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Walk Soft: Nerve Rewiring Restores Most Movement Post–Spinal Injury

When nerves connecting the brain and spinal cord are severed, rerouting signals through local nerve cells can make movement possible again

aching spine 
AFTER CUTTING THE CORD: Scientists showed that intrinsic spine neurons can substitute for long nerve fibers (which connect directly to the brain) that are severed in spinal cord injury to restore waling ability. 

Often spinal cord injuries result in the severing of the long nerve fibers connecting the brain to the spinal cord, disrupting one's ability to walk, among other things. But even with the primary top-to-bottom signal highway rendered out of order, the nervous system can, over time, reroute itself, finding neural detours and side streets that restore movement, according to a new study out of the University of California, Los Angeles (U.C.L.A.).

"It's been known for some time that after certain types of lesions, animals and human[s] will recover their ability to walk," notes Michael Sofroniew, a professor of neurobiology at U.C.L.A.'s David Geffen School of Medicine. For instance, if the long nerve fibers on only one side of the spinal cord are damaged, "the previous explanation is that the other [intact] side was able to activate things," he adds.

Recent work in Sofroniew's lab contradicts that theory. Using mice, the U.C.L.A. researchers first severed the nerve fibers coming from the brain to one side of lumbar spinal cord (in the lower back), which controls walking. This resulted in a complete loss of movement in the corresponding hind limb, causing the animal to drag it along when it moved. Over a period of 10 weeks, Sofroniew says, "the swing of the injured leg starts coming back and gets to become 80 percent of normal," on average.

If the relay neurons in the spinal cord located near the area where the injury occurred were chemically blocked, however, the restoration of movement disappeared. "That basically proves that these cells are essential for the recovered function," Sofroniew explains. But it leaves open the possibility that the still-intact long nerve fibers on the other side of the spinal cord may be contributing to this recovery.

So the team repeated the study, again severing the nerves on one side of the lumbar spine and letting function return via new connections. Then they damaged the nerves on the other side of the lower spinal cord as well. Between the two injuries was a zone of spinal cord tissue left unharmed.

Without help from long nerve fibers from the brain on either side spinal cord, which, at this point, were both cut from their normal connections, the mouse could still recover walking function, implying that the intact zone of relay neurons in the spinal cord had been able to transmit signals from the brain and restore movement.

"It should be emphasized that the final walking that the mice had at the end was not as fast, not nearly as efficient," Sofroniew notes. Again, when the unharmed zone was chemically disrupted, the mouse's ability to walk disappeared.

The U.C.L.A. team next hopes to determine how to enhance signal rerouting from the brain to the spinall walking centers. Sofroniew believes that prodding these intrinsic spinal cord neurons with drugs to form new connections combined with physical rehabilitation programs may maximize patient recovery.

Karim Fouad, an associate professor of rehabilitation medicine at the University of Alberta in Edmonton, says that the new work firmly establishes that these "interneurons" that make up the spinal cord can substitute to receive the signals that control movement when long nerve fibers are damaged. He adds, however, that the proposed path to maximizing recovery from spinal cord damage has already been explored in two papers he co-authored in the journal Brain.

"We actually showed just recently that if we give a certain drug to the brain, we can promote this rewiring into these 'interneurons'," he explains, referring to a 2006 study in rats involving brain-derived neurotrophic factor (BDNF), a protein that encouraged new connections between neurons in the brain and the relay neurons in the spinal cord. Further, in a study published last year, his lab demonstrated that reaching exercises undertaken by animals also encouraged the creation of these connections.

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Pro-Drug Gets Attention

The latest on drug approvals, warnings and research 

ALL-DAY RELIEF FROM ADHD: The U.S. Food and Drug Administration is now considering whether to approve the marketing of Vyvanse (lisdexamfetamine dimesylate, made by Shire) to adults with attention-deficit hyperactivity disorder (ADHD).

Shire filed for that application in June, following up on the FDA’s approval of Vyvanse last February as a treatment for ADHD in children.

Like many ADHD medications, Vyvanse acts as a stimulant. (Paradoxically, stimulants can help offset such hyperactivity problems, possibly by leveling out inconsistencies in how fast different parts of patients’ brains process in­formation.) Vyvanse, however, is a “pro-drug” com­pound that does not exert its therapeutic effect until after the body has metabolized it. That ­delayed action can stretch out how long the drug works: in studies, a dose of Vyvanse was able to combat ADHD symptoms for a full day. (The delay may also make it less appealing for abuse than conventional amphetamine stimulants are.)

The review period for the adult application is 10 months; look for a decision in spring 2008.

Last June the FDA also issued an “approvable letter” to Shire for another of its pending anti-ADHD products, Intuniv (guanfacine), a once-a-day extended-release tablet. An approvable letter indicates that the FDA is prepared to approve a new drug application once certain specified conditions, such as a request for additional information, are met. According to the filed application, Intuniv, which is not a stimulant, acts specifically on the brain’s prefrontal cortex to improve executive functions, such as working memory, impulse control, tolerance of frustration and regulation of attention.

More: www.shireadhdtreatments.com

EASING FIBROMYALGIA: Sufferers of fibromyalgia, a painful and frustratingly mysterious affliction of the muscles and connective tissue, can finally hope for some relief. Lyrica (pregabalin, made by Pfizer) became the first FDA-approved drug treatment for fibromyalgia in June. Not all fibromyalgia patients have found that Lyrica reduced their discomfort, and common side effects have included dizziness and sleepiness. The drug had previously been approved for use in treating the nerve pain of shingles. Still more applications may yet emerge: Lyrica is also in advanced clinical trials as a treatment for epilepsy and for generalized anxiety disorder.

More: www.lyrica.com

NEW HOPE AGAINST RESISTANT BREAST CANCER: Ixabepilone, a compound being investigated by Bristol-Myers Squibb, shows some encouraging effectiveness against metastatic breast cancers that are resistant to three other standard che­motherapy drugs (anthracycline, taxane and capecitabine). That was the finding of a phase II clinical trial published in the Journal of Clinical Oncology in August. Ixabepilone belongs to a new class of potential chemotherapy agents called epothilones that inhibit the growth of cancer cells. In June the FDA accepted the company’s New Drug application for ixabepilone, and, based on expectations, a decision should have been announced in October.

More: www.bms.com

NEW HIV TREATMENT: For the first time in 10 years, the FDA has approved a member of a new class of oral HIV medication. Selzentry (maraviroc, made by Pfizer) prevents HIV from entering white blood cells. The FDA gran­ted the approval in August on an accelerated basis, after only 24 weeks of data collection during a clinical trial. The drug, however, is so far meant for use only by patients infected with a particular strain of the virus—CCR5-tropic HIV-1—that is resistant to many other antiretroviral therapies.

More: www.pfizer.com

LIVING WELL IS THE BEST PROVENGE? One of the most contentious and closely scrutinized decisions before the FDA concerns Provenge, a proposed therapeutic vaccine made by Dendreon for use against prostate cancer. Better options for controlling or treating prostate cancer are desperately in demand because existing treatments often fail or carry undesirable consequences (such as impotence or incontinence). A therapeutic vaccine would not be intended to prevent the disease but rather to help patients’ immune systems mobilize against the cancer cells, without recourse to surgery or radiation.

An advisory panel to the FDA recommended approval of Provenge on the basis of good early clinical results, but the FDA instead requested more information last May after a second phase III clinical trial seemed more equivocal. Outraged patient groups (and investors in Dendreon) have protested this decision, at times alleging that hidden interests sabotaged the drug’s approval.

Turning up the heat was a July report in the journal Clinical Cancer Research, which argued that clinical trials often misjudge cancer vaccines: in the case of Provenge, its failure to shrink tumors may be less significant than its success in raising survival rates. Dendreon is planning a new trial for Provenge that focuses on survival, and it could submit preliminary data from that work during 2008.

More: www.dendreon.com, www.provengenow.org

PULLING THE PLUG ON A NOVEL PAINKILLER: Neuromed Pharmaceuticals and Merck announced in early August that they were suspending development of a compound called MK-6721 as a treatment for chronic pain, after disappointing results in a phase II clinical trial.

MK-6721 belongs to an innovative class of analgesic compounds, called N-type calcium channel blockers, that block pain signals in the nervous system. It reportedly showed no adverse side effects in earlier trials, but according to the pharmaceutical makers, in the more recent tests MK-6721 lacked “the ideal pharmaceutical characteristics considered necessary” to justify further development. Nevertheless, Neuromed and Merck indicated they would continue to investigate other N-type calcium channel blockers for treating pain.

More: www.neuromed.com, www.merck.com

HEARTBURN DRUGS OKAY FOR HEART: Two studies released in May had suggested that two popular prescription heartburn drugs made by AstraZeneca, Prilosec (omeprazole) and Nexium (esomeprazole), might increase users’ risks of heart problems. In August, however, the FDA concluded that the preponderance of available evidence did not support that worry and recommended that consumers continue to take the pills while investigations continued. The FDA expects to have concluded a more thorough review of the evidence by November.

More: www.astrazeneca.com

NEW MEDS FOR FIDO: Two recently approved veterinary drugs made by Pfizer Animal Health can help keep the family dog feeling fit.

Cerenia (maropitant citrate) is the first FDA-approved prescription medication specifically for the prevention and treatment of canine nausea. Motion sickness strikes one in six dogs during car trips and other travel. More­over, acute vomiting from other causes is a common reason for owners to take their dogs to the vet. Unlike some other nausea remedies, Cerenia does not make dogs drowsy.

Another problem for dogs that is increasingly widespread is obesity: as many as 40 percent of American dogs are overweight, according to Pfizer. The new prescription compound Slentrol (dirlotapide) decreases dogs’ appetite and food consumption: almost 98 percent of the animals in tests lowered their weight by an average of 11.8 percent. (Sorry, Garfield—Slentrol is not suitable for cats or humans.)

More:
www.pfizerah.com 

An Abundance of Remedies but Little Relief

Think again.

Most of the estimated 50 million Americans who suffer the runny noses, raw and itchy eyes, clogged sinuses and hammering headaches of allergic rhinitis, as hay fever is medically known, aren’t getting the relief they seek. According to a 2005 survey conducted by the Asthma and Allergy Foundation of America, more than half say they’re “very interested” in finding a new medication. One in four reports “constantly trying different medications to find one that works for me.”

Why is it so hard to find an effective treatment?

One problem, experts say, is that allergic rhinitis isn’t taken seriously enough, by doctors or allergy sufferers. “Allergic rhinitis is typically a doorknob complaint,” said Dr. Bradley Marple, professor of otolaryngology at the University of Texas Southwestern Medical School in Dallas. “Patients wait until they’re almost out the door before they say, ’Oh, and by the way, my allergies have been acting up.’” Too many doctors quickly write a prescription or recommend an over-the-counter antihistamine but fail to follow up to see if it worked.

Four out of five allergy sufferers never even make it to the doctor’s office, relying instead on over-the-counter remedies, according to the A.A.F.A. survey. “Unfortunately, that usually means there’s no treatment plan in place,” said Dr. Marple. “A patient may try one antihistamine and if it doesn’t work try another, when what they really need is a decongestant, or a drug that targets another part of the allergic reaction, or a corticosteroid nasal spray.”

That’s too bad, and not only because it means needless suffering. Allergies can lead to sleep problems and set sufferers up for more serious respiratory problems. Children with allergic rhinitis are three times more likely than their non-sniffling counterparts to develop asthma. Kids and adults alike are more likely to develop sinus and ear infections, especially if their allergies go untreated.

The strongest argument for taking allergies seriously comes from results of an ongoing experiment called the Preventive Allergy Treatment Study in Denmark. Seven years after completing a course of allergy shots aimed at quieting an overcharged immune response to harmless substances such as pollen, children in the study were more than four times less likely to develop asthma.

“Those results are really remarkable,” said Dr. Harold Nelson, an allergist at the National Jewish Medical and Research Center in Denver. Along with other evidence, he explained, they show that immunotherapy doesn’t just alleviate symptoms but actually changes the immune system of people with allergies, restoring it to normal.

Unfortunately, few studies have been done to compare one course of allergy treatment with another. Instead, physicians must rely not on evidence-based research but what’s referred to as “expert opinion.” And as Dr. Marple said, “experts can disagree.”

Still, a consensus on the basic plan of attack is emerging.

For mild to moderate allergic rhinitis, over-the-counter remedies are a reasonable first step. Decongestants work by constricting tiny blood vessels and shrinking swollen and inflamed tissue in the lining of the sinuses. Antihistamines block one of the biochemical steps of the allergic process.

If over-the-counter medicines don’t work, it’s time to talk to a doctor or allergist. Many prescribe corticosteroid nasal sprays, which suppress the allergic process at the heart of the problem.

Typically, immunotherapy is the last resort. The treatment involves identifying the specific culprit that’s causing the problem through a series of skin tests or, in some cases, a blood test. Tiny doses of allergen are then injected under the skin in a weekly series of allergy shots to desensitize the immune system.

Some doctors now offer an accelerated protocol called rush or cluster immunotherapy, in which patients receive several shots a day, spaced half an hour apart. “Instead of the six to eight months it usually takes with standard immunotherapy, we can get to maintenance levels in four weeks,” said Dr. Nelson. Because this rush procedure can lead to serious immune reactions, including shock, it must be closely monitored. A ragweed vaccine given over six weeks is also currently in testing.

For the needle-shy, another advance is making immunotherapy more attractive: the use of allergens that dissolve under the tongue. Although widely used in Europe, sublingual allergens haven’t yet won F.D.A. approval in the United States. Allergists are free to prescribe them, but insurance companies won’t cover the cost. Another drawback is that sublingual allergens are only about half as effective as injections in desensitizing the immune system. But patients can take them at home, rather than having to make an office visit for each treatment - an important advantage.

For his part, Dr. Nelson thinks more patients should consider immunotherapy, especially those with severe and persistent allergic rhinitis. “Medications work only as long as you keep taking them,” he said. “Immunotherapy is the only treatment we have that alters the immune system, restoring the same response to allergens like ragweed that we see in normal nonallergic people.”

Unlike pills and nasal sprays, in other words, immunotherapy holds out the possibility of something far better: a cure.

The Claim: Drinking Makes You Warmer in Winter

In moderation, the right beverage can bring cheer on a cold winter night. But will it really warm you up?

According to studies over the years, while alcohol may seem like the perfect cold-weather beverage because it creates a sensation of warmth, it actually decreases core body temperature — regardless of the temperature outside — and increases the risk of hypothermia.

The normal process that makes us feel cold occurs when blood flows away from the skin and into the organs, which increases core body temperature. Alcohol reverses this process, increasing the flow of blood to the skin and setting off a sharp drop in body temperature.

It also reverses other reflexes that control body temperature. A study by the Army Research Institute of Environmental Medicine found that the “primary mechanism by which alcohol exacerbates the fall in body core temperature” is by reducing the ability to shiver, the body’s way of creating warmth.

Another study, published in 2005, found that after a single drink, the body tries to counteract the brief sensation of warmth caused by increased blood flow to the skin by ramping up its rate of sweating, which only decreases body temperature even further.

This may not sound like much. But several studies have found that alcohol ingestion often plays a role in hypothermia-related injuries and deaths. Experts say it’s something to keep in mind at tailgates and other outdoor activities.

The New Year’s Cocktail: Regret With a Dash of Bitters

An opportunity, that is, to forestall the traditional morning-after descent into self-examination, that lonely echo chamber of what should and could be.

Ghosts roam around down there, after all, and they are the worst kind — alternate versions of oneself. The one who did not quit graduate school, for instance. The one who made the marriage work. Or stuck with singing, playwriting or painting and made a career of it.

Lost possible selves, some psychologists call them. Others are more blunt: the person you could have been.

Over the past decade and a half, psychologists have studied how regrets — large and small, recent and distant — affect people’s mental well-being. They have shown, convincingly though not surprisingly, that ruminating on paths not taken is an emotionally corrosive exercise. The common wisdom about regret — that what hurts the most is not what you did but what you didn’t do — also appears to be true, at least in the long run.

Yet it is partly from studies of lost possible selves that psychologists have come to a more complete understanding of how regret molds personality. These studies, in people recently divorced and those caring for a sick child, among others, suggest that it is possible to entertain idealized versions of oneself without being mocked or shamed. And they suggest that doing so may serve an important psychological purpose.

Researchers find that people think about past foul-ups or missed opportunities in several ways. Some tend to fixate and are at an elevated risk for mood problems. Others have learned to ignore regrets and seem to live more lighthearted, if less-examined, lives. In between are those who walk carefully through the minefield of past choices, gamely digging up traps and doing what they can to defuse the live ones.

A 2003 study at Concordia University in Montreal and the University of California, Irvine, for instance, suggested that young adults who scored high on measures of psychological well-being tended to think of regretted decisions as all their own — perhaps because they still had time to change course. By contrast, older people who scored highly tended to share blame for their regretted decisions. “I tried to reach out to him, but the effort wasn’t returned.”

With age, people apparently detoxified their regrets by reframing them as shared misunderstandings, a retrospective touching-up that in many cases might have been more accurate.

In a series of studies, Laura A. King, a psychologist at the University of Missouri, has had people write down a description of their future as they imagined it before a life-altering event, like divorce. She has found that those who are able to talk or write about this lost future without sinking into despair or losing hope tend to have developed another quality, called complexity.

Complexity reflects an ability to incorporate various points of view into a recollection, to vividly describe the circumstances, context and other dimensions. It is the sort of trait that would probably get you killed instantly in a firefight; but in the mental war of attrition through middle age and after, its value only increases.

Here is how a woman from Dallas described the impact of an early and devastating divorce, in one of Dr. King’s studies:

“I feel fortunate in a backhanded way to have experienced misfortune as a young woman. I feel it taught me humility ... and the ability to regroup. ... Life is good but not lavish. It’s hard work and we have to give each other a hand once in a while.”

Another woman in the same study, who had scored lower on a measure of complexity, described her life after divorce: “What good is anything without someone to share it with? My current goal is only to make enough money to make my monthly bills without withdrawing money from my savings account.”

Dr. King has followed groups of people for years and found that this knack for self-evaluation develops over time; it is a learned ability. “To elaborate on loss, to look for some insight in it, is not just what a psychologically mature person does,” Dr. King said. “It’s how a person matures. That’s what the studies show.”

Good therapists have long known the value of seeing regretted choices in the context of what has been gained as well as lost. A full-blown career in dance leaves little time for a family, or much else. The reverse is also true, of course. Starting a family with that perfect someone at age 22 makes it hard to tour South America with a guitar on your back. And was he really so perfect?

“The idea is move people away from this element of resentment, the sense that if only my parents this or I had done that, I would have what I want,” said Dr. Gary Kennedy, director of geriatric psychiatry at Montefiore Medical Center in the Bronx. “That’s a dead end.”

Even the perspective from which people remember slights or mistakes can affect the memories’ emotional impact, new research suggests. A recent Columbia study found that reimagining painful scenes from a third-person point of view, as if seeing oneself in a movie, blunted their emotional sting and facilitated precisely the sort of clearheaded self-perception that Dr. King described.

Widen the screen just a little, in fact, and a particularly prominent and disturbing lost self can be seen as merely one guest in a room full of permutations, good and bad. And each of those selves must have an idealized doppelgänger of its own.

Granted, it may be hard to make the case that one of those is the person capsized on the couch, recovering from last year’s last party. But give it a few days. Ghost-busting is possible, but best done without a hangover.

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