Strong evidence has accumulated over the last several years, showing that low sleep quantity and/or quality plays an important role in the elevation of blood pressure. We hypothesized that increasing sleep duration serves as an effective behavioral strategy to reduce blood pressure in prehypertension or type 1 hypertension. Twenty-two participants with prehypertension or stage 1 hypertension, and habitual sleep durations of 7 h or less, participated in a 6-week intervention study. Subjects were randomized to a sleep extension group (48 ± 12 years, N = 13) aiming to increase bedtime by 1 h daily over a 6-week intervention period, or to a sleep maintenance group (47 ± 12 years, N = 9) aiming to maintain habitual bedtimes. Both groups received sleep hygiene instructions. Beat-to-beat blood pressure was monitored over 24 h, and 24-h urine and a fasting blood sample were collected pre- and post-intervention. Subjects in the sleep extension group increased their actigraphy-assessed daily sleep duration by 35 ± 9 min, while subjects in the sleep maintenance condition increased slightly by 4 ± 9 min (P = 0.03 for group effect). Systolic and diastolic beat-to-beat blood pressure averaged across the 24-h recording period significantly decreased from pre- to post-intervention visit in the sleep extension group by 14 ± 3 and 8 ± 3 mmHg, respectively (P < 0.05). Though the reduction of 7 ± 5 and 3 ± 4 mmHg in the sleep maintenance group was not significant, it did not differ from the blood pressure reduction in the sleep extension group (P = 0.15 for interaction effect). These changes were not paralleled by pre- to post-intervention changes in inflammatory or sympatho-adrenal markers, nor by changes in caloric intake. While these preliminary findings have to be interpreted with caution due to the small sample size, they encourage future investigations to test whether behavioral interventions designed to increase sleep duration serve as an effective strategy in the treatment of hypertension.
Genetic variants responsible for susceptibility to obesity and its comorbidities among Hispanic children have not been identified. The VIVA LA FAMILIA Study was designed to genetically map childhood obesity and associated biological processes in the Hispanic population. A genome-wide association study (GWAS) entailed genotyping 1.1 million single nucleotide polymorphisms (SNPs) using the Illumina Infinium technology in 815 children. Measured genotype analysis was performed between genetic markers and obesity-related traits i.e., anthropometry, body composition, growth, metabolites, hormones, inflammation, diet, energy expenditure, substrate utilization and physical activity. Identified genome-wide significant loci: 1) corroborated genes implicated in other studies (MTNR1B, ZNF259/APOA5, XPA/FOXE1 (TTF-2), DARC, CCR3, ABO); 2) localized novel genes in plausible biological pathways (PCSK2, ARHGAP11A, CHRNA3); and 3) revealed novel genes with unknown function in obesity pathogenesis (MATK, COL4A1). Salient findings include a nonsynonymous SNP (rs1056513) in INADL (p = 1.2E-07) for weight; an intronic variant in MTNR1B associated with fasting glucose (p = 3.7E-08); variants in the APOA5-ZNF259 region associated with triglycerides (p = 2.5-4.8E-08); an intronic variant in PCSK2 associated with total antioxidants (p = 7.6E-08); a block of 23 SNPs in XPA/FOXE1 (TTF-2) associated with serum TSH (p = 5.5E-08 to 1.0E-09); a nonsynonymous SNP (p = 1.3E-21), an intronic SNP (p = 3.6E-13) in DARC identified for MCP-1; an intronic variant in ARHGAP11A associated with sleep duration (p = 5.0E-08); and, after adjusting for body weight, variants in MATK for total energy expenditure (p = 2.7E-08) and in CHRNA3 for sleeping energy expenditure (p = 6.0E-08). Unprecedented phenotyping and high-density SNP genotyping enabled localization of novel genetic loci associated with the pathophysiology of childhood obesity.
OBJECTIVE: To investigate the effect of treatment with the glucagon-like peptide 1 receptor agonist exenatide on weight loss and metabolic parameters in obese nondiabetic women.
RESEARCH DESIGN AND METHODS: Forty-one obese women (aged 48 ± 11 years and BMI 33.1 ± 4.1 kg/m(2)) participated in a 35-week randomized, double-blind, placebo-controlled, crossover study, including two 16-week treatment periods separated by a 3-week washout period. There was no lifestyle intervention. The primary outcome was change in body weight.
RESULTS: Subjects treated with exenatide lost an average of 2.49 ± 0.66 kg compared with a 0.43 ± 0.63 kg weight gain during placebo treatment. Weight loss with exenatide treatment was noted at 2 weeks. The degree of weight loss could be stratified. A total of 30% of subjects were high responders who lost ≥5% body weight (-7.96 ± 0.52%), 39% were moderate responders who lost <5% body weight (-2.43 ± 0.45%), and 31% were nonresponders who gained weight (1.93 ± 0.53%). Waist circumference also decreased significantly with exenatide treatment. Subjects experienced more nausea during exenatide treatment compared with placebo, but the severity decreased over time and did not correlate with weight loss.
CONCLUSIONS: Short-term exenatide treatment was associated with modest weight loss and decreased waist circumference in a cohort of obese nondiabetic women. A subset of individuals demonstrated robust weight loss that was detected very early in the course of treatment.
Sleep of good quantity and quality is considered a biologically important resource necessary to maintain homeostasis of pain-regulatory processes. To assess the role of chronic sleep disturbances in pain processing, we conducted laboratory pain testing in subjects with primary insomnia. Seventeen participants with primary insomnia (mean ± SEM 22.6 ± 0.9 yrs, 11 women) were individually matched with 17 healthy participants. All participants wore an actigraph device over a 2-week period and completed daily sleep and pain diaries. Laboratory pain testing was conducted in a controlled environment and included (1) warmth detection threshold testing, (2) pain sensitivity testing (threshold detection for heat and pressure pain), and (3) tests to access pain modulatory mechanisms (pain facilitation and inhibition). Primary insomnia subjects reported experiencing spontaneous pain on twice as many days as healthy controls during the at-home recording phase (p < 0.05). During laboratory testing, primary insomnia subjects had lower pain thresholds than healthy controls (p < 0.05 for heat pain detection threshold, p < 0.08 for pressure pain detection threshold). Unexpectedly, pain facilitation, as assessed with temporal summation of pain responses, was reduced in primary insomnia compared to healthy controls (p < 0.05). Pain inhibition, as assessed with the diffuse noxious inhibitory control paradigm (DNIC), was attenuated in insomnia subjects when compared to controls (p < 0.05). Based on these findings, we propose that pain-inhibitory circuits in patients with insomnia are in a state of constant activation to compensate for ongoing subclinical pain. This constant activation ultimately may result in a ceiling effect of pain-inhibitory efforts, as indicated by the inability of the system to adequately function during challenge.
In data from prospective cohort studies, self report of insufficient or disturbed sleep is related to increased overall and cardiovascular morbidity. Inflammation is established as a key mechanism in the development of arteriosclerotic heart and vascular disease. Inflammation has been considered a possible link between short sleep and cardiovascular disease and morbidity. Measures of inflammation are increased by experimental sleep deprivation, but in cohort studies a relationship of sleep duration to inflammatory markers is less clear. In these studies the association of self reported short sleep to cardiac morbidity is confounded by many psychological and socioeconomic variables. More studies are needed to explain the link between short sleep duration and cardiac morbidity. Experimental studies of sleep deprivation mimicking habitual shortened sleep over long time intervals, and studies employing sleep extension in habitual short sleepers will allow better characterization of the health benefits of adequate sleep duration. Prospective cohort studies should include objective measures of sleep duration and should to control for the known confounding variables.
Controlled, experimental studies on the effects of acute sleep loss in humans have shown that mediators of inflammation are altered by sleep loss. Elevations in these mediators have been found to occur in healthy, rigorously screened individuals undergoing experimental vigils of more than 24h, and have also been seen in response to various durations of sleep restricted to between 25 and 50% of a normal 8h sleep amount. While these altered profiles represent small changes, such sub-clinical shifts in basal inflammatory cytokines are known to be associated with the future development of metabolic syndrome disease in healthy, asymptomatic individuals. Although the mechanism of this altered inflammatory status in humans undergoing experimental sleep loss is unknown, it is likely that autonomic activation and metabolic changes play key roles.
Insufficient duration of sleep is a highly prevalent behavioral pattern in society that has been shown to cause an increase in spontaneous pain and sensitivity to noxious stimuli. Prostaglandins (PGs), in particular PGE2, are key mediators of inflammation and pain, and we investigated whether PGE2 is a potential mediator in sleep-loss-induced changes in nociceptive processing. Twenty-four participants (7 females, age 35.1+/-7.1 years) stayed for 7 days in the Clinical Research Center. After two baseline days, participants were randomly assigned to either 3 days of 88 h of sleep deprivation (TSD, N=15) or 8h of sleep per night (N=9), followed by a night of recovery sleep. Participants rated the intensity of various pain-related symptoms every 2h across waking periods on computerized visual analog scales. PGE2 was measured in 24-h-urine collections during baseline and third sleep deprivation day. Spontaneous pain, including headache, muscle pain, stomach pain, generalized body pain, and physical discomfort significantly increased by 5-14 units on a 100-unit scale during TSD, compared to the sleep condition. Urinary PGE2 metabolite significantly increased by about 30% in TSD over sleep condition. TSD-induced increase in spontaneous pain, in particular headache and muscle pain, was significantly correlated with increase in PGE2 metabolite. Activation of the PGE2 system appears to be a potential mediator of increased spontaneous pain in response to insufficient sleep.
That insufficient sleep is associated with poor attention and performance deficits is becoming widely recognized. Fewer people are aware that chronic sleep complaints in epidemiologic studies have also been associated with an increase in overall mortality and morbidity. This article summarizes findings of known effects of insufficient sleep on cardiovascular risk factors including blood pressure, glucose metabolism, hormonal regulation, and inflammation with particular emphasis on experimental sleep loss, using models of total and partial sleep deprivation, in healthy individuals who normally sleep in the range of 7 to 8 hours and have no sleep disorders. These studies show that insufficient sleep alters established cardiovascular risk factors in a direction that is known to increase the risk of cardiac morbidity.
CONTEXT: Sleep disturbances, pain, and inflammation co-occur in various medical conditions, but their interrelationships are poorly understood.
OBJECTIVE: We investigated the effects of reduced sleep duration (by approximately 50%) to 4 h/night across 10 days, on peripherally circulating inflammatory mediators. In addition, we tested the prediction that degree of inflammation is quantitatively related to the extent to which pain is increased in response to prolonged sleep restriction.
DESIGN: Randomized, 16 day controlled in-laboratory study conducted in GCRC.
METHODS: Eighteen volunteers were randomly assigned to either 12 days of sleeping 8 h/night or 4 h/night. Participants rated mood and pain symptoms throughout experimental days. Urine was collected and blood was drawn frequently on the baseline day and after the 10th experimental day for 25 hours.
OUTCOME MEASURES: Levels of plasma interleukin (IL)-6, serum C-reactive protein (CRP), plasma soluble tumor necrosis factor receptor p55 (sTNF-R p55), urinary levels of prostaglandin (PG) metabolites D2 and E2, subjective assessment of pain and tiredness-fatigue.
RESULTS: IL-6 levels were elevated in the 4-h sleep condition over the 8-h sleep condition (P <0.05). CRP levels showed the same trend as IL-6, but did not differ significantly between groups (P = 0.11). Levels of sTNF-R p55 were unchanged in both groups. PG E2 and 11beta-F2alpha metabolite increased in 4-h sleepers, but did not differ significantly from the 8-h sleepers. Elevated IL-6 levels were strongly associated with increased pain ratings in response to sleep restriction (r = 0.67, P <0.01), and this association could not be explained by elevations in tiredness-fatigue.
CONCLUSION: Insufficient sleep quantity may facilitate and/or exacerbate pain through elevations of IL-6. In disorders where sleep disturbances are common, insufficient sleep quantity itself may establish and maintain its co-occurrence with pain and increased inflammation.
Working memory scanning and motor response speeds were assessed in chronically sleep restricted participants using the Sternberg item recognition paradigm (SIRP). Twenty-two healthy volunteers (ages 21-30) living in a controlled hospital environment were allowed either 4h of sleep opportunity (50% of habitual sleep) or 8h of sleep opportunity (100% of habitual sleep) for 12 days. Working memory scanning efficiency (time taken to access an item in working memory) was tested for the first 9 days of sleep restriction and improved over time in participants permitted an 8h sleep period, but did not change significantly in participants permitted a 4h sleep period. Speed of motor response (reaction time independent of cognitive processing) did not change significantly in either group. These results indicate that the efficiency of working memory scanning can improve with repeated practice given sufficient sleep, and that prolonged sleep restriction to 50% of habitual sleep prevents this improvement.
Sepsis, the systemic inflammatory response to infection, is a leading cause of morbidity and mortality. The mechanisms of sepsis pathophysiology remain obscure but are likely to involve a complex interplay between mediators of the inflammatory and coagulation pathways. An improved understanding of these mechanisms should provide an important foundation for developing novel therapies. In this study, we show that sepsis is associated with a time-dependent increase in circulating levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF) in animal and human models of sepsis. Adenovirus-mediated overexpression of soluble Flt-1 (sFlt-1) in a mouse model of endotoxemia attenuated the rise in VEGF and PlGF levels and blocked the effect of endotoxemia on cardiac function, vascular permeability, and mortality. Similarly, in a cecal ligation puncture (CLP) model, adenovirus-sFlt-1 protected against cardiac dysfunction and mortality. When administered in a therapeutic regimen beginning 1 h after the onset of endotoxemia or CLP, sFlt peptide resulted in marked improvement in cardiac physiology and survival. Systemic administration of antibodies against the transmembrane receptor Flk-1 but not Flt-1 protected against sepsis mortality. Adenovirus-mediated overexpression of VEGF but not PlGF exacerbated the lipopolysaccharide-mediated toxic effects. Together, these data support a pathophysiological role for VEGF in mediating the sepsis phenotype.
Sleepiness and increased sleep pressure are typical symptoms of inflammation and infection. Moreover, it is a pre-scientific belief that sleep supports host defense. The present paper summarizes the experimental evidence regarding the interaction between sleep and the immune system in humans. Sleep-wake behavior is very sensitive to experimental host defense activation, for example, by bacterial endotoxin. When the injection of endotoxin is accompanied by fever and a prominent neuroendocrine activation, sleep continuity will be disturbed. When the production of inflammatory cytokines is stimulated by smaller amounts of endotoxin, but no fever and no neuroendocrine activation are apparent, the nonREM-sleep amount will increase. This is possibly due to changes in the biological activity of the tumor necrosis factor-alpha (TNF-alpha) system. Besides their important function in sleep regulation during acute immune response, cytokines also seem to be involved in physiological sleep regulation, although there still is not very much data on this issue. So far, it remains largely unknown whether or not sleep supports host defense. In humans, for example, acute sleep deprivation up to 55 hours has only minor effects on endotoxin-induced host responses. In contrast, there is preliminary and yet inconsistent evidence that sleep deprivation might impair antibody formation in response to viral challenges.
BACKGROUND: Chronic insufficient sleep is a common finding in many pain-related and other medical diseases and is frequently experienced in the general population. Prolonged curtailment of nocturnal sleep has been studied for its adverse effect on cognitive functioning and subjective tiredness, but relatively little is known about its effect on mood and physical symptoms.
OBJECTIVE: In order to test whether sleep restriction to 50% of the habitual time over 12 days affects diurnal and day-to-day variation of subjective ratings of mood and physical symptoms, 108 adjectives and statements were self-rated using visual analog scales every 2h during the waking period.
DESIGN: Randomized, 16-day controlled in-laboratory study.
SETTING: General Clinical Research Center (GCRC).
PARTICIPANTS: Forty healthy subjects aged 21-40 years (14 females, 26 males).
INTERVENTION: Subjects were randomized to either 4h of sleep per night (11 pm-3 am, N=22) or 8h of sleep per night (11 pm-7 am, N=18) for 12 consecutive days.
MAIN OUTCOME MEASURE: Changes in the factor-derived variables optimism-sociability, tiredness-fatigue, anger-aggression, bodily discomfort, and items constituting bodily discomfort were compared between groups.
RESULTS: Optimism-sociability progressively declined over consecutive days of sleep restriction by 15%. Bodily discomfort showed a slight, but significant interindividual increase of 3% across days of sleep restriction due to significant increases of generalized body pain, back pain, and stomach pain. Optimism-sociability and tiredness-fatigue showed diurnal variations with a quadratic function period within each day in both conditions.
CONCLUSION: The data suggest that chronic insufficient sleep may contribute to the onset and amplification of pain and affect health by compromising optimistic outlook and psychosocial functioning.
OBJECTIVES: We sought to investigate the effects of sleep loss on high-sensitivity C-reactive protein (CRP) levels.
BACKGROUND: Concentrations of high-sensitivity CRP are predictive of future cardiovascular morbidity. In epidemiologic studies, short sleep duration and sleep complaints have also been associated with increased cardiovascular morbidity. Two studies were undertaken to examine the effect of acute total and short-term partial sleep deprivation on concentrations of high-sensitivity CRP in healthy human subjects.
METHODS: In Experiment 1, 10 healthy adult subjects stayed awake for 88 continuous hours. Samples of high-sensitivity CRP were collected every 90 min for 5 consecutive days, encompassing the vigil. In Experiment 2, 10 subjects were randomly assigned to either 8.2 h (control) or 4.2 h (partial sleep deprivation) of nighttime sleep for 10 consecutive days. Hourly samples of high-sensitivity CRP were taken during a baseline night and on day 10 of the study protocol.
RESULTS: The CRP concentrations increased during both total and partial sleep deprivation conditions, but remained stable in the control condition. Systolic blood pressure increased across deprivation in Experiment 1, and heart rate increased in Experiment 2.
CONCLUSIONS: Both acute total and short-term partial sleep deprivation resulted in elevated high-sensitivity CRP concentrations, a stable marker of inflammation that has been shown to be predictive of cardiovascular morbidity. We propose that sleep loss may be one of the ways that inflammatory processes are activated and contribute to the association of sleep complaints, short sleep duration, and cardiovascular morbidity observed in epidemiologic surveys.
There is very little published information on the diurnal variation of cytokines and their receptors, in healthy individuals during normal sleep-wake patterns or during sustained wakefulness. The aim of the current investigation was to characterize concentrations of soluble tumor necrosis factor receptors (sTNF-Rs) and interleukin-2 receptor (sIL-2R) during normal sleep and wakefulness, as well as during a 24 h vigil. Plasma levels of the sTNF-R p55, sTNF-R p75, and sIL-2R did not differ significantly between nocturnal sleep and nocturnal wakefulness. Rhythmic analysis (2-h intervals) revealed significant diurnal variations for both sTNF-R p55 and sTNF-R p75, but not levels of sIL-2R. Diurnal variations of both sTNF-Rs were characterized by a single cosine curve with an average peak near 06:00 h in the morning. This peak occurred well before that of cortisol, and fluctuated inversely with the diurnal rhythm of temperature. These diurnal variations in sTNF-Rs levels are consistent with the hypothesis that the TNF system plays a role in normal diurnal temperature regulation.
OBJECTIVES: To inform the debate over whether human sleep can be chronically reduced without consequences, we conducted a dose-response chronic sleep restriction experiment in which waking neurobehavioral and sleep physiological functions were monitored and compared to those for total sleep deprivation.
DESIGN: The chronic sleep restriction experiment involved randomization to one of three sleep doses (4 h, 6 h, or 8 h time in bed per night), which were maintained for 14 consecutive days. The total sleep deprivation experiment involved 3 nights without sleep (0 h time in bed). Each study also involved 3 baseline (pre-deprivation) days and 3 recovery days.
SETTING: Both experiments were conducted under standardized laboratory conditions with continuous behavioral, physiological and medical monitoring.
PARTICIPANTS: A total of n = 48 healthy adults (ages 21-38) participated in the experiments.
INTERVENTIONS: Noctumal sleep periods were restricted to 8 h, 6 h or 4 h per day for 14 days, or to 0 h for 3 days. All other sleep was prohibited.
RESULTS: Chronic restriction of sleep periods to 4 h or 6 h per night over 14 consecutive days resulted in significant cumulative, dose-dependent deficits in cognitive performance on all tasks. Subjective sleepiness ratings showed an acute response to sleep restriction but only small further increases on subsequent days, and did not significantly differentiate the 6 h and 4 h conditions. Polysomnographic variables and delta power in the non-REM sleep EEG-a putative marker of sleep homeostasis--displayed an acute response to sleep restriction with negligible further changes across the 14 restricted nights. Comparison of chronic sleep restriction to total sleep deprivation showed that the latter resulted in disproportionately large waking neurobehavioral and sleep delta power responses relative to how much sleep was lost. A statistical model revealed that, regardless of the mode of sleep deprivation, lapses in behavioral alertness were near-linearly related to the cumulative duration of wakefulness in excess of 15.84 h (s.e. 0.73 h).
CONCLUSIONS: Since chronic restriction of sleep to 6 h or less per night produced cognitive performance deficits equivalent to up to 2 nights of total sleep deprivation, it appears that even relatively moderate sleep restriction can seriously impair waking neurobehavioral functions in healthy adults. Sleepiness ratings suggest that subjects were largely unaware of these increasing cognitive deficits, which may explain why the impact of chronic sleep restriction on waking cognitive functions is often assumed to be benign. Physiological sleep responses to chronic restriction did not mirror waking neurobehavioral responses, but cumulative wakefulness in excess of a 15.84 h predicted performance lapses across all four experimental conditions. This suggests that sleep debt is perhaps best understood as resulting in additional wakefulness that has a neurobiological "cost" which accumulates over time.
The aim of the current study was to investigate the effects of sleep loss on the diurnal rhythm of circulating leptin levels. An indwelling forearm catheter was used to sample blood at 90-min intervals for a total of 120 h, which included 88 h of sustained sleeplessness, in 10 healthy men. The diurnal amplitude of leptin was reduced during total sleep deprivation and returned toward normal during the period of recovery sleep. This finding provides evidence that sleep influences the nocturnal leptin profile, and may have implications for the understanding of the role of sleep in metabolic regulation and the aetiologies of obesity and the night eating syndrome.
Animal studies provide consistent evidence for the pivotal role of inflammatory cytokines in inducing sickness behavior during systemic infection and inflammation. Because depression in humans shows a considerable symptomatic overlap with sickness behavior, it has been hypothesized that cytokines are also involved in affective disorders. This view is supported by studies showing that therapeutic administration of inflammatory cytokines can induce typical major depression and by evidence that stimulated cytokine-release during experimental endotoxemia provokes transient deterioration in mood and memory. However, in these conditions, similar to the animal models of acute infections, huge amounts of cytokines produced in the periphery act on the brain. In contrast, during most clinical conditions where depression might involve cytokine actions, such as chronic infection and inflammation, only low amounts of cytokines are circulating. The present paper addresses the question whether and how low amounts of circulating cytokines act on the human brain. Evidence is presented that very low amounts of circulating cytokines are likely to influence brain functions, even under baseline conditions. It is also likely that low levels of cytokines affect the same brain function as high levels do. However, it is uncertain whether these effects go in the same direction. NonREM sleep, for example, is promoted by a slight increase in cytokine levels, but suppressed by prominent increases. Because no comparable data are available for mood and other brain functions, the answer to the question whether and how low circulating amounts of cytokines affect mood depends on further experimental studies.