Chapter 14. Biological Rhythms, Sleep, and Dreaming
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Rae Ellen Bichell Ever notice the catnaps that older relatives take in the middle of the day? Or how grandparents tend to be early risers? You're not alone. Colleen McClung did, too. A neuroscientist at the University of Pittsburgh Medical Center, McClung wanted to know what was going on in the brain that changes people's daily rhythms as they age. We all have a set of so-called clock genes that keep us on a 24-hour cycle. In the morning they wind us up, and at night they help us wind down. A study out Monday in Proceedings of the National Academy of Sciences found that those genes might beat to a different rhythm in older folks. "When you think about the early bird dinner specials, it sort of fits in with their natural shift in circadian rhythms," says McClung. "There is a core set of genes that has been described in every animal — every plant all the way down from fungus to humans — and they're pretty much the same set of genes." The genes are the master controllers of a bunch of other genes that control processes ranging from metabolism to sleep. When you woke up this morning, the timekeeping genes told a gland in your brain to give a jolt of the stress hormone cortisol to wake up. Tonight, they'll tell a gland to spit out melatonin, a hormone that makes you sleepy. "You can think of them as sort of the conductor of an orchestra," says McClung. They make sure all the other genes keep time. © 2015 npr
Carl Zimmer Over the past few million years, the ancestors of modern humans became dramatically different from other primates. Our forebears began walking upright, and they lost much of their body hair; they gained precision-grip fingers and developed gigantic brains. But early humans also may have evolved a less obvious but equally important advantage: a peculiar sleep pattern. “It’s really weird, compared to other primates,” said Dr. David R. Samson, a senior research scientist at Duke University. In the journal Evolutionary Anthropology, Dr. Samson and Dr. Charles L. Nunn, an evolutionary biologist at Duke, reported that human sleep is exceptionally short and deep, a pattern that may have helped give rise to our powerful minds. Until recently, scientists knew very little about how primates sleep. To document orangutan slumber, for example, Dr. Samson once rigged up infrared cameras at the Indianapolis Zoo and stayed up each night to watch the apes nod off. By observing their movements, he tracked when the orangutans fell in and out of REM sleep, in which humans experience dreams. “I became nocturnal for about seven months,” Dr. Samson said. “It takes someone who wants to get their Ph.D. to be motivated enough to do that.” In the new study. Dr. Samson and Dr. Nunn combined that information with studies of 19 other primate species. The researchers found wide variations in how long the animals slept. Mouse lemurs doze for seventeen hours a day, for example, while humans sleep just seven hours or so a day — “the least of any primate on the planet,” said Dr. Samson. © 2015 The New York Times Company
Scientists hunting for a drug that speeds stroke recovery might find one in the bedside cabinets of millions of Americans. Mice treated with small doses of the sleeping pill Ambien recovered more quickly from strokes than those given a placebo. Ambien is the best-known incarnation of the drug zolpidem, which was prescribed 40 million times in the US in 2011. The researchers say that the finding should be replicated by other labs before proceeding with clinical trials, but it’s an intriguing result for a problem in desperate need of solutions. Strokes cut off the blood supply to part of the brain, leading to the death of oxygen-starved tissue. Some tissue repair can take place in the months afterwards, but most people never fully recover. Although physical therapy can help, there are no drugs that increase the amount of brain tissue repaired. “There are various natural mechanisms that promote a degree of normal recovery in animals and people, but it’s limited”, says Gary Steinberg of Stanford University School of Medicine, who was lead author of the study. One such mechanism may be an increase in signalling by the GABA neurotransmitter in parts of the brain that are able to rewire themselves. Because Ambien acts on GABA receptors, Steinberg and his team wondered whether they could use it to hack this mechanism to improve recovery. © Copyright Reed Business Information Ltd.
Tina Hesman Saey SAN DIEGO — New research may help explain why chronic stress, sleep deprivation and other disruptions in the body’s daily rhythms are linked to obesity. Chronic exposure to stress hormones stimulates growth of fat cells, Mary Teruel of Stanford University reported December 16 at the annual meeting of the American Society for Cell Biology. Normally, stress hormones, such as cortisol, are released during waking hours in regular bursts that follow daily, or circadian, rhythms. Those regular pulses don’t cause fat growth, Teruel and colleagues discovered. But extended periods of exposure to the hormones, caused by such things as too little sleep, break up that rhythm and lead to more fat cells. Even though only about 10 percent of fat cells are replaced each year, the body maintains a pool of prefat cells that are poised to turn into fat. “If they all differentiated at once, you’d be drowning in fat,” Teruel said. Previous studies have shown that a protein called PPAR-gamma controls the development of fat cells and that stress hormones turn on production of PPAR-gamma. Teruel’s team discovered that prefat cells with levels of PPAR-gamma below a certain threshold don’t transform into fat in laboratory tests. Steady hormone exposure eventually allowed the precursor cells to build up enough PPAR-gamma to cross the threshold into fat making. But in cells given the same total amount of stress hormone in short pulses, PPAR-gamma levels rose and fell. © Society for Science & the Public 2000 - 2015
By Karen Weintraub Is sleep induced by a benzodiazepine counted as restorative sleep? Researchers hate to admit it, but they don’t know enough about sleep to answer this question. Their best guess, several experts said, is that sleep is sleep. Dr. John Weyl Winkelman, a sleep disorders expert at Massachusetts General Hospital and Harvard Medical School, said if a patient asked him whether medicated sleep was restorative, “I’d say: ‘You tell me.’” There is quite a bit of evidence about the negative health consequences of insomnia, but researchers don’t know precisely what it is in the brain and body that is "restored" by sleep to aid optimal function. And it is unlikely that any specific stage of sleep is uniquely restorative, said Dr. Daniel J. Buysse, a sleep medicine expert and professor of psychiatry at the University of Pittsburgh. More sleep, less interrupted sleep, and sleep at the right time of night are all likely to be important, he said. There are two types of sleep: REM, when people dream, and non-REM, which has light, medium and deep portions. Sleeping pills mainly increase the amount of medium-depth non-REM sleep, Dr. Buysse said. Medications can help people fall asleep faster and reduce nighttime wakefulness, he said, and those changes are usually considered to contribute to restorative sleep. But different people respond differently. “Do you feel more rested, more alert, more able to concentrate, less irritable on medication versus off?" Dr. Buysse said. "If all those things are true then I would say it’s more restorative. If a hypnotic drug leaves you feeling hung over or more anxious, if it causes you to order five hickory smoked turkeys on the Internet without remembering, then it’s probably not good.” © 2015 The New York Times Company
Link ID: 21691 - Posted: 12.12.2015
By Lindzi Wessel Nighttime restlessness is common among people with Alzheimer’s, and many stay awake agitated and pacing long after their family members have gone to sleep. Now, scientists may have figured out why: The disease appears to degrade a special type of eye cell that tells the brain when it’s day or night. If the discovery holds up, it might offer clinicians a new way to monitor the progression of Alzheimer’s and could lead to treatments that restore a good night’s sleep. The cells in question are known as melanopsin retinal ganglion cells. They send signals to the brain center responsible for circadian rhythms, our body’s daily clock. The cells make up 1% to 2% of the eye’s light-responsive sensors, but they play no role in vision, says lead author Chiara La Morgia, a neuroscientist at the University of Bologna in Italy. Rather, they sense light levels around us, telling us when to get sleepy and when to be alert. La Morgia and her colleagues, aware of the profound sleep problems often seen in Alzheimer’s, wondered whether the cells may stop doing their job as the disease progresses. “If you lose them, you should see dysfunction of the circadian rhythms and see disrupted sleep,” says Alfredo Sadun, neuro-opthamologist at the University of California, Los Angeles, and co-author of the study. “That is the exact symptomology we see in Alzheimer’s disease.” To learn more, the researchers used dyes to mark melanopsin cells in the eyes of 30 recently deceased organ donors. They found approximately 24% fewer melanopsin cells in the eyes of people with Alzheimer’s than in the eyes of donors without the disease. © 2015 American Association for the Advancement of Science.
Aimee Cunningham For a child with attention deficit hyperactivity disorder, meeting the daily expectations of home and school life can be a struggle that extends to bedtime. The stimulant medications commonly used to treat ADHD can cause difficulty falling and staying asleep, a study finds. And that can make the next day that much harder. As parents are well aware, sleep affects a child's emotional and physical well-being, and it is no different for those with ADHD. "Poor sleep makes ADHD symptoms worse," says Katherine M. Kidwell, a doctoral student in clinical psychology at the University of Nebraska, Lincoln, who led the study. "When children with ADHD don't sleep well, they have problems paying attention the next day, and they are more impulsive and emotionally reactive." Stimulant medications boost alertness, and some studies have found a detrimental effect on children's sleep. However, other studies have concluded that the stimulants' ameliorating effects improve sleep. The drugs include amphetamines such as Adderall and methylphenidate such as Ritalin. To reconcile the mixed results on stimulants and children's sleep, Kidwell and her colleagues undertook a meta-analysis, a type of study that summarizes the results of existing research. The team found nine studies that met their criteria. These studies compared children who were taking stimulant medication with those who weren't. The studies also randomly assigned children to the experimental group or the control group and used objective measures of sleep quality and quantity, such as assessing sleep in a lab setting or with a wristwatch-like monitor at home rather than a parent's report. © 2015 npr
By Nicholas Bakalar Bright light therapy has been used effectively for seasonal affective disorder, the kind of depression that comes on at a specific time every year, often the dark days of late fall and winter, and then lifts. Now a new study has found that it may work to treat nonseasonal depression as well. Researchers randomly assigned 122 patients, 19 to 60 years old, with major depression to receive one of four treatments: 30 minutes of daily exposure to fluorescent light; 20 milligrams of Prozac daily; both light and Prozac; and a control group that received a dummy pill and exposure to an electric air purifier. The study, in JAMA Psychiatry, lasted eight weeks. Using well-validated scales that quantify depression severity, the researchers found improvements in all four groups. The difference between Prozac alone and the placebo was not statistically significant, but light therapy alone was significantly better than placebo, and light therapy with medication was the most effective treatment of all. “This is the first study to show that light treatment is an option for people with nonseasonal depression, which is much more common than seasonal depression,” said the lead author, Dr. Raymond W. Lam, a professor of psychiatry at the University of British Columbia. “Light treatment can be combined with medicine and psychotherapy, and it’s a safe treatment without a lot of side effects.” © 2015 The New York Times Company
By Nicholas Bakalar Several studies have shown that there is an association between shift work and an increased risk for heart disease and diabetes. Now a new study, in the Journal of Clinical Endocrinology & Metabolism, has found a similar association in people whose sleeping schedules change on the weekend. For seven days, 447 men and women ages 30 to 54 wore devices that measured movement and tracked when they fell asleep and woke. Almost 85 percent of the group went to sleep and woke later on their days off than during the workweek. The researchers found that the greater the mismatch in sleep timing between weekdays and weekends, the higher the metabolic risk. Sleeping late on days off was linked to lower HDL (good) cholesterol, higher triglycerides, higher insulin resistance and higher body mass index. The associations persisted after controlling for physical activity, caloric intake, alcohol use and other factors. “It’s not clear yet that this is a long-term effect,” said the lead author, Patricia M. Wong, a graduate student at the University of Pittsburgh. “But we think of this as people having to sleep and work out of sync with their internal clock, and that having to be out of sync may be having these health effects.” © 2015 The New York Times Company
Link ID: 21651 - Posted: 11.21.2015
By Elahe Izadi The days growing shorter and colder can be more than just a nuisance; the seasonal change can also trigger clinical depression. Those who suffer from seasonal affective disorder, or SAD, may turn to a light box to help make them feel better. But a new study suggests another form of therapy could be more powerful and enduring: talking. The benefits of cognitive behavioral therapy — a form of talk therapy — outlasted light therapy sessions for people suffering from SAD, according to a study published Thursday in the American Journal of Psychiatry. "Light therapy is a treatment that suppresses symptoms as long as you're using it," said lead author Kelly Rohan, a psychology professor at the University of Vermont. "So if you're not using it, there's no reason to expect the continued benefit for a treatment that works that way, whereas cognitive behavioral therapy teaches skills." And the people who learn those skills can use them long after their therapy sessions. For the study, researchers tracked 177 people who suffer from major depression that follows a recurring seasonal pattern. About half of the subjects received six weeks of daily light therapy; the others received 12 sessions of cognitive behavioral therapy over the same period of time.
By Rachel E. Gross For decades, Michael Jackson had struggled to fall asleep at night. But in 2009 the pop singer was preparing for his worldwide comeback tour, and he couldn’t afford to be at anything less than 100 percent. Desperate for sleep, he convinced an unscrupulous physician to give it to him synthetically in the form of an anesthetic so strong that it sent him almost immediately into a “druglike coma.” At first, Jackson would wake up feeling refreshed. But the nightly injections conferred only the shadow of true sleep, with none of the deep, dream-filled REM cycles that his body needed. Soon he was fading fast, his mind and mood slipping away. Within two months Jackson was dead of an overdose. If that hadn’t killed him, doctors later testified during his wrongful death trial, he would have died of sleep deprivation. Jackson’s is a particularly dramatic case. But his struggle for oblivion rings true to anyone who has dealt with insomnia. “I’m for anything that gets you through the night,” Frank Sinatra once said, “be it prayer, tranquilizers, or a bottle of Jack Daniel’s.” If you have insomnia, you’ll understand this sentiment, and you’re not alone: Regular sleep eludes up to 15 percent of the population, making insomnia the most commonly diagnosed sleep problem in America. Fortunately, the nighttime affliction is becoming steadily less mysterious—at least from the perspective of neuroscience. While insomniacs toss and turn, researchers are finally starting to understand this elusive disease. As it turns out, chronic insomnia may be more hard-wired into our brains than we had thought, and indicative of larger differences that separate the brains of the sleepless from those who so effortlessly enter the land of dreams. © 2015 The Slate Group LLC
Link ID: 21614 - Posted: 11.07.2015
By Jan Hoffman As the first semester of the school year reaches the halfway mark, countless college freshmen are becoming aware that their clothes are feeling rather snug. While the so-called freshman 15 may be hyperbole, studies confirm that many students do put on five to 10 pounds during that first year away from home. Now new research suggests that an underlying cause for the weight gain may be the students’ widely vacillating patterns of sleep. A study in the journal Behavioral Sleep Medicine looked at the sleep habits of first-semester freshmen. Researchers followed 132 first-year students at Brown University who kept daily sleep diaries. After nine weeks, more than half of them had gained nearly six pounds. There are many poor sleep habits that might have exacerbated their weight gains, a growing body of research indicates. Was it abbreviated sleep? Optimally, experts say, teenagers need about nine hours and 15 minutes a night. These freshmen averaged about seven hours and 15 minutes. In a study earlier this year, in the journal PLOS One, researchers found that when teenagers are sleep-deprived, they more readily reach for candy and desserts. Or were the Brown students’ late bedtimes the scale-tipping factor? On average, they went to bed around 1:30 a.m. A study this month in the journal Sleep that followed teenagers into adulthood found that each hour later bedtime was pushed during the school or workweek was associated with about a two-point increase in body mass index. While both the amount of sleep and the lateness of bedtime may have played a role, the researchers in the Brown study identified a new sleep factor for predicting weight gain: variability, or the extent to which a student’s bedtime and waking time changed daily. © 2015 The New York Times Company
By Dina Fine Maron Early-life exposure to anesthesia does not appear to lead to long-term cognitive problems, researchers announced today. New evidence from the first, randomized anesthesia trial in kids provides the strongest indication yet that exposing young children to anesthesia—at least for a brief time—will not saddle them with developmental deficits. The news comes just a couple of weeks after a medical advisory group reiterated its concerns about such exposures among children younger than four years. Previously, multiple animal and human studies have linked such exposure with cognitive impairment, but none of the information on humans came from a gold-standard, randomized study design that could help eliminate other reasons to explain such a connection. This is a “reassuring finding, but it is not the final answer,” says Dean Andropoulos, anesthesiologist in chief at Texas Children’s Hospital and an expert who was not involved in the work. The new study assesses only what happens to youngsters after a relatively brief bout with anesthetics, so it is possible that longer or repeated exposures to such chemicals may still cause neurodevelopmental issues. There may also be deficits in anesthesia-exposed children that are not measurable until later in life. The study followed more than 500 infants undergoing hernia repair across the U.S., Australia, the U.K., Canada, the Netherlands, New Zealand and Italy. The surgeries lasted an average of roughly an hour. About half of the children were randomly selected to be put under with general anesthesia, and the other half stayed awake during the surgery and received targeted anesthesic in a specific body region. The kids in the study were all younger than 60 weeks and were matched by where they had the surgery and whether they were born prematurely. © 2015 Scientific American
By Nicholas Bakalar A new study has found that sleep apnea is associated with an increased risk for gout, a painful disease of the big toe and other joints caused by elevated levels of uric acid in the blood. Observational studies have shown that people with sleep apnea have a higher prevalence of excess uric acid, but until now it has been unclear whether sleep apnea is associated with gout, and how strongly. Using records in a British health database, researchers studied 9,865 people, average age 54, with sleep apnea and matched them to 43,598 controls without the disorder. Because sleep apnea is associated with being overweight, the participants were matched for B.M.I., among many other characteristics. The study is in Arthritis & Rheumatology. After one year, compared with controls, people with sleep apnea were about 50 percent more likely to have had an attack of gout, and the increased risk was found without regard to sex, age or obesity. The conclusion suggests that treating sleep apnea would reduce gout attacks, but the lead author, Yuqing Zhang, a professor of medicine at Boston University, is cautious. “Our findings call for future studies to evaluate the effect of treating sleep apnea on serum uric acid levels and the risk of gout,” he said. © 2015 The New York Times Company
Link ID: 21563 - Posted: 10.26.2015
By Jonathan Webb Science reporter, BBC News Crocodiles can sleep with one eye open, according to a study from Australia. In doing so they join a list of animals with this ability, which includes some birds, dolphins and other reptiles. Writing in the Journal of Experimental Biology, the researchers say the crocs are probably sleeping with one brain hemisphere at a time, leaving one half of the brain active and on the lookout. Consistent with this idea, the crocs in the study were more likely to leave one eye open in the presence of a human. They also kept that single eye trained directly on the interloper, said senior author John Lesku. "They definitely monitored the human when they were in the room. But even after the human left the room, the animal still kept its open eye… directed towards the location where the human had been - suggesting that they were keeping an eye out for potential threats." The experiments were done in an aquarium lined with infrared cameras, to monitor juvenile crocodiles day and night. "These animals are not particularly amenable to handling; they are a little snippy. So we had to limit all of our work to juvenile crocodiles, about 40-50cm long," said Dr Lesku, from La Trobe University in Melbourne. As well as placing a human in the room for certain periods, the team tested the effect of having other young crocs around. Sure enough, these also tended to attract the gaze of any reptiles dozing with only one eye. This matches what is known of "unihemispheric sleep" in aquatic mammals, such as walruses and dolphins, which seem to use one eye to make sure they stick together in a group. © 2015 BBC.
By Nicholas Bakalar Sleep apnea may be even more dangerous for women than for men, a new study suggests. Epidemiological studies have linked sleep apnea to heart disease in men, but the differences in risk between men and women have been largely unexplored. For the current study, researchers measured sleep quality electronically in 737 men and 879 women, average age 63, who were free of cardiovascular disease at the start of the study. They also tested all of them for troponin T, a protein that can be released into the bloodstream if the heart is damaged, and whose presence in otherwise healthy people indicates an increased risk for heart disease. They tracked the participants for 14 years, recording incidents of coronary artery disease, heart failure and death from cardiovascular disease or other causes. The study was published in Circulation. Obstructive sleep apnea was independently associated with increased troponin T, heart failure and death in women, but not in men. And in women, but not men, sleep apnea was associated with an enlarged heart, another risk factor for cardiovascular disease. “Most people who have sleep apnea have a lot of other risks for heart disease,” said the lead author, Dr. Amil M. Shah, an assistant professor of medicine at Harvard. “But in women, the relationship between sleep apnea and heart disease persisted even after accounting for the other risks.” “Even among women with sleep apnea who don’t get heart failure,” he continued, “it’s associated with changes in the heart that lead to worse outcomes.” © 2015 The New York Times Company
By Anahad O'Connor For years, public health authorities have warned that smartphones, television screens and the hectic pace of modern life are disrupting natural sleep patterns, fueling an epidemic of sleep deprivation. By some estimates, Americans sleep two to three hours fewer today than they did before the industrial revolution. But now a new study is challenging that notion. It found that Americans on average sleep as much as people in three different hunter-gatherer societies where there is no electricity and the lifestyles have remained largely the same for thousands of years. If anything, the hunter-gatherer communities included in the new study — the Hadza and San tribes in Africa, and the Tsimané people in South America — tend to sleep even less than many Americans. The findings are striking because health authorities have long suggested that poor sleep is rampant in America, and that getting a minimum of seven hours on a consistent basis is a necessity for good health. Many studies suggest that lack of sleep, independent of other factors like physical activity, is associated with obesity and chronic disease. Yet the hunter-gatherers included in the new study, which was published in Current Biology, were relatively fit and healthy despite regularly sleeping amounts that are near the low end of those in industrialized societies. Previous research shows that their daily energy expenditure is about the same as most Americans, suggesting physical activity is not the reason for their relative good health. The prevailing notion in sleep medicine is that humans evolved to go to bed when the sun goes down, and that by and large we stay up much later than we should because we are flooded with artificial light, said Jerome Siegel, the lead author of the new study and a professor of psychiatry at the Semel Institute of Neuroscience and Human Behavior at U.C.L.A. © 2015 The New York Times Company
Link ID: 21523 - Posted: 10.17.2015
Chris Samoray People in the postindustrial world don’t always get a sound night sleep. But they appear to spend a similar amount of time sleeping as do people in hunter-gatherer communities in Africa and South America, a new study finds. “It’s absolutely clear that they don’t sleep more than we do,” says Jerome Siegel, a UCLA sleep scientist. In fact, on average, hunter-gatherers may sleep a little less. Recommended nightly sleep for adults is typically seven to nine hours; a 2013 Gallup poll showed that most Americans get around 6.8 hours. On most nights, members of three hunter-gatherer groups — the Hadza of Tanzania, the Ju/’hoansi San of Namibia and the Tsimane of Bolivia — sleep 5.7 to 7.1 hours, Siegel and colleagues report online October 15 in Current Biology. That’s on the lower end of the sleep spectrum in postindustrial societies, the researchers say. Evidence from the new study also suggests that these groups experience less insomnia than sleepers in postindustrial societies. (The three hunter-gatherer languages even lack a word for insomnia.) Hunter-gatherer sleep patterns are closely tied to temperature, a new study shows. Among the Hadza of Tanzania, for instance, people fell asleep about three hours after sunset, on average, as ambient temperatures decreased. People then woke up about an hour before sunrise, when temperatures reached their lowest point. © Society for Science & the Public 2000 - 2015.
Link ID: 21520 - Posted: 10.16.2015
The month of your birth influences your risk of developing dementia. Although the effect is small compared to risk factors such as obesity, it may show how the first few months of life can affect cognitive health for decades to come. Demographers Gabriele Doblhammer and Thomas Fritze from the University of Rostock, Germany, studied data from the Allgemeine Ortskrankenkasse – Germany’s largest public health insurer – for nearly 150,000 people aged 65 and over. After adjusting for age, they found that those born in the three months from December to February had a 7 per cent lower risk of developing dementia than those born in June to August, with the risk for other months falling in between. There’s nothing astrological about the effect, however. Instead, birth month is a marker for environmental conditions such as weather and nutrition, says Gerard van den Berg, an economist at the University of Bristol, UK, who studies the effects of economic circumstances on health. Summer-born babies are younger when they face the respiratory infections of their first winter, for example. And in the past, babies born in spring and summer would have been in late gestation when the supply of fresh fruit and vegetables from the autumn harvest would have largely run out. Pollution from wood fires or coal heating might also have played a role. There’s evidence from other studies that such factors can have lifelong effects on metabolism and the immune system, increasing the risk of conditions such as diabetes, obesity and high blood pressure. Doblhammer and Fritze’s results show this is true for dementia too. © Copyright Reed Business Information Ltd.
by Sarah Schwartz People with multiple sclerosis who got less sun exposure and had higher body mass as young adults developed the disease sooner than those who spent more time in the sun and were a normal weight, a new study finds. In a study of over 1,100 Danish people with MS — a nervous system condition that causes muscle weakness and pain — patients who were overweight at age 20 developed multiple sclerosis an average of 1.5 years sooner than patients of normal weight. And subjects who reported spending time in the sun every summer’s day during adolescence developed the disease 1.8 years later, on average, than patients who got less sun exposure, Danish researchers report online October 7 in Neurology. The results echo earlier work that found a link between adolescent obesity and risk of MS. And sun exposure may increase patients’ levels of vitamin D, which has been shown to protect against the disease, the researchers say. © Society for Science & the Public 2000 - 2015