Chronic Fatigue Syndrome Subjects Research Articles

Cortisol levels in chronic fatigue syndrome and atypical depression measured using hair and saliva specimens

BackgroundSeveral diagnostic criteria for major depressive disorder (MDE) overlap with those of Chronic Fatigue Syndrome (CFS). Furthermore, atypical MDE (A-MDE), a subtype of MDE characterised by profound fatigue and which has frequently been linked with CFS, exhibits similar low cortisol levels to CFS. However, this result has been only found in specimens designed for measuring acute cortisol levels. In this study, we measure cortisol levels in subjects with CFS and in subjects with A-MDE, without psychiatric comorbidity, using both hair and saliva specimens, to gain a measure of both short and long-term cortisol levels in these two conditions. MethodsHair cortisol concentration, representing the cortisol concentration of the previous three months, and salivary cortisol, measured at six time-points across one day and including the cortisol awakening response (CAR), post-awakening delta cortisol and the total daily output, were assessed in an age and gender matched group of 34 controls, 15 subjects with A-MDE and 17 with CFS. ResultsCFS (mean 92.2 nmol/l.h, s.d. 33.2 nmol/l.h) and A-MDE (mean 89.1 nmol/l.h, s.d. 22.6 nmol/l.h) subjects both showed lower cortisol total daily output in saliva (AUCg) in comparison to healthy controls (mean 125.5 nmol/l.h, s.d. 40.6 nmol/l.h). However, hair cortisol concentration was not lower than that of controls in either patient group. CFS and A-MDE did not differ from one another on any cortisol measures. CFS subjects reported fewer daily hassles and less severe psychic anxiety symptoms in comparison to A-MDE subjects (all p < 0.05). However, they did not differ in the severity of somatic anxiety symptoms. There was also no difference in the presence of overlapping symptoms such as fatigability and concentration/memory problems between A-MDE and CFS subjects. ConclusionLow levels of cortisol found using short-term measures of daily output may be transient, since cortisol levels were normal when a long-term measure (hair) was studied. This might be explained by a potential cortisol rhythm alteration. Although these disorders have their distinctive depressive and somatic features, they may from part of a wider group of Somatic Symptom Disorders (SSD), given the findings of the same pattern of cortisol secretion in both disorders and increased frequency of overlapping clinical features.

Orthostatic intolerance in chronic fatigue syndrome

BackgroundOrthostatic intolerance (OI) is a significant problem for those with chronic fatigue syndrome (CFS). We aimed to characterize orthostatic intolerance in CFS and to study the effects of exercise on OI.MethodsCFS (n = 39) and control (n = 25) subjects had recumbent and standing symptoms assessed using the 20-point, anchored, ordinal Gracely Box Scale before and after submaximal exercise. The change in heart rate (ΔHR ≥ 30 bpm) identified Postural Orthostatic Tachycardia Syndrome (POTS) before and after exercise, and the transient, exercise-induced postural tachycardia Stress Test Activated Reversible Tachycardia (START) phenotype only after exercise.ResultsDizziness and lightheadedness were found in 41% of recumbent CFS subjects and in 72% of standing CFS subjects. Orthostatic tachycardia did not account for OI symptoms in CFS. ROC analysis with a threshold ≥ 2/20 on the Gracely Box Scale stratified CFS subjects into three groups: No OI (symptoms < 2), Postural OI (only standing symptoms ≥ 2), and Persistent OI (recumbent and standing symptoms ≥ 2).ConclusionsDizziness and Lightheadedness symptoms while recumbent are an underreported finding in CFS and should be measured when doing a clinical evaluation to diagnose orthostatic intolerance. POTS was found in 6 and START was found in 10 CFS subjects. Persistent OI had symptoms while recumbent and standing, highest symptom severity, and lability in symptoms after exercise.Trial registration The trial was registered at the following: https://clinicaltrials.gov/ct2/show/NCT03567811

Multidimensional Comparison of Cancer-Related Fatigue and Chronic Fatigue Syndrome: The Role of Psychophysiological Markers.

ObjectiveThe present study compared cancer-related fatigue (CRF) and chronic fatigue syndrome (CFS) using multidimensional measurements with the aim of better understanding characteristics and exploring markers of two similar fatigue syndromes. MethodsTwenty-five patients with CRF and twenty patients with CFS completed questionnaires, including the Fatigue Severity Scale (FSS), Hospital Anxiety Depression Scale (HADS), Perceived Stress Scale (PSS), and Pittsburgh Sleep Quality Index (PSQI). Additionally, levels of high sensitivity C-reactive protein (hs-CRP), heart rate variability (HRV), and electroencephalography (EEG) were obtained. Neurocognitive functioning was also evaluated. ResultsBoth groups showed comparable levels of psychological variables, including fatigue. Compared to CFS subjects, CRF patients had significantly higher hs-CRP levels and a reduced HRV-index. The within-group analyses revealed that the FSS score of the CRF group was significantly related to scores on the HADS-anxiety, HADS-depression, and PSQI scales. In the CFS group, FSS scores were significantly associated with scores on the PSS and the absolute delta, theta, and alpha powers in frontal EEG. Conclusion Findings indicate that different pathophysiological mechanisms underlie CFS and CRF. Inflammatory marker and HRV may be potential biomarkers for distinguishing two fatigue syndromes and frontal EEG parameters may be quantitative biomarkers for CFS.

Exercise \u2013 induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, Chronic Fatigue Syndrome and sedentary control subjects

Gulf War Illness (GWI) and Chronic Fatigue Syndrome (CFS) have similar profiles of pain, fatigue, cognitive dysfunction and exertional exhaustion. Post-exertional malaise suggests exercise alters central nervous system functions. Lumbar punctures were performed in GWI, CFS and control subjects after (i) overnight rest (nonexercise) or (ii) submaximal bicycle exercise. Exercise induced postural tachycardia in one third of GWI subjects (Stress Test Activated Reversible Tachycardia, START). The remainder were Stress Test Originated Phantom Perception (STOPP) subjects. MicroRNAs (miRNA) in cerebrospinal fluid were amplified by quantitative PCR. Levels were equivalent between nonexercise GWI (n = 22), CFS (n = 43) and control (n = 22) groups. After exercise, START (n = 22) had significantly lower miR-22-3p than control (n = 15) and STOPP (n = 42), but higher miR-9-3p than STOPP. All post-exercise groups had significantly reduced miR-328 and miR-608 compared to nonexercise groups; these may be markers of exercise effects on the brain. Six miRNAs were significantly elevated and 12 diminished in post-exercise START, STOPP and control compared to nonexercise groups. CFS had 12 diminished miRNAs after exercise. Despite symptom overlap of CFS, GWI and other illnesses in their differential diagnosis, exercise-induced miRNA patterns in cerebrospinal fluid indicated distinct mechanisms for post-exertional malaise in CFS and START and STOPP phenotypes of GWI.

Are current chronic fatigue syndrome criteria diagnosing different disease phenotypes?

ImportanceChronic fatigue syndrome (CFS) is characterised by a constellation of symptoms diagnosed with a number of different polythetic criteria. Heterogeneity across these diagnostic criteria is likely to be confounding research into the as-yet-unknown pathophysiology underlying this stigmatised and debilitating condition and may diagnose a disease spectrum with significant implications for clinical management. No studies to date have objectively investigated this possibility using a validated measure of CFS symptoms–the DePaul Symptom Questionnaire (DSQ).ObjectiveTo examine whether current CFS diagnostic criteria are identifying different disease phenotypes using the DSQ.DesignCase control study.SettingClinical Research Facility of the Royal Victoria Infirmary, Newcastle upon Tyne, UK.Participants49 CFS subjects and ten matched, sedentary community controls, excluded for co-morbid depression.Main outcomes and measuresSelf-reported autonomic and cognitive features were assessed with the Composite Autonomic Symptom Score (COMPASS) and Cognitive Failures Questionnaire (COGFAIL) respectively. Objective autonomic cardiovascular parameters were examined using the Task Force® Monitor and a battery of neuropsychological tests administered for objective cognitive assessment.ResultsSelf-reported autonomic and cognitive symptoms were significantly greater in CFS subjects compared to controls. There were no statistically significant differences in objective autonomic measures between CFS and controls. There were clinically significant differences between DSQ subgroups on objective autonomic testing. Visuospatial memory, verbal memory and psychomotor speed were significantly different between DSQ subgroups.Conclusions and relevanceThe finding of no significant differences in objective autonomic testing between CFS and control subjects may reflect the inclusion of sedentary controls or exclusion for co-morbid depression. Consistent exclusion criteria would enable better delineation of these two conditions and their presenting symptoms. Findings across CFS subgroups suggest subjects have a different disease burden on subjective and objective measures of function, autonomic parameters and cognitive impairment when categorised using the DSQ. Different CFS criteria may at best be diagnosing a spectrum of disease severities and at worst different CFS phenotypes or even different diseases. This complicates research and disease management and may contribute to the significant stigma associated with the condition.

Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in Chronic Fatigue Syndrome.

Autonomic changes are often associated with the chronic fatigue syndrome (CFS), but their pathogenetic role is unclear and brain imaging investigations are lacking. The vasomotor centre and, through it, nuclei in the midbrain and hypothalamus play a key role in autonomic nervous system regulation of steady state blood pressure (BP) and heart rate (HR). In this exploratory cross-sectional study, BP and HR, as indicators of autonomic function, were correlated with volumetric and T1- and T2-weighted spin-echo (T1w and T2w) brain MRI in 25 CFS subjects and 25 normal controls (NC). Steady state BP (systolic, diastolic and pulse pressure) and HR in two postures were extracted from 24 h blood pressure monitoring. We performed (1) MRI versus autonomic score interaction-with-group regressions to detect locations where regression slopes differed in the CFS and NC groups (collectively indicating abnormality in CFS), and (2) MRI regressions in the CFS and NC groups alone to detect additional locations with abnormal correlations in CFS. Significant CFS regressions were repeated controlling for anxiety and depression (A&D). Abnormal regressions were detected in nuclei of the brainstem vasomotor centre, midbrain reticular formation and hypothalamus, but also in limbic nuclei involved in stress responses and in prefrontal white matter. Group comparisons of CFS and NC did not find MRI differences in these locations. We propose therefore that these regulatory nuclei are functioning correctly, but that two-way communication between them is impaired in CFS and this affects signalling to/from peripheral effectors/sensors, culminating in inverted or magnified correlations. This single explanation for the diverse abnormal correlations detected here consolidates the conclusion for a brainstem/midbrain nerve conduction deficit inferred earlier (Barnden et al., 2015). Strong correlations were also detected in isolated NC regressions.

Abnormalities of AMPK activation and glucose uptake in cultured skeletal muscle cells from individuals with chronic fatigue syndrome.

BackgroundPost exertional muscle fatigue is a key feature in Chronic Fatigue Syndrome (CFS). Abnormalities of skeletal muscle function have been identified in some but not all patients with CFS. To try to limit potential confounders that might contribute to this clinical heterogeneity, we developed a novel in vitro system that allows comparison of AMP kinase (AMPK) activation and metabolic responses to exercise in cultured skeletal muscle cells from CFS patients and control subjects.MethodsSkeletal muscle cell cultures were established from 10 subjects with CFS and 7 age-matched controls, subjected to electrical pulse stimulation (EPS) for up to 24h and examined for changes associated with exercise.ResultsIn the basal state, CFS cultures showed increased myogenin expression but decreased IL6 secretion during differentiation compared with control cultures. Control cultures subjected to 16h EPS showed a significant increase in both AMPK phosphorylation and glucose uptake compared with unstimulated cells. In contrast, CFS cultures showed no increase in AMPK phosphorylation or glucose uptake after 16h EPS. However, glucose uptake remained responsive to insulin in the CFS cells pointing to an exercise-related defect. IL6 secretion in response to EPS was significantly reduced in CFS compared with control cultures at all time points measured.ConclusionEPS is an effective model for eliciting muscle contraction and the metabolic changes associated with exercise in cultured skeletal muscle cells. We found four main differences in cultured skeletal muscle cells from subjects with CFS; increased myogenin expression in the basal state, impaired activation of AMPK, impaired stimulation of glucose uptake and diminished release of IL6. The retention of these differences in cultured muscle cells from CFS subjects points to a genetic/epigenetic mechanism, and provides a system to identify novel therapeutic targets.

Evidence for sensitized fatigue pathways in patients with chronic fatigue syndrome.

Patients with chronic fatigue syndrome (CFS) frequently demonstrate intolerance to physical exertion that is often reported as increased and long-lasting fatigue. Because no specific metabolic alterations have been identified in CFS patients, we hypothesized that sensitized fatigue pathways become activated during exercise corresponding with increased fatigue. After exhausting handgrip exercise, muscle metabolites were trapped in the forearm tissues of 39 CFS patients and 29 normal control (NC) by sudden occlusion for up to 5 minutes. A nonocclusive condition of similar duration was used as control. Repeated fatigue and pain ratings were obtained before and after exercise. Mechanical and heat hyperalgesia were assessed by quantitative sensory testing. All subjects fulfilled the 1994 Fukuda Criteria for CFS. Normal control and CFS subjects exercised for 6.6 (2.4) and 7.0 (2.7) minutes (P > 0.05). Forearm occlusion lasted for 4.7 (1.3) and 4.9 (1.8) minutes in NC and CFS subjects, respectively (P > 0.05). Although fatigue ratings of CFS subjects increased from 4.8 (2.0) to 5.6 (2.1) visual analogue scale (VAS) units during forearm occlusion, they decreased from 5.0 (1.8) to 4.8 (2.0) VAS units during the control condition without occlusion (P = 0.04). A similar time course of fatigue ratings was observed in NC (P > 0.05), although their ratings were significantly lower than those of CFS subjects (P < 0.001). Quantitative sensory testing demonstrated heat and mechanical hyperalgesia in CFS subjects. Our findings provide indirect evidence for significant contributions of peripheral tissues to the increased exercise-related fatigue in CFS patients consistent with sensitization of fatigue pathways. Future interventions that reduce sensitization of fatigue pathways in CFS patients may be of therapeutic benefit.

Chronic fatigue syndrome and personality: A case-control study using the alternative five factor model

Neuroticism is the personality dimension most frequently associated with chronic fatigue syndrome (CFS). Most studies have also shown that CFS patients are less extraverted than non-CFS patients, but results have been inconsistent, possibly because the facets of the extraversion dimension have not been separately analyzed. This study has the following aims: to assess the personality profile of adults with CFS using the Alternative Five-Factor Model (AFFM), which considers Activity and Sociability as two separate factors of Extraversion, and to test the discriminant validity of a measure of the AFFM, the Zuckerman–Kuhlman Personality Questionnaire, in differentiating CFS subjects from normal-range matched controls. The CFS sample consisted of 132 consecutive patients referred for persistent fatigue or pain to the Department of Medicine of a university hospital. These were compared with 132 matched normal population controls. Significantly lower levels of Activity and significantly higher levels of Neuroticism-Anxiety best discriminated CFS patients from controls. The results are consistent with existing data on the relationship between Neuroticism and CFS, and clarify the relationship between Extraversion and CFS by providing new data on the relationship of Activity to CFS.

Agomelatine but not melatonin improves fatigue perception: A longitudinal proof-of-concept study

Chronic Fatigue Syndrome (CFS) represents a disabling condition characterized by persistent mental and physical fatigue, bodily discomfort and cognitive difficulties. To date the neural bases of CFS are poorly understood; however, mono-aminergic abnormalities, sleep–wake cycle changes and prefrontal dysfunctions are all thought to play a role in the development and maintenance of this condition. Here we explored in a group of 62 CFS subjects the impact on fatigue levels of agomelatine, an antidepressant with agonist activity at melatonin receptors (MT1 and MT2) and antagonist activity at serotoninergic 2C receptors (5HT2C). To tease out the relative effects of MT-agonism and 5HT2C antagonism on fatigue, we compared agomelatine 50mg u.i.d. with sustained release melatonin 10mg u.i.d. in the first 12-week-long phase of the study, and then switched all melatonin-treated subjects to agomelatine in the second 12-week-long phase of the study. Agomelatine treatment, but not melatonin, was associated with a significant reduction of perceived fatigue and an increase in perceived quality of life. Moreover the switch from melatonin to agomelatine was associated with a reduction of fatigue levels. Agomelatine was well tolerated by all enrolled subjects. Our data, albeit preliminary, suggest that agomelatine treatment could represent a novel useful approach to the clinical care of subjects with CFS.

A Role for Homeostatic Drive in the Perpetuation of Complex Chronic Illness: Gulf War Illness and Chronic Fatigue Syndrome

A key component in the body's stress response, the hypothalamic-pituitary-adrenal (HPA) axis orchestrates changes across a broad range of major biological systems. Its dysfunction has been associated with numerous chronic diseases including Gulf War Illness (GWI) and chronic fatigue syndrome (CFS). Though tightly coupled with other components of endocrine and immune function, few models of HPA function account for these interactions. Here we extend conventional models of HPA function by including feed-forward and feedback interaction with sex hormone regulation and immune response. We use this multi-axis model to explore the role of homeostatic regulation in perpetuating chronic conditions, specifically GWI and CFS. An important obstacle in building these models across regulatory systems remains the scarcity of detailed human in vivo kinetic data as its collection can present significant health risks to subjects. We circumvented this using a discrete logic representation based solely on literature of physiological and biochemical connectivity to provide a qualitative description of system behavior. This connectivity model linked molecular variables across the HPA axis, hypothalamic-pituitary-gonadal (HPG) axis in men and women, as well as a simple immune network. Inclusion of these interactions produced multiple alternate homeostatic states and sexually dimorphic responses. Experimental data for endocrine-immune markers measured in male GWI subjects showed the greatest alignment with predictions of a naturally occurring alternate steady state presenting with hypercortisolism, low testosterone and a shift towards a Th1 immune response. In female CFS subjects, expression of these markers aligned with an alternate homeostatic state displaying hypocortisolism, high estradiol, and a shift towards an anti-inflammatory Th2 activation. These results support a role for homeostatic drive in perpetuating dysfunctional cortisol levels through persistent interaction with the immune system and HPG axis. Though coarse, these models may nonetheless support the design of robust treatments that might exploit these regulatory regimes.

Could Mitochondrial Dysfunction Be a Differentiating Marker Between Chronic Fatigue Syndrome and Fibromyalgia?

Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are complex and serious illnesses that affect approximately 2.5% and 5% of the general population worldwide, respectively. The etiology is unknown; however, recent studies suggest that mitochondrial dysfunction has been involved in the pathophysiology of both conditions. We have investigated the possible association between mitochondrial biogenesis and oxidative stress in patients with CFS and FM. We studied 23 CFS patients, 20 FM patients, and 15 healthy controls. Peripheral blood mononuclear cell showed decreased levels of Coenzyme Q10 from CFS patients (p<0.001 compared with controls) and from FM subjects (p<0.001 compared with controls) and ATP levels for CFS patients (p<0.001 compared with controls) and for FM subjects (p<0.001 compared with controls). On the contrary, CFS/FM patients had significantly increased levels of lipid peroxidation, respectively (p<0.001 for both CFS and FM patients with regard to controls) that were indicative of oxidative stress-induced damage. Mitochondrial citrate synthase activity was significantly lower in FM patients (p<0.001) and, however, in CFS, it resulted in similar levels than controls. Mitochondrial DNA content (mtDNA/gDNA ratio) was normal in CFS and reduced in FM patients versus healthy controls, respectively (p<0.001). Expression levels of peroxisome proliferator-activated receptor gamma-coactivator 1-alpha and transcription factor A, mitochondrial by immunoblotting were significantly lower in FM patients (p<0.001) and were normal in CFS subjects compared with healthy controls. These data lead to the hypothesis that mitochondrial dysfunction-dependent events could be a marker of differentiation between CFS and FM, indicating the mitochondria as a new potential therapeutic target for these conditions.

Assessment of Natural Killer Cell Receptors and Activity in Severe and Moderate Chronic Fatigue Syndrome.

Event Abstract Back to Event Assessment of Natural Killer Cell Receptors and Activity in Severe and Moderate Chronic Fatigue Syndrome. Sharni L. Hardcastle1, 2, Ekua W. Brenu1, 2*, Don R. Staines2, 3 and Sonya M. Marshall-Gradisnik1, 2 1 Griffith University, School of Medical Sciences, Australia 2 Griffith University, Griffith Health Institute, Australia 3 Queensland Health, Australia Abnormalities in the immune system are a common finding within sufferers of Chronic Fatigue Syndrome (CFS). Research has consistently found compromised Natural Killer (NK) cell function in CFS subjects. The mechanism of the reduced NK function is unknown and however this may potentially be related to the presence of NK receptors. It is also unknown whether reduced NK function is further compromised within CFS subjects who are very severely affected by the disease. The purpose of this study was to examine NK activity and Killer Immunoglobulin-like Receptors (KIRs) in moderate (MFS) and severely affected CFS (SFS) subjects in comparison to controls. CFS subjects were characterised as either moderate or severely affected based on health and quality of life questionnaires. Severe subjects were housebound. Blood samples were collected s from controls (n=9; 50.9 + 2.5 years), MFS (n=9; 49.9+ 3.7years) and SFS subjects (n=9; 42.3 + 3.9 years). Using flow cytometry NK cells were measured for their activity based on their ability to lyse K562 cells and cell surface expression of KIRs. ANOVA was the statistical method used to assess all data collected. Preliminary data from CFS subjects showed significant reductions NK cell activity and an increase in KIR3DL1 in CFS subjects when compared to the controls. Results suggest that CFS patients have further compromised immune function, particularly reduced NK cell activity, when compared to controls. Additionally, increased levels of KIR, particularly KIR3DL1 in CFS patients, may potentially explain why these patients have a decrease in NK lysis. Keywords: CFS, Severe, Natural Killer, receptors, Lysis Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Innate immunity Citation: Hardcastle SL, Brenu EW, Staines DR and Marshall-Gradisnik SM (2013). Assessment of Natural Killer Cell Receptors and Activity in Severe and Moderate Chronic Fatigue Syndrome.. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.01040 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 30 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Ekua W Brenu, Griffith University, School of Medical Sciences, Gold Coast, Queensland, 4222, Australia, e.brenu@griffith.edu.au Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Sharni L Hardcastle Ekua W Brenu Don R Staines Sonya M Marshall-Gradisnik Google Sharni L Hardcastle Ekua W Brenu Don R Staines Sonya M Marshall-Gradisnik Google Scholar Sharni L Hardcastle Ekua W Brenu Don R Staines Sonya M Marshall-Gradisnik PubMed Sharni L Hardcastle Ekua W Brenu Don R Staines Sonya M Marshall-Gradisnik Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Analysis of Neutrophil Function in Severe and Moderately Affected Chronic Fatigue Syndrome Subjects.

Event Abstract Back to Event Analysis of Neutrophil Function in Severe and Moderately Affected Chronic Fatigue Syndrome Subjects. Sharni L. Hardcastle1, 2, Ekua W. Brenu1, 2*, Don R. Staines2, 3 and Sonya M. Marshall-Gradisnik1, 2 1 Griffith University, School of Medical Sciences, Australia 2 Griffith University, Griffith Health Institute, Australia 3 Gold Coast Public Health Unit , Queensland Health, Australia Research has commonly shown that people with Chronic Fatigue Syndrome (CFS) have immune system abnormalities. Decreases have been found in neutrophil respiratory burst in a CFS cohort. Reduced ability of neutrophils to eliminate pathogens can contribute to the impaired immune function in CFS subjects. It is unknown whether neutrophil function is more impaired in patients severely affected by CFS. The purpose of this study was to examine neutrophil activity including phagocytosis and respiratory burst in patients with severe CFS in comparison to those with moderate symptoms and non-fatigued controls. CFS subjects were characterised using the CDC Case Definition and the International Consensus Criteria for CFS. CFS subjects were then grouped as either moderate or severely affected based on health and quality of life questionnaires. Blood samples were taken from age and sex matched non-fatigued controls, moderately affected and severely affected CFS subjects. Response to E.coli bacteria was measured in neutrophils by assessing phagocytic activity and respiratory burst, these were then analysed on the flow cytometer. Preliminary data from CFS subjects showed differences in neutrophil function based on respiratory burst and phagocytic activity when compared to the control group. These results suggest that differences in neutrophil function in CFS patients may contribute to CFS related immune dysfunction. Keywords: CFS, Severe, Neutrophil, Respiratory Burst, Phagocyte Conference: 15th International Congress of Immunology (ICI), Milan, Italy, 22 Aug - 27 Aug, 2013. Presentation Type: Abstract Topic: Innate immunity Citation: Hardcastle SL, Brenu EW, Staines DR and Marshall-Gradisnik SM (2013). Analysis of Neutrophil Function in Severe and Moderately Affected Chronic Fatigue Syndrome Subjects.. Front. Immunol. Conference Abstract: 15th International Congress of Immunology (ICI). doi: 10.3389/conf.fimmu.2013.02.01039 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 30 Jun 2013; Published Online: 22 Aug 2013. * Correspondence: Dr. Ekua W Brenu, Griffith University, School of Medical Sciences, Gold Coast, Queensland, 4222, Australia, e.brenu@griffith.edu.au Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Sharni L Hardcastle Ekua W Brenu Don R Staines Sonya M Marshall-Gradisnik Google Sharni L Hardcastle Ekua W Brenu Don R Staines Sonya M Marshall-Gradisnik Google Scholar Sharni L Hardcastle Ekua W Brenu Don R Staines Sonya M Marshall-Gradisnik PubMed Sharni L Hardcastle Ekua W Brenu Don R Staines Sonya M Marshall-Gradisnik Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Migraine in gulf war illness and chronic fatigue syndrome: prevalence, potential mechanisms, and evaluation

Objective: To assess the prevalence of headache subtypes in Gulf War Illness (GWI) and Chronic Fatigue Syndrome (CFS) compared to controls.Background: Approximately, 25% of the military personnel who served in the 1990–1991 Persian Gulf War have developed GWI. Symptoms of GWI and CFS have considerable overlap, including headache complaints. Migraines are reported in CFS. The type and prevalence of headaches in GWI have not been adequately assessed.Methods: 50 GWI, 39 CFS and 45 controls had structured headache evaluations based on the 2004 International Headache Society criteria. All subjects had history and physical examinations, fatigue and symptom related questionnaires, measurements of systemic hyperalgesia (dolorimetry), and assessments for exclusionary conditions.Results: Migraines were detected in 64% of GWI (odds ratio = 11.6 [4.1–32.5]) (mean [±95% CI]) and 82% of CFS subjects (odds ratio = 22.5 [7.8–64.8]) compared to only 13% of controls. There was a predominance of females in the CFS compared to GWI and controls. However, migraine status was independent of gender in GWI and CFS groups (x2 = 2.7; P = 0.101). Measures of fatigue, pain, and other ancillary criteria were comparable between GWI and CFS subjects with and without headache.Conclusion: The high prevalence of migraine in CFS was confirmed and extended to GWI subjects. GWI and CFS may share dysfunctional central pathophysiological pathways that contribute to migraine and subjective symptoms. The high migraine prevalence warrants the inclusion of a structured headache evaluation in GWI and CFS subjects, and treatment when present.

Acute psychosocial stress-mediated changes in the expression and methylation of perforin in chronic fatigue syndrome.

Perforin (PRF1) is essential for immune surveillance and studies report decreased perforin in chronic fatigue syndrome (CFS), an illness potentially associated with stress and/or infection. We hypothesize that stress can influence regulation of PRF1 expression, and that this regulation will differ between CFS and non-fatigued (NF) controls. We used the Trier Social Stress Test (TSST) as a standardized acute psychosocial stress, and evaluated its effect on PRF1 expression and methylation in CFS (n = 34) compared with NF (n = 47) participants. During the TSST, natural killer (NK) cells increased significantly in both CFS (P = <0.0001) and NF subjects (P = <0.0001). Unlike previous reports, there was no significant difference in PRF1 expression at baseline or during TSST between CFS and NF. However, whole blood PRF1 expression increased 1.6 fold during the TSST in both CFS (P = 0.0003) and NF (P = <0.0001). Further, the peak response immediately following the TSST was lower in CFS compared with NF (P = 0.04). In addition, at 1.5 hours post TSST, PRF1 expression was elevated in CFS compared with NF (whole blood, P = 0.06; PBMC, P = 0.02). Methylation of seven CpG sites in the methylation sensitive region of the PRF1 promoter ranged from 38%–79% with no significant differences between CFS and NF. Although, the average baseline methylation of all seven CpG sites did not differ between CFS and NF groups, it showed a significant negative correlation with PRF1 expression at all TSST time points in both CFS (r = −0.56, P = <0.0001) and NF (r = −0.38, P = <0.0001). Among participants with high average methylation (≥65%), PRF1 expression was significantly lower in CFS than NF subjects immediately following TSST. These findings suggest methylation could be an important epigenetic determinant of inter-individual differences in PRF1 expression and that the differences in PRF1 expression and methylation between CFS and NF in the acute stress response require further investigation.

Modulation of the axon-reflex response to local heat by reactive oxygen species in subjects with chronic fatigue syndrome

Local cutaneous heating causes vasodilation as an initial first peak, a nadir, and increase to plateau. Reactive oxygen species (ROS) modulate the heat plateau in healthy controls. The initial peak, due to C-fiber nociceptor-mediated axon reflexes, is blunted with local anesthetics and may serve as a surrogate for the cutaneous response to peripheral heat. Chronic fatigue syndrome (CFS) subjects report increased perception of pain. To determine the role of ROS in this neurally mediated response, we evaluated changes in cutaneous blood flow from local heat in nine CFS subjects (16-22 yr) compared with eight healthy controls (18-26 yr). We heated skin to 42°C and measured local blood flow as a percentage of maximum cutaneous vascular conductance (%CVC(max)). Although CFS subjects had significantly lower baseline flow [8.75 ± 0.56 vs. 12.27 ± 1.07 (%CVC(max), CFS vs. control)], there were no differences between groups to local heat. We then remeasured this with apocynin to inhibit NADPH oxidase, allopurinol to inhibit xanthine oxidase, tempol to inhibit superoxide, and ebselen to reduce H(2)O(2). Apocynin significantly increased baseline blood flow (before heat, 14.91 ± 2.21 vs. 8.75 ± 1.66) and the first heat peak (69.33 ± 3.36 vs. 59.75 ± 2.75). Allopurinol and ebselen only enhanced the first heat peaks (71.55 ± 2.48 vs. 61.72 ± 2.01 and 76.55 ± 5.21 vs. 58.56 ± 3.66, respectively). Tempol had no effect on local heating. None of these agents changed the response to local heat in control subjects. Thus the response to heat may be altered by local levels of ROS, particularly H(2)O(2) in CFS subjects, and may be related to their hyperesthesia/hyperalgesia.

Reactive Oxygen Species (ROS) from NADPH and Xanthine Oxidase Modulate the Cutaneous Local Heating Response in Chronic Fatigue Syndrome

Local cutaneous heating causes vasodilation as an initial peak, a nadir, and increase to plateau. We showed reactive oxygen species (ROS) produced by Ang‐II via NADPH and xanthine oxidase, modulates this response in healthy controls. The initial peak, due to C‐fibre nociceptor‐mediated axon reflex and local release of calcitonin gene‐related peptide, substance P and neuropeptide Y, is blunted with local anesthetics. To determine the role of ROS in this neurovascular response, we studied orthostatically‐challenged, Chronic Fatigue Syndrome (CFS) subjects. We heated the skin of 9 CFS subjects (15.8–22.0 years) to 42°C and measured local blood flow. While CFS subjects had lower baseline blood flow (79% of control), there were no differences between groups to local heat. We then measured CFS subjects while perfusing apocynin (NADPH oxidase inhibitor), allopurinol (xanthine oxidase inhibitor), tempol (superoxide inhibitor), and ebselen to reduce H2O2 via microdialysis catheters. Allopurinol and ebselen only enhanced the first heat peak (117% and 126% of heat‐alone, respectively). Heat with apocynin caused an increase in baseline (170% of non‐drug) and of the first heat peak (114% of heat‐alone). Tempol had no effect. Thus the response to heat, as indicated by the first peak, may be altered by local levels of ROS in CFS subjects, and may be related to hyperesthesia/hyperalgesia reported by many individuals with CFS. Supported by the National Heart, Lung, and Blood Institute Grants 1‐RO1‐HL‐074873, 1‐RO1‐HL‐087803 and 1‐F30‐HL‐097380 and a grant from the Chronic Fatigue and Immune Dysfunction Syndrome Association.

Decreased basal ganglia activation in Chronic Fatigue Syndrome subjects is associated with increased fatigue

ObjectivesConduct a functional magnetic resonance (fMRI) study using a monetary win‐lose gambling task that strongly activates basal ganglia to test hypothesis of decreased basal ganglia function in chronic fatigue syndrome (CFS).MethodsParticipants included 18 CFS subjects (1994 case definition) and 41 non‐fatigued controls matched on age, sex and race who were free of psychotropic medications and significant depression (Zung Depression score &lt;60). The general activation pattern for win‐lose contrast across all subjects was determined. The resulting statistical parametric brain map thresholded at p&lt;0.05, corrected for multiple comparisons, was intersected with basal ganglia regions of interest (ROIs). For each subject, the average value of win‐lose activation contrast in each ROI was extracted.ResultsCFS subjects showed decreased right caudate (p=0.01) and right globus pallidus (p=0.02) activation compared to controls. The decreased globus pallidus activation correlated with increased mental fatigue (r2=0.49, p=0.001), general fatigue (r2=0.34, p=0.01) and reduced activity (r2=0.29, p=0.02) Multidimensional Fatigue Inventory scores of CFS subjects but not controls.ConclusionReduced basal ganglia activation may contribute to symptoms of fatigue in CFS subjects.The findings in this report are those of the authors and do not necessarily reflect the views of the funding agency (CDC).

Postural neurocognitive and neuronal activated cerebral blood flow deficits in young chronic fatigue syndrome patients with postural tachycardia syndrome

Neurocognition is impaired in chronic fatigue syndrome (CFS). We propose that the impairment relates to postural cerebral hemodynamics. Twenty-five CFS subjects and twenty control subjects underwent incremental upright tilt at 0, 15, 30, 45, 60, and 75° with continuous measurement of arterial blood pressure and cerebral blood flow velocity (CBFV). We used an n-back task with n ranging from 0 to 4 (increased n = increased task difficulty) to test working memory and information processing. We measured n-back outcomes by the number of correct answers and by reaction time. We measured CBFV, critical closing pressure (CCP), and CBFV altered by neuronal activity (activated CBFV) during each n value and every tilt angle using transcranial Doppler ultrasound. N-back outcome in control subjects decreased with n valve but was independent of tilt angle. N-back outcome in CFS subjects decreased with n value but deteriorated as orthostasis progressed. Absolute mean CBFV was slightly less than in control subjects in CFS subject at each angle. Activated CBFV in control subjects was independent of tilt angle and increased with n value. In contrast, activated CBFV averaged 0 in CFS subjects, decreased with angle, and was less than in control subjects. CCP was increased in CFS subjects, suggesting increased vasomotor tone and decreased metabolic control of CBFV. CCP did not change with orthostasis in CFS subjects but decreased monotonically in control subjects, consistent with vasodilation as compensation for the orthostatic reduction of cerebral perfusion pressure. Increasing orthostatic stress impairs neurocognition in CFS subjects. CBFV activation, normally tightly linked to cognitive neuronal activity, is unrelated to cognitive performance in CFS subjects; the increased CCP and vasomotor tone may indicate an uncoupling of the neurovascular unit during orthostasis.