Category: Insomnia

Obese, asthmatic, anxious or depressed children are more likely to experience excessive daytime sleepiness, or EDS, according to Penn State College of Medicine sleep researchers.

"Although EDS in children is commonly assumed by physicians and the public to be the result of sleep-disordered breathing or inadequate sleep, our data suggest that EDS in young children is more strongly associated with obesity and mood issues as it is in adults," said Edward Bixler, Ph.D., professor of psychiatry and vice chair of research, Sleep Research and Treatment Center.

EDS is the inability to stay awake during the day, while sleep-disordered breathing is a group of disorders that includes sleep apnea, characterized by pauses in breathing.

"EDS may interfere with daytime functioning in children, including academic performance," said Bixler. "Although excessive daytime sleepiness in adults has been the focus of extensive research, studies on the risk factors associated with EDS in children have been limited."

The researchers studied 508 children and found EDS in 15 percent of them.

"Our study indicates that EDS is highly prevalent in children, a symptom that may adversely affect daytime functioning," said Bixler.

This study suggests an association between childhood EDS and medical factors, medication for asthma, waist circumference, and parent-reported anxiety/depression and parent-reported sleep difficulties — trouble falling asleep, restless sleep and waking often during the night.

Researchers conducted a two-phase study to look at the issue. In phase I, a screening questionnaire to identify children at high risk for sleep-disordered breathing was sent to parents of every student in kindergarten through fifth grade in four school districts. The questionnaire asked for general information from parents about their child's sleep and behavioral patterns.

In phase II, the researchers randomly selected 200 children each year for five years based on grade, gender and risk for sleep-disordered breathing. In all, they chose 508 children for the study, including those with medical problems and mental health disorders, to represent the general population.

The researchers recorded height, weight, body mass index, and waist circumference — a marker of central obesity and metabolic abnormalities — for each child. All children spent one night in a sleep laboratory and were screened for sleep apnea — defined as at least five seconds of breathing stoppage while sleeping.

Parents completed a sleep questionnaire to assess EDS. If the parent reported yes for one or both of the questions, "Does your child have a problem with sleepiness during the day?" and "Has a teacher or other supervisor commented that your child appears sleepy during the day?" the researchers classified the children as having EDS.

The 508 children consisted of 431 children without EDS and 77 children with EDS. They ranged in age from 5 to 12 years old. One-quarter were minority, and 51.8 percent were boys.

The researchers found waist circumference, positive history of asthma, use of asthma medication, heartburn, and parent-reported symptoms of anxiety/depression and of sleep difficulty significantly associated with EDS. The researchers published their results in the journal Sleep.

Waist circumference alone contributed to the independent prediction of EDS, suggesting that metabolic factors may play a contributing role in the mechanisms of EDS.

"Primary lines of treatment might include weight loss if the child is overweight, treatment for underlying depressive and anxious symptoms, and implementation of nocturnal asthma prevention methods if the child is diagnosed with asthma," said Bixler.

Other researchers on this project were Susan L. Calhoun, Ph.D., Alexandros N. Vgontzas, M.D., Julio Fernandez-Mendoza, Ph.D., Susan D. Mayes, Ph.D., Marina Tsaoussoglou, B.S., and Maria Basta, M.D., all of the Sleep Research and Treatment Center.

The National Institutes of Health funded this project.

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Journal Reference:

1. Calhoun SL; Vgontzas AN; Fernandez-Mendoza J; Mayes SD; Tsaoussoglou M; Basta M; Bixler EO. Prevalence and risk factors of excessive daytime sleepiness in a community sample of young children: the role of obesity, asthma, anxiety/depression, and sleep. Sleep, 2011;34(4):503-507 [link]

Sleep problems among urban minority children, including resistance to going to bed, shortened sleep duration, and daytime sleepiness are much more common than previously thought, according to a study conducted by researchers in New York.

The results of the study were presented at the ATS 2011 International Conference in Denver.

"Although studies have shown that children from minority populations take more daytime naps and have shorter nighttime sleep durations than their non-minority peers, no studies to date have focused on sleep patterns and objectively measured sleep duration in early school-aged African-American and Latino children living in urban, economically disadvantaged communities," said study author Beverley J. Sheares, MD, associate professor of clinical pediatrics at Columbia University. "We studied this high-risk population because at age 5 and 6 years, children are starting school and thus may have less time available for sleep at night or for daytime naps, thereby reducing the amount of sleep at a time when the effect of shortened sleep on learning, behavior and health is critically important.

"The results of this study will be of significance to healthcare providers, researchers, parents and educational professionals, and will have significant public health implications for a highly vulnerable population of early school-aged children," she said.

Researchers randomly enrolled 160 parents of healthy 5- and 6-year-old children. Data were obtained using parental sleep log records and through face-to-face interviews using the Children's Sleep Habits Questionnaire (CSHQ), a validated tool commonly used to screen for childhood sleep problems. CHSQ data were used to identify and characterize the nature of the sleep disturbances. In addition, researchers were able to obtain data from 30 children who underwent sleep monitoring at home for five to seven days using actigraphy, an objective method of continuous, direct-motion monitoring used to measure sleep and awake time. The monitors were worn 24-hours a day during the monitoring period.

"To our knowledge, neither the CHSQ nor actigraphy has been used extensively in this population of early school-aged children to examine sleep," Dr. Sheares noted.

Evaluating the results of the sleep questionnaire, researchers found that 147 of the 160 children, or 92 percent, had scores indicating the presence of a sleep problem. In addition, parents reported the following behaviors were the specific sleep problems for their children: parasomnias, a group of sleep events that includes nightmares, sleepwalking and other events (51 percent); bedtime resistance (50 percent); shortened sleep duration (50 percent); daytime sleepiness (47 percent); night waking (41 percent); sleep-onset delay (27 percent); sleep anxiety (19 percent); and sleep-disordered breathing (11 percent).

All children who completed actigraphy monitoring had shortened sleep duration, with a mean sleep duration of seven hours 45 minutes per night on average, significantly less than the 10 to 11 hours recommended by the National Sleep Foundation for children in this age group.

"We expected to find behavioral sleep problems in this population, but we did not expect over 90 percent of the children in this community sample to have a behavioral sleep problem as indicated by the CSHQ," Dr. Sheares said. "While studies consistently show that 20 percent to 43 percent of school-aged children experience a range of sleep problems, there is mounting evidence, and our study supports this, suggesting that children from minority groups have significantly shorter sleep durations and increased sleep disruptions."

"Our study also demonstrates the need to use objective measures of sleep in urban populations of young children," she said. "While parental reports of children's sleep behaviors have been widely used in both clinical practice and in pediatric sleep research, our findings suggest that parental reports of sleep duration are not reliable because parents in our study consistently overestimated sleep duration."

"Although previous studies have shown that parental reports are closely correlated with sleep schedule variables such as bedtime, wake time and sleep duration, they are less sensitive in assessing sleep quality variables such as sleep fragmentation as a result of night awakening," she explained. "Parents may not have been aware of time spent awake during the night which could have led to an overestimation of sleep duration."

Dr. Sheares said future studies will focus on developing intervention programs aimed at improving children's sleep disorders.

"The study's results may have significant implications for this group of children because while pediatric sleep problems are universal and exist across all cultures, the impact of poor sleep is magnified in vulnerable children," she said.

"Inadequate sleep is a major health problem of childhood that often fails to receive attention until significant health problems are noted, such as inattentiveness, memory loss and impaired learning," Dr. Sheares added. "The next step of this research is to carry out and evaluate the efficacy of a tailored, interactive, educational and behavioral intervention that utilizes trained sleep counselors to assist parents in improving their children's sleep hygiene and reducing risk factors for poor sleep, thereby increasing sleep duration over a 12-month period in a randomized controlled trial of children identified with sleep problems."

Continuous positive airway pressure, or CPAP, can increase alertness and even improve quality of life for sufferers of obstructive sleep apnea (OSA), even if their symptoms are minimal, according to a study conducted by researchers in Europe. Patients enrolled in the study reported an improvement in daytime sleepiness within six months of beginning CPAP treatment.

The study was presented at the ATS 2011 International Conference in Denver.

"Treatment with CPAP clearly reduces daytime sleepiness and improves quality of life in patients with very limited symptoms, at a rate of about half the improvement seen in patients with more severe symptoms," said Sonya Craig, research fellow at Churchill Hospital, Oxford.

"It is well-known that CPAP treatment greatly improves OSA patients who have substantial symptoms of daytime sleepiness," she added. "However, OSA with few symptoms, and sometimes no symptoms, is much more common, yet the effect of CPAP on these patients has not been adequately evaluated. In this study, we wanted to investigate the effect of CPAP on sleepiness and quality of life measurements in patients with minimally symptomatic OSA."

Researchers analyzed data from 341 patients from 10 medical centers, with proven OSA but insufficient current symptoms as judged by both the patient and the sleep physician to justify CPAP therapy. Patients were randomized to receive either six months of CPAP or no treatment. The Epworth Sleepiness Score, a standard scoring system used in sleep studies, was used to determine the change in daytime sleepiness measured at the start of the study, and again at follow-up six months later. Wakefulness and sleepiness were also measured using a second test, called the Oxford Sleep Resistance Test (OSLER), and quality of life was assessed using a standard questionnaire.

The researchers found that after six months of treatment, CPAP significantly reduced daytime sleepiness and increased wakefulness compared to the standard treatment group. They also found that the odds of falling asleep during the OSLER test, which requires patients to lie quietly and react to a flashing light for prolonged periods of time at repeated intervals, were 49 percent lower in the CPAP treatment group compared to those in the standard care group. Quality of life scores were also significantly higher in the CPAP group compared to standard care patients. Ironically, about 25 percent of patients stopped treatment prior to the end of the study, reporting that they did not perceive adequate benefit.

Dr. Craig said the results of the study were surprising.

"The magnitude of the improvement in sleepiness and quality of life scores wasgreater than expected, particularly given that the patients were considered to have only very mild symptoms when assessed in clinic," she said.

"It appears clinical assessment of patients with OSA does not reliably identify all patients likely to benefit from treatment with CPAP," she added. "This suggests that a greater number of patients than originally thought may benefit from a trial of CPAP therapy."

Dr. Craig said further evaluation will focus on determining if the improvements noted in the study are short-term improvement, or if they are long-lasting.

"We are continuing to follow these patients for a longer term to assess whether the improvements in quality of life and daytime symptoms are maintained over a longer time scale," she said. "If the benefits persist for a longer time period, it would strengthen the argument to expand the patient population that could benefit significantly from CPAP therapy."

— A new study of more than 350 families has found that instability in the parents' relationship when the children are 9 months old predicted difficulties falling asleep and staying asleep when they were 18 months old. The findings suggest that the effects of marital instability on children's sleep problems emerge earlier in development than has been demonstrated previously.

We know that marriage problems can have a negative effect on families, especially children. Now a new study of more than 350 families has found that marital instability when children are 9 months old may also affect youngsters' sleep, predicting sleep problems when children are 18 months old. Specifically, instability in the parents' relationship when the children are 9 months old predicted difficulties falling asleep and staying asleep when they were 18 months old.

The findings appear in the journal Child Development. The study was conducted by researchers at the Oregon Social Learning Center, University of Leicester, Cardiff University, University of Pittsburgh, University of California at Davis, The Pennsylvania State University, University of New Orleans, and Yale Child Study Center.

The researchers sought to assess the relationship between marital instability — for example, parents who were contemplating divorce — and children's sleep problems — namely, difficulties getting to sleep or staying asleep. Their inquiry was based, in part, on the possibility that changes in the brain systems involved in how children develop and regulate their sleep patterns reflect the impact of family stress on children.

They followed more than 350 families starting when their babies were 9 months old and continuing over a nine-month period. The researchers chose to study adoptive families to rule out the possibility that any ties between parents' behavior and children's sleep were due to shared genes; previous studies into this issue have looked at families who were biologically related.

The researchers found that marital instability when the children were 9 months old predicted increases in children's sleep problems when they were 18 months old. This finding held true even after taking into consideration such factors as children's difficult temperaments, parents' anxiety levels, and birth order. But the researchers also found that the inverse wasn't true — that is, children's sleep problems didn't predict marital instability.

"Our findings suggest that the effects of marital instability on children's sleep problems emerge earlier in development than has been demonstrated previously," according to Anne M. Mannering, who was a research associate at the Oregon Social Learning Center when she worked on the study; she is currently with Oregon State University. "Parents should be aware that marital stress may affect the well-being of their children even in the first year or two of life."

The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Institute on Drug Abuse, and the Office of the Director of the National Institutes of Health.

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Journal Reference:

1. Anne M. Mannering, Gordon T. Harold, Leslie D. Leve, Katherine H. Shelton, Daniel S. Shaw, Rand D. Conger, Jenae M. Neiderhiser, Laura V. Scaramella, David Reiss. Longitudinal Associations Between Marital Instability and Child Sleep Problems Across Infancy and Toddlerhood in Adoptive Families. Child Development, 2011; DOI: 10.1111/j.1467-8624.2011.01594.x

A study in the May 1 issue of the journal Sleep describes how changes in sleep that occur over a five-year period in late middle age affect cognitive function in later life. The findings suggest that women and men who begin sleeping more or less than 6 to 8 hours per night are subject to an accelerated cognitive decline that is equivalent to four to seven years of aging.

Results show that the sleep duration at follow-up of 7.4 percent of women and 8.6 percent of men had increased from "7 or 8 hours" per weeknight at baseline. Compared with participants whose sleep duration was unchanged, this change to a longer sleep duration was associated with lower scores at follow-up on five of six cognitive function tests, with the only exception being the test of short-term verbal memory. The sleep duration at follow-up of about 25 percent of women and 18 percent of men had decreased from "6, 7, or 8 hours" per night at baseline. This change to a shorter sleep duration was associated with lower scores at follow-up on three of the six cognitive tests, with reasoning, vocabulary and global cognitive status all being affected adversely. Surprisingly, an increase in sleep duration from six hours or less showed no evidence of a beneficial effect.

"The main result to come out of our study was that adverse changes in sleep duration appear to be associated with poorer cognitive function in later-middle age," said lead author Jane Ferrie, PhD, senior research fellow in the University College London Medical School De¬partment of Epidemiology and Public Health in the U.K.

The researchers also found that, in women, sleep duration of 7 hours of sleep per night was associated with the highest score for every cognitive measure, followed closely by 6 hours of nightly sleep. Among men, cognitive function was similar for those who reported sleeping 6, 7 or 8 hours; only short and long sleep durations of less than 6 hours or more than 8 hours appeared to be associated with lower scores.

The study used data for 5,431 participants (1,459 women and 3,972 men) from Phase 5 (1997-1999) and Phase 7 (2003-2004) of the Whitehall II study, which included more than 10,000 London-based office staff aged 35-55 working in 20 civil service departments in 1985. Phase 5 and Phase 7 follow-ups involved postal questionnaires and clinical examinations. Cognitive function was assessed at Phase 7 using six standard tests that measured memory, reasoning, vocabulary, phonemic fluency, semantic fluency, and global cognitive status.

Habitual sleep duration was measured at Phase 5 (baseline) and Phase 7 (follow-up) using a single question: "How many hours of sleep do you have on an average week night?" Participants were divided into four groupings based on the change in sleep duration between the two checkpoints: an increase from ≤ 5 hours or 6 hours per night; an increase from 7 or 8 hours per night; a decrease from 6, 7, or 8 hours per night; and a decrease from ≥ 9 hours per night. These groups were compared with reference groups who reported no change in sleep duration between Phase 5 and Phase 7. Overall, about 58 percent of men and 50 percent of women had no change in their self-reported nightly sleep duration during the study period.

Although participants were mostly white-collar workers, the study group covered a wide socioeconomic range with a 10-fold difference in salary across the occupational hierarchy. The researchers adjusted for the effects of education and occupational position due to their known association with cognitive performance. Socioeconomic status did not account for all the observed associations, indicating either a direct association between change in sleep and cognitive function, or an association mediated or confounded by factors other than education and occupational position.

According to the authors, adequate, good quality sleep is fundamental to human functioning and well-being. Sleep deprivation and sleepiness have adverse effects on performance, response times, errors of commission, and attention or concentration. Furthermore, sleep duration has been found to be associated with a wide range of quality of life measures, such as social functioning, mental and physical health, and early death.

"The detrimental effects of too much, too little and poor quality sleep on various aspects of health have begun to receive more attention," Ferrie added. "Given that our 24/7 society increasingly impinges on the lives of many people, it is important to consider what effects changes in sleep duration may have on health and well-being in the long term."

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Journal Reference:

1. Ferrie JE; Shipley MJ; Akbaraly TN; Marmot MG; Kivimäki M; Singh-Manoux A. Change in sleep duration and cognitive function: findings from the Whitehall II study. Sleep, 2011; 34 (5): 565-573 [link]

Over seven million people in Spain are at risk of developing sleep apnoea (SA), a health problem caused by obstructed air intake during sleep. The disorder has become a common issue in public health, affecting patients' quality of life and potentially leading to hypertension, cardiovascular disease and neurological disorders, as well as increasing the likelihood of traffic, workplace and domestic accidents with personal, financial and healthcare repercussions. In children, SA is often associated with learning difficulties and behavioural and attention disorders.

Almost two million people in Spain show symptoms of SA requiring treatment, but only 5% are conclusively diagnosed. Following almost a decade of research, in 2009 the Snoring and Sleep Apnoea Diagnosis and Treatment Unit was opened in the UB's Josep Finestres Foundation-Dental Clinic (Bellvitge Health Sciences Campus). The specialized unit is devoted to the study and treatment of respiratory sleep disorders from a novel perspective that places dentists at the centre of research, diagnosis and treatment. The unit is formed by Maribel Pascual, qualified in medicine and surgery and a specialist in stomatology, and the qualified dental physicians Eva Willaert and Lluís Nogués, lecturers at the Department of Dentistry and Stomatology of the UB's Faculty of Dentistry, and experts in dental prosthetics and craniomandibular dysfunction for the UB-specific master's degree in Occlusion and Oral Rehabilitation directed by Dr. Joan Salsench, Dr. Maria Peraire and Dr. Jordi Samsó from the University of Barcelona (UB).

The team was created in 2000 through an initial collaboration agreement between the experts Maribel Pascual and Carme Monasterio (director of the Sleep Unit of the Pneumology Service at Bellvitge University Hospital) and was the first in Spain to introduce the study of respiratory sleep disorders, sleep apnoea and treatment with mandibular advancement devices (MAD) at postgraduate level for the master's degree they contribute to as experts.

A disease largely unknown among the public

Maribel Pascual explains that, "diagnosis and treatment of sleep apnoea are placing a strain on the healthcare system and generating substantial expense. As dentists, we can bring a new therapeutic perspective to deal with the complex symptoms involved, which can be exhibited in the respiratory apparatus but treated through the stomatognathic system, that is, the oral cavity, so we can add to the treatment options provided by other experts (pneumologists, neurophysiologists, maxillofacial surgeons, dieticians, etc). According to the National Consensus Document on Sleep Apnoea, drawn up by the Spanish Sleep and Breathing Group, patients with SA are between seven and eight times more likely to suffer traffic or workplace accidents than the general population.

Excess weight, alcohol consumption, smoking, polymedication, nasal obstruction, menopause and unhealthy lifestyle habits in general have a negative impact on health and the sleep cycle. "As healthcare professionals, our obligation is to encourage people to correct habits that are harmful to their health to improve sleep hygiene and quality of life. We must use our knowledge to guarantee effective medical treatment for patients. Professionals with responsibility for the health and safety of others, such as ourselves, or chauffeurs and pilots, for example, know that our work is helping to save lives and to save companies money," says Maribel Pascual. As Eva Willaert explains, "In the case of snoring, the model has changed completely: before we thought it was a sign of sleeping well, but snoring can be the first sign of respiratory difficulties during sleep. Statistics show that 60% of men over 50 and 40% of women in the same age group snore. Not everyone that snores develops SA, but snoring can lead to other health conditions and it is always worth reviewing clinical histories."

Dentists, the key to early diagnosis

Dentists play a vital role in detecting diseases associated with dental health and facilitating earlier and less costly treatment of snoring and SA. In the specific case of sleep apnoea, failure to treat the disorder in its early stages can increase the cost of subsequent treatment two- or threefold. Lluís Nogués believes that, "dentistry has an increasing presence in the field of respiratory diseases, but hospital Sleep Units rarely have dentists as part of their teams. When dental professionals are required, hospitals seek the help of external partners to ensure the best service for their patients." Nogués goes on to explain that, "At present, dental sleep medicine is a highly specialized area of study and requires specific postgraduate training. In the university sphere, we are pioneers not only in the teaching of this specialism but also in the care setting. Nevertheless, in Spain, the dental profession has become synonymous with business, and we must fight against this image and seek ways to work more closely with other specialists in the public healthcare system."

Conducting research to improve quality of life

The standard diagnostic test for respiratory sleep disorders is polysomnography, which records respiratory flow, heart rate, blood oxygen and sleep phases, etc. The most common treatment for snoring and SA until recently was continuous positive airway pressure (CPAP), administered using a device consisting of a nose piece or full mask that supplies a constant air pressure during sleep. A newer alternative, the mandibular advancement device (MAD), alters certain characteristics of the upper airways, leading to improvements in people affected by snoring and by mild and moderate cases of SA, making it the preferred treatment option for both disorders. MAD can also be used intermittently to aid or replace CPAP if this option is rejected or due to other considerations such as travel or social commitments.

The Snoring and Sleep Apnoea Diagnosis and Treatment Unit, which receives referrals from the public healthcare system (Bellvitge University Hospital, Hospital Clínic, Hospital del Mar, Hospital de Viladecans, Hospital de Terrassa, etc.), also applies diagnostic techniques (imaging, polygraphs, etc.) to potential SA patients to establish the best course of treatment in each case or to identify the appropriate specialist unit for referral. As such, it functions essentially as a screening unit."Our main mission is to assess the patient as thoroughly as possible," says Maribel Pascual. "As dentists, we are in the best position to detect cases that have not been diagnosed. In lower-risk patients, MAD can be useful for reducing the symptoms of the disease and preventing further development, but the devices must be tailored to each case to match the specific clinical diagnosis."

The unit conducts exhaustive follow-up of each patient and their symptoms and has also achieved recognition for its research, in particular "for studies published in prestigious dentistry journals on the impact of MAD and the possible side effects appearing in the mouth, which are often extremely minor, provided that patients are monitored thoroughly," says Eva Willaert, who explains that, "We have also set up a research area that focuses on the quality of life of patients fitted with MAD, which are among the most recent treatments to emerge in the field of dental health." As Maribel Pascual explains, "in ten years of clinical experience we have also observed that certain prosthetic dental treatments can aggravate snoring and SA in some patients."

As many as 25 percent of hospital nurses go without sleep for up to 24 hours in order to adjust to working on the night shift, which is the least effective strategy for adapting their internal, circadian clocks to a night-time schedule.

That is one of the results of the first study to examine the strategies that night nurses use to adjust between day and night sleep cycles. The study was based on questionnaires from 388 nurses who work at the Vanderbilt University Medical Center and the results are published in the April 13 issue of the scientific journal, Public Library of Science One.

The study also found that variations in individuals' circadian clock genes have a discernible impact on the nurses' ability to adapt.

Disruptions to circadian rhythm unhealthy

A number of previous studies have found that repeated incidence of circadian misalignment — the condition that occurs when individuals' sleep/wake patterns are out of sync with their biological clocks — is not healthy. Jet lag is the most familiar example of this condition. Circadian misalignment has been associated with increased risk of developing cardiovascular, metabolic and gastrointestinal disorders, some types of cancer and several mental disorders.

The way that nursing shifts have been scheduled since the nurse shortages of the 1980's makes nurses particularly susceptible to this problem. Hospital nurses who work with inpatients do so almost exclusively in 12-hour shifts. The day shift normally runs from 7 a.m. to 7 p.m. and the night shift covers 7 p.m. to 7 a.m.

Vanderbilt night shift nurses typically work a schedule that includes three days on night shift followed by two to five days off, when most switch back to a normal sleep cycle. That means most of them are shifting sleep cycles as frequently as twice a week.

"I was very surprised to find that nurses' second most frequent strategy was the 'no sleep' strategy that often involved staying awake for the 12 hours before starting the night shift," said Karen Gamble, an assistant professor of psychiatry and behavioral neurobiology at the University of Alabama at Birmingham, who worked on the study as a post-doctoral fellow at Vanderbilt. "That means they are skipping sleep for at least 24 hours straight."

Five distinct sleep strategies

The researchers identified five distinct strategies that the nurses used to adjust their circadian clocks. The most common approach, used by about half the participants, was to sleep in late on the morning before their first night shift. A small percentage maintained a nighttime schedule on their days off. The other two strategies were intermediates.

It's not often that you identify and characterize a human behavior for the first time, let alone one that has an effect on human health"It's not often that you identify and characterize a human behavior for the first time, let alone one that has an effect on human health," said Vanderbilt graduate student and co-author Chris Ciarleglio.

It was beyond the scope of the study to determine the effect that the nurses' sleep strategies have on their performance. "It's very difficult to differentiate between the strategies and the individual variations of the people who choose them," Gamble acknowledged.

However, the study did ask the nurses several questions designed to assess their adaptation. For example, they asked how well adapted they felt; how long it takes them to get out of bed; how much caffeine they use; and how likely they are to fall asleep during the day. The answers to these questions indicate that the nurses who use the sleep deprivation strategy are the most poorly adapted of the five groups.

The researchers recommend that nurses should be advised to avoid the "no sleep" strategy when working nights and suggest that hospitals re-evaluate the way that they schedule nurses to reduce the frequency with which nurses switch sleep schedules.

"Most people don't want to work at night and those that do use what works best for them and their lifestyle," observed co-investigator Nancy Wells, director of nursing research at Vanderbilt.

Scheduling is a very touchy issue and many nurses, particularly the younger ones, like the current system because it allows them to string together a number of days off without taking vacation, she added.

Genetics affect adaptation

The researchers also took DNA samples from all the participants to investigate the extent to which their circadian clocks influenced their adaptation. They determined the nurses' "chronotype" — whether they are natural early risers (larks) or late risers (owls) — and which of seven well-known variations, or polymorphisms, in human circadian clock genes that each nurse possessed.

This information allowed the researchers to determine that larks adapt particularly well to day shifts and particularly poorly to night shifts, while owls do not adapt particularly well or poorly to either shift. In addition, they found that variants in one gene, called PER3, appear to have a major impact on the effectiveness of the no sleep strategy. Individuals with one variant of this genotype appear to respond more poorly than average to the strategy while those with the other genotype appear to respond better than average.

Vanderbilt Professor of Biological Sciences Carl Johnson, Alison Motsinger-Reif, assistant professor of statistics at Northern Carolina State University, Marshall Summar at Children's National Medical Center in Washington, D.C. and Douglas McMahon, Vanderbilt professor of biological sciences, also contributed to the research.

The research was initially funded by Vanderbilt's Discovery Grant program and then by a grant from the National Institute of Mental Health.

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Journal Reference:

1. Karen L. Gamble, Alison A. Motsinger-Reif, Akiko Hida, Hugo M. Borsetti, Stein V. Servick, Christopher M. Ciarleglio, Sam Robbins, Jennifer Hicks, Krista Carver, Nalo Hamilton, Nancy Wells, Marshall L. Summar, Douglas G. McMahon, Carl Hirschie Johnson. Shift Work in Nurses: Contribution of Phenotypes and Genotypes to Adaptation. PLoS ONE, 2011; 6 (4): e18395 DOI: 10.1371/journal.pone.0018395

 — In Civilization and Its Discontents, Sigmund Freud argued that modern society was hard on human psychology, forcing people to get along in unnaturally close quarters. Now newly published research from The Rockefeller University points out a different discontent in the developed world, namely, the disruption of our natural sleep cycles, thanks to the ubiquity of electric lighting.

Experiments on mice, published this month in Proceedings of the National Academy of Sciences, found that throwing off their evolutionarily ancient circadian rhythms by artificially altering the length of their days has a substantial impact on the body and the brain. The work suggests that our modern, round-the-clock lifestyle could disrupt metabolism, interfere with learning and impact behavior in ways that we're just beginning to understand.

Researchers led by Ilia Karatsoreos, a postdoc in Bruce S. McEwen's Harold and Margaret Milliken Hatch Laboratory of Neuroendocrinology, housed mice for 10 weeks in 20-hour light-dark cycles, at odds with their natural 24-hour circadian cycle. They found that after six weeks, the disrupted mice got fatter, showed less mental flexibility and were more impulsive than mice kept on their natural schedule. The findings were originally presented at a Society for Neuroscience's conference in 2009.

Looking ahead, Karatsoreos says, a main goal is to understand how this environmental disruption works at the biochemical level. "We are interested in how the light cycle changes affects 'clock genes' — the actual molecular gears of the circadian clock within cells — in different brain regions, particularly the prefrontal cortex, and how this translates to changes in the functioning of the cells in that region."

At the same time, the researchers are working to understand the changes at the cellular and molecular level of peripheral tissues, especially those involved in metabolism and energy usage, such as the liver and the adipose tissues.

"The circadian system is a 'web,' with rhythms at the molecular level driving rhythms at the cellular level, which results in rhythms at the tissue level," Karatsoreos says. "This can lead to a cascading set of effects throughout the whole organism, and we want to understand how exactly that happens."

The researchers believe that this cascade may affect how an individual, whether animal or human, responds to additional challenges to the immune or metabolic systems, such as infection or high fat food, both ubiquitous realities of modern life. They are also working on models to understand the impact of different kinds of light-dark shifting such as those experienced by flight crews, shift workers, military personnel and medical residents. "We want to know how different patterns affect the brain and body, and if they share similar mechanisms of action," says Karatsoreos.

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Journal Reference:

1. I. N. Karatsoreos, S. Bhagat, E. B. Bloss, J. H. Morrison, B. S. McEwen. Disruption of circadian clocks has ramifications for metabolism, brain, and behavior. Proceedings of the National Academy of Sciences, 2011; 108 (4): 1657 DOI: 10.1073/pnas.1018375108

— In a new paper published this week in the Proceedings of the National Academy of Sciences, Aziz Sancar, MD, PhD, the Sarah Graham Kenan Professor of Biochemistry and Biophysics in the UNC School of Medicine, and his colleagues have taken an important step in understanding the underlying molecular signals that influence a broad array of biological processes ranging from the sleep-wake cycle to cancer growth and development.

Scientists who work in this field, known as chronobiology, have identified the genes that direct circadian rhythms in people, mice, fruit flies, fungi and several other organisms. However, the mechanisms by which those genes interact with light in the organism's environment have not been well understood.

Circadian rhythms are the physical, mental and behavioral changes that follow the earth's 24 hour cycle, responding primarily to light and darkness in an organism's environment.

About 15 years ago, Sancar discovered a human protein called cryptochrome which acts as a core component of the molecular clock in mammals. The protein is also found in fruit flies, other insects, and plants.

"Cryptochrome 'resets' the circadian clock, but we were not sure how it worked," said Sancar, who is also a member of UNC Lineberger Comprehensive Cancer Center.

Using fruit flies (Drosophilia melanogaster), the team purified cryptochrome and developed a biochemical test that shows when and how the protein transmits signals.

"We can now detect the protein at work. When we expose cryptochrome to blue light in fruit flies, a millisecond of light exposure has a half-life during which we can examine the mechanism in the laboratory," said Sancar. "We can follow the molecular signals after light exposure and have a reliable model to test various hypotheses about how light interacts with the circadian systems we know are so important to biological processes."

The research may be useful to scientists who study the circadian clock's relationship to sleep disorders, jet lag, cancer, bipolar disorder, depression and other diseases.

Sancar's research collaborators include Nuri Ozturk, PhD, Christopher Selby, PhD, and Yunus Annayev, BSc, of UNC-Chapel Hill's Department of Biochemistry and Biophysics and Donping Zhong, PhD from the Ohio State University.

The research was supported by the US National Institutes of Health.

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Journal Reference:

1. N. Ozturk, C. P. Selby, Y. Annayev, D. Zhong, A. Sancar. Reaction mechanism of Drosophila cryptochrome. Proceedings of the National Academy of Sciences, 2010; DOI: 10.1073/pnas.1017093108

 Using an automated screening technique developed by pharmaceutical companies to find new drugs, a team of researchers from UC San Diego and three other research institutions has discovered a molecule with the most potent effects ever seen on the biological clock.

Dubbed by the scientists "longdaysin," for its ability to dramatically slow down the biological clock, the new compound and the application of their screening method to the discovery of other clock-shifting chemicals could pave the way for a host of new drugs to treat severe sleep disorders or quickly reset the biological clocks of jet-lagged travelers who regularly travel across multiple time zones.

"Theoretically, longdaysin or a compound like it could be used to correct sleep disorders such as the genetic disorder familial advanced sleep syndrome, which is characterized by a clock that's running too fast," said Steve Kay, dean of UCSD's Division of Biological Sciences, who headed the research team, which published its findings in the December 14 issue of the journal PLoS Biology. "A compound that makes the clock slow down or speed up can also be used to phase-shift the clock — in other words, to bump or reset the hands of the clock. This would help your body catch up when it is jet lagged or reset it to a normal day-night cycle when it has been thrown out of phase by shift work."

The researchers demonstrated the dramatic effects of longdaysin by lengthening the biological clocks of larval zebra fish by more than 10 hours.

"Longdaysin is the champion by far in how much it can move the clock," said Kay, whose laboratory at UCSD had found compounds in previous studies that could shift the biological clock by as much as several hours at most. "We were really surprised to find out how much you can slow down the biological clock with this compound and still have a clock that is running."

Biologists in Kay's laboratory and the nearby Genomics Institute of the Novartis Research Foundation, who were led by Tsuyoshi Hirota, the first author of the paper, discovered longdaysin by screening thousands of compounds with a chemical robot that tested the reaction of each compound with a line of human bone cancer cells that the researchers' genetically modified so that they could visually see changes in the cells' circadian rhythms. This was done by attaching in the cells a clock gene to a luciferase gene used by fireflies to glow at night, so that the cells glowed when the biological clock was activated. A chemical robot screened more than 120,000 potential compounds from a chemical library into individual micro-titer wells, a system used by drug companies called high-throughput screening, and automatically singled out those molecules found to have the biggest effects on the biological clock.

Once Kay's group had isolated longdaysin, it turned to biological chemists in Peter Schultz's laboratory at The Scripps Research Institute to characterize the molecule and figure out the mechanisms of how it lengthened the biological clock. That analysis showed that three separate protein kinases on the compound were responsible for the dramatic effect of longdaysin, one of which, CK1alpha, had previously been ignored by chronobiology researchers.

"Because this compound doesn't just hit one target, but multiple targets, it showed us that if you want to shift the biological clock in a major way you have to hit multiple kinases," said Kay.

The researchers then showed that longdaysin had the same effect of lengthening the biological clock in mouse tissue samples and zebra fish larvae that carried luciferase genes attached to their clock genes.

"We were really encouraged to find that when we added longdaysin to these living zebra fish, we lengthened the biological clock and didn't see any obvious deleterious effects," said Kay. "They grow normally while they are exposed to this compound. That showed us that our high-throughput assay works and accurately predicts how the compound works on the biological clock of a living fish. The next thing to do is to try this in a mammalian system."

Kay's research team plans to test longdaysin on mice in the near future, but its goal isn't to develop longdaysin into a drug.

"Longdaysin is not as potent as we would like," he adds. "This will be a tool for research."

Other co-authors of the paper besides Hirota and Schultz were Warren Lewis, Eric Zhang, Ghislain Breton and David Traver of UCSD; Jae Wook Lee of TSRI; Xianzhong Liu, Michael Garcia Eric Peters of the Genomics Institute of the Novartis Research Foundation; and Pierre Etchegaray of the University of Massachusetts Medical School.

The study was funded by grants from the National Institutes of Health.

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Journal Reference:

1. Tsuyoshi Hirota, Jae Wook Lee, Warren G. Lewis, Eric E. Zhang, Ghislain Breton, Xianzhong Liu, Michael Garcia, Eric C. Peters, Jean-Pierre Etchegaray, David Traver, Peter G. Schultz, Steve A. Kay. High-Throughput Chemical Screen Identifies a Novel Potent Modulator of Cellular Circadian Rhythms and Reveals CKIa as a Clock Regulatory Kinase. PLoS Biology, 2010; 8(12): e1000559 DOI: 10.1371/journal.pbio.1000559