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    Oxidative stress in exercise training: the involvement of inflammation and peripheral signals. Magherini Francesca,Fiaschi Tania,Marzocchini Riccardo,Mannelli Michele,Gamberi Tania,Modesti Pietro Amedeo,Modesti Alessandra Free radical research The evidence about the health benefits of regular physical activity is well established. Exercise intensity is a significant variable and structured high-intensity interval training (HIIT) has been demonstrated to improve both whole-body and skeletal muscle metabolic health in different populations. Conversely, fatigue accumulation, if not resolved, leads to overwork, chronic fatigue syndrome (CFS), overtraining syndrome up to alterations of endocrine function, immune, systemic inflammation, and organic diseases with health threat. In response to temporary increases in stress during training, some athletes are unable to maintain sufficient caloric intake, thus suffering a negative energy balance that causes further stress. The regulation of the energy balance is controlled by the central nervous system through an elaborate interaction of the signalling that involves different tissues such as leptin, adiponectin and ghrelin whose provide important feedback to the hypothalamus to regulate the energy balance. Although exercise-induced reactive oxygen species are required for normal force production in muscle, high levels of ROS appear to promote contractile dysfunction. However, a high level of oxidative stress in may induce a rise in inflammatory markers and a disregulation in expression of adiponectin, leptin and grelin. 10.1080/10715762.2019.1697438
    Physician-Training Stress and Accelerated Cellular Aging. Ridout Kathryn K,Ridout Samuel J,Guille Constance,Mata Douglas A,Akil Huda,Sen Srijan Biological psychiatry BACKGROUND:Stress is a key precipitant for many common diseases, but established biological markers to track stress and guide investigations into mechanisms linking stress and disease are lacking. Cross-sectional studies have identified correlations between stress and telomere attrition, but no large, longitudinal studies examining the impacts of chronic stress on telomere length exist. Residency training for physicians is a well-established stressful experience and can be used as a prospective stress model. METHODS:In a longitudinal cohort study of 250 interns (first-year residents) at 55 United States hospital systems serving during the 2015-2016 academic year, we examined associations between measures of the residency experience and saliva-measured telomere attrition. RESULTS:Telomere length shortened significantly over the course of internship year, from mean ± SD of 6465.1 ± 876.8 base pairs before internship to 6321.5 ± 630.6 base pairs at the end of internship (t = 2.69; p = .008). Stressful early family environments and neuroticism were significantly associated with shorter preinternship telomere length. Longer work hours were associated with greater telomere intern telomere loss over the year (p = .002). Of note, the mean telomere attrition during internship year was six times greater than the typical annual attrition rate identified in a recent meta-analysis. CONCLUSIONS:This work implicates telomere attrition as a biologically measurable consequence of physician training, with the magnitude of attrition associated with workload. Identification of an objective, biological sequela of residency stress may help to facilitate the development of effective interventions. Further, the findings implicate telomere attrition as an objective biomarker to follow the pathologic effects of stress, in general. 10.1016/j.biopsych.2019.04.030
    Long-term performance of instrumental activities of daily living in young and middle-aged stroke survivors-Impact of cognitive dysfunction, emotional problems and fatigue. Blomgren Charlotte,Samuelsson Hans,Blomstrand Christian,Jern Christina,Jood Katarina,Claesson Lisbeth PloS one BACKGROUND:With an upward trend in the number of people who return home to independent living after stroke, the ability to perform more complex activities is becoming an increasingly important long-term outcome after stroke. Although associations between Instrumental Activities of Daily Living (IADL) and cognitive dysfunction, emotional problems, and fatigue have been reported, less is known about the long-term impact of these stroke consequences on the performance of everyday activities in young and middle-aged stroke survivors. OBJECTIVE:To explore the impact of cognitive dysfunction, emotional problems, and fatigue on long-term performance of instrumental activities of daily living in young and middle-aged stroke survivors. METHOD:Data on stroke survivors, aged 18-69 at index stroke, were collected from the Sahlgrenska Academy Study on Ischaemic Stroke. IADL outcome was assessed using the Frenchay Activities Index (FAI), and the impact of chosen variables was assessed using Spearman´s rank-order correlation and logistic regression. RESULTS:Seven years after index stroke, 296 stroke survivors (median age of 64) were included in this study. Cognitive dysfunction showed the strongest correlations with FAI outcome and independently explained worse outcome on FAI summary score and the domain of work/leisure activities. Fatigue was independently explanatory of worse outcome on FAI summary score and domestic chores, while depressive symptoms independently explained worse outcome on work/leisure activities. In a subgroup with only those participants who had no or minimal residual neurological deficits at follow-up (NIHSS score 0), cognitive dysfunction independently explained worse outcome on FAI summary score and work/leisure activities. Depressive symptoms independently explained worse outcome on FAI summary score and domestic chores. CONCLUSION:Our results show that in young and middle-aged stroke survivors, cognitive dysfunction, depressive symptoms, and fatigue negatively impact performance of IADL even at seven years post stroke onset. Further, we have shown that an impact of both cognitive dysfunction and depressive symptoms can be found also among stroke survivors with mild or no remaining neurological deficits. 10.1371/journal.pone.0216822
    Inhibition of apoptosis exacerbates fatigue-damage tendon injuries in an in vivo rat model. Bell R,Robles-Harris M A,Anderson M,Laudier D,Schaffler M B,Flatow E L,Andarawis-Puri N European cells & materials Tendinopathy is a common and progressive musculoskeletal disease. Increased apoptosis is an end-stage tendinopathy manifestation, but its contribution to the pathology of the disease is unknown. A previously established in vivo model of fatigue damage accumulation shows that increased apoptosis is correlated with the severity of induced tendon damage, even in early onset of the disease, supporting its implication in the pathogenesis of the disease. Consequently, this study aimed to determine: (1) whether apoptosis could be inhibited after fatigue damage and (2) whether its inhibition could lead to remodeling of the extracellular matrix (ECM) and pericellular matrix (PCM), to ultimately improve the mechanical properties of fatigue-damaged tendons. The working hypothesis was that, despite the low vascular nature of the tendon, apoptosis would be inhibited, prompting increased production of matrix proteins and restoring tendon mechanical properties. Rats received 2 or 5 d of systemic pan-caspase inhibitor (Q-VD-OPh) or dimethyl sulfoxide (DMSO) carrier control injections starting immediately prior to fatigue loading and were sacrificed at days 7 and 14 post-fatigue-loading. Systemic pan-caspase inhibition for 2 d led to a surprising increase in apoptosis, but inhibition for 5 d increased the population of live cells that could repair the fatigue damage. Further analysis of the 5 d group showed that effective inhibition led to an increased population of cells producing ECM and PCM proteins, although typically in conjunction with oxidative stress markers. Ultimately, inhibition of apoptosis led to further deterioration in mechanical properties of fatigue-damaged tendons. 10.22203/eCM.v036a04
    Effect of Long Working Hours on Self-reported Hypertension among Middle-aged and Older Wage Workers. Yoo Dong Hyun,Kang Mo-Yeol,Paek Domyung,Min Bokki,Cho Sung-Il Annals of occupational and environmental medicine OBJECTIVES:Many studies have reported an association between overwork and hypertension. However, research on the health effects of long working hours has yielded inconclusive results. The objective of this study was to identify an association between overtime work and hypertension in wage workers 45 years and over of age using prospective data. METHODS:Wage workers in Korea aged 45 years and over were selected for inclusion in this study from among 10,254 subjects from the Korean Longitudinal Study of Ageing. Workers with baseline hypertension and those with other major diseases were excluded. In the end, a total of 1,079 subjects were included. A Cox proportional hazards model was used to calculate hazard ratios and adjust for baseline characteristics such as sex, age, education, income, occupation, form of employment, body mass index, alcohol habit, smoking habit, regular exercise, and number of working days per week. Additional models were used to calculate hazard ratios after gender stratification. RESULTS:Among the 1,079 subjects, 85 workers were diagnosed with hypertension during 3974.2 person-months. The average number of working hours per week for all subjects was 47.68. The proportion of overtime workers was 61.0% (cutoff, 40 h per week). Compared with those working 40 h and less per week, the hazard ratio of subjects in the final model, which adjusted for all selected variables, working 41-50 h per week was 2.20 (95% confidence interval [CI], 1.19-4.06), that of subjects working 51-60 h per week was 2.40 (95% CI, 1.07-5.39), and that of subjects working 61 h and over per week was 2.87 (95% CI, 1.33-6.20). In gender stratification models, the hazard ratio of the females tended to be higher than that of the males. CONCLUSION:As the number of working hours per week increased, the hazard ratio for diagnosis of hypertension significantly increased. This result suggests a positive association between overtime work and the risk of hypertension. 10.1186/s40557-014-0025-0
    Expression of Cx43 and Cx45 in Cardiomyocytes of an Overworked Rat Model. Yang B F,Shi J Z,Li J,Pan Y P,Xiao N,Yu Y G,Zhang F,Wang H J,Li D R Fa yi xue za zhi Abstract:Objective To study the effect of overwork stress response on the expression of connexin 43(Cx43) and connexin 45(Cx45) in cardiomyocytes and on cardiac function. Methods The experimental animals were divided into control group, overworked 1-month group and overworked 2-month group. A overworked rat model was established by forcing swimming of overworked group. The expressions of Cx43 and Cx45 in myocardial tissues of experimental animals were detected by Western blotting, while the corresponding myocardial tissues were stained with hematoxylin-eosin (HE) staining and Masson's staining, then histologically observed. Results Western blotting results showed that, compared with the control group, Cx43 expression in myocardial tissues of overworked rats decreased while Cx45 expression increased. HE staining and Masson's staining results showed that hypertrophy, rupture and interstitial fiber tissue hyperplasia were observed in myocardial fibers of overworked rats. Conclusion Overwork stress response may affect cardiac function as an independent factor and may even cause heart failure or arrhythmias and lead to death. 10.12116/j.issn.1004-5619.2019.05.010
    Nonlinear associations between working hours and overwork-related cerebrovascular and cardiovascular diseases (CCVD). Lin Ro-Ting,Chien Lung-Chang,Kawachi Ichiro Scientific reports Long working hours are recognized as a risk factor for cerebrovascular and cardiovascular diseases (CCVD). We investigated the relationship between working hours and different CCVD severity outcomes-death, disability, and illness-across industries in Taiwan from 2006 to 2016. We applied a generalized additive mixed model to estimate the association between working hours and the rate of each severity outcome, adjusted for salary, unemployment rate, time, and a random intercept. Industry-average working hours were significantly associated with each outcome level of overwork-related CCVD, especially when monthly working hours increased from 169 (relative risk [RR] = 1.46, 95% confidence interval [CI] 1.002-2.12) to 187 (RR = 5.73, 95% CI 3.61-9.08). Although RR trends declined after monthly working hours exceeded 187, excess risks remained statistically significant. Each 1-hour increase in working hours had a stronger effect on the RR increase in death and disability than on illness. Variations in CCVD risks existed across industries, with the highest risk in transportation and information. Reducing working hours is essential to preventing overwork-related CCVD, especially the more severe outcomes. We recommend further research to address possible underreporting of less severe cases, and to explore actions to narrow the gaps in risk across industries. 10.1038/s41598-018-28141-2
    Overwork death among doctors a challenging issue in China. Gao Xiujuan,Xu Yingjiang International journal of cardiology 10.1016/j.ijcard.2019.04.073
    Overwork accelerates thrombotic reaction: implications for the pathogenesis of Karoshi. Otsui Kazunori,Yamamoto Junichiro,Inoue Nobutaka Journal of thrombosis and thrombolysis Work-related stressors are potential causes of cardiovascular diseases (CVDs) and stroke; however, the pathophysiological mechanisms by which occupational stress induces and exacerbates CVDs remain unclear. The global thrombosis test (GTT) is a novel in vitro assay for evaluating both thrombotic reactions and subsequent thrombolysis. The time required to form an occlusive thrombus with the GTT, called as the occlusion time (OT), and the time to lyse the thrombus, the lysis time (LT), are markers of thrombotic and thrombolytic reactions, respectively. We investigated the impact of work-related stress on the thrombotic and thrombolytic reactions in 46 healthy medical residents. Off-duty or on-duty blood samples were collected on the mornings of non-work days or after the night duty on the emergent room respectively. The duration of sleep was significantly shorter during night duty than during off-duty nights [2.25 (1.0, 3.0) h vs. 6.0 (5.0, 7.0) h; p < 0.001]. Baseline OT was 310.3 (260.9, 437.7) s. whereas the on-duty OT was significantly shortened [284.2 (230.5, 355.8) s; p < 0.01]. LT was significantly prolonged during overwork conditions compared with off-duty conditions [1547 (1346, 1908) s vs. 1470 (1219, 1692) s; p < 0.05]. Overwork accelerates the thrombotic reactions. These reactions might explain the pathogenesis of overwork-related CVDs. The GTT is a good tool for evaluating of the level of fatigue. 10.1007/s11239-017-1605-y
    Is there an influence on the coronary vessels in the event of a lack of sleep? MAJER R F Wiener medizinische Wochenschrift (1946)
    Mortality associated with sleep duration and insomnia. Kripke Daniel F,Garfinkel Lawrence,Wingard Deborah L,Klauber Melville R,Marler Matthew R Archives of general psychiatry BACKGROUND:Patients often complain about insufficient sleep or chronic insomnia in the belief that they need 8 hours of sleep. Treatment strategies may be guided by what sleep durations predict optimal survival and whether insomnia might signal mortality risks. METHODS:In 1982, the Cancer Prevention Study II of the American Cancer Society asked participants about their sleep duration and frequency of insomnia. Cox proportional hazards survival models were computed to determine whether sleep duration or frequency of insomnia was associated with excess mortality up to 1988, controlling simultaneously for demographics, habits, health factors, and use of various medications. RESULTS:Participants were more than 1.1 million men and women from 30 to 102 years of age. The best survival was found among those who slept 7 hours per night. Participants who reported sleeping 8 hours or more experienced significantly increased mortality hazard, as did those who slept 6 hours or less. The increased risk exceeded 15% for those reporting more than 8.5 hours sleep or less than 3.5 or 4.5 hours. In contrast, reports of "insomnia" were not associated with excess mortality hazard. As previously described, prescription sleeping pill use was associated with significantly increased mortality after control for reported sleep durations and insomnia. CONCLUSIONS:Patients can be reassured that short sleep and insomnia seem associated with little risk distinct from comorbidities. Slight risks associated with 8 or more hours of sleep and sleeping pill use need further study. Causality is unproven. 10.1001/archpsyc.59.2.131
    Patterns of performance degradation and restoration during sleep restriction and subsequent recovery: a sleep dose-response study. Belenky Gregory,Wesensten Nancy J,Thorne David R,Thomas Maria L,Sing Helen C,Redmond Daniel P,Russo Michael B,Balkin Thomas J Journal of sleep research Daytime performance changes were examined during chronic sleep restriction or augmentation and following subsequent recovery sleep. Sixty-six normal volunteers spent either 3 (n = 18), 5 (n= 16), 7 (n = 16), or 9 h (n = 16) daily time in bed (TIB) for 7 days (restriction/augmentation) followed by 3 days with 8 h daily TIB (recovery). In the 3-h group, speed (mean and fastest 10% of responses) on the psychomotor vigilance task (PVT) declined, and PVT lapses (reaction times greater than 500 ms) increased steadily across the 7 days of sleep restriction. In the 7- and 5-h groups speed initially declined, then appeared to stabilize at a reduced level; lapses were increased only in the 5-h group. In the 9-h group, speed and lapses remained at baseline levels. During recovery, PVT speed in the 7- and 5-h groups (and lapses in the 5-h group) remained at the stable, but reduced levels seen during the last days of the experimental phase, with no evidence of recovery. Speed and lapses in the 3-h group recovered rapidly following the first night of recovery sleep; however, recovery was incomplete with speed and lapses stabilizing at a level comparable with the 7- and 5-h groups. Performance in the 9-h group remained at baseline levels during the recovery phase. These results suggest that the brain adapts to chronic sleep restriction. In mild to moderate sleep restriction this adaptation is sufficient to stabilize performance, although at a reduced level. These adaptive changes are hypothesized to restrict brain operational capacity and to persist for several days after normal sleep duration is restored, delaying recovery. 10.1046/j.1365-2869.2003.00337.x
    Sympathetic and angiotensinergic responses mediated by paradoxical sleep loss in rats. Perry Juliana C,Bergamaschi Cássia T,Campos Ruy R,Andersen Monica L,Montano Nicola,Casarini Dulce E,Tufik Sergio Journal of the renin-angiotensin-aldosterone system : JRAAS INTRODUCTION:Recent investigations over the past decade have linked the development of hypertension to sleep loss, although the mechanisms underlying this association are still under scrutiny. To determine the relationship between sleep deprivation and cardiovascular dysfunction, we examined the effects of paradoxical sleep deprivation on heart rate, blood pressure, sympathetic nerve activity (SNA) and their consequences in the blood renin-angiotensin system. MATERIALS AND METHODS:Wistar-Hannover male rats were randomly assigned to three experimental groups: 1) control, 2) paradoxical sleep deprivation for 24 h and 3) paradoxical sleep deprivation for 96 h. Blood pressure and heart rate were recorded in awake, freely moving rats. RESULTS:Heart rate was higher in the 96 h paradoxical sleep deprivation group compared with the control group. Renal SNA was increased in all deprived groups. However, no significant statistical differences were observed in blood pressure or splanchnic SNA among groups. Paradoxical sleep deprivation (24 and 96 h) reduced plasma angiotensin II (Ang II) concentrations. CONCLUSIONS:The results suggest that selective sleep deprivation produces an increase in SNA, preferentially in the kidney. Thus, alterations in the sympathetic system in response to sleep loss may be an important pathway through which hypertension develops. 10.1177/1470320310391504
    Age-related difference in the sleep pressure-lowering effect between an angiotensin II receptor blocker and a calcium channel blocker in Asian hypertensives: the ACS1 Study. Kario Kazuomi,Hoshide Satoshi Hypertension (Dallas, Tex. : 1979) Sleep blood pressure (BP), which is partly determined by salt sensitivity and intake, is an important cardiovascular risk in hypertensives. However, there have been no studies on age-related differences in the sleep BP-lowering effect between angiotensin II receptor blockers and calcium channel blockers in Asians. Azilsartan Circadian and Sleep Pressure-the 1st Study was a multicenter, randomized, open-label, 2-parallel-group study conducted to compare the efficacy of 8-week oral treatment with an angiotensin II receptor blocker (azilsartan 20 mg) or a calcium channel blocker (amlodipine 5 mg) on sleep BP as evaluated by ambulatory BP monitoring. Among the overall population, amlodipine treatment achieved significantly greater reduction in sleep BP, awake BP, and 24-hour BP than azilsartan treatment. BP reduction by amlodipine was particularly pronounced in elderly hypertensive patients aged ≥60 years old. Among patients ≥60 years old, the amlodipine group had numerically, but not significantly, higher control rate of sleep BP compared with the azilsartan group. Similar results were found for awake BP and 24-hour BP. These results suggest a greater BP reduction/control by amlodipine compared with azilsartan and that reduction/control of BP by amlodipine was also more effective in the elderly population. As recommended in the American Society of Hypertension/The international Society of Hypertension and the National Institute for Health and Clinical Excellence guidelines for differentiating treatment according to age, amlodipine should be one of the options for starting treatment in the elderly population. CLINICAL TRIAL URL: http://clinicaltrials.gov/show/NCT01762501 CLINICAL TRIAL ID: NCT01762501. 10.1161/HYPERTENSIONAHA.114.04935
    Effects of mental resilience on neuroendocrine hormones level changes induced by sleep deprivation in servicemen. Sun Xinyang,Dai Xuyan,Yang Tingshu,Song Hongtao,Yang Jialin,Bai Jing,Zhang Liyi Endocrine The aim of this study was to investigate the effects of mental resilience on the changes of serum rennin, angiotensin, and cortisol level induced by sleep deprivation in servicemen. By random cluster sampling, a total of 160 servicemen, aged from 18 to 30, were selected to undergo 24-hour total sleep deprivation and administered the military personnel mental resilience scale after the deprivation procedure. The sleep deprivation procedure started at 8 a.m. on Day 8 and ended at 8 a.m. on Day 9 after 7 days of normal sleep for baseline preparation. Blood samples were drawn from the 160 participants at 8 a.m. respectively on Day 8 and Day 9 for hormonal measurements. All blood samples were analyzed using radioimmunoassay. As hypothesized, serum rennin, angiotensin II, and cortisol level of the participants after sleep deprivation were significantly higher than those before (P < 0.05). The changes of serum rennin and cortisol in the lower mental resilience subgroup were significantly greater (P < 0.05); problem-solving skill and willpower were the leading influence factors for the increases of serum rennin and cortisol respectively induced by sleep deprivation. We conclude that mental resilience plays a significant role in alleviating the changes of neurohormones level induced by sleep deprivation in servicemen. 10.1007/s12020-014-0228-8
    Neural mechanism of angiotensin-converting enzyme inhibitors in improving heart rate variability and sleep disturbance after myocardial infarction. Lin Wei-Lun,Chen Yu-Ruey,Lai Chun-Ting,Yamada Shinya,Liu Shin-Huei,Chou Yu-Hui,Fu Yun-Ching,Yang Cheryl C H,Kuo Terry B J,Lo Li-Wei,Chen Shih-Ann Sleep medicine BACKGROUND:Sympathetic hyperactivity and poor sleep quality are reported in myocardial infarction (MI) patients and angiotensin-converting enzyme inhibitors (ACEI) can improve long-term survival in these patients. We aimed to evaluate ACEI effects on cardiac autonomic activity (CAA) and disordered sleep patterns in ambulatory rats after MI. METHODS:Polysomnographic recording was performed in sham (n = 8) and MI (n = 9) male rats during normal daytime sleep before and after captopril treatment. Spectral analyses of the electroencephalogram and electromyogram were evaluated to define active waking (AW), quiet sleep (QS), and paradoxical sleep (PS). Central sleep apnea (CSA) events were measured by analyzing the electromyogram of the diaphragm. CAA was measured by power spectrum analyses of heart rate variability (HRV). RESULTS:In the MI group, there was a higher low frequency/high frequency ratio during sleep, which reduced significantly after captopril treatment, especially at the QS stage compared to that before captopril treatment. The frequency of sleep interruption was higher in the MI group than the sham group. Increased AW and PS, and decreased QS times were noted in the MI group compared to the sham group. These changes were restored to baseline after captopril treatment in the MI group. CSA events were significantly increased in the MI group, and were restored to the normal level after captopril treatment. CONCLUSIONS:Our results demonstrate significant sleep fragmentation with sympathetic hyperactivity after MI, and that captopril restores the autonomic dysfunction and sleep disorder. These findings suggest that ACEI improved sleep-related respiration disorder after MI by restoring autonomic homeostasis, and provide a hypothesis generating for future studies in humans. 10.1016/j.sleep.2018.04.007
    Angiotensin II-mediated nondipping during sleep in healthy humans: effects on baroreflex function at subsequent daytime. Sayk Friedhelm,Twesten Christoph,Adametz Isabel,Franzen Klaas,Vonthein Reinhard,Dodt Christoph,Meusel Moritz American journal of physiology. Regulatory, integrative and comparative physiology Blood pressure dipping at night is mediated by sleep-inherent, active downregulation of sympathetic vascular tone. Concomitantly, activity of the renin-angiotensin system is reduced, which might contribute to the beneficial effect of baroreflex downward resetting on daytime blood pressure homeostasis. To evaluate whether experimental nondipping mediated by angiotensin II during sleep would alter blood pressure and baroreflex function the next day in healthy humans, angiotensin-II or placebo (saline) was infused for a 7-h period at night, preventing blood pressure dipping in 11 sleeping normotensive individuals (5 males, balanced, crossover design). Baroreflex function was assessed about 1 h upon awakening and stop of infusion via microneurographic recordings of muscle sympathetic nerve activity (MSNA), showing that resting MSNA was significantly increased following angiotensin II nondipping compared with placebo ( = 0.029), whereas blood pressure and heart rate remained unchanged. Baroreflex sensitivity in response to vasoactive drug challenge was preserved, and neuroendocrine markers of fluid balance and electrolytes did not differ between conditions. Ambulatory blood pressure during subsequent daytime was not altered. Data were compared with analog experiments previously performed within the same subjects during awake daytime (ANCOVA). We conclude that angiotensin-II mediated nocturnal nondipping did not induce blood pressure elevation at subsequent daytime in healthy humans but was linked to increased vasoconstrictive sympathetic activity. This is in contrast to a prolonged increase in blood pressure in corresponding daytime experiments of the same individuals. Evidently, sleep strongly preserves normotensive blood pressure homeostasis in healthy humans. 10.1152/ajpregu.00355.2019
    Receptors for vasoactive intestinal peptide (VIP) on human mononuclear leucocytes are upregulated during prolonged strain and energy deficiency. Wiik P,Opstad P K,Knardahl S,Bøyum A Peptides VIP receptors on blood mononuclear leucocytes and plasma VIP concentrations were studied during a ranger training course lasting for five days with almost continuous physical activity, and energy deficiency. The maximum binding capacity (Bmax) for the high affinity receptor increased (p less than 0.0005) from 0.71 (SEM = 0.11, N = 10) fmol/million cells to a maximum of 7.33 (SEM = 1.0) fmol/million cells on Day 4. There was no significant change in the dissociation constant (Kd) for the high affinity receptor, and no effect on Kd nor Bmax for the low affinity VIP receptor was detected. Plasma VIP concentration increased (p less than 0.0005) from 8.8 pmol/l (SEM = 0.6) to a maximum of 23.4 (SEM = 1.9) on the second day of the course. However, the highest plasma concentrations were about one order of magnitude lower than the dissociation constant (Kd) for the high affinity VIP receptor on the mononuclear leucocytes. These data indicate that heterologous upregulation of the high affinity VIP receptor on mononuclear blood cells takes place during combined strenuous physical exercise, and calorie deficiency.
    Vasoactive intestinal polypeptide (VIP) and cerebrospinal fluid (CSF) of sleep-deprived cats restores REM sleep in insomniac recipients. Prospéro-Garcia O,Morales M,Arankowsky-Sandoval G,Drucker-Colin R Brain research In the past few years a steadily increasing number of substances have been suggested to qualify as sleep-inducing factors. Most 'sleep factors' appear to exert their effects on slow-wave sleep. Recently, however, it has been shown that the cerebrospinal fluid (CSF) of sleep-deprived cats may contain a rapid eye movement (REM) sleep factor, and that vasoactive intestinal peptide (VIP) may be a specific REM sleep inducer. The purpose of this study is to determine whether the CSF of sleep-deprived cats and VIP can reverse insomnia produced by parachlorophenylalanine (PCPA). Donor cats were sleep-deprived for 24 h and their CSF extracted. Some donor cats were additionally pre-treated with chloramphenicol, and some extracted CSF was heated. Recipient cats were injected with 400 mg/kg i.p. of PCPA on two consecutive days. Twenty-four h after the second injection, the recipient cats were intraventricularly injected with a 100-microliters of the various CSF types or 200 ng of VIP. The results showed that only CSF from sleep-deprived cats and VIP were capable of restoring REM sleep in the otherwise PCPA insomniac cats. Since the return of REM sleep was through an increase in its frequency, it is suggested that the CSF of sleep-deprived cats contains a VIP-like sleep factor possibly involved in triggering REM sleep. 10.1016/0006-8993(86)91561-1
    Brain distribution of vasoactive intestinal peptide receptors following REM sleep deprivation. Jiménez-Anguiano A,García-García F,Mendoza-Ramírez J L,Durán- Vázquez A,Drucker-Colín R Brain research Vasoactive intestinal peptide (VIP) has been shown to increase rapid eye movement (REM) sleep in normal and insomniac animals, while the administration of anti-VIP antibodies or an antagonist of VIP receptors decreases REM sleep. In addition, recently, it has been suggested that a VIP-like substance accumulates in the CSF during waking and that it may be involved in the production of the REM rebound normally seen following REM sleep deprivation. This evidence suggests that VIP may be important in modulating REM sleep in normal conditions and during REM sleep rebound. To determine whether VIP is involved in REM sleep homeostasis, VIP receptors of discrete brain areas was determined by autoradiography after 24 and 72 h of REM sleep deprivation (REM SD) by the water tank technique. Since this procedure has been suggested to produce some stress, an additional group adapted for 7 days to the sleep deprivation situation was tested. The results showed that REM SD produces an increase in the density of VIP receptors in several brainstem and forebrain structures at 24 h of REM SD and more so at 72 h of REM SD. Interestingly, results showed that habituation to the REM SD procedure decreases the density of VIP receptors in some areas of the brain of the REM sleep-deprived rats. The results are discussed in terms of the possibility that waking induces an increase of VIP receptors in several structures, which in turn are responsible for modulating REM sleep, but that stress contributes in part to VIP receptor changes.
    Decreased REM sleep and altered circadian sleep regulation in mice lacking vasoactive intestinal polypeptide. Hu Wang-Ping,Li Jia-Da,Colwell Christopher S,Zhou Qun-Yong Sleep OBJECTIVES:Vasoactive intestinal polypeptide (VIP) has been implicated in sleep regulation as a promoter of rapid eye movement (REM) sleep. Previous work has shown that the amount of time spent in REM sleep is increased by intracerebroventricular administration of VIP, and reduced by treatment with VIP antagonists or antibodies against VIP. A variety of evidence suggests that VIP is critical for normal expression of circadian rhythmicity of diverse physiological and behavioral parameters. In the present study, we investigated the role of this peptide in sleep regulation using VIP-deficient (VIP-/-) mice. METHODS:EEG/EMG sleep-wake patterns were recorded in VIP-/- mice and their wild-type littermate controls under normal light-dark (LD), constant darkness (DD) and sleep deprivation conditions. RESULTS:VIP-/- mice exhibited reduced REM sleep time over the 24-h cycle while total daily amounts of NREM sleep and wakefulness were not altered significantly. The reduced REM sleep time in VIP-/- mice occurred entirely during the day due to a reduction in the duration, but not the frequency, of REM sleep bouts. In response to sleep deprivation, compensatory rebounds in NREM sleep and REM sleep were also attenuated in VIP-/- mice. Finally, the loss of VIP altered the temporal distribution of sleep in that the VIP -/- mice exhibited smaller amplitude rhythms in total sleep, NREM sleep, and REM sleep under both LD and DD. CONCLUSIONS:These results indicate that VIP regulates the duration of REM sleep, sleep homeostatic mechanisms as well as the temporal patterning of sleep. 10.1093/sleep/34.1.49
    Sleep debt: the impact of weekday sleep deprivation on cardiovascular health in older women. Cabeza de Baca Tomás,Chayama Koharu Loulou,Redline Susan,Slopen Natalie,Matsushita Fumika,Prather Aric A,Williams David R,Buring Julie E,Zaslavsky Alan M,Albert Michelle A Sleep STUDY OBJECTIVES:Short sleep duration is associated with increased cardiovascular disease (CVD) risk. However, it is uncertain whether sleep debt, a measure of sleep deficiency during the week compared to the weekend, confers increased cardiovascular risk. Because sleep disturbances increase with age particularly in women, we examined the relationship between sleep debt and ideal cardiovascular health (ICH) in older women. METHODS:Sleep debt is defined as the difference between self-reported total weekday and weekend sleep hours of at least 2 hours among women without apparent CVD and cancer participating in the Women's Health Stress Study follow-up cohort of female health professionals (N = 22 082). The ICH consisted of seven health factors and behaviors as defined by the American Heart Association Strategic 2020 goals including body mass index, smoking, physical activity, diet, blood pressure, total cholesterol, and glucose. RESULTS:Mean age was 72.1 ± 6.0 years. Compared to women with no sleep debt, women with sleep debt were more likely to be obese and have hypertension (pall < .05). Linear regression models adjusted for age and race/ethnicity revealed that sleep debt was significantly associated with poorer ICH (B = -0.13 [95% CI = -0.18 to -0.08]). The relationship was attenuated but remained significant after adjustment for education, income, depression/anxiety, cumulative stress, and snoring. CONCLUSION:Sleep debt was associated with poorer ICH, despite taking into account socioeconomic status and psychosocial factors. These results suggest that weekly sleep duration variation, possibly leading to circadian misalignment, may be associated with cardiovascular risk in older women. 10.1093/sleep/zsz149
    A laboratory approach for characterizing chronic fatigue: what does metabolomics tell us? Erasmus Elardus,Mason Shayne,van Reenen Mari,Steffens Francois E,Vorster B Chris,Reinecke Carolus J Metabolomics : Official journal of the Metabolomic Society INTRODUCTION:Manifestations of fatigue range from chronic fatigue up to a severe syndrome and myalgic encephalomyelitis. Fatigue grossly affects the functional status and quality of life of affected individuals, prompting the World Health Organization to recognize it as a chronic non-communicable condition. OBJECTIVES:Here, we explore the potential of urinary metabolite information to complement clinical criteria of fatigue, providing an avenue towards an objective measure of fatigue in patients presenting with the full spectrum of fatigue levels. METHODS:The experimental group consisted of 578 chronic fatigue female patients. The measurement design was composed of (1) existing clinical fatigue scales, (2) a hepatic detoxification challenge test, and (3) untargeted proton nuclear magnetic resonance (H-NMR) procedure to generate metabolomics data. Data analysed via an in-house Matlab script that combines functions from a Statistics and a PLS Toolbox. RESULTS:Multivariate analysis of the original 459 profiled H-NMR bins for the low (control) and high (patient) fatigue groups indicated complete separation following the detoxification experimental challenge. Important bins identified from the H-NMR spectra provided quantitative metabolite information on the detoxification challenge for the fatigue groups. CONCLUSIONS:Untargeted H-NMR metabolomics proved its applicability as a global profiling tool to reveal the impact of toxicological interventions in chronic fatigue patients. No clear potential biomarker emerged from this study, but the quantitative profile of the phase II biotransformation products provide a practical visible effect directing to up-regulation of crucial phase II enzyme systems in the high fatigue group in response to a high xenobiotic-load. 10.1007/s11306-019-1620-4
    REM sleep vs exploratory wakefulness: Alternatives within adult 'sleep debt'? Horne Jim Sleep medicine reviews Our declining sleep duration over early human infant development is largely through REM sleep (REM), loss, not of nonREM. It coincides with the infant's increasing locomotion providing for multisensory inputs ('exploratory wakefulness' - EW), together facilitating neural restructuring and behavioural adaptations ('neuroplasticity'). EW also involves curiosity, novelty, navigation, spatial memory, associated emotions, and feeding; all having brain processes particularly active in REM. It is proposed that: 1) REM is a proxy for EW in facilitating neuroplasticity; 2) necessitating REM having a locomotor output, actively inhibited (the atonia); 3) human adults retain many (neotenous) infant characteristics including large amounts of REM towards the end of usual sleep, where REM's qualitative changes indicate reduced sleep pressure, 4) as in infancy, some of our adult REM remains replaceable by EW (without REM rebounds), mostly in this final REM episode whenever EW need prevails. Accordingly, our adult sleep duration is adaptable to habitual shortening via this REM episode substituted by purposeful EW, which could provide extra (day) light exposure for circadian synchrony. Such processes may underlie seasonally shorter (6 h) sleep, eg in hunter-gather people. This flexibility of REM questions the extent of our western 'chronic sleep debt'. Evidence is provided to counter claims that this absent REM would cause obesity and related disorders. 200w. 10.1016/j.smrv.2019.101252
    Postulated vasoactive neuropeptide autoimmunity in fatigue-related conditions: a brief review and hypothesis. Staines Donald R Clinical & developmental immunology Disorders such as chronic fatigue syndrome (CFS) and gulf war syndrome (GWS) are characterised by prolonged fatigue and a range of debilitating symptoms of pain, intellectual and emotional impairment, chemical sensitivities and immunological dysfunction. Sudden infant death syndrome (SIDS) surprisingly may have certain features in common with these conditions. Post-infection sequelae may be possible contributing factors although ongoing infection is unproven. Immunological aberration may prove to be associated with certain vasoactive neuropeptides (VN) in the context of molecular mimicry, inappropriate immunological memory and autoimmunity. Adenylate cyclase-activating VNs including pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP) and calcitonin gene-related peptide (CGRP) act as hormones, neurotransmitters, neuroregulators, immune modulators and neurotrophic substances. They and their receptors are potentially immunogenic. VNs are widely distributed in the body particularly in the central and peripheral nervous systems and have been identified in the gut, adrenal gland, blood cells, reproductive system, lung, heart and other tissues. They have a vital role in maintaining cardio-respiratory function, thermoregulation, memory, concentration and executive functions such as emotional responses including social cues and appropriate behaviour. They are co-transmitters for a number of neurotransmitters including acetylcholine and gaseous transmitters, are potent immune regulators with primarily anti-inflammatory activity, and have a significant role in protection of the nervous system against toxic assault as well as being important in the maintenance of homeostasis. This paper describes a biologically plausible mechanism for the development of certain fatigue-related syndromes based on loss of immunological tolerance to these VNs or their receptors following infection, other events or de novo resulting in significant pathophysiology possibly mediated via CpG fragments and heat shock (stress) proteins. These conditions extend the public health context of autoimmunity and VN dysregulation and have implications for military medicine where radiological, biological and chemical agents may have a role in pathogenesis. Possible treatment and prevention options are considered. 10.1080/17402520600568252
    Do cytosine guanine dinucleotide (CpG) fragments induce vasoactive neuropeptide mediated fatigue-related autoimmune disorders? Staines Donald R Medical hypotheses Autoimmune dysfunction of certain vasoactive neuropeptides (e.g., vasoactive intestinal peptide, pituitary adenylate cyclase activating polypeptide) may be implicated in a range of disorders associated with fatigue-like states (chronic fatigue syndrome, Gulf War syndrome) and even sudden infant death syndrome (SIDS). The important roles of these vasoactive neuropeptides make them a vulnerable target for autoimmune dysfunction. They are known to be associated with heat shock proteins for intracellular functioning with which they may form immunostimulating complexes. Cytosine guanine dinucleotide (CpG) fragments are potently immunogenic DNA fragments which serve as friend or foe recognition systems between bacterial (hypomethylated) and mammalian (methylated) DNA and are being assessed for suitability for use in human vaccines as adjuvants. Interactions between CpG fragments, heat shock proteins and vasoactive neuropeptides may be associated with fatigue-related autoimmune conditions. 10.1016/j.mehy.2005.02.014
    Do vasoactive neuropeptides and heat shock proteins mediate fatigue-related autoimmune disorders? Staines Donald R Medical hypotheses Autoimmune dysfunction of certain vasoactive neuropeptides may be implicated in a range of disorders associated with fatigue like states (chronic fatigue syndrome, Gulf War syndrome) and even sudden infant death syndrome. These substances have neurotrophic, neuroregulatory, and neurotransmission functions, as well as that of immune modulators and hormones. They exert significant control over carbohydrate and lipid metabolism. The hypothesis is that because these substances have vital and indispensable roles in cellular processes, loss or compromise of these roles would lead to predictable and severe cellular and systemic effects. The important roles of certain VNs make them a vulnerable target for autoimmune dysfunction. They are known to be associated with heat shock proteins for intracellular functioning with which they may form immunostimulating complexes. While peptide-HSP complexes are a relatively new area for research, this paper asserts that attention could be focused on these substances and complexes in an effort to elucidate a number of perplexing fatigue-associated disorders. 10.1016/j.mehy.2004.08.013
    Infant stress and sleep deprivation as an aetiological basis for the sudden infant death syndrome. Simpson J M Early human development SIDS is almost invariably sleep-related. Viable syndrome aetiology must be compatible with its many epidemiologically diverse risk factors, each of which directly or indirectly associates with the creation of psychological and/or physiological infant stress, and the subsequent disruption of normal, contented sleep. During essential deep 'rebound' recovery sleep, arousal ability and upper airway muscle tone decrease further to that in normal sleep, with subsequent upper airway obstruction. When stress impact causes sufficient sleep disruption and physiological fatigue, a failure to arouse and so restore sufficient tone to overcome such obstruction results in sudden, unexpected death. SIDS has therefore many causes which share a final lethal mechanical pathway. Evidence is presented for obstructive apnoea during sleep as being the primary syndrome death mode, for sleep disruption, reduced arousal ability, and infant stress in SIDS, and for risk factor association with the creation of this stress. Specific infant vulnerability in the first 6 months of life to stress predominantly related to total dependency on a carer for gratification of need, and to obstructive sleep apnoea due to normal anatomical, physical, and respiratory immaturity, including rapid physiological fatigue, and peaks in sleep and thermal stress vulnerability, are discussed. Further reasons for the limited age period of SIDS, and for reduced neonatal risk, are given. Prone sleeping risk can relate to positional airway obstruction during normal sleep without prior infant stress. Much of SIDS aetiology appears to concern factors related to socio-economic deprivation and subsequent sub-optimal infant care.
    Persistent fatigue induced by interferon-alpha: a novel, inflammation-based, proxy model of chronic fatigue syndrome. Russell Alice,Hepgul Nilay,Nikkheslat Naghmeh,Borsini Alessandra,Zajkowska Zuzanna,Moll Natalie,Forton Daniel,Agarwal Kosh,Chalder Trudie,Mondelli Valeria,Hotopf Matthew,Cleare Anthony,Murphy Gabrielle,Foster Graham,Wong Terry,Schütze Gregor A,Schwarz Markus J,Harrison Neil,Zunszain Patricia A,Pariante Carmine M Psychoneuroendocrinology The role of immune or infective triggers in the pathogenesis of Chronic Fatigue Syndrome (CFS) is not yet fully understood. Barriers to obtaining immune measures at baseline (i.e., before the trigger) in CFS and post-infective fatigue model cohorts have prevented the study of pre-existing immune dysfunction and subsequent immune changes in response to the trigger. This study presents interferon-alpha (IFN-α)-induced persistent fatigue as a model of CFS. IFN-α, which is used in the treatment of chronic Hepatitis C Virus (HCV) infection, induces a persistent fatigue in some individuals, which does not abate post-treatment, that is, once there is no longer immune activation. This model allows for the assessment of patients before and during exposure to the immune trigger, and afterwards when the original trigger is no longer present. Fifty-five patients undergoing IFN-α treatment for chronic HCV were assessed at baseline, during the 6-12 months of IFN-α treatment, and at six-months post-treatment. Measures of fatigue, cytokines and kynurenine pathway metabolites were obtained. Fifty-four CFS patients and 57 healthy volunteers completed the same measures at a one-off assessment, which were compared with post-treatment follow-up measures from the HCV patients. Eighteen patients undergoing IFN-α treatment (33%) were subsequently defined as having 'persistent fatigue' (the proposed model for CFS), if their levels of fatigue were higher six-months post-treatment than at baseline; the other 67% were considered 'resolved fatigue'. Patients who went on to develop persistent fatigue experienced a greater increase in fatigue symptoms over the first four weeks of IFN-α, compared with patients who did not (Δ Treatment Week (TW)-0 vs. TW4; PF: 7.1 ± 1.5 vs. RF: 4.0 ± 0.8, p = 0.046). Moreover, there was a trend towards increased baseline interleukin (IL)-6, and significantly higher baseline IL-10 levels, as well as higher levels of these cytokines in response to IFN-α treatment, alongside concurrent increases in fatigue. Levels increased to more than double those of the other patients by Treatment Week (TW)4 (p =  0.011 for IL-6 and p = 0.001 for IL-10). There was no evidence of an association between persistent fatigue and peripheral inflammation six-months post-treatment, nor did we observe peripheral inflammation in the CFS cohort. While there were changes in kynurenine metabolites in response to IFN-α, there was no association with persistent fatigue. CFS patients had lower levels of the ratio of kynurenine to tryptophan and 3-hydroxykynurenine than controls. Future studies are needed to elucidate the mechanisms behind the initial exaggerated response of the immune system in those who go on to experience persistent fatigue even if the immune trigger is no longer present, and the change from acute to chronic fatigue in the absence of continued peripheral immune activation. 10.1016/j.psyneuen.2018.11.032
    Altered neuroendocrine control and association to clinical symptoms in adolescent chronic fatigue syndrome: a cross-sectional study. Wyller Vegard Bruun,Vitelli Valieria,Sulheim Dag,Fagermoen Even,Winger Anette,Godang Kristin,Bollerslev Jens Journal of translational medicine BACKGROUND:Chronic fatigue syndrome (CFS) is a common and disabling disorder, and a major threat against adolescent health. The pathophysiology is unknown, but alteration of neuroendocrine control systems might be a central element, resulting in attenuation of the hypothalamus-pituitary-adrenalin (HPA) axis and enhancement of the sympathetic/adrenal medulla (SAM) system. This study explored differences in neuroendocrine control mechanisms between adolescent CFS patients and healthy controls, and whether characteristics of the control mechanisms are associated with important clinical variables within the CFS group. METHODS:CFS patients 12-18 years of age were recruited nation-wide to a single referral center as part of the NorCAPITAL project. A broad case definition of CFS was applied. A comparable group of healthy controls were recruited from local schools. A total of nine hormones were assayed and subjected to network analyses using the ARACNE algorithm. Symptoms were charted by a questionnaire, and daily physical activity was recorded by an accelerometer. RESULTS:A total of 120 CFS patients and 68 healthy controls were included. CFS patients had significantly higher levels of plasma norepinephrine, plasma epinephrine and plasma FT4, and significantly lower levels of urine cortisol/creatinine ratio. Subgrouping according to other case definitions as well as adjusting for confounding factors did not alter the results. Multivariate linear regression models as well as network analyses revealed different interrelations between hormones of the HPA axis, the SAM system, and the thyroid system in CFS patients and healthy controls. Also, single hormone degree centrality was associated with clinical markers within the CFS group. CONCLUSION:This study reveals different interrelation between hormones of the HPA axis, the SAM system, and the thyroid system in CFS patients and healthy controls, and an association between hormone control characteristics and important clinical variables in the CFS group. These results add to the growing insight of CFS disease mechanisms. Trial registration Clinical Trials NCT01040429. 10.1186/s12967-016-0873-1
    Karoshi, a new epidemic in Chinese medical practitioners. Yin Rui-Xing,Huang Feng,Zhang Qing-Hui Intensive care medicine 10.1007/s00134-018-5138-4
    Chronically restricted sleep leads to depression-like changes in neurotransmitter receptor sensitivity and neuroendocrine stress reactivity in rats. Novati Arianna,Roman Viktor,Cetin Timur,Hagewoud Roelina,den Boer Johan A,Luiten Paul G M,Meerlo Peter Sleep STUDY OBJECTIVES:Frequently disrupted and restricted sleep is a common problem for many people in our Western society. In the long run, insufficient sleep may have repercussions for health and may sensitize individuals to psychiatric diseases. In this context, we applied an animal model of chronic sleep restriction to study effects of sleep loss on neurobiological and neuroendocrine systems that have been implied in the pathophysiology of depression, particularly the serotonergic system and the hypothalamic-pituitary-adrenal (HPA) axis. DESIGN:Adult rats were exposed to a schedule of chronic partial sleep deprivation allowing them only 4 h of sleep per day. Sleep restriction was achieved by placing the animals in slowly rotating drums. To examine the regulation and reactivity of the HPA axis, blood samples were collected to measure adrenocorticotropin (ACTH) and corticosterone (CORT) responses. MEASUREMENTS AND RESULTS:While one day of restricted sleep had no significant effect on HPA axis stress reactivity, sleep restriction for a week caused a blunted pituitary ACTH response in a conditioned fear paradigm. Despite this lower ACTH response, adrenal CORT release was normal. The blunted pituitary response may be related to reduced sensitivity of serotonin-1A receptors and/or receptors for corticotropin-releasing hormone (CRH), since sleep restricted rats showed similar reductions in ACTH release to direct pharmacological stimulation with a serotonin-1A agonist or CRH. CONCLUSIONS:Chronic sleep restriction may lead to changes in neurotransmitter receptor systems and neuroendocrine reactivity in a manner similar to that seen in depression. This experimental study thus supports the hypothesis that disrupted and restricted sleep may contribute to the symptomatology of psychiatric disorders. 10.1093/sleep/31.11.1579
    Too little sleep gradually desensitizes the serotonin 1A receptor system. Roman Viktor,Walstra Irene,Luiten Paul G M,Meerlo Peter Sleep STUDY OBJECTIVES:In our 24-hour society, frequently disrupted and restricted sleep is a rapidly increasing problem that may contribute to the development of diseases such as depression. One of the proposed neurobiological mechanisms underlying depression is a disturbance in the brain's serotonergic neurotransmission, particularly a desensitization of the serotonin (5-HT)1A receptor system. However, a relationship between chronic sleep loss and changes in (5-HT)1A receptors has not been established yet. Therefore, in the present study, we experimentally tested the hypothesis that chronic sleep restriction leads to desensitization of the (5-HT)1A receptor system. DESIGN:Rats were subjected to a schedule of restricted sleep allowing them 4 hours of sleep per day. Sleep restriction was achieved by placing the animals in slowly rotating wheels. The sensitivity of the (5-HT)1A receptor system was examined by measuring the hypothermic response to a standard injection of a 1A agonist. RESULTS:After 2 days of restricted sleep, the sensitivity of the (5-HT)1A receptor system was not yet affected; however, after 8 days of sleep restriction, it was desensitized. Control experiments indicated that the effect of sleep restriction was not due to forced activity or stress. Importantly, the desensitization of the (5-HT)1A system persisted for many days even with unlimited recovery sleep. Normalization occurred gradually but required at least 7 days. CONCLUSIONS:Chronic sleep restriction causes a gradual and persistent desensitization of the (5-HT)1A receptor system. This finding provides a link between chronic sleep loss and sensitivity for disorders that are associated with altered serotonergic neurotransmission.
    A comparison of the recognition of overwork-related cardiovascular disease in Japan, Korea, and Taiwan. Park Jungsun,Kim Yangho,Cheng Yawen,Horie Seichi Industrial health In Japan, Korea, and Taiwan, cerebrovascular and cardiovascular diseases (CVDs) caused by overwork are recognized by government as work-related. These three countries are the only countries in the world that officially recognize CVDs caused by psychosocial factors (e.g., overwork) as work-related cerebrovascular and cardiovascular diseases (WR-CVDs), and compensate employees accordingly. The present study compared the similarities and differences among the recognition of overwork-related CVDs in Japan, Korea, and Taiwan. The criteria by which WR-CVDs are identified are very similar in the three countries. However, in the interval surveyed (1996-2009), Korea had a remarkably larger number of recognized WR-CVD patients than did Japan or Taiwan. Recognition of occupational diseases is influenced by various factors, including socio-cultural values, the nature of occupational health care schemes, the extent of the social security umbrella, national health insurance policy, and scientific evidence. Our results show that social factors may be very different among the three countries studied, although the recognition criteria for WR-CVDs are quite similar. 10.2486/indhealth.ms1317
    Compensation for work-related cerebrocardiovascular diseases. Won Jong-Uk,Kim Inah Journal of Korean medical science The purpose of this study was to discuss the history of, and concerns regarding, the newly amended criteria of occupational cerebrovascular or cardiovascular diseases (CCVDs). Since the early 1990s, CCVDs have been the second most common occupational disease, despite fluctuations in their criteria. The first issue was the deletion of cerebral hemorrhage on duty as a recognized occupational disease in 2008. The second issue was the obscurity regarding definitions of an acute stressful event (within 24 hr before disease occurrence), short-term overwork (within 1 week), and chronic overwork (for 3 or more months). In this amendment, chronic overwork was defined as work exceeding 60 hr per week. If the average number of weekly working hours does not exceed 60 hr, night work, physical or psychological workload, or other risk factors should be considered for the recognition of occupational CCVDs. However, these newly amended criteria still have a few limitations, considering that there is research evidence for the occurrence of disease in those working fewer than 60 hr per week, and other risk factors, particularly night work, are underestimated in these criteria. Thus, we suggest that these concerns be actively considered during future amendment and approval processes. 10.3346/jkms.2014.29.S.S12
    Napping and weekend catchup sleep do not fully compensate for high rates of sleep debt and short sleep at a population level (in a representative nationwide sample of 12,637 adults). Leger Damien,Richard Jean-Baptiste,Collin Olivier,Sauvet Fabien,Faraut Brice Sleep medicine INTRODUCTION:Short total sleep time (TST < 6 h) is a strong major health determinant that correlates with numerous metabolic, cardiovascular and mental comorbidities, as well as accidents. Our aim was to better understand, at a population level, how adults adapt their TST during the week, and how short sleepers and those with sleep debt and sleep restriction use napping or catching up on sleep during weekends (ie, sleep debt compensation by sleeping longer), which may prevent these comorbidities. METHODS:A large representative sample of 12,367 subjects (18-75 years old) responded by phone to questions about sleep on a national recurrent health poll (Health Barometer, Santé Publique France 2017) assessing sleep schedules (TST) at night, when napping, and over the course of a 24-h period while using a sleep log on workdays and weekends. Retained items were: (1) short sleep (TST ≤ 6 h/24 h); (2) chronic insomnia (international classification of sleep disorders third edition, ICSD-3 criteria); (3) sleep debt (self-reported ideal TST - TST > 60 min, severe > 90 min); and (4) sleep restriction (weekend TST - workday TST = 1-2 h, severe > 2 h). RESULTS:Average TST/24 h was 6h42 (± 3 min) on weekdays and 7h26 (± 3 min) during weekends. In addition, 35.9% (± 1.0%) of the subjects were short sleepers, 27.7% (± 1.0%) had sleep debt (18.8% (± 0.9%) severe), and 17.4% (± 0.9%) showed sleep restriction (14.4% (± 0.8%) severe). Moreover, 27.4% (± 0.9%) napped at least once per week on weekdays (average: 8.3 min (± 0.5 min)) and 32.2% (± 1.0%) on weekend days (13.7 min (± 0.7 min)). Of the 24.2% (± 0.9%) of subjects with severe sleep debt (> 90 min), only 18.2% (± 1.6%) balanced their sleep debt by catching up on sleep on weekends (14.9% (± 0.8%) of men and 21.5% (± 0.9%) of women), and 7.4% (± 1.2%) of these subjects balanced their sleep debt by napping (7.8% (± 0.5%) of men and 6.6% (± 0.4%) of women). The remaining 75.8% (± 5.4%) did not do anything to balance their severe sleep debt during the week. DISCUSSION AND CONCLUSIONS:Short sleep, sleep debt, and sleep restriction during weekdays affected about one third of adults in our study group. Napping and weekend catch-up sleep only compensated for severe sleep debt in one in four subjects. 10.1016/j.sleep.2020.05.030
    Sleep debt elicits negative emotional reaction through diminished amygdala-anterior cingulate functional connectivity. Motomura Yuki,Kitamura Shingo,Oba Kentaro,Terasawa Yuri,Enomoto Minori,Katayose Yasuko,Hida Akiko,Moriguchi Yoshiya,Higuchi Shigekazu,Mishima Kazuo PloS one OBJECTIVES:Sleep debt reportedly increases emotional instability, such as anxiety and confusion, in addition to sleepiness and psychomotor impairment. However, the neural basis of emotional instability due to sleep debt has yet to be elucidated. This study investigated changes in emotional responses that are elicited by the simulation of short-term sleep loss and the brain regions responsible for these changes. SUBJECTS AND METHODS:Fourteen healthy adult men aged 24.1±3.3 years (range, 20-32 years) participated in a within-subject crossover study consisting of 5-day sessions of both sleep debt (4 h for time in bed) and sleep control (8 h for time in bed). On the last day of each session, participants underwent polysomnography and completed the State-Trait Anxiety Inventory and Profile of Mood States questionnaires. In addition, functional magnetic resonance imaging was conducted while performing an emotional face viewing task. RESULTS:Restricted sleep over the 5-day period increased the activity of the left amygdala in response to the facial expression of fear, whereas a happy facial expression did not change the activity. Restricted sleep also resulted in a significant decrease in the functional connectivity between the amygdala and the ventral anterior cingulate cortex (vACC) in proportion to the degree of sleep debt (as indicated by the percentage of slow wave sleep and δ wave power). This decrease was significantly correlated with activation of the left amygdala and deterioration of subjective mood state. CONCLUSION:The results of this study suggest that continuous and accumulating sleep debt that can be experienced in everyday life can downregulate the functional suppression of the amygdala by the vACC and consequently enhance the response of the amygdala to negative emotional stimuli. Such functional alteration in emotional control may, in part, be attributed to the neural basis of emotional instability during sleep debt. 10.1371/journal.pone.0056578
    Local modulation of human brain responses by circadian rhythmicity and sleep debt. Muto Vincenzo,Jaspar Mathieu,Meyer Christelle,Kussé Caroline,Chellappa Sarah L,Degueldre Christian,Balteau Evelyne,Shaffii-Le Bourdiec Anahita,Luxen André,Middleton Benita,Archer Simon N,Phillips Christophe,Collette Fabienne,Vandewalle Gilles,Dijk Derk-Jan,Maquet Pierre Science (New York, N.Y.) Human performance is modulated by circadian rhythmicity and homeostatic sleep pressure. Whether and how this interaction is represented at the regional brain level has not been established. We quantified changes in brain responses to a sustained-attention task during 13 functional magnetic resonance imaging sessions scheduled across the circadian cycle, during 42 hours of wakefulness and after recovery sleep, in 33 healthy participants. Cortical responses showed significant circadian rhythmicity, the phase of which varied across brain regions. Cortical responses also significantly decreased with accrued sleep debt. Subcortical areas exhibited primarily a circadian modulation that closely followed the melatonin profile. These findings expand our understanding of the mechanisms involved in maintaining cognition during the day and its deterioration during sleep deprivation and circadian misalignment. 10.1126/science.aad2993
    Unrecognized Sleep Loss Accumulated in Daily Life Can Promote Brain Hyperreactivity to Food Cue. Katsunuma Ruri,Oba Kentaro,Kitamura Shingo,Motomura Yuki,Terasawa Yuri,Nakazaki Kyoko,Hida Akiko,Moriguchi Yoshiya,Mishima Kazuo Sleep Epidemiological studies have shown that sleep debt increases the risk of obesity. Experimental total sleep deprivation (TSD) has been reported to activate the reward system in response to food stimuli, but food-related responses in everyday sleep habits, which could lead to obesity, have not been addressed. Here, we report that habitual sleep time at home among volunteers without any sleep concerns was shorter than their optimal sleep time estimated by the 9-day extended sleep intervention, which indicates that participants had already been in sleep debt in their usual sleep habits. The amygdala and anterior insula, which are responsible for both affective responses and reward prediction, were found to exhibit significantly lowered activity in the optimal sleep condition. Additionally, a subsequent one-night period of TSD reactivated the right anterior insula in response to food images; however, the activity level of amygdala remained lowered. These findings indicate that (1) our brain is at risk of hyperactivation to food triggers in everyday life, which could be a risk factor for obesity and lifestyle diseases, and (2) optimal sleep appears to reduce this hypersensitivity to food stimuli. 10.1093/sleep/zsx137
    Fatigue in childhood chronic disease. Nap-van der Vlist Merel M,Dalmeijer Geertje W,Grootenhuis Martha A,van der Ent Cornelis K,van den Heuvel-Eibrink Marry M,Wulffraat Nico M,Swart Joost F,van Litsenburg Raphaële R L,van de Putte Elise M,Nijhof Sanne L Archives of disease in childhood BACKGROUND AND OBJECTIVES:Recently, in adults, the incidence and severity of fatigue was found to exist rather independently from the somatic diagnosis. Since fatigue is distressing when growing up with a chronic disease, we aim to investigate: (1) the prevalence and extent of fatigue among various paediatric chronic diseases and (2) the effect of fatigue on health-related quality of life (HRQoL). DESIGN AND SETTING:Cross-sectional study in two children's hospitals. PATIENTS:Children and adolescents 2-18 years of age with cystic fibrosis, an autoimmune disease or postcancer treatment visiting the outpatient clinic. OUTCOME MEASURES:Fatigue and HRQoL were assessed using the Pediatric Quality of Life Inventory (PedsQL) multidimensional fatigue scale (with lower scores indicating more fatigue) and PedsQL generic core scales, respectively. Linear regression analysis and analysis of covariance were used to compare fatigue scores across disease groups and against two control groups. The effect of fatigue on HRQoL was calculated. Data were adjusted for age, sex and reporting method. RESULTS:481 children and adolescents were assessed (60% participation rate, mean age 10.7±4.9, 42% men). Children and adolescents with chronic disease reported more fatigue than the general population (mean difference -6.6, 95% CI -8.9 to -4.3 (range 0-100)), with a prevalence of severe fatigue of 21.2%. Fatigue scores did not differ significantly between disease groups on any fatigue domain. Fatigue was associated with lower HRQoL on all domains. CONCLUSIONS:Fatigue in childhood chronic disease is a common symptom that presents across disease, age and sex groups. Fatigue affects HRQoL. Our findings underscore the need to systematically assess fatigue. Future studies should determine possible biological and psychosocial treatment targets. 10.1136/archdischild-2019-316782
    The Role of Sleep Quality and Fatigue on the Benefits of an Interdisciplinary Treatment for Adults With Chronic Pain. de la Vega Rocío,Racine Melanie,Castarlenas Elena,Solé Ester,Roy Rubén,Jensen Mark P,Miró Jordi,Cane Douglas Pain practice : the official journal of World Institute of Pain BACKGROUND:Interdisciplinary chronic pain treatment is effective for reducing pain intensity and pain-related disability, and for improving psychological function. However, the mechanisms that underlie these treatment-related benefits are not yet well understood. Sleep problems and fatigue are modifiable factors often comorbid with chronic pain. The goal of this study was to evaluate the role that changes in sleep quality and fatigue might have on the benefits of an interdisciplinary chronic pain treatment. METHODS:A total of 125 adults with chronic pain participated in a 4-week interdisciplinary pain management program. Measures of depression, sleep disturbance, fatigue, pain intensity, and physical function were administered at pre- and post-treatment. Three regression analyses were conducted to evaluate the contribution of pre- to post-treatment improvements in fatigue and sleep disturbance to the pre- to post-treatment improvements in pain intensity, disability, and depression, while controlling for demographic characteristics (age and sex) and pain intensity. RESULTS:Changes in fatigue and sleep disturbance made independent and significant contributions to the prediction of treatment-related benefits in pain intensity; improvements in depressive symptoms were predicted by improvements in fatigue, and improvements in disability were only predicted by pre-treatment and pre- to post-treatment decreases in pain intensity (one of the control variables). CONCLUSIONS:In addition to sleep, fatigue emerged as a key potential mechanism of multidisciplinary chronic pain treatment-related improvements, suggesting that interventions including elements that effectively target sleep and fatigue may enhance the efficacy of interdisciplinary chronic pain programs. This possibility should be evaluated in future research. 10.1111/papr.12746
    Chronic stress exposure, diurnal cortisol slope, and implications for mood and fatigue: Moderation by multilocus HPA-Axis genetic variation. Starr Lisa R,Dienes Kimberly,Li Y Irina,Shaw Zoey A Psychoneuroendocrinology Chronic stress exposure has been shown to alter hypothalamic-pituitary-adrenal (HPA) axis functioning, which may mediate its effects on psychopathology and negative health outcomes. The nature of the chronic stress-HPA axis dysregulation is unclear and individuals likely vary in the extent to and manner in which indices of HPA axis regulation, such as diurnal cortisol slope, are influenced by chronic stress. We examined whether HPA-axis-linked genetic variation moderates the association between chronic stress and diurnal cortisol slope, and potential implications for mood and fatigue (possible manifestations of negative clinical outcomes). 211 adolescents (M age 15.89, 54.5% female) completed chronic stress interviews and provided DNA samples. Participants then provided saliva samples at waking and 12 h post-waking for two consecutive weekdays. HPA-axis genetic variation was calculated using a multilocus genetic profile score (MGPS) approach, using ten SNPs from CRHR1, NR3C1, NR3C2, and FKBP5 to generate an additive score of HPA-axis-linked genetic risk. Neither chronic stress nor MGPS directly predicted diurnal slope, but MGPS moderated the association between chronic stress and diurnal slope, with stress predicting a high waking cortisol followed by steep slope among youth with low but not high MGPS scores. MGPS also interacted with chronic stress to predict both negative affect and fatigue, and moderated the indirect effect of chronic stress on mood and fatigue via diurnal slope. Results suggest that diurnal cortisol regulation may be one mechanism by which genetic risk intensifies the association between chronic stress and negative outcomes. 10.1016/j.psyneuen.2018.10.003
    Identifying and validating blood mRNA biomarkers for acute and chronic insufficient sleep in humans: a machine learning approach. Laing Emma E,Möller-Levet Carla S,Dijk Derk-Jan,Archer Simon N Sleep Acute and chronic insufficient sleep are associated with adverse health outcomes and risk of accidents. There is therefore a need for biomarkers to monitor sleep debt status. None are currently available. We applied elastic net and ridge regression to transcriptome samples collected in 36 healthy young adults during acute total sleep deprivation and following 1 week of either chronic insufficient (<6 hr) or sufficient sleep (~8.6 hr) to identify panels of mRNA biomarkers of sleep debt status. The size of identified panels ranged from 9 to 74 biomarkers. Panel performance, assessed by leave-one-subject-out cross-validation and independent validation, varied between sleep debt conditions. Using between-subject assessments based on one blood sample, the accuracy of classifying "acute sleep loss" was 92%, but only 57% for classifying "chronic sleep insufficiency." A reasonable accuracy for classifying "chronic sleep insufficiency" could only be achieved by a within-subject comparison of blood samples. Biomarkers for sleep debt status showed little overlap with previously identified biomarkers for circadian phase. Biomarkers for acute and chronic sleep loss also showed little overlap but were associated with common functions related to the cellular stress response, such as heat shock protein activity, the unfolded protein response, protein ubiquitination and endoplasmic reticulum-associated protein degradation, and apoptosis. This characteristic response of whole blood to sleep loss can further aid our understanding of how sleep insufficiencies negatively affect health. Further development of these novel biomarkers for research and clinical practice requires validation in other protocols and age groups. 10.1093/sleep/zsy186
    Sleep debt at the community level: impact of age, sex, race/ethnicity and health. Fox Elliott C,Wang Kairuo,Aquino Melissa,Grandner Michael A,Xie Dawei,Branas Charles C,Gooneratne Nalaka S Sleep health OBJECTIVES:Insufficient sleep has become recognized as a pervasive problem in modern society. Sleep debt is a novel measure of sleep adequacy that may be useful in describing those at risk for inadequate sleep. Our objective was to investigate factors that may be associated with sleep debt at the population level, as well as build upon previous data that showed that minority groups may be more likely to have sleep debt. DESIGN:A cross-sectional population phone survey included questions regarding amount of sleep required and amount of sleep achieved. Sleep debt was calculated by subtracting sleep achieved from sleep required. SETTING:This study was designed by the Philadelphia Health Management Corporation and conducted over landlines and cell phones. PARTICIPANTS:The Random Digit Dialing method was used to randomly choose 8,752 adults older than 18 years from several counties in and around Philadelphia to answer questions about sleep. MEASUREMENTS:Logistic regression was performed to test associations between sleep debt and various sociodemographic factors in different population subgroups to identify those at risk for sub-optimal sleep duration. RESULTS:Sleep debt was seen to decrease with age, a novel finding that is in contrast with literature suggesting that older adults have poor sleep. Greater sleep debt was also associated with female gender, Hispanic/Latino ethnicity, <40 years of age, self-reported poor health, and increased stress. CONCLUSIONS:Although older adults may sleep less as they age, they may also require less sleep to feel rested, resulting in less sleep debt. This and other demographic factors, such as female gender and Hispanic/Latino ethnicity, can be used to identify those at higher risk of inadequate sleep and potentially manage their sleep debt. 10.1016/j.sleh.2018.05.007
    New occupational threats to Japanese physicians: karoshi (death due to overwork) and karojisatsu (suicide due to overwork). Hiyama T,Yoshihara M Occupational and environmental medicine 10.1136/oem.2007.037473
    Overwork, stroke, and karoshi-death from overwork. Ke Der-Shin Acta neurologica Taiwanica Karoshi, death from over-work, is usually the extreme result of acute cardiovascular events including stroke. Among 203 karoshi cases received worker compensation in Japan, sixty percent died of stroke. Karoshi is a term for social medicine originated form Japan. Literature reviews on karoshi found that long overtime at work, on duty in holidays, attending a new job with no family members around, and working at night shift are risk factors. Work stress increases secretion of catecholamines (epinephrine and norepinephrine) and cortisol which is associated with progression of atherosclerosis and increased risk of cardiovascular diseases and stroke. To avoid long working hours, stress management and treatment of hypertension, diabetes, and hyperlipidemia are key issues in preventing karoshi caused by stroke.
    Overwork and cerebrocardiovascular disease in Korean adult workers. Jang Tae-Won,Kim Hyoung-Ryoul,Lee Hye-Eun,Myong Jun-Pyo,Koo Jung-Wan,Ye Byeong-Jin,Won Jong-Uk Journal of occupational health OBJECTIVES:Long work hours and overwork may increase the cardiovascular load of workers. But long work hours and overwork are not the same. Cardiovascular overload from working is dependent on the physical demand of the work and the worker's physical fitness, as well as the working hours. This cross-sectional study was designed to identify the association between overwork and cerebrocardiovascular disease, taking into account the physical demand of work, physical fitness, and work hours. METHODS:Study data were obtained from surveillance of occupational cerebrocardiovascular disease. Questionnaire surveys including general and work-related characteristics were conducted. Maximum acceptable work time was estimated using the physical work demand and physical fitness of the subjects. The overwork index, which was the ratio of maximum acceptable work time and actual work hours of the subjects, was calculated. RESULTS:In the workers with a moderate or high physical demand of work, the adjusted odds ratios for overwork indexes of 1.01-1.20, 1.21-1.50, and >1.50 were 2.679 (95% confidence interval (CI) 1.025-6.999), 3.124 (95% CI 1.111-8.783), and 4.331 (95% CI 1.719-10.908), respectively. CONCLUSIONS:The results indicate that the risk of cerebrocardiovascular disease might be high in the workers with long working hours, high physical demand of work, and poor physical fitness engaged in work with a moderate to high physical work demand. Work hours should be accommodated according to the worker's physical fitness and the physical demand of work, and this could lower the risk of cerebrocardiovascular disease. 10.1539/joh.14-0086-OA
    Overwork is a silent killer of Chinese doctors: a review of Karoshi in China 2013-2015. Shan H P,Yang X H,Zhan X L,Feng C C,Li Y Q,Guo L L,Jin H M Public health 10.1016/j.puhe.2017.02.014
    Karoshi May Be a Consequence of Overwork-Related Malignant Arrhythmia. Xiao Ning,Yang Bo-Fan,Shi Jing-Zhuo,Yu Yan-Geng,Zhang Fu,Miao Qi,Li Dong-Ri Medical science monitor : international medical journal of experimental and clinical research BACKGROUND Karoshi, which is sudden death associated with overwork, has become a serious problem in China. Many studies have examined the relationship between cardiovascular risks and karoshi, but there is little evidence that explains the exact mechanism by which overwork induces sudden death. In these cases, there are few obvious positive findings from forensic autopsies except for histories of overwork prior to death. Therefore, we assume that abnormalities, such as cardiac arrhythmia, rather than organic changes are the cause of karoshi. MATERIAL AND METHODS In the present study, the forced swim test (FST) was used to establish models of overwork. The myocardial tissues of SD rats taking FST (1 h per day, for 30 consecutive days) were collected. The arrhythmia-related molecule CX43 as well as its upstream regulation molecule Cav-1 and cSrc were tested by Western blot (WB) and immunohistochemistry (IHC). HE staining and Masson's staining were performed in the myocardium tissue section. RESULTS We observed downregulation of caveolin-1 (Cav1) followed by cSrc activation, resulting in the decrease of connexin43 (Cx43) levels in overwork models. Myocardial interstitial fibrosis, which is associated with electrophysiological aberrances that result in arrhythmia, was also found in the overwork models. CONCLUSIONS These data provide a mechanistic explanation for the speculated link between karoshi and cardiac arrhythmias. 10.12659/MSM.911685
    The Concept, Status Quo and Forensic Pathology of Karoshi. Yang B F,Shi J Z,Li Q J,Xia L C,Zhang F,Yu Y G,Xiao N,Li D R Fa yi xue za zhi Abstract:"Karoshi" originates from Japan's economic take-off period in the 1960s and 1970s. It is generally believed that overwork lead to the accumulation of fatigue, which triggers the outbreak of potential diseases, and results in sudden death. Karoshi causes great harm to both the community and families because it occurs primarily in 30 to 60 year old young adults. Japan put Karoshi into the category of industrial injury for the first time in 2001 and started to undertake a series of studies in the sociological and pathological fields. However, there is a tremendous gap in the forensic pathological diagnosis domain. In China, research on Karoshi started from the 1990s and is closely related to the reform and opening up policy as well as economic development. According to the incomplete statistics, 600 thousand people die from overwork each year in China, the highest in the world. Karoshi has become one of the most serious social problems in China at the present stage, thus a systematic study in the sociology and forensic pathology fields is urgently required. This paper summarizes the past and present status of Karoshi, and puts forward the problems that need attention during the judicial expertise of Karoshi from forensic pathology perspective. 10.12116/j.issn.1004-5619.2019.04.015
    Overwork-Induced Sudden Death: A Sword of Damocles Hanging over Chinese Medical Staff. Yang Ce,Chen Zhilan,Chen Liyong Iranian journal of public health
    Three Cases of Karoshi Without the Typical Pathomorphological Features of Cardiovascular/Cerebrovascular Disease. Miao Qi,Li Jing,Pan Yu-Peng,Yu Yan-Geng,Zhang Fu,Xiao Ning,Li Dong-Ri The American journal of forensic medicine and pathology Karoshi is a term used to describe unexplained sudden death associated with overwork and has become a serious public health issue in China. Cases have occurred in physicians, university professors, engineers in high-tech companies, and blue-collar workers. The mechanisms associated with death by overwork are very complex. According to most researchers, karoshi is considered to be caused by an excessive workload that induces deterioration of underlying hypertension or atherosclerosis. These conditions inevitably lead to death from cardiovascular or cerebrovascular diseases. However, in our own experience, we have found that in some cases, the victims of karoshi were in a chronic state of overwork but without a history of cardiovascular or cerebrovascular diseases. In support of this, we have found that even autopsies have revealed few positive findings except for cardiac hypertrophy. In this article, we report 3 typical cases of karoshi but without the typical pathomorphological features of cardiovascular or cerebrovascular disease. 10.1097/PAF.0000000000000600
    Oxalic acid and diacylglycerol 36:3 are cross-species markers of sleep debt. Weljie Aalim M,Meerlo Peter,Goel Namni,Sengupta Arjun,Kayser Matthew S,Abel Ted,Birnbaum Morris J,Dinges David F,Sehgal Amita Proceedings of the National Academy of Sciences of the United States of America Sleep is an essential biological process that is thought to have a critical role in metabolic regulation. In humans, reduced sleep duration has been associated with risk for metabolic disorders, including weight gain, diabetes, obesity, and cardiovascular disease. However, our understanding of the molecular mechanisms underlying effects of sleep loss is only in its nascent stages. In this study we used rat and human models to simulate modern-day conditions of restricted sleep and addressed cross-species consequences via comprehensive metabolite profiling. Serum from sleep-restricted rats was analyzed using polar and nonpolar methods in two independent datasets (n = 10 per study, 3,380 measured features, 407 identified). A total of 38 features were changed across independent experiments, with the majority classified as lipids (18 from 28 identified). In a parallel human study, 92 metabolites were identified as potentially significant, with the majority also classified as lipids (32 of 37 identified). Intriguingly, two metabolites, oxalic acid and diacylglycerol 36:3, were robustly and quantitatively reduced in both species following sleep restriction, and recovered to near baseline levels after sleep restriction (P < 0.05, false-discovery rate < 0.2). Elevated phospholipids were also noted after sleep restriction in both species, as well as metabolites associated with an oxidizing environment. In addition, polar metabolites reflective of neurotransmitters, vitamin B3, and gut metabolism were elevated in sleep-restricted humans. These results are consistent with induction of peroxisome proliferator-activated receptors and disruptions of the circadian clock. The findings provide a potential link between known pathologies of reduced sleep duration and metabolic dysfunction, and potential biomarkers for sleep loss. 10.1073/pnas.1417432112
    Normative variation in self-reported sleep quality and sleep debt is associated with stimulated pro-inflammatory cytokine production. Prather Aric A,Marsland Anna L,Hall Martica,Neumann Serina A,Muldoon Matthew F,Manuck Stephen B Biological psychology Activation of innate inflammatory pathways, marked by increased production of pro-inflammatory cytokines, has been proposed as a potential mechanism linking poor sleep and inflammatory disease risk. In the present study, we examined associations of self-reported sleep quality and duration, and a calculated measure of sleep debt with the production of pro-inflammatory cytokines, interleukin (IL)-6, IL-1beta, and tumor necrosis factor (TNF)-alpha among a community sample of 156 healthy adults. Bivariate correlations revealed an inverse association between sleep quality and production of all the three pro-inflammatory cytokines that was retained for IL-1beta after controlling for demographic and health characteristics. Hierarchical linear regressions also revealed that higher sleep debt scores predicted greater production of IL-1beta and IL-6 after adjusting for covariates. Secondary analyses showed an interaction between sleep debt and body mass index (BMI) in the prediction IL-1beta, suggesting that the impact of sleep debt on cytokine production is greater among participants with lower BMI scores. Further exploration of this potential psychophysiological pathway linking sleep difficulty and inflammatory disease susceptibility is warranted. 10.1016/j.biopsycho.2009.04.008
    Rapid eye movement sleep debt accrues in mice exposed to volatile anesthetics. Pick Jeremy,Chen Yihan,Moore Jason T,Sun Yi,Wyner Abraham J,Friedman Eliot B,Kelz Max B Anesthesiology BACKGROUND:General anesthesia has been likened to a state in which anesthetized subjects are locked out of access to both rapid eye movement (REM) sleep and wakefulness. Were this true for all anesthetics, a significant REM rebound after anesthetic exposure might be expected. However, for the intravenous anesthetic propofol, studies demonstrate that no sleep debt accrues. Moreover, preexisting sleep debts dissipate during propofol anesthesia. To determine whether these effects are specific to propofol or are typical of volatile anesthetics, the authors tested the hypothesis that REM sleep debt would accrue in rodents anesthetized with volatile anesthetics. METHODS:Electroencephalographic and electromyographic electrodes were implanted in 10 mice. After 9-11 days of recovery and habituation to a 12 h:12 h light-dark cycle, baseline states of wakefulness, nonrapid eye movement sleep, and REM sleep were recorded in mice exposed to 6 h of an oxygen control and on separate days to 6 h of isoflurane, sevoflurane, or halothane in oxygen. All exposures were conducted at the onset of light. RESULTS:Mice in all three anesthetized groups exhibited a significant doubling of REM sleep during the first 6 h of the dark phase of the circadian schedule, whereas only mice exposed to halothane displayed a significant increase in nonrapid eye movement sleep that peaked at 152% of baseline. CONCLUSION:REM sleep rebound after exposure to volatile anesthetics suggests that these volatile anesthetics do not fully substitute for natural sleep. This result contrasts with the published actions of propofol for which no REM sleep rebound occurred. 10.1097/ALN.0b013e31822ddd72
    Does our sleep debt affect patients' safety? Tewari Anurag,Soliz Jose,Billota Federico,Garg Shuchita,Singh Harsimran Indian journal of anaesthesia The provision of anaesthesia requires a high level of knowledge, sound judgement, fast and accurate responses to clinical situations, and the capacity for extended periods of vigilance. With changing expectations and arising medico-legal issues, anaesthesiologists are working round the clock to provide efficient and timely health care services, but little is thought whether the "sleep provider" is having adequate sleep. Decreased performance of motor and cognitive functions in a fatigued anaesthesiologist may result in impaired judgement, late and inadequate responses to clinical changes, poor communication and inadequate record keeping, all of which affect the patient safety, showing without doubt the association of sleep debt to the adverse events and critical incidents. Perhaps it is time that these issues be promptly addressed to prevent the silent perpetuation of a problem that is pertinent to our health and our profession. We endeavour to focus on the evidence that links patient safety to fatigue and sleepiness of health care workers and specifically on anaesthesiologists. The implications of sleep debt are deep on patient safety and strategies to prevent this are the need of the hour. 10.4103/0019-5049.76572
    Sleep Restriction Enhances the Daily Rhythm of Circulating Levels of Endocannabinoid 2-Arachidonoylglycerol. Hanlon Erin C,Tasali Esra,Leproult Rachel,Stuhr Kara L,Doncheck Elizabeth,de Wit Harriet,Hillard Cecilia J,Van Cauter Eve Sleep STUDY OBJECTIVES:Increasing evidence from laboratory and epidemiologic studies indicates that insufficient sleep may be a risk factor for obesity. Sleep curtailment results in stimulation of hunger and food intake that exceeds the energy cost of extended wakefulness, suggesting the involvement of reward mechanisms. The current study tested the hypothesis that sleep restriction is associated with activation of the endocannabinoid (eCB) system, a key component of hedonic pathways involved in modulating appetite and food intake. METHODS:In a randomized crossover study comparing 4 nights of normal (8.5 h) versus restricted sleep (4.5 h) in healthy young adults, we examined the 24-h profiles of circulating concentrations of the endocannabinoid 2-arachidonoylglycerol (2-AG) and its structural analog 2-oleoylglycerol (2-OG). We concomitantly assessed hunger, appetite, and food intake under controlled conditions. RESULTS:A robust daily variation of 2-AG concentrations with a nadir around the middle of the sleep/overnight fast, followed by a continuous increase culminating in the early afternoon, was evident under both sleep conditions but sleep restriction resulted in an amplification of this rhythm with delayed and extended maximum values. Concentrations of 2-OG followed a similar pattern, but with a lesser amplitude. When sleep deprived, participants reported increases in hunger and appetite concomitant with the afternoon elevation of 2-AG concentrations, and were less able to inhibit intake of palatable snacks. CONCLUSIONS:Our findings suggest that activation of the eCB system may be involved in excessive food intake in a state of sleep debt and contribute to the increased risk of obesity associated with insufficient sleep. COMMENTARY:A commentary on this article appears in this issue on page 495. 10.5665/sleep.5546
    Human brain patterns underlying vigilant attention: impact of sleep debt, circadian phase and attentional engagement. Maire Micheline,Reichert Carolin F,Gabel Virginie,Viola Antoine U,Phillips Christophe,Berthomier Christian,Borgwardt Stefan,Cajochen Christian,Schmidt Christina Scientific reports Sleepiness and cognitive function vary over the 24-h day due to circadian and sleep-wake-dependent mechanisms. However, the underlying cerebral hallmarks associated with these variations remain to be fully established. Using functional magnetic resonance imaging (fMRI), we investigated brain responses associated with circadian and homeostatic sleep-wake-driven dynamics of subjective sleepiness throughout day and night. Healthy volunteers regularly performed a psychomotor vigilance task (PVT) in the MR-scanner during a 40-h sleep deprivation (high sleep pressure) and a 40-h multiple nap protocol (low sleep pressure). When sleep deprived, arousal-promoting thalamic activation during optimal PVT performance paralleled the time course of subjective sleepiness with peaks at night and troughs on the subsequent day. Conversely, task-related cortical activation decreased when sleepiness increased as a consequence of higher sleep debt. Under low sleep pressure, we did not observe any significant temporal association between PVT-related brain activation and subjective sleepiness. Thus, a circadian modulation in brain correlates of vigilant attention was only detectable under high sleep pressure conditions. Our data indicate that circadian and sleep homeostatic processes impact on vigilant attention via specific mechanisms; mirrored in a decline of cortical resources under high sleep pressure, opposed by a subcortical "rescuing" at adverse circadian times. 10.1038/s41598-017-17022-9
    Mouse Gambling Task reveals differential effects of acute sleep debt on decision-making and associated neurochemical changes. Pittaras Elsa,Callebert Jacques,Dorey Rodolphe,Chennaoui Mounir,Granon Sylvie,Rabat Arnaud Sleep Sleep loss is associated with sleepiness, sustained attention, and memory deficits. However, vulnerability of higher cognitive processes (i.e. decision making) to sleep debt is less understood. Therefore, a major challenge is to understand why and how higher cognitive processes are affected by sleep debt. We had established in mice correlations between individual decision-making strategies, prefrontal activity, and regional monoaminergic levels. Now, we show that acute sleep debt (ASD) disturbs decision-making processes and provokes brain regional modifications of serotonin and dopamine that could explain why ASD promotes inflexible and more risk-prone behaviors. Finally, we highlight, for the first time, that in a large group of healthy inbred mice some of them are more sensitive to ASD by showing inflexible behavior and decision-making deficits. We were also able to predict mice that would be the most vulnerable to ASD depending of their behavior before ASD exposure. 10.1093/sleep/zsy168
    Importance of fatigue and its measurement in chronic liver disease. Gerber Lynn H,Weinstein Ali A,Mehta Rohini,Younossi Zobair M World journal of gastroenterology The mechanisms of fatigue in the group of people with non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are protean. The liver is central in the pathogenesis of fatigue because it uniquely regulates much of the storage, release and production of substrate for energy generation. It is exquisitely sensitive to the feedback controlling the uptake and release of these energy generation substrates. Metabolic contributors to fatigue, beginning with the uptake of substrate from the gut, the passage through the portal system to hepatic storage and release of energy to target organs (muscle and brain) are central to understanding fatigue in patients with chronic liver disease. Inflammation either causing or resulting from chronic liver disease contributes to fatigue, although inflammation has not been demonstrated to be causal. It is this unique combination of factors, the nexus of metabolic abnormality and the inflammatory burden of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis that creates pathways to different types of fatigue. Many use the terms central and peripheral fatigue. Central fatigue is characterized by a lack of self-motivation and can manifest both in physical and mental activities. Peripheral fatigue is classically manifested by neuromuscular dysfunction and muscle weakness. Therefore, the distinction is often seen as a difference between intention (central fatigue) ability (peripheral fatigue). New approaches to measuring fatigue include the use of objective measures as well as patient reported outcomes. These measures have improved the precision with which we are able to describe fatigue. The measures of fatigue severity and its impact on usual daily routines in this population have also been improved, and they are more generally accepted as reliable and sensitive. Several approaches to evaluating fatigue and developing endpoints for treatment have relied of biosignatures associated with fatigue. These have been used singly or in combination and include: physical performance measures, cognitive performance measures, mood/behavioral measures, brain imaging and serological measures. Treatment with non-pharmacological agents have been shown to be effective in symptom reduction, whereas pharmacological agents have not been shown effective. 10.3748/wjg.v25.i28.3669
    Fatigue in chronic liver disease: New insights and therapeutic approaches. Swain Mark G,Jones David E J Liver international : official journal of the International Association for the Study of the Liver The management of fatigue associated with chronic liver disease is a complex and major clinical challenge. Although fatigue can complicate many chronic diseases, it is particularly common in diseases with an inflammatory component. Fatigue can have both peripheral (i.e., neuromuscular) and central (i.e., resulting from changes in neurotransmission within the brain) causes. However, fatigue in chronic liver disease has strong social/contextual components and is often associated with behavioural alterations including depression and anxiety. Given the increasing awareness of patient-reported outcomes as important components of treatment outcomes and clinical research, there is a growing need to better understand and manage this poorly understood yet debilitating symptom. Although several pathophysiological mechanisms for explaining the development of fatigue have been generated, our understanding of fatigue in patients with chronic liver disease remains incomplete. A better understanding of the pathways and neurotransmitter systems involved may provide specific directed therapies. Currently, the management of fatigue in chronic liver disease can involve a combined use of methods to beneficially alter behavioural components and pharmacological interventions, of which several treatments have potential for the improved management of fatigue in chronic liver disease. However, evidence and consensus are lacking on the best approach and the most appropriate biochemical target(s) whilst clinical trials to address this issue have been few and limited by small sample size. In this review, we outline current understanding of the impact of fatigue and related symptoms in chronic liver disease, discuss theories of pathogenesis, and examine current and emerging approaches to its treatment. 10.1111/liv.13919
    A Systematic Review of Biological Mechanisms of Fatigue in Chronic Illness. Matura Lea Ann,Malone Susan,Jaime-Lara Rosario,Riegel Barbara Biological research for nursing Fatigue, a commonly reported symptom, is defined as an overwhelming, debilitating, and sustained sense of exhaustion that decreases the ability to function and carry out daily activities. To date, cancer researchers have been in the forefront in investigating the possible biological mechanisms of fatigue, identifying inflammation, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and activation of the autonomic nervous system. The purpose of this systematic review is to describe fatigue and what is known about the biological mechanisms described in cancer in five chronic, noninfectious illnesses: heart failure, multiple sclerosis, chronic kidney disease, rheumatoid arthritis, and chronic obstructive pulmonary disease. We searched PubMed and EMBASE using fatigue as a major Medical subject headings (MeSH) heading with each individual disease added as a search term followed by each biological mechanism. We included only primary research articles published in English between 1996 and 2016 describing studies conducted in adult humans. We identified 26 relevant articles. While there is some evidence that the biological mechanisms causing fatigue in cancer are also associated with fatigue in other chronic illnesses, more research is needed to explore inflammation, the HPA axis, and the autonomic nervous system, and other mechanisms in relation to fatigue in a variety of chronic illnesses. 10.1177/1099800418764326
    Fatigue interventions in long term, physical health conditions: A scoping review of systematic reviews. Hulme Katrin,Safari Reza,Thomas Sarah,Mercer Tom,White Claire,Van der Linden Marietta,Moss-Morris Rona PloS one OBJECTIVE:Fatigue is prominent across many long term physical health conditions. This scoping review aimed to map the fatigue intervention literature, to ascertain if certain interventions may be effective across conditions, and if novel interventions tested in specific long term conditions may be promising for other conditions. METHODS:Scoping review methodological frameworks were used. Electronic bibliographic databases were searched (inception to November 2016) for systematic reviews of fatigue interventions in long term conditions. Inclusion criteria were: long term physical health condition; review focus on fatigue management; objective and systematic review process; primary review outcome is fatigue. Articles focussing on surgical interventions or treatments thought to trigger fatigue were excluded. A narrative synthesis was performed. RESULTS:Of 115 full texts screened, 52 reviews were included. Interventions were categorised as pharmacological and non-pharmacological (exercise, psychological/behavioural and complementary medicine). Pharmacological interventions did not consistently demonstrate benefit, except for anti-TNFs and methylphenidate which may be effective at reducing fatigue. Non-pharmacological interventions such as graded exercise and fatigue-specific psychological interventions may be effective, but heterogeneous intervention components limit conclusions. 'Complementary medicine' interventions (e.g. Chinese herbal medicines) showed promise, but the possibility of publication bias must be considered. CONCLUSIONS:Further research is necessary to inform clinical practice. The reported effectiveness of some interventions across inflammatory health conditions, such as anti-TNFs, aerobic exercise, and psychologically based approaches such as CBT, highlights a potential transdiagnostic avenue for fatigue management. More novel strategies that may be worth exploring include expressive writing and mindfulness, although the mechanisms for these in relation to fatigue are unclear. More work is needed to identify transdiagnostic mechanisms of fatigue and to design interventions based on these. 10.1371/journal.pone.0203367