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1.  Fatigue and Sleep Quality are Associated with Changes in Inflammatory Markers in Breast Cancer Patients Undergoing Chemotherapy 
Brain, Behavior, and Immunity  2012;26(5):706-713.
Fatigue and sleep disturbances are two of the most common and distressing symptoms reported by cancer patients. Fatigue and sleep are also correlated with each other. While fatigue has been reported to be associated with some inflammatory markers, data about the relationship between cancer-related sleep disturbances and inflammatory markers are limited. This study examined the relationship between fatigue and sleep, measured both subjectively and objectively, and inflammatory markers in a sample of breast cancer patients before and during chemotherapy. Fifty-three women with newly diagnosed stage I–III breast cancer scheduled to receive at least four 3-week cycles of chemotherapy participated in this longitudinal study. Fatigue was assessed with the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF), sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI) and objective sleep was measured with actigraphy. Three inflammatory markers were examined: Interleukin-6 (IL-6), Interleukin-1 receptor antagonist (IL-1RA) and C-reactive protein (CRP). Data were collected before (baseline) and during cycle 1 and cycle 4 of chemotherapy. Compared to baseline, more fatigue was reported, levels of IL-6 increased and IL-1RA decreased during chemotherapy. Reports of sleep quality remained poor. Mixed model analyses examining changes from baseline to each treatment time point revealed overall positive relationships between changes in total MFSI-SF scores and IL-6, between changes in total PSQI scores and IL-6 and IL-1RA, and between total wake time at night and CRP (all p’s<0.05). These relationships suggest that cancer-related fatigue and sleep disturbances may share common underlying biochemical mechanisms.
doi:10.1016/j.bbi.2012.02.001
PMCID: PMC3372667  PMID: 22406004
breast cancer; chemotherapy; fatigue; sleep; inflammatory markers
2.  Pre-treatment Symptom Cluster in Breast Cancer Patients is Associated with Worse Sleep, Fatigue and Depression during Chemotherapy 
Psycho-oncology  2009;18(2):187-194.
Objective
The concept of symptom clusters is relatively new in cancer patients' symptom management. This study, which spanned four cycles of chemotherapy, combined three commonly seen pre-treatment symptoms in cancer patients (i.e., sleep disturbances, fatigue and depression) into one symptom cluster, to explore the associations between pre-treatment cluster categories and longitudinal profiles of these same symptoms during chemotherapy.
Methods
This was a prospective study. Seventy-six women with newly diagnosed stage I–III breast cancer, scheduled to receive at least four cycles of adjuvant or neoadjuvant anthracycline-based chemotherapy participated. Data were collected at seven time points before and during treatment. Sleep quality was measured with the Pittsburgh Sleep Quality Index (PSQI). Fatigue was measured with the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF). Depressive symptoms were measured with the Center of Epidemiological Studies-Depression (CES-D). Patients were divided into three groups based on the number of symptoms they experienced before the start of chemotherapy (i.e., no symptoms, 1–2 symptoms or all three symptoms) and a symptom cluster index (SCI) was computed.
Results
All women reported worse sleep, more fatigue and more depressive symptoms during treatment compared to baseline (all p's <0.01); however, those women with a higher symptom cluster index (i.e., more symptoms pre-treatment) continued to experience worse symptoms during treatment compared to those who began with fewer symptoms (all p's <0.01).
Conclusions
A higher clinically relevant-based pre-treatment symptom cluster was associated with more sleep disturbances, greater fatigue and more depressive symptoms during chemotherapy. Specific interventions for these pre-treatment symptoms may improve the frequency and severity of these same symptoms during chemotherapy, when they are most severe and most disruptive to quality of life.
doi:10.1002/pon.1412
PMCID: PMC2762479  PMID: 18677716
breast cancer; symptom cluster; sleep disturbances; fatigue; depression
3.  A comparison of disrupted sleep patterns in women with cancer-related fatigue and postmenopausal women without cancer (Resubmission) 
Purpose
Fatigue and disrupted sleep often coexist and both are prominent clinical problems in cancer affecting quality of life. Disrupted sleep patterns are likely related to cancer-related fatigue. The relationship needs further investigation. This study aimed to characterize and compare disrupted sleep patterns in fatigued breast cancer patients receiving chemotherapy with postmenopausal women without a history of cancer. Anxiety levels were also examined.
Methods
Data for this secondary analysis came from two studies. Global sleep quality and state anxiety were self-reported by 30 fatigued female breast cancer chemotherapy outpatients and 32 non-cancer postmenopausal women using Pittsburgh Sleep Quality Index (PSQI) and State-Trait Anxiety Inventory, respectively.
Results
Fatigued breast cancer patients showed significant sleep difficulties, characterized by prolonged sleep onset latency (M= 54.3, SD= 49.2 minutes) and frequent nighttime awakenings, despite 40% of the patients using sleep medications three or more times a week. Compared to the non-cancer comparison group, fatigued patients reported significantly longer sleep latency (p=0.041), more use of sleep medications (p=0.006), and higher total PSQI scores (p=0.005). State anxiety levels did not differ between the two groups (p=0.88).
Conclusions
Sleep is disrupted in fatigued breast cancer women undergoing chemotherapy. Nearly all fatigued patients (97%) had trouble sleeping (global PSQI scores >5), indicating significant difficulties in overall sleep quality among those patients. Knowledge of the nature of sleep disruption among cancer patients may contribute to CRF symptom management leading to tailored interventions designed to improve sleep quality in cancer patients thereby managing fatigue and improving quality of life.
doi:10.1016/j.ejon.2010.10.003
PMCID: PMC3117033  PMID: 21093372
symptom management; cancer-related fatigue; disrupted sleep patterns; breast cancer
4.  Circadian rhythm sleep disorders in patients with multiple sclerosis and its association with fatigue: A case-control study 
Background:
Circadian rhythm sleep disorders are a presentation of sleep disorders in patients with multiple sclerosis (MS). This study aims to compare this problem in MS patients with healthy people and to determine its association with chronic fatigue in MS patients.
Materials and Methods:
A case-control study was performed on 120 MS patients and 60 healthy subjects matched for age and sex, in 2009 in MS Clinic Alzahra Hospital. Sleep quality, rhythm and fatigue severity were assessed using PSQI (Pittsburgh sleep quality index) and FSS (Fatigue severity Scale) questionnaires, respectively. Its reliability and validity has been confirmed in several studies (Cronbach's alpha = 0.83). This index has seven sections including patient's assessment of his/her sleep, sleep duration, efficacy of routine sleep, sleep disorders, use of hypnotic medication, and dysfunction in daily activities.
Results:
Circadian rhythm sleep disorder was more frequent in MS patients relative to healthy subjects (P: 0.002). It was higher in MS patients with severe fatigue relative to MS patients with mild fatigue (P: 0.05). Fatigue severity was 49.9 ± 8.2 and 22.5 ± 7.4 in the first and second group, respectively. PSQI index was 7.9 ± 4.5 in patients with severe fatigue and 5.9 ± 4.5 in patients with mild fatigue and 4.5 ± 2.4 in the control group (P: 0.0001).
Conclusion:
Circadian rhythm sleep disorders are more frequent in MS patients and those with fatigue. Recognition and management of circadian rhythm sleep disorders in MS patients, especially those with fatigue may be helpful in improving care of these patients.
PMCID: PMC3743326  PMID: 23961292
Chronic fatigue; circadian rhythm sleep disorder; fatigue severity scale; multiple sclerosis; Pittsburg sleep quality index
5.  Shift Work in Nurses: Contribution of Phenotypes and Genotypes to Adaptation 
PLoS ONE  2011;6(4):e18395.
Background
Daily cycles of sleep/wake, hormones, and physiological processes are often misaligned with behavioral patterns during shift work, leading to an increased risk of developing cardiovascular/metabolic/gastrointestinal disorders, some types of cancer, and mental disorders including depression and anxiety. It is unclear how sleep timing, chronotype, and circadian clock gene variation contribute to adaptation to shift work.
Methods
Newly defined sleep strategies, chronotype, and genotype for polymorphisms in circadian clock genes were assessed in 388 hospital day- and night-shift nurses.
Results
Night-shift nurses who used sleep deprivation as a means to switch to and from diurnal sleep on work days (∼25%) were the most poorly adapted to their work schedule. Chronotype also influenced efficacy of adaptation. In addition, polymorphisms in CLOCK, NPAS2, PER2, and PER3 were significantly associated with outcomes such as alcohol/caffeine consumption and sleepiness, as well as sleep phase, inertia and duration in both single- and multi-locus models. Many of these results were specific to shift type suggesting an interaction between genotype and environment (in this case, shift work).
Conclusions
Sleep strategy, chronotype, and genotype contribute to the adaptation of the circadian system to an environment that switches frequently and/or irregularly between different schedules of the light-dark cycle and social/workplace time. This study of shift work nurses illustrates how an environmental “stress” to the temporal organization of physiology and metabolism can have behavioral and health-related consequences. Because nurses are a key component of health care, these findings could have important implications for health-care policy.
doi:10.1371/journal.pone.0018395
PMCID: PMC3076422  PMID: 21533241
6.  Reduced Anxiety and Depression-Like Behaviours in the Circadian Period Mutant Mouse Afterhours 
PLoS ONE  2012;7(6):e38263.
Background
Disruption of the circadian rhythm is a key feature of bipolar disorder. Variation in genes encoding components of the molecular circadian clock has been associated with increased risk of the disorder in clinical populations. Similarly in animal models, disruption of the circadian clock can result in altered mood and anxiety which resemble features of human mania; including hyperactivity, reduced anxiety and reduced depression-like behaviour. One such mutant, after hours (Afh), an ENU-derived mutant with a mutation in a recently identified circadian clock gene Fbxl3, results in a disturbed (long) circadian rhythm of approximately 27 hours.
Methodology
Anxiety, exploratory and depression-like behaviours were evaluated in Afh mice using the open-field, elevated plus maze, light-dark box, holeboard and forced swim test. To further validate findings for human mania, polymorphisms in the human homologue of FBXL3, genotyped by three genome wide case control studies, were tested for association with bipolar disorder.
Principal Findings
Afh mice showed reduced anxiety- and depression-like behaviour in all of the behavioural tests employed, and some evidence of increased locomotor activity in some tests. An analysis of three separate human data sets revealed a gene wide association between variation in FBXL3 and bipolar disorder (P = 0.009).
Conclusions
Our results are consistent with previous studies of mutants with extended circadian periods and suggest that disruption of FBXL3 is associated with mania-like behaviours in both mice and humans.
doi:10.1371/journal.pone.0038263
PMCID: PMC3376117  PMID: 22719873
7.  The relationship between fatigue and light exposure during chemotherapy 
Background
Fatigue is one of the most common and distressing complaints among cancer patients, not only during radiation and chemotherapy, but also for months to years after the completion of treatment. Fatigue interferes with patients’ daily lives, reduces their quality of life, and is often a significant reason why patients discontinue treatment. We hypothesized that some of the fatigue may be related to disrupted circadian rhythms and low light exposure. The main objective of this study therefore was to investigate the association between fatigue and light exposure among patients with breast cancer.
Methods
As part of a larger, ongoing prospective study on fatigue, sleep, and circadian rhythms in patients with breast cancer, an analysis of 63 women newly diagnosed with stage I–IIIA breast cancer and scheduled to receive four cycles of adjuvant or neoadjuvant anthracycline-based chemotherapy was conducted. Data were collected before and during weeks 1, 2, and 3 of cycle 1 and cycle 4. Fatigue was assessed using the Short Form of Multidimensional Fatigue Symptom Inventory. Light exposure was recorded with a wrist actigraph.
Results
There were significant correlations between fatigue levels and light exposure (r=−0.28 to −0.45) within both cycle 1 and cycle 4, such that higher levels of fatigue were associated with less light exposure. There were also significant correlations between changes in light exposure and changes in fatigue within the first 2 weeks of each cycle (r=−0.28 to −0.52).
Conclusions
Increased fatigue was significantly correlated with decreased light exposure among patients with breast cancer. Although the cause and effect of exacerbated fatigue and decreased light exposure cannot be confirmed by the current study, and lower light exposure may just in part be due to the fatigued patients spending less time outdoors in bright light, two hypotheses are proposed about the mechanisms by which light may alleviate the fatigue of patients with breast cancer. These results suggest the need for prospective intervention studies of light therapy for breast-cancer-related fatigue.
doi:10.1007/s00520-005-0824-5
PMCID: PMC1599705  PMID: 15864659
Breast cancer; Fatigue; Light; Chemotherapy
8.  Chronic Interferon-Alpha Administration Disrupts Sleep Continuity and Depth in Patients with Hepatitis C: Association with Fatigue, Motor Slowing and Increased Evening Cortisol 
Biological psychiatry  2010;68(10):942-949.
Background
Consequences of chronic exposure to cytokines of the innate immune system on sleep in humans and the association of cytokine-induced sleep alterations with behavior, motor performance and cortisol secretion are unknown.
Methods
Thirty-one patients with hepatitis C without pre-existing sleep disorders underwent nighttime polysomnography, daytime multiple sleep latency testing, behavioral assessments, neuropsychological testing and serial blood sampling at baseline and after ~12 weeks of either treatment with the innate immune cytokine, interferon (IFN)-alpha (n=19) or no treatment (n=12). Fatigue and sleepiness were assessed using the Multidimensional Fatigue Inventory and Epworth Sleepiness Scale.
Results
IFN-alpha administration led to significant increases in wake after sleep onset and significant decreases in Stage 3/4 sleep and sleep efficiency. REM latency and Stage 2 sleep were significantly increased during IFN-alpha treatment. Decreases in Stage 3/4 sleep and increases in REM latency were associated with increases in fatigue, whereas decreases in sleep efficiency were associated with reduced motor speed. Increased wake after sleep onset was associated with increased evening plasma cortisol. Despite IFN-alpha-induced increases in fatigue, daytime sleepiness did not increase. In fact, IFN-alpha-treated patients exhibited decreased propensity to fall asleep during daytime nap opportunities.
Conclusions
Chronic exposure to an innate immune cytokine reduced sleep continuity and depth, and induced a sleep pattern consistent with insomnia and hyperarousal. These data suggest that innate immune cytokines may provide a mechanistic link between disorders associated with chronic inflammation including medical and/or psychiatric illnesses and insomnia, which in turn is associated with fatigue, motor slowing and altered cortisol.
doi:10.1016/j.biopsych.2010.04.019
PMCID: PMC2937202  PMID: 20537611
Sleep; insomnia; hyperarousal; polysomnography; fatigue; depression; interferon-alpha; hepatitis C; neuropsychology; cortisol; cytokines
9.  Arousal frequency is associated with increased fatigue in obstructive sleep apnea 
Objective
Fatigue is an important and often underemphasized symptom in patients with obstructive sleep apnea (OSA). Sleep fragmentation, i.e., arousals and disruptions in sleep architecture, is common in patients with OSA and may potentially contribute to their fatigue. We hypothesized that arousal frequency and changes in sleep architecture contribute to the fatigue experienced by patients with OSA.
Design
Seventy-three patients with diagnosed but untreated OSA (AHI ≥ 15) were enrolled in this study. A baseline polysomnogram was obtained, and fatigue was measured with the Multidimensional Fatigue Symptom Inventory-short form (MFSI-sf). We evaluated the association between fatigue and arousals and various polysomongraphic variables, including sleep stages and sleep efficiency.
Results
Significant correlations between MFSI-sf subscale scores and various arousal indices were noted. Emotional fatigue scores were associated with total arousal index (r = 0.416, p = .021), respiratory movement arousal index (r = 0.346, p = .025), and spontaneous movement arousal index (r = 0.378, p = .025). Physical fatigue scores were associated with total arousal index (r = 0.360, p = .033) and respiratory movement arousal index (r = 0.304, p = .040). Percent of stage 1 sleep and REM sleep were also associated with physical and emotional fatigue scores. Hierarchal linear regression analysis demonstrated that emotional fatigue scores were independently associated with spontaneous movement arousals after controlling for age, body mass index, depression, and sleep apnea severity.
Conclusions
These findings suggest that arousals may contribute to the fatigue seen in patients with OSA.
doi:10.1007/s11325-009-0252-8
PMCID: PMC2764080  PMID: 19319586
Obstructive sleep apnea; Fatigue; Sleep architecture; Arousals
10.  Fatigue in patients with COPD participating in a pulmonary rehabilitation program 
Background
Fatigue is a distressing, complex, multidimensional sensation common in individuals with chronic obstructive pulmonary disease (COPD). While fatigue negatively impacts functional performance and quality of life, there has been little study of the fatigue that affects participants in pulmonary rehabilitation programs. The purpose of this study was to examine the emotional, behavioral, cognitive, and physical dimensions of fatigue and their relationships to dyspnea, mental health, sleep, and physiologic factors.
Patients and methods
A convenience sample of 42 pulmonary rehabilitation participants with COPD completed self-report questionnaires which measured dimensions of fatigue using the Multidimensional Fatigue Inventory, anxiety and depression using the Hospital Anxiety and Depression Scale, and sleep quality using the Pittsburgh Sleep Quality Index. Data on other clinical variables were abstracted from pulmonary rehabilitation program health records.
Results
Almost all (95.3%) participants experienced high levels of physical fatigue. High levels of fatigue were also reported for the dimensions of reduced activity (88.1%), reduced motivation (83.3%), mental fatigue (69.9%), and general fatigue (54.5%). Close to half (42.9%) of participants reported symptoms of anxiety, while almost one quarter (21.4%) reported depressive symptoms. Age was related to the fatigue dimensions of reduced activity (ρ = 0.43, P < 0.01) and reduced motivation (ρ = 0.31, P < 0.05). Anxiety was related to reduced motivation (ρ = −0.47, P < 0.01). Fatigue was not associated with symptoms of depression, sleep quality, gender, supplemental oxygen use, smoking status, or Medical Research Council dyspnea scores.
Conclusions
Fatigue (particularly the physical and reduced motivation dimensions of fatigue) was experienced by almost all participants with COPD attending this pulmonary rehabilitation program. Fatigue affected greater proportions of participants than either anxiety or depression. The high prevalence of fatigue may impact on enrolment, participation, and attrition in pulmonary rehabilitation programs. Further investigation of the nature, correlates, and impact of fatigue in this population is required.
doi:10.2147/COPD.S12321
PMCID: PMC2962297  PMID: 21037955
COPD; fatigue; pulmonary rehabilitation; anxiety; depression; sleep quality
11.  Systematic Analysis of Circadian Genes in a Population-Based Sample Reveals Association of TIMELESS with Depression and Sleep Disturbance 
PLoS ONE  2010;5(2):e9259.
Disturbances in the circadian pacemaker system are commonly found in individuals with depression and sleep-related problems. We hypothesized that some of the canonical circadian clock genes would be associated with depression accompanied by signs of disturbed sleep, early morning awakening, or daytime fatigue. We tested this hypothesis in a population-based sample of the Health 2000 dataset from Finland, including 384 depressed individuals and 1270 controls, all with detailed information on sleep and daytime vigilance, and analyzed this set of individuals with regard to 113 single-nucleotide polymorphisms of 18 genes of the circadian system. We found significant association between TIMELESS variants and depression with fatigue (D+FAT+) (rs7486220: pointwise P = 0.000099, OR = 1.66; corrected empirical P for the model of D+FAT+  = 0.0056; haplotype ‘C-A-A-C’ of rs2291739-rs2291738-rs7486220-rs1082214: P = 0.0000075, OR = 1.72) in females, and association to depression with early morning awakening (D+EMA+) (rs1082214: pointwise P = 0.0009, OR = 2.70; corrected empirical P = 0.0374 for the model D+EMA+; haplotype ‘G-T’ of rs7486220 and rs1082214: P = 0.0001, OR = 3.01) in males. There was significant interaction of gender and TIMELESS (for example with rs1082214, P = 0.000023 to D+EMA+ and P = 0.005 to D+FAT+). We obtained supported evidence for involvement of TIMELESS in sleeping problems in an independent set of control individuals with seasonal changes in mood, sleep duration, energy level and social activity in females (P = 0.036, ® = 0.123 for rs1082214) and with early morning awakening or fatigue in males (P = 0.038 and P = 0.0016, respectively, for rs1082214). There was also some evidence of interaction between TIMELESS and PER1 in females to D+FAT+ as well as between TIMELESS and ARNTL, RORA or NR1D1 in males to D+EMA+. These findings support a connection between circadian genes and gender-dependent depression and defective sleep regulation.
doi:10.1371/journal.pone.0009259
PMCID: PMC2823770  PMID: 20174623
12.  Fatigue, Depression, Sleep, and Activity During Chemotherapy: Daily and Intraday Variation and Relationships Among Symptom Changes 
Background
Previous research suggests that cancer patients frequently experience multiple symptoms during chemotherapy; however, relationships among symptom changes are largely unknown.
Purpose
The aim of the current study was to examine daily and intraday changes and interrelationships among fatigue, depression, and objectively measured disruptions in sleep and activity during chemotherapy.
Methods
Participants were 78 women with gynecologic cancer. Fatigue, depression, sleep, and activity were assessed the week before and the week after the participants’ first three infusions.
Results
Significant changes in fatigue, depression, sleep, and activity were observed over time. Before infusions, increases in fatigue were associated with increases in depression. After infusions, increases in fatigue were associated with increases in depression and minutes awake at night, as well as decreases in daytime activity and regularity of sleep/activity patterns (ps<.05).
Conclusions
This study is among the first to track daily and intraday changes in symptoms and interrelationships during chemotherapy. Results indicate that symptoms are interrelated and return to baseline levels after infusions.
doi:10.1007/s12160-011-9294-9
PMCID: PMC3432914  PMID: 21785899
Gynecologic cancer; Fatigue; Depression; Actigraphy; Sleep; Chemotherapy
13.  The effect of MELatOnin on Depression, anxietY, cognitive function and sleep disturbances in patients with breast cancer. The MELODY trial: protocol for a randomised, placebo-controlled, double-blinded trial 
BMJ Open  2012;2(1):e000647.
Introduction
Breast cancer represents about one-third of all cancer diagnoses and accounts for about 15% of cancer deaths in women. Many of these patients experience depression, anxiety, sleep disturbances and cognitive dysfunction. This may adversely affect quality of life and also contribute to morbidity and mortality. Melatonin is a regulatory circadian hormone having, among others, a hypnotic and an antidepressive effect. It has very low toxicity and very few adverse effects compared with the more commonly used antidepressants and hypnotics.
Methods and analysis
The objective of this double-blind, randomised, placebo-controlled trial is to investigate whether treatment with oral melatonin has a prophylactic or ameliorating effect on depressive symptoms, anxiety, sleep disturbances and cognitive dysfunction in women with breast cancer. Furthermore, the authors will examine whether a specific clock-gene, PER3, is correlated with an increased risk of depressive symptoms, sleep disturbances or cognitive dysfunction. The MELODY trial is a prospective double-blinded, randomised, placebo-controlled trial in which the authors intend to include 260 patients. The primary outcome is depressive symptoms measured by the Major Depression Inventory. The secondary outcomes are anxiety measured by a Visual Analogue Scale, total sleep time, sleep efficiency, sleep latency and periods awake measured by actigraphy and changes in cognitive function measured by a neuropsychological test battery. Tertiary outcomes are fatigue, pain, well-being and sleep quality/quantity measured by Visual Analogue Scale and sleep diary and sleepiness measured by the Karolinska Sleepiness Scale. The PER3 genotype is also to be determined in blood samples.
Article summary
This is a protocol article on the MELODY trial. The objective of this double-blind randomized, placebo-controlled trial is to investigate whether daily treatment with 6 mg oral melatonin has a prophylactic or ameliorating effect on depressive symptoms, anxiety, sleep disturbances and cognitive dysfunction in women with breast cancer. Furthermore to examine whether a specific clock-gene PER3 is correlated with an increased risk of depressive symptoms, sleep disturbances or cognitive dysfunction.
doi:10.1136/bmjopen-2011-000647
PMCID: PMC3278491  PMID: 22240653
14.  Circadian function in patients with advanced non-small-cell lung cancer 
British Journal of Cancer  2005;93(11):1202-1208.
This study aimed to evaluate whether patients with advanced non-small-cell lung cancer experience disrupted rest–activity daily rhythms, poor sleep quality, weakness, and maintain attributes that are linked to circadian function such as fatigue. This report describes the rest–activity patterns of 33 non-small-cell lung cancer patients who participated in a randomised clinical trial evaluating the benefits of melatonin. Data are reported on circadian function, health-related quality of life (QoL), subjective sleep quality, and anxiety/depression levels prior to randomisation and treatment. Actigraphy data, an objective measure of circadian function, demonstrated that patients' rest–activity circadian function differs significantly from control subjects. Our patients reported poor sleep quality and high levels of fatigue. Ferrans and Powers QoL Index instrument found a high level of dissatisfaction with health-related QoL. Data from the European Organization for Research and Treatment for Cancer reported poor capacity to fulfil the activities of daily living. Patients studied in the hospital during or near chemotherapy had significantly more abnormal circadian function than those studied in the ambulatory setting. Our data indicate that measurement of circadian sleep/activity dynamics should be accomplished in the outpatient/home setting for a minimum of 4–7 circadian cycles to assure that they are most representative of the patients' true condition. We conclude that the daily sleep/activity patterns of patients with advanced lung cancer are disturbed. These are accompanied by marked disruption of QoL and function. These data argue for investigating how much of this poor functioning and QoL are actually caused by this circadian disruption, and, whether behavioural, light-based, and or pharmacologic strategies to correct the circadian/sleep activity patterns can improve function and QoL.
doi:10.1038/sj.bjc.6602859
PMCID: PMC2361523  PMID: 16265345
circadian function; non-small-cell lung cancer; rest/activity function; sleep quality; quality of life; actigraphy
15.  Shift work: health, performance and safety problems, traditional countermeasures, and innovative management strategies to reduce circadian misalignment 
Nature and Science of Sleep  2012;4:111-132.
There are three mechanisms that may contribute to the health, performance, and safety problems associated with night-shift work: (1) circadian misalignment between the internal circadian clock and activities such as work, sleep, and eating, (2) chronic, partial sleep deprivation, and (3) melatonin suppression by light at night. The typical countermeasures, such as caffeine, naps, and melatonin (for its sleep-promoting effect), along with education about sleep and circadian rhythms, are the components of most fatigue risk-management plans. We contend that these, while better than nothing, are not enough because they do not address the underlying cause of the problems, which is circadian misalignment. We explain how to reset (phase-shift) the circadian clock to partially align with the night-work, day-sleep schedule, and thus reduce circadian misalignment while preserving sleep and functioning on days off. This involves controlling light and dark using outdoor light exposure, sunglasses, sleep in the dark, and a little bright light during night work. We present a diagram of a sleep-and-light schedule to reduce circadian misalignment in permanent night work, or a rotation between evenings and nights, and give practical advice on how to implement this type of plan.
doi:10.2147/NSS.S10372
PMCID: PMC3630978  PMID: 23620685
circadian rhythms; night work; bright light; phase-shifting; sleep; melatonin
16.  Clock-Cancer Connection in Non-Hodgkin’s Lymphoma 
Medical hypotheses  2007;70(4):788-792.
The universal 24-hour circadian clock has a profound impact on many daily biological processes. Disturbance of circadian rhythms has been implicated in the etiologies of many chronic illnesses, including cancer; with correlations most profoundly found among hormone-related breast and prostate cancers. Given the fact that circadian disruption can cause immune deregulation, which is so far the only established risk factor for non-Hodgkin's lymphoma (NHL), we hypothesize that altered circadian rhythms due to environmental factors and/or genetic variations in genes responsible for maintaining circadian rhythms may result in the deregulation of clock-associated biological processes such as immune responses and activities, and consequently influence an individual’s risk of developing NHL. Our recent findings provided the first molecular epidemiological evidence linking a major circadian gene to NHL and warrant further investigation. Confirmation of this hypothesis will further add to our understanding of the role of the circadian clock in lymphomagenesis and facilitate the development of novel risk and prognostic biomarkers for NHL.
doi:10.1016/j.mehy.2007.07.040
PMCID: PMC2377031  PMID: 17935900
Circadian Clock; Cancer; NHL
17.  Depressive Symptoms in Crohn's Disease: Relationship with Immune Activation and Tryptophan Availability 
PLoS ONE  2013;8(3):e60435.
Crohn's disease (CD) is associated with immune activation and depressive symptoms. This study determines the impact of anti-tumor necrosis factor (TNF)-α treatment in CD patients on depressive symptoms and the degree to which tryptophan (TRP) availability and immune markers mediate this effect. Fifteen patients with CD, eligible for anti-TNF-α treatment were recruited. Disease activity (Harvey-Bradshaw Index (HBI), Crohn's Disease Activity Index (CDAI)), fatigue (Multidimensional Fatigue Inventory (MFI)), quality of life (Inflammatory Bowel Disease Questionnaire (IBDQ)), symptoms of depression and anxiety (Symptom Checklist (SCL-90), Beck Depression Inventory (BDI), Hamilton Depression Rating Scale (HDRS)), immune activation (acute phase proteins (APP)), zinc and TRP availability were assessed before treatment and after 2, 4 and 8 weeks. Anti-TNF-α increased IBDQ scores and reduced all depression scores; however only SCL-90 depression scores remained decreased after correction for HBI. Positive APPs decreased, while negative APPs increased after treatment. After correction for HBI, both level and percentage of γ fraction were associated with SCL-90 depression scores over time. After correction for HBI, patients with current/past depressive disorder displayed higher levels of positive APPs and lower levels of negative APPs and zinc. TRP availability remained invariant over time and there was no association between SCL-90 depression scores and TRP availability. Inflammatory reactions in CD are more evident in patients with comorbid depression, regardless of disease activity. Anti-TNF-α treatment in CD reduces depressive symptoms, in part independently of disease activity; there was no evidence that this effect was mediated by immune-induced changes in TRP availability.
doi:10.1371/journal.pone.0060435
PMCID: PMC3609785  PMID: 23544139
18.  NPAS2 and PER2 are linked to risk factors of the metabolic syndrome 
Background
Mammalian circadian clocks control multiple physiological events. The principal circadian clock generates seasonal variations in behavior as well. Seasonality elevates the risk for metabolic syndrome, and evidence suggests that disruption of the clockwork can lead to alterations in metabolism. Our aim was to analyze whether circadian clock polymorphisms contribute to seasonal variations in behavior and to the metabolic syndrome.
Methods
We genotyped 39 single-nucleotide polymorphisms (SNP) from 19 genes which were either canonical circadian clock genes or genes related to the circadian clockwork from 517 individuals drawn from a nationwide population-based sample. Associations between these SNPs and seasonality, metabolic syndrome and its risk factors were analyzed using regression analysis. The p-values were corrected for multiple testing.
Results
Our findings link circadian gene variants to the risk factors of the metabolic syndrome, since Npas2 was associated with hypertension (P-value corrected for multiple testing = 0.0024) and Per2 was associated with high fasting blood glucose (P-value corrected for multiple testing = 0.049).
Conclusion
Our findings support the view that relevant relationships between circadian clocks and the metabolic syndrome in humans exist.
doi:10.1186/1740-3391-7-5
PMCID: PMC2697141  PMID: 19470168
19.  Shift Work, Jet Lag, and Female Reproduction 
Circadian rhythms and “clock gene” expression are involved in successful reproductive cycles, mating, and pregnancy. Alterations or disruptions of biological rhythms, as commonly occurs in shift work, jet lag, sleep deprivation, or clock gene knock out models, are linked to significant disruptions in reproductive function. These impairments include altered hormonal secretion patterns, reduced conception rates, increased miscarriage rates and an increased risk of breast cancer. Female health may be particularly susceptible to the impact of desynchronizing work schedules as perturbed hormonal rhythms can further influence the expression patterns of clock genes. Estrogen modifies clock gene expression in the uterus, ovaries, and suprachiasmatic nucleus, the site of the primary circadian clock mechanism. Further work investigating clock genes, light exposure, ovarian hormones, and reproductive function will be critical for indentifying how these factors interact to impact health and susceptibility to disease.
doi:10.1155/2010/813764
PMCID: PMC2834958  PMID: 20224815
20.  Circadian Disruption, Sleep Loss and Prostate Cancer Risk: A Systematic Review of Epidemiological Studies 
Disruption of the circadian system has been hypothesized to increase cancer risk, either due to direct disruption of the molecular machinery generating circadian rhythms or due to disruption of parameters controlled by the clock such as melatonin levels or sleep duration. This hypothesis has been studied in hormone-dependent cancers among women, but data are sparse regarding potential effects of circadian disruption on the risk of prostate cancer. This review systematically examines available data evaluating the effects of light at night, sleep patterns, and night shift work on prostate cancer risk.
doi:10.1158/1055-9965.EPI-12-0116
PMCID: PMC3392423  PMID: 22564869
prostate cancer; circadian disruption; sleep disruption; shift work; melatonin; light at night
21.  Depression and sleep disturbances in patients with multiple sclerosis and correlation with associated fatigue 
Objective:
To observe prevalence of depression and sleep disturbances in multiple sclerosis (MS) patients and their correlation with associated fatigue.
Study Design and Setting:
Prospective observation study in a university tertiary research hospital in India.
Materials and Methods:
Thirty-one patients (6 male and 25 female) with definite MS (McDonald's criteria) presented in out-patient/admitted in the department of neurology (between February 2010 and December 2011) were included in the study. Depression was assessed using Beck's Depression Inventory (BDI). Sleep quality was assessed using Pittsburg Sleep Quality Index (PSQI). Disease severity was evaluated using the Kurtzke's expanded disability status scale (EDSS). Fatigue was assessed using Krupp's fatigue severity scale (FSS). We tried to observe correlation of depression and sleep disturbance with associated fatigue in MS patients.
Results:
The age of patients varied between 16 and 50 years (30.1 ± 9.1). The mean age at first symptom was 25.2 ± 6.4 years (range 14-39 years). The prevalence of sleep disturbance and depression was 51.6% (16/31) each and fatigue 58.1% (18/31) in the study group. The PSQI scores were significantly greater in the patients with fatigue as compared with those without fatigue indicating poorer sleep quality is associated with fatigue in MS (P = 0.005). The BDI scores were also significantly higher in the fatigue group showing that severity of depression also strongly correlated with fatigue (P = 0.001).
Conclusions:
Depression and sleep disturbance in patients with MS is significantly correlated with associated fatigue.
doi:10.4103/0976-3147.120201
PMCID: PMC3858754  PMID: 24347942
Depression; fatigue; multiple sclerosis; sleep disturbance
22.  Disruption of Circadian Rhythms: A Crucial Factor in the Etiology of Depression 
Circadian factors might play a crucial role in the etiology of depression. It has been demonstrated that the disruption of circadian rhythms by lighting conditions and lifestyle predisposes individuals to a wide range of mood disorders, including impulsivity, mania and depression. Also, associated with depression, there is the impairment of circadian rhythmicity of behavioral, endocrine, and metabolic functions. Inspite of this close relationship between both processes, the complex relationship between the biological clock and the incidence of depressive symptoms is far from being understood. The efficiency and the timing of treatments based on chronotherapy (e.g., light treatment, sleep deprivation, and scheduled medication) indicate that the circadian system is an essential target in the therapy of depression. The aim of the present review is to analyze the biological and clinical data that link depression with the disruption of circadian rhythms, emphasizing the contribution of circadian desynchrony. Therefore, we examine the conditions that may lead to circadian disruption of physiology and behavior as described in depressive states, and, according to this approach, we discuss therapeutic strategies aimed at treating the circadian system and depression.
doi:10.1155/2011/839743
PMCID: PMC3154570  PMID: 21845223
23.  Differential Association of Circadian Genes with Mood Disorders: CRY1 and NPAS2 are Associated with Unipolar Major Depression and CLOCK and VIP with Bipolar Disorder 
Neuropsychopharmacology  2010;35(6):1279-1289.
Disruptions in circadian rhythms have been described in mood disorders (MD), but the involvement of genetic variation in genes pertaining to the molecular circadian machinery in the susceptibility to MD has not been conclusively determined. We examined 209 single-nucleotide polymorphisms (SNPs) covering 19 circadian genes (ADCYAP1, ARNTL, ARNTL2, BHLHB2, BHLHB3, CLOCK, CRY1, CRY2, CSNK1E, DBP, NPAS2, NR1D1, PER1, PER2, PER3, RORA, TIMELESS, VIP, and VIPR2) in a sample of 534 MD patients (335 with unipolar major mood depression (MDD) and 199 with bipolar disorder (BD)) and 440 community-based screened controls. Nominally, statistically significant associations were found in 15 circadian genes. The gene-wide test, corrected for the number of SNPs analyzed in each gene, identified significant associations in CRY1 (rs2287161), NPAS2 (rs11123857), and VIPR2 (rs885861) genes with the combined MD sample. In the MDD subsample, the same SNPs in CRY1 and NPAS2 of the combined sample remained associated, whereas in the BD subsample CLOCK (rs10462028) and VIP (rs17083008) were specifically associated. The association with an SNP located 3′ near CRY1 gene in MDD remained statistically significant after permutation correction at experiment level (p=0.007). Significant additive effects were found between the SNPs that were statistically significant at the gene-wide level. We also found evidence of associations between two-marker haplotypes in CRY1 and NPAS2 genes and MD. Our data support the contribution of the circadian system to the genetic susceptibility to MD and suggest that different circadian genes may have specific effects on MD polarity.
doi:10.1038/npp.2009.230
PMCID: PMC3055337  PMID: 20072116
clock genes; mood disorders; circadian rhythms; association; polymorphism; haplotype; association; Biological Psychiatry, Chronobiology/Sleep; circadian rhythm; Depression; Unipolar/Bipolar; mood disorders; Neurogenetics; polymorphism
24.  Regulation of Circadian Blood Pressure—From Mice to Astronauts 
Purpose of Review
Circadian variation is commonly seen in healthy people; aberration in these biological rhythms is an early sign of disease. Impaired circadian variation of BP has been shown to be associated with greater target organ damage and to be associated with an elevated risk of cardiovascular events independent of the BP load. The purpose of this review is to examine the physiology of circadian BP variation and propose a tripartite model that explains the regulation of circadian BP
Recent findings
The time-keeper of the mammals resides centrally in the suprachiasmatic nucleus. Besides this central clock, molecular clocks exist in most peripheral tissues including vascular tissue and the kidney. These molecular clocks regulate sodium balance, sympathetic function and vascular tone. A physiological model is proposed that integrates our understanding of molecular clocks in mice to the circadian BP variation among humans. The master regulator in this proposed model is the sleep-activity cycle. The equivalents of peripheral clocks are endothelial and adrenergic functions. Thus, in the proposed model, the variation in circadian BP is dependent upon 3 major factors: physical activity, autonomic function, and sodium sensitivity.
Summary
The integrated consideration of physical activity, autonomic function, and sodium sensitivity appear to explain the physiology of circadian BP variation and the pathophysiology of disrupted BP rhythms in various conditions and disease states. Our understanding of molecular clocks in mice may help to explain the provenance of blunted circadian BP variation even among astronauts.
doi:10.1097/MNH.0b013e3283336ddb
PMCID: PMC2876349  PMID: 19864947
blood pressure; circadian rhythms; molecular clocks; cosinor modeling; chronic kidney disease; pathophysiology
25.  Sleep, Fatigue, and Functional Health in Psychotic Patients 
This study sought to examine the association between sleep, fatigue, and functional health in psychotic patients. Participants included 93 psychotic inpatients (n = 67 with schizophrenia) who completed the Chalder Fatigue Scale (ChFS), the Fatigue Symptom Inventory (FSI), the Pittsburgh Sleep Quality Index (PSQI), and the SF36 Health Survey. Patients were classified on the basis of their performance on sleep and fatigue measures: 60% reported significant levels of fatigue and 67% significant sleep disturbances. 28.4% reported both, suggesting that fatigue and sleep dysfunctions do not necessarily cooccur. A closer examination of patterns showed that fatigue was only related to qualitative aspects of sleep and not quantifiable aspects of sleep disturbances. The results also showed that functional health was the lowest in patients with high levels of fatigue, compared to patients with sleep problems only or patients with neither symptom. A regression analysis further showed that the size of the contribution of fatigue onto functional health was twice as much as that of sleep dysfunctions. In conclusion, the results show that (i) dissatisfaction with sleep—and not sleep itself—is related to fatigue symptoms and that (ii) fatigue is particularly detrimental to functional health, regardless of the presence of sleep dysfunctions.
doi:10.1155/2013/425826
PMCID: PMC3659476  PMID: 23738067

Results 1-25 (959398)