worse. Injuries that can occur on a chiropractor’s table include soft tissue damage, joint dislocations and bone fractures in the neck and back. The most common problem is disk injury in the neck or lower back, which can be extraordinarily painful. (In 1999, Karen Santorum, wife of former Pennsylvania Senator Rick Santorum, won $175,000 in court after suffering a herniated disk at the hands of a chiropractor.) But only neck manipulation, not back adjustments, can cause the life-altering side effect Christa Heck had.
According to Heck’s medical records, the chiropractor’s neck adjustment left a 4.5-centimeter tear in her left vertebral artery, one of four pathways that control blood flow to the brain (the others are the right vertebral artery and the left and right carotid arteries).
Extreme or abrupt twisting of the neck can damage the inner layer of these arteries, creating a blood clot. If the clot travels north, it can cut off blood flow to part of the brain — the definition of a stroke. In fact, Dr. Kazmi believes Heck had two strokes, one the day after her first neck adjustment, and another immediately following her second. “The damage was done after the first manipulation, then she started throwing clots,” he says.
Heck’s chiropractor (who Heck asked not be identified for fear of jeopardizing a legal settlement) said through his lawyer, Stephen P. Haber of White Plains, New York, that Heck’s version of events was contradicted by “sworn deposition testimony, records of care and test results to say nothing of established principles of chiropractic and medical science” and that he looks forward to trying the matter in court.
Heck’s vertigo and queasiness after her first appointment should have been red flags because both are symptoms of stroke. Chiropractors should tread carefully and do extra screening tests before manipulating the neck of a patient who complains of unusual dizziness, vertigo or nausea, according to an instructional guide published by National Chiropractic Mutual Insurance Company in Clive, Iowa, the nation’s largest chiropractic insurer. “A good chiropractor doesn’t merely grab people’s necks and crack them,” the ACA’s Lauretti says. “You take a thorough exam. If there is a history of dizziness, stroke, visual or auditory disturbances, and to a certain extent a history of migraine, I’m going to be much more cautious.”
Wade S. Smith, M.D., director of the Neuro-vascular Service at the University of California at San Francisco, was the lead author of a 2003 study in the journal Neurology that confirmed the connection between cervical manipulation and stroke. In the study, Dr. Smith says, patients with strokes caused by torn arteries were nearly five times more likely to have had a recent neck adjustment than those with strokes caused by something else, indicating that “recently seeing a chiropractor is an independent risk factor for stroke.”
And although researchers aren’t sure why, young women tend to have slightly more of the injuries. Brittmarie Harwe, 40, of Wethersfield, Connecticut, received an out-of-court settlement of $900,000 after a 1993 manipulation that permanently paralyzed one of her vocal cords and left her unable to swallow food; she nourishes herself through a stomach tube. In December 2006, Rachelle Smith, a 32-year-old mother of five in Olathe, Kansas, settled a case with her chiropractor for undisclosed damages and $70,000 in medical costs. She says that when she began to vomit after a neck adjustment — a sign of what would turn out to be a stroke — the chiropractor assured her that her body was simply “releasing toxins.”
“I’ve seen more cases of vascular injury following chiropractic manipulations than just about anybody, and these people’s lives are ruined,” says Alan Bragman, an Atlanta chiropractor who has served as an expert witness in some 900 chiropractic cases in the United States, Canada and Puerto Rico. “I’ve known of seven or eight people who died right on the table or shortly thereafter,” he adds. Kristi Alaine Bedenbaugh, 24, of Little Mountain, South Carolina, died in 1993 three days after a cervical manipulation for a sinus headache and a few months before her wedding. In 1998 in Saskatoon, Saskatchewan, 20-year-old restaurant supervisor Laurie Jean Mathiason fell into a coma on her chiropractor’s table minutes after a neck manipulation she received for a tailbone injury; she was dead three days later.
“The twist was so violent that it tore her artery clear through,” says her mother, Sharon Mathiason. “In our wildest dreams, our family had never imagined that a perfectly healthy kid in the prime of her life could have a stroke. But at the hospital, we were bombarded with doctors coming into the waiting room and saying, ‘Don’t you know that (if you go to the chiropractor), never let them touch you above the shoulders?’ I have made it my life’s campaign to warn people of the risks of chiropractic neck adjustment.”
Risks vs. benefits
The stories are frightening. But the actual risk for injury remains a topic of fierce debate. Estimates vary wildly as to how many neck manipulations will lead to a stroke — numbers from 1 in 5.8 million treatments (from an analysis of data from the Canadian Chiropractic Protective Association, a chiropractic malpractice insurer in Toronto) to 1 in 400,000, according to a study published in a 1996 issue of the Journal of Manipulative and Physiological Therapeutics. A 2003 survey of French doctors by the Hospitals of the University of Strasbourg, France, found that the incidence of post-manipulation vascular injuries was 30 times higher than had been published in medical journals. One reason the numbers are so varied may be that there is no formal system for reporting complications from chiropractic manipulation.
Chiropractors and the organizations that represent them say the dangers of manipulating the neck have been overplayed. In all but a handful of states, no law or written ethical guideline requires them to alert patients about the possibilities of damage, and most of them don’t. “A stroke following a manipulation is phenomenally rare,” Lauretti says. “We want to give information to patients to empower them, but at what point does that information become meaningless? With this issue, we are approaching that point.”
Statistically speaking, taking aspirin or another nonsteroidal anti-inflammatory drug for pain is potentially far more toxic than getting one’s neck cracked; NSAIDs account for about 7,500 deaths per year, according to researchers from Stanford University in California. The difference is that aspirin is a scientifically proven pain reliever, and neck manipulation is not, says Brad Stewart, M.D., a neurologist in Edmonton, Alberta, with a special interest in chiropractic stroke.
“The expectation of benefit is almost negligible. The risk, though small, is very real,” says Dr. Stewart, one of whose patients had part of her brain removed after a cervical manipulation mangled both of her vertebral arteries. “You can’t predict who this will happen to, and for that reason alone, it just shouldn’t be done.”
As Lauretti notes, almost any sudden movement of the neck can tear an artery — leaning your head back to drink a soda, for instance, doing yoga, stargazing or craning to check your blind spot as you back out of the driveway. Medical journals have reported numerous cases of women who have been seriously injured having their hair washed at a salon. According to a study from Cedars-Sinai Medical Center in Los Angeles, one-fourth of arterial dissections are caused by abnormalities that already exist in the connective tissue that make certain people particularly vulnerable to the injury. “It’s not a simple black-and-white issue that someone who visits the chiropractor and then suffers a stroke can say clearly it’s the chiropractor’s fault,” says Wouter I. Schievink, M.D., director of the vascular neurosurgery program at Cedars-Sinai. “It’s not always clear what came first, the dissection or the manipulation.”
Given the enormous amount of chiropractic visits in this country, Dr. Schievink says, the risk per visit is tiny. On the other hand, patients see chiropractors an average of 10 times during treatment. “If you take into consideration how many times they go and how many manipulations are performed, it does become a public health concern,” he says. “It’s a low risk but potentially a life-threatening one.”
‘I miss the old Christa’
It’s the late fall of 2006 and Christa Heck looks like any other professional woman walking along Manhattan’s East Side. Her light-brown hair is freshly highlighted, her dark-blue pantsuit neat and stylish. But when she steps from the street to the curb, she stumbles to the right. Certain the fumbling has gone unnoticed, she continues to chat, but her words are ever so slightly slurred.
To remember her meeting today, Heck says that she placed notes by her bed, on her bathroom door and on the microwave oven in the kitchen. “Otherwise, I might not have remembered to come,” she says, pulling medical records from a large manila envelope. She points to a 2005 neurology report that suggests she has a generalized brain injury with symptoms such as memory loss, impaired motor coordination and slower mental processing.
Heck speaks as if her true self was lost in the past — about her 3.97 grade point average in college, her plans before the stroke to go to law school and her once phenomenal ability to multitask, caring for four children while being the sole breadwinner for her family when Ed was forced onto disability. These days, her girls — ranging in age from 15 to 25, three of them stepdaughters from Ed’s previous marriage — don’t rely on her so much. “I can’t tell you how many times I’ve simply forgotten to pick up my youngest daughter from soccer practice,” she says. Nor does she see her friends as often as she used to. “I asked one of my friends if I had changed, and she said, ‘Honestly, Christa, you’ve changed a lot.’ It breaks my heart.”
Heck continued to work for two years after the stroke, her manager adjusting her assignments to help her cope. But when her company introduced a new product for her to sell, Heck resigned. “I couldn’t handle too many things at once,” she says. She has considered a job in retail, but her psychiatrist told her she might find it difficult when the store got busy and recommended she take a quiet back-office job.
Meanwhile, she spends time working with Victims of Irresponsible Chiropractic Education and Standards (VOICES), a fledgling advocacy group comprising families of 60 victims of chiropractic stroke, five of whom have died. The group is urging Congress to ban cervical manipulation. While federal action seems unlikely, another group of victims in Connecticut is supporting bills that would require that state to track chiropractic injuries and add chiropractors to a public database of physician credentials, disciplinary actions and malpractice suits. A third proposed law would require Connecticut chiropractors to obtain written consent before doing a neck adjustment, explain the risk for stroke and detail its symptoms.
“Had I known stroke was a risk, I would have recognized that something was wrong before going back a second time,” Heck says with tears in her eyes. “I miss the old Christa so much. Had I known better, I’d still have her.”
This article was originally published in the May 2007 issue of SELF.
Copyright © 2007 CondéNet. All rights reserved.

Human instruction book not so simple: studies

Wed Jun 13, 2007 3:52 PM ET
By Maggie Fox, Health and Science Editor
WASHINGTON (Reuters) – An in-depth examination of the human DNA map has turned basic biology concepts upside-down and may even rewrite the book on evolution and some causes of disease, researchers said on Wednesday.
They found there was far more to genetics than the genes themselves and determined there was no such thing as “junk DNA” but that some of the most useless-looking stretches of DNA may carry important information.
Thirty-five teams of researchers from 80 different organizations in 11 countries teamed up to share notes on just 1 percent of the human genome.
Their findings, the start of the Encyclopedia of DNA Elements or ENCODE Project, were published in the journals Nature and Genome Research.
“This is a landmark in our understanding of human biology,” said Dr. Francis Collins, head of the National Human Genome Research Institute, which funded much of the work.
When the human genome was published in 2003, some scientists voiced surprise that human beings had only about 30,000 genes. Rice, for instance, has 50,000.
The new study confirms what many genetics experts had suspected — the genes are important, but so is the other DNA, the biological code for every living thing.
What they discovered is that even DNA outside the genes transcribes information. Transcription is the process that turns DNA into something useful — such as a protein.
ACTION OUTSIDE THE GENES
Much of this action is going on outside the genes in the so-called regulatory regions that affect how and when a gene activates, Collins said.
The researchers discovered 4,491 of these so-called transcription start sites, “almost tenfold more than the number of established genes,” they wrote in the Nature paper.
Ewan Birney of the European Molecular Biology Laboratory’s European Bioinformatics Institute in Cambridge said this helped explain how such a complex creature as a human arose from just four letters of code repeated over and over.
“The junk is not junk. It is really active,” Birney told reporters. This could be useful in understanding and treating disease.
“One could imagine that that actually could be a good thing because it would tell you that there is a subtle tweaking of the expression of that particular gene, and therefore that particular protein in a person at high risk — they are making a little too much or not quite enough,” Collins added.
Drugs might easily be designed to compensate, he said.
The researchers did find some DNA that appears to do nothing, and it can mutate without causing any damage.
Collins likened these stretches of DNA to boxes in the attic.
“It is not the sort of clutter that you get rid of without consequences because you might need it. Evolution may need it,” he said.
That little extra padding might be just what an animal needs to adapt to some unforeseen circumstance, the researchers said. “They may become useful in the future,” Birney said.

Fleeting glances help eyes sharpen focus – Study

CHICAGO (Reuters) – Our eyes are moving constantly, and it now appears this motion helps to refine and sharpen the images we see, U.S. researchers said on Wednesday.
“It’s impossible to keep your eyes perfectly still,” said Michele Rucci, director of the Active Perception Laboratory in Boston University’s Department of Cognitive and Neural Systems.
Rucci said researchers have long believed these rapid movements help refresh images we see, but his work shows they do something more.
“It tells us these very small eye movements, which are always there and which we almost always ignore, are rather important. They actually provide useful information,” said Rucci, whose work appears in the journal Nature.
“These are very tiny eye movements. We perform them without being aware of doing so,” he said in a telephone interview.
To study this phenomenon, he and colleagues asked people with good vision to report which direction an image tilted after it was briefly flashed on a computer screen.
Next, they simulated what the image would look like if the eyes were fixed, moving the image on the monitor in concert with their eyes.
“We removed the effect of these small eye movements,” Rucci said.
What they found is that subjects were significantly more efficient at discriminating fine patterns when their eyes flitted around than when the image remained fixed.
He said the results explain the function of our constantly roving eyes, which may be part of a strategy used by the brain to extract useful visual information.
His work may also have some implications for people with certain eye problems, such as nystagmus, a condition characterized by involuntary eye movements that can impair vision.
“Our results may help explain the reasons behind part of these visual deficits and may contribute to the development of treatments,” he said.

Revealed: how drug firms ‘hoodwink’ medical journals

Pharmaceutical giants hire ghostwriters to produce articles – then put doctors’ names on them
Antony Barnett, public affairs editor
Sunday December 7, 2003
Observer
Hundreds of articles in medical journals claiming to be written by academics or doctors have been penned by ghostwriters in the pay of drug companies, an Observer inquiry reveals.
The journals, bibles of the profession, have huge influence on which drugs doctors prescribe and the treatment hospitals provide. But The Observer has uncovered evidence that many articles written by so-called independent academics may have been penned by writers working for agencies which receive huge sums from drug companies to plug their products.
Estimates suggest that almost half of all articles published in journals are by ghostwriters. While doctors who have put their names to the papers can be paid handsomely for ‘lending’ their reputations, the ghostwriters remain hidden. They, and the involvement of the pharmaceutical firms, are rarely revealed.
These papers endorsing certain drugs are paraded in front of GPs as independent research to persuade them to prescribe the drugs.
In February the New England Journal of Medicine was forced to retract an article published last year by doctors from Imperial College in London and the National Heart Institute on treating a type of heart problem. It emerged that several of the listed authors had little or nothing to do with the research. The deception was revealed only when German cardiologist Dr Hubert Seggewiss, one of the eight listed authors, called the editor of the journal to say he had never seen any version of the paper.
An article published last February in the Journal of Alimentary Pharmacology , which specialises in stomach disorders, involved a medical writer working for drug giant AstraZeneca – a fact that was not revealed by the author.
The article, by a German doctor, acknowledged the ‘contribution’ of Dr Madeline Frame, but did not admit that she was a senior medical writer for AstraZeneca. The article essentially supported the use of a drug called Omeprazole – which is manufactured by AstraZeneca – for gastric ulcers, despite suggestions that it gave rise to more adverse reactions than similar drugs.
Few within the industry are brave enough to break cover. However, Susanna Rees, an editorial assistant with a medical writing agency until 2002, was so concerned about what she witnessed that she posted a letter on the British Medical Journal website.
‘Medical writing agencies go to great lengths to disguise the fact that the papers they ghostwrite and submit to journals and conferences are ghostwritten on behalf of pharmaceutical companies and not by the named authors,’ she wrote. ‘There is a relatively high success rate for ghostwritten submissions – not outstanding, but consistent.’
Rees said part of her job had been to ensure that any article that was submitted electronically would give no clues as to the origin of the research.
‘One standard procedure I have used states that before a paper is submitted to a journal electronically or on disc, the editorial assistant must open the file properties of the Word document manuscript and remove the names of the medical writing agency or agency ghostwriter or pharmaceutical company and replace these with the name and institution of the person who has been invited by the pharmaceutical drug company (or the agency acting on its behalf) to be named as lead author, but who may have had no actual input into the paper,’ she wrote.
When contacted, Rees declined to give any details. ‘I signed a confidentiality agreement and am unable to comment,’ she said.
A medical writer who has worked for a number of agencies did not want to be identified for fear he would not get any work again.
‘It is true that sometimes a drug company will pay a medical writer to write a review article supporting a particular drug,’ he said. ‘This will mean using all published information to write an article explaining the benefits of a particular treatment.
‘A recognised doctor will then be found to put his or her name to it and it will be submitted to a journal without anybody knowing that a ghostwriter or a drug company is behind it. I agree this is probably unethical, but all the firms are at it.’
One field where ghostwriting is becoming an increasing problem is psychiatry.
Dr David Healy, of the University of Wales, was doing research on the possible dangers of anti-depressants, when a drug manufacturer’s representative emailed him with an offer of help.
The email, seen by The Observer, said: ‘In order to reduce your workload to a minimum, we have had our ghostwriter produce a first draft based on your published work. I attach it here.’
The article was a 12-page review paper ready to be presented at an forthcoming conference. Healy’s name appeared as the sole author, even though he had never seen a single word of it before. But he was unhappy with the glowing review of the drug in question, so he suggested some changes.
The company replied, saying he had missed some ‘commercially important’ points. In the end, the ghostwritten paper appeared at the conference and in a psychiatric journal in its original form – under another doctor’s name.
Healy says such deception is becoming more frequent. ‘I believe 50 per cent of articles on drugs in the major medical journals are not written in a way that the average person would expect them to be… the evidence I have seen would suggest there are grounds to think a significant proportion of the articles in journals such as the New England Journal of Medicine, the British Medical Journal and the Lancet may be written with help from medical writing agencies,’ he said. ‘They are no more than infomercials paid for by drug firms.’
In the United States a legal case brought against drug firm Pfizer turned up internal company documents showing that it employed a New York medical writing agency. One document analyses articles about the anti-depressant Zoloft. Some of the articles lacked only one thing: a doctor’s name. In the margin the agency had put the initials TBD, which Healy assumes means ‘to be determined’.
Dr Richard Smith, editor of the British Journal of Medicine, admitted ghostwriting was a ‘very big problem’ .
‘We are being hoodwinked by the drug companies. The articles come in with doctors’ names on them and we often find some of them have little or no idea about what they have written,’ he said.
‘When we find out, we reject the paper, but it is very difficult. In a sense, we have brought it on ourselves by insisting that any involvement by a drug company should be made explicit. They have just found ways to get round this and go undercover.’

Safety of Children’s Cough Drugs Reviewed

By GARDINER HARRIS
The New York Times
WASHINGTON (March 2) Federal drug regulators have started a broad review of the safety of popular cough and cold remedies meant for children, a top official said Thursday.
Concerns About Cold Remedies
Craig Mitchelldyer, Getty ImagesCold medicines line a pharmacy shelf. The government review began after doctors and health officials demanded that drug makers be stopped from marketing certain remedies for children under age 6.
The official, Dr. Charles J. Ganley, director of the office of nonprescription drug products at the Food and Drug Administration, said in an interview that the agency was “revisiting the risks and benefits of the use of these drugs in children” and that “were particularly concerned about the use of these drugs in children less than 2 years of age.” In higher than normal doses, cold medicines can affect the hearts electrical system, leading to arrhythmias. Some medicines affect the blood vessels and, in high doses, have been associated with hypertension and stroke. In rare cases, children have been injured even when given recommended doses. In a recent study of hospital emergency room records from 2004 and 2005, the Centers for Disease Control and Prevention found that at least 1,519 children under age 2 had suffered serious health problems after being treated with common cough and cold medicines. Three of the children died, the disease control agency found. The F.D.A. said it was too early to predict whether the review would lead to new regulations. Its comments came in response to a petition filed on Thursday by a group of prominent pediatricians and public health officials demanding that the agency stop drug makers from marketing cold and cough medicines for children under age 6. The petition says that the medicines do not work and that in rare cases they can cause serious injury. Popular medicines like Toddlers Dimetapp, Infant Triaminic and Little Colds, which are marketed for use in children as young as 2, should not be given to children younger than 6 under any circumstances, the petition says. Like hundreds of older drugs, many of the medicines in these products did not receive thorough safety reviews by the F.D.A, many people use these products even though they have no effect on colds, and theres a real risk of a problem,” said an author of the petition, Dr. Joshua Sharfstein, a pediatrician and the health commissioner of Baltimore. Dr. Ganley of the F.D.A. said most over-the-counter cold and cough medicines had not been adequately tested in children. The doses recommended on many of the products labels were no better than educated guesses, he said. “We have no data on these agents of whats a safe and effective dose in children,” Dr. Ganley said. Linda A. Suydam, president of the Consumer Healthcare Products Association, a trade group of companies that market over-the-counter cold remedies, said the remedies had been approved by the F.D.A. and had been used for decades by millions of Americans. Consumers should take only the recommended doses, Ms. Suydam said. Doug Petkus, a spokesman for Wyeth, which makes Toddlers Dimetapp, agreed, adding that “parents of children under the age of 2 are encouraged to seek the advice of a physician before administering any over-the-counter medicine.”
Such cautions “are clearly stated in product labeling,” Mr. Petkus said. The agency has for decades promised to review systematically the safety of all old drugs, but for a variety of reasons like budgetary constraints, time and popularity of a particular drug has not done so. The pediatricians who petitioned the drug agency acknowledged that childrens cough and cold medicines were generally safe when given in recommended doses. But they added that overdoses were common, for a variety of reasons. Parents sometimes give their children two different brands, unaware that they contain the same active ingredients. Overdoses can also result when frantic parents try to shove eyedroppers or cups of medicine into the mouths of crying, spitting babies. The safety problems might be worth risking, the petitioners said, if the medicines worked to suppress coughs or clear stuffy noses. But according to a growing number of studies in children, the drugs are no better than placebos. “There is widespread consensus that there is no good evidence for the effectiveness of several of the compounds used in cold medicines,” said Dr. Ian M. Paul, an assistant professor of pediatrics at Penn State College of Medicine who has studied the medicines. Last year, the American College of Chest Physicians recommended that parents avoid using cough and cold medicines in children, especially young ones. Despite these growing worries, sales of the drugs are booming. Most major pharmacies carry a dozen or more brands. The market for the medicines is fed by parents looking for anything to have their children sleep peacefully. Children suffer an average of six to 10 colds each year, far more than adults. A 1994 study found that during one 30-day span, more than a third of the nations 3-year-olds were estimated to have been given over-the-counter cough and cold remedies. The products labels and advertising strongly suggest that they work, many with flavors like grape and cherry. Little Colds has a cartoon of a cheerful, crawling infant wearing only a diaper. It promises that it “safely and gently relieves.” Childrens Vicks NyQuil has a cartoon that shows a small, sleeping child hugging a sleeping puppy. “Parents will do anything for their kids,” Dr. Sharfstein said. “They will buy expensive syrups if they think their kid will do better.” Most cough and cold concoctions have nasal decongestants, antihistamines, cough suppressants or expectorants common ingredients with names like dextromethorphan, guaifenesin and phenylephrine. Most of these drugs have been around for decades and were approved for sale by the F.D.A. when standards were far lower than they are today. Medicines were often approved with little or no testing before 1970 to ensure that they were safe or effective. Since then, the agency has gradually tightened standards and occasionally revisits old standards. The agency has put all the compounds on a “monograph,” meaning that manufacturers can use and combine them in pills and syrups without doing any of the expensive and lengthy studies that would be needed for a new drug. Because the drugs are so widely available, there is no incentive for manufacturers to perform such studies. Information about their lack of efficacy and worrisome side effects have trickled out. Dr. Sidney Wolfe, director of Public Citizens Health Research Group and a longtime critic of the F.D.A., noted that cold medicines had a troubled history. A decade ago, many such medicines contained phenylpropanolamine, or PPA, until studies showing that it could cause hemorrhagic stroke led the F.D.A. to ban it. Given such problems, Dr. Wolfe said, the agency years ago should have taken a closer look at all common cold medicines. Dr. Sharfstein said there was now enough evidence about the dangers of the drugs for the F.D.A. to act. “There is this incredible disparity between how the products are regulated and what the scientific evidence and consensus states,” Dr. Sharfstein said. John Schwartz contributed reporting from New York.

Smoking changes brain the same way as drugs: study

Tue Feb 20, 2007 9:14pm ET
Science News
WASHINGTON (Reuters) – Smoking causes long-lasting changes in the brain similar to changes seen in animals when they are given cocaine, heroin and other addictive drugs, U.S. researchers said on Tuesday.
A study of the brain tissue of smokers and nonsmokers who had died showed that smokers had the changes, even if they had quit years before, the team at the National Institute on Drug Abuse reported.
“The data show that there are long-lasting chemical changes in the brains of humans,” said Michael Kuhar of Emory University in Atlanta, who was not involved in the study.
“The chemical changes alone suggest a physiological basis for nicotine addiction.”
A team led by Bruce Hope of NIDA, one of the National Institutes of Health, analyzed levels of two enzymes found inside brain cells known as neurons.
These enzymes help the neurons use chemical signals such as those made by the message-carrying compound dopamine.
Smokers and former smokers had high levels of these enzymes, the researchers reported in the Journal of Neuroscience.
Hope said other studies had seen the same thing in animals given cocaine and heroin — and it was clear that the drugs were causing the effects.
“This strongly suggests that the similar changes observed in smokers and former smokers contributed to their addiction,” he added in a statement.
Experts on smoking have long said that nicotine is at least as addictive as heroin.
The U.S. Centers for Disease Control and Prevention estimates that 20.9 percent of all adults smoke in the United States, which adds up to 45 million people. And 23 percent of high school students smoke.
© Reuters 2007. All Rights Reserved

Flu Virus Coat Key to Disease Spread

Lauran Neergaard, Associated Press
Feb. 2, 2007 — Making a small change in the outer coating of the lethal 1918 flu virus was enough to stop it from spreading, a discovery that may help scientists monitor today’s bird flu and other influenza strains for signs of the next pandemic.
The 1918 pandemic was triggered by a bird virus that mutated into one that could attack humans, going on to kill a staggering 50 million people worldwide in a matter of months.
To learn what caused that catastrophic bird-to-human transformation, scientists with the Centers for Disease Control and Prevention turned back the clock: They worked with recreated batches of the actual H1N1 flu strain that spawned the 1918 pandemic, but they altered two spots in a key protein to make that virus a little more birdlike again.
Then the researchers dripped the altered virus into the noses of ferrets, who catch and spread influenza like humans do.
The infected ferrets still sickened and died as the flu ravaged their lungs. But remarkably, they didn’t infect healthy ferrets caged right next to them, the CDC team reports in Friday’s edition of the journal Science.
Why not? Most flu spreads when an infected person coughs or sneezes out droplets of virus. Ferrets infected with the altered 1918 virus didn’t sneeze at all.
The research suggests that for a new flu strain to become a pandemic threat, a protein called hemagglutinin that coats the virus’ surface must prefer attaching to cells found mostly in the human nose and windpipe, where it can be sneezed easily.
That’s good news when it comes to the notorious Asian bird flu that scientists are watching anxiously today. That strain, known as H5N1, bears hemagglutinin — the H in its name — that still prefers cells mostly found in the gastrointestinal tracts of birds.
While it has killed at least 164 people worldwide and killed or prompted the slaughter of millions of birds across Asia since late 2003, the H5N1 virus can’t yet spread easily from person to person.
“This is very, very elegant work,” said Dr. William Schaffner, an infectious disease specialist at Vanderbilt University who advises the federal government on flu issues.
“It may not be exactly the same mutations that would change an H5 virus,” Schaffner cautioned. Still, he said, “We appear to be narrowing down our understanding of the kinds of mutations it might take to change a bird-specific virus to one that could be transmitted readily among humans.”
The CDC’s next step, in fact, is to study these same changes in hemagglutinin amino acids, the protein’s building blocks, in H5N1.
But it will almost certainly take additional genetic changes to turn the H5N1 bird flu into a major human killer, changes that probably involve other proteins than just hemagglutinin, contends lead researcher Dr. Terrence Tumpey, a CDC microbiologist.
“I think that researchers may discover that the combination of genes needed is maybe unlikely to occur in nature,” he said.