A multidisciplinary approach to study a couple of monozygotic twins discordant for the chronic fatigue syndrome: a focus on potential salivary biomarkers

Abstract:

BACKGROUND: Chronic Fatigue Syndrome (CFS) is a severe, systemic illness characterized by persistent, debilitating and medically unexplained fatigue. The etiology and pathophysiology of CFS remains obscure, and diagnosis is formulated through the patient’s history and exclusion of other medical causes. Thereby, the availability of biomarkers for CFS could be useful for clinical research. In the present study, we used a proteomic approach to evaluate the global changes in the salivary profile in a couple of monozygotic twins who were discordant for CFS. The aim was to evaluate differences of salivary protein expression in the CFS patient in respect to his healthy twin.

METHODS: Saliva samples were submitted to two-dimensional electrophoresis (2DE). The gels were stained with Sypro, and a comparison between CFS subject and the healthy one was performed by the software Progenesis Same Spot including the Analysis of variance (ANOVA test). The proteins spot found with a ≥2-fold spot quantity change and p<0.05 were identified by Nano-liquid chromatography electrospray ionization tandem mass spectrometry. To validate the expression changes found with 2DE of 5 proteins (14-3-3 protein zeta/delta, cyclophilin A, Cystatin-C, Protein S100-A7, and zinc-alpha-2-glycoprotein), we used the western blot analysis. Moreover, proteins differentially expressed were functionally analyzed using the Ingenuity Pathways Analysis software with the aim to determine the predominant canonical pathways and the interaction network involved.

RESULTS: The analysis of the protein profiles allowed us to find 13 proteins with a different expression in CFS in respect to control. Nine spots were up-regulated in CFS and 4 down-regulated. These proteins belong to different functional classes, such as inflammatory response, immune system and metabolism. In particular, as shown by the pathway analysis, the network built with our proteins highlights the involvement of inflammatory response in CFS pathogenesis.

CONCLUSIONS: This study shows the presence of differentially expressed proteins in the saliva of the couple of monozygotic twins discordant for CFS, probably related to the disease. Consequently, we believe the proteomic approach could be useful both to define a panel of potential diagnostic biomarkers and to shed new light on the comprehension of the pathogenetic pathways of CFS.

 

Source: Ciregia F, Giusti L, Da Valle Y, Donadio E, Consensi A, Giacomelli C, Sernissi F, Scarpellini P, Maggi F, Lucacchini A, Bazzichi L. A multidisciplinary approach to study a couple of monozygotic twins discordant for the chronic fatigue syndrome: a focus on potential salivary biomarkers. J Transl Med. 2013 Oct 2;11:243. doi: 10.1186/1479-5876-11-243. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3850462/ (Full article)

 

The emerging role of autoimmunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs)

Abstract:

The World Health Organization classifies myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs) as a nervous system disease. Together with other diseases under the G93 heading, ME/cfs shares a triad of abnormalities involving elevated oxidative and nitrosative stress (O&NS), activation of immuno-inflammatory pathways, and mitochondrial dysfunctions with depleted levels of adenosine triphosphate (ATP) synthesis. There is also abundant evidence that many patients with ME/cfs (up to around 60 %) may suffer from autoimmune responses.

A wide range of reported abnormalities in ME/cfs are highly pertinent to the generation of autoimmunity. Here we review the potential sources of autoimmunity which are observed in people with ME/cfs. The increased levels of pro-inflammatory cytokines, e.g., interleukin-1 and tumor necrosis factor-α, and increased levels of nuclear factor-κB predispose to an autoimmune environment. Many cytokine abnormalities conspire to produce a predominance of effector B cells and autoreactive T cells. The common observation of reduced natural killer cell function in ME/cfs is a source of disrupted homeostasis and prolonged effector T cell survival. B cells may be pathogenic by playing a role in autoimmunity independent of their ability to produce antibodies.

The chronic or recurrent viral infections seen in many patients with ME/cfs can induce autoimmunity by mechanisms involving molecular mimicry and bystander activation. Increased bacterial translocation, as observed in ME/cfs, is known to induce chronic inflammation and autoimmunity. Low ATP production and mitochondrial dysfunction is a source of autoimmunity by inhibiting apoptosis and stimulating necrotic cell death. Self-epitopes may be damaged by exposure to prolonged O&NS, altering their immunogenic profile and become a target for the host’s immune system. Nitric oxide may induce many faces of autoimmunity stemming from elevated mitochondrial membrane hyperpolarization and blockade of the methionine cycle with subsequent hypomethylation of DNA. Here we also outline options for treatment involving rituximab and endotherapia.

 

Source: Morris G, Berk M, Galecki P, Maes M. The emerging role of autoimmunity in myalgic encephalomyelitis/chronic fatigue syndrome (ME/cfs). Mol Neurobiol. 2014 Apr;49(2):741-56. doi: 10.1007/s12035-013-8553-0. Epub 2013 Sep 26. https://www.ncbi.nlm.nih.gov/pubmed/24068616 (Full article)

 

Effects of Time Frame on the Recall Reliability of CFS Symptoms

Abstract:

This study serves as an investigation of the reliability of symptom data as reported by individuals with chronic fatigue syndrome (CFS), across three recall time frames (the past week, the past month, and the past 6 months), and at two assessment points (with 1 week in between each assessment). Multilevel model analyses were used to determine the optimal recall time frame, in terms of test -retest reliability, for each of the Fukuda et al. (1994) case defining symptoms.

Results suggested that the optimal time frame for reliably reporting CFS symptoms was six months for sore throat, lymph node pain, muscle pain, post-exertional malaise, headaches, memory/concentration difficulties, and unrefreshing sleep. For joint pain, the optimal time frame was one month. Researchers who are interested in the assessment of CFS symptoms need to take recall time frame into account, especially when the intended goal is to standardize and improve the methods used to reliably and accurately diagnose this complex illness.

© The Author(s) 2013

 

Source: Evans M, Jason LA. Effects of Time Frame on the Recall Reliability of CFS Symptoms. Eval Health Prof. 2015 Sep;38(3):367-81. doi: 10.1177/0163278713497014. Epub 2013 Sep 23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3874064/ (Full article)

 

Understanding medical students’ views of chronic fatigue syndrome: a qualitative study

Abstract:

Chronic fatigue syndrome receives little attention in the medical curriculum. This study explores UK medical students’ knowledge of and attitudes towards chronic fatigue syndrome. Semi-structured interviews (average length 22 minutes) were conducted with 21 participants (7 females and 14 males) in years 3 (n = 4), 4 (n = 11) and 5 (n = 6) of their studies. Inductive thematic analysis taking a realist perspective produced three themes: limited knowledge, influences on attitudes and training needs.

Students acquired their knowledge and attitudes largely from informal sources and expressed difficulty understanding chronic fatigue syndrome within a traditional biomedical framework. Incorporating teaching about chronic fatigue syndrome into the medical curriculum within the context of a biopsychosocial understanding of illness could encourage more positive attitudes towards chronic fatigue syndrome.

© The Author(s) 2013

 

Source: Stenhoff AL, Sadreddini S, Peters S, Wearden A. Understanding medical students’ views of chronic fatigue syndrome: a qualitative study. J Health Psychol. 2015 Feb;20(2):198-209. doi: 10.1177/1359105313501534. Epub 2013 Sep 20. https://www.ncbi.nlm.nih.gov/pubmed/24058124

 

Differing leukocyte gene expression profiles associated with fatigue in patients with prostate cancer versus chronic fatigue syndrome

Abstract:

BACKGROUND: Androgen deprivation therapy (ADT) often worsens fatigue in patients with prostate cancer, producing symptoms similar to chronic fatigue syndrome (CFS). Comparing expression (mRNA) of many fatigue-related genes in patients with ADT-treated prostate cancer versus with CFS versus healthy controls, and correlating mRNA with fatigue severity may clarify the differing pathways underlying fatigue in these conditions.

METHODS: Quantitative real-time PCR was performed on leukocytes from 30 fatigued, ADT-treated prostate cancer patients (PCF), 39 patients with CFS and 22 controls aged 40-79, together with ratings of fatigue and pain severity. 46 genes from these pathways were included: (1) adrenergic/monoamine/neuropeptides, (2) immune, (3) metabolite-detecting, (4) mitochondrial/energy, (5) transcription factors.

RESULTS: PCF patients showed higher expression than controls or CFS of 2 immune transcription genes (NR3C1 and TLR4), chemokine CXCR4, and mitochondrial gene SOD2. They showed lower expression of 2 vasodilation-related genes (ADRB2 and VIPR2), 2 cytokines (TNF and LTA), and 2 metabolite-detecting receptors (ASIC3 and P2RX7). CFS patients showed higher P2RX7 and lower HSPA2 versus controls and PCF. Correlations with fatigue severity were similar in PCF and CFS for only DBI, the GABA-A receptor modulator (r=-0.50, p<0.005 and r=-0.34, p<0.05). Purinergic P2RY1 was correlated only with PCF fatigue and pain severity (r=+0.43 and +0.59, p=0.025 and p=0.001).

CONCLUSIONS: PCF patients differed from controls and CFS in mean expression of 10 genes from all 5 pathways. Correlations with fatigue severity implicated DBI for both patient groups and P2RY1 for PCF only. These pathways may provide new targets for interventions to reduce fatigue.

Copyright © 2013 Elsevier Ltd. All rights reserved.

 

Source: Light KC, Agarwal N, Iacob E, White AT, Kinney AY, VanHaitsma TA, Aizad H, Hughen RW, Bateman L, Light AR. Differing leukocyte gene expression profiles associated with fatigue in patients with prostate cancer versus chronic fatigue syndrome. Psychoneuroendocrinology. 2013 Dec;38(12):2983-95. doi: 10.1016/j.psyneuen.2013.08.008. Epub 2013 Sep 6. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848711/ (Full article)

 

Exercise and sleep deprivation do not change cytokine expression levels in patients with chronic fatigue syndrome

Abstract:

A major hypothesis regarding the cause of chronic fatigue syndrome (CFS) is immune dysregulation, thought to be reflected in upregulated proinflammatory cytokines leading to the symptoms that are characteristic of this illness. Because the symptoms worsen with physical exertion or sleep loss, we hypothesized that we could use these stressors to magnify the underlying potential pathogenic abnormalities in the cytokine systems of people with CFS.

We conducted repeat blood sampling for cytokine levels from healthy subjects and CFS patients during both postexercise and total sleep deprivation nights and assayed for protein levels in the blood samples, mRNA activity in peripheral blood lymphocytes (PBLs), and function in resting and stimulated PBLs. We found that these environmental manipulations did not produce clinically significant upregulation of proinflammatory cytokines. These data do not support an important role of immune dysregulation in the genesis of stress-induced worsening of CFS.

 

Source: Nakamura T, Schwander S, Donnelly R, Cook DB, Ortega F, Togo F, Yamamoto Y, Cherniack NS, Klapholz M, Rapoport D, Natelson BH. Exercise and sleep deprivation do not change cytokine expression levels in patients with chronic fatigue syndrome. Clin Vaccine Immunol. 2013 Nov;20(11):1736-42. doi: 10.1128/CVI.00527-13. Epub 2013 Sep 11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3837776/ (Full article)

 

The protocol for a randomised controlled trial comparing intermittent and graded exercise to usual care for chronic fatigue syndrome patients

Abstract:

BACKGROUND: Chronic Fatigue Syndrome is a debilitating disorder with an unknown aetiology but suspected multifactorial origins. Common “triggers” include severe viral infections and emotional stress. Recent studies have also found evidence of immune dysfunction and elevated inflammatory cytokines in CFS patients, but there has been considerable variation in the outcome measures and magnitude of these studies. Currently, there is no cure for CFS but treatments include rest, specialist medical care, cognitive behavioural therapy, and graded (self-paced) exercise. To date, several studies have examined the efficacy of graded exercise with or without Cognitive Behavioural Therapy, with some success for patients. However, improvements in functional capacity have not necessarily correlated with improvements in immune function, fatigue or other symptoms. This 12-week pilot trial compares graded and intermittent exercise to normal care, measuring physiological outcomes, fatigue levels, immune function and wellness.

METHODS/DESIGN: 90 patients aged between 16 to 60 years, who meet the diagnostic criteria for CFS and have been diagnosed by their medical practitioner, will be randomly recruited into groups consisting of Intermittent exercise, Graded exercise and usual care (Control). The outcomes will be measured pre-study (Week 0) and post-study (Week 13). Primary outcomes are VO2peak, anaerobic threshold, peak power, levels of fatigue, immune cell (CD3+CD4+, CD3+CD8+, CD19+, CD 16+CD56+) concentrations and activation. Secondary outcomes include onset of secondary CFS symptoms (e.g. fever, swollen lymph nodes), wellness, mood and sleep patterns. Primary analysis will be based on intention to treat using logistic regression models to compare treatments. Quantitative data will be analysed using repeated measures ANOVA with a linear model, and Cohen’s effect size. Qualitative data such as participants’ responses (e.g. changes in mood and other reactions) following the exercise modalities will be read and sections demarcated. A code will be applied to each segment. A prevalence of codes will be considered thematically.

DISCUSSION: The results of the trial will provide information about the efficacy of intermittent and graded exercise compared to usual care (rest and lifestyle recommendations), contributing to the evidence for best-practice CFS management.

TRIAL REGISTRATION: Australia and New Zealand Clinical Trials Registry ACTRN12612001241820.

 

Source: Broadbent S, Coutts R. The protocol for a randomised controlled trial comparing intermittent and graded exercise to usual care for chronic fatigue syndrome patients. BMC Sports Sci Med Rehabil. 2013 Aug 30;5(1):16. doi: 10.1186/2052-1847-5-16. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3848853/ (Full article)

 

Effects of qigong exercise on fatigue, anxiety, and depressive symptoms of patients with chronic fatigue syndrome-like illness: a randomized controlled trial

Abstract:

Background. Anxiety/depressive symptoms are common in patients with chronic fatigue syndrome- (CFS-) like illness. Qigong as a modality of complementary and alternative therapy has been increasingly applied by patients with chronic illnesses, but little is known about the effect of Qigong on anxiety/depressive symptoms of the patients with CFS-like illness.

Purpose. To investigate the effects of Qigong on fatigue, anxiety, and depressive symptoms in patients with CFS-illness.

Methods. One hundred and thirty-seven participants who met the diagnostic criteria for CFS-like illness were randomly assigned to either an intervention group or a waitlist control group. Participants in the intervention group received 10 sessions of Qigong training twice a week for 5 consecutive weeks, followed by home-based practice for 12 weeks. Fatigue, anxiety, and depressive symptoms were assessed at baseline and postintervention.

Results. Total fatigue score [F(1,135) = 13.888, P < 0.001], physical fatigue score [F(1,135) = 20.852, P < 0.001] and depression score [F(1,135) = 9.918, P = 0.002] were significantly improved and mental fatigue score [F(1,135) = 3.902, P = 0.050] was marginally significantly improved in the Qigong group compared to controls. The anxiety score was not significantly improved in the Qigong group.

Conclusion. Qigong may not only reduce the fatigue symptoms, but also has antidepressive effect for patients with CFS-like illness.

Trial registration HKCTR-1200.

 

Source: Chan JS, Ho RT, Wang CW, Yuen LP, Sham JS, Chan CL. Effects of qigong exercise on fatigue, anxiety, and depressive symptoms of patients with chronic fatigue syndrome-like illness: a randomized controlled trial. Evid Based Complement Alternat Med. 2013;2013:485341. doi: 10.1155/2013/485341. Epub 2013 Jul 31. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3747479/ (Full article)

 

Acupuncture for chronic fatigue syndrome: a randomized, sham-controlled trial with single-blinded design

Abstract:

CONTEXT: Given that the etiology of chronic fatigue syndrome (CFS) is believed to be multidimensional, interventions generally have been nonspecific and typically produce only mild to moderate effects. In medical practice, treatment for CFS remains largely symptomatic. Preliminary evidence of the efficacy of acupuncture for CFS is available, but the field has lacked high-quality trials.

OBJECTIVE: The research team conducted the study to determine the efficacy of acupuncture for CFS.

DESIGN: A two-arm, randomized, controlled, singleblinded design was adopted.

SETTING: The study took place in a teaching laboratory at the School of Chinese Medicine at the University of Hong Kong, Hong Kong, China.

PARTICIPANTS: Recruited through press publicity in Hong Kong, 127 individuals–40 men and 87 women–participated in the study. Intervention Through careful implementation of sham acupuncture in the control group (CG), the study blinded all participants with regard to their experimental or control status. The treatment regime was 2 sessions/wk for 4 consecutive wk.

OUTCOME MEASURES: Measures of fatigue (Chalder’s Fatigue Scale), health-related quality of life (SF-12), and general mental health (GH Q-12) were taken at baseline and upon completion of treatment.

RESULTS: Ninety-nine participants completed the interventions, with 50 and 49 participants in the experimental group (EG) and CG respectively. Repeated measures ANOVA revealed a significant decrease in physical (F(1,93) = 4.327; P = .040) and mental fatigue (F(1,96) = 10.451; P = .002) and improvement in the physical component score of SF-12 (F(1,93) = 4.774; P = .031). Considerable effects with Cohen’s d were observed in the sham-control group: 0.92, 0.78, and 0.38 for the three scores, respectively. These positive effects could have included some therapeutic effects due to pressure on the acupuncture points from the sham needles in addition to normal placebo effects. The EG showed moderate net effect sizes with Cohen’s d: 0.52, 0.63, and 0.54 for the three outcome measures, respectively.

CONCLUSION: Despite considerable positive effects for the CG, the EG demonstrated significant net-effect sizes at a moderate magnitude in physical and mental fatigue and in the physical component of health-related quality of life. The impacts on general mental health outcomes appeared to be smaller.

 

Source: Ng SM, Yiu YM. Acupuncture for chronic fatigue syndrome: a randomized, sham-controlled trial with single-blinded design. Altern Ther Health Med. 2013 Jul-Aug;19(4):21-6. https://www.ncbi.nlm.nih.gov/pubmed/23981369

 

Differences in physical functioning between relatively active and passive patients with Chronic Fatigue Syndrome

Abstract:

OBJECTIVE: According to the Cognitive behavioral therapy (CBT) protocol for patients with Chronic Fatigue Syndrome (CFS), therapists are advised to categorize patients in relatively active and passive patients. However, evidence to support the differences in physical functioning between these subgroups is limited. Using the baseline data from a multicentre randomized controlled trial (FatiGo), the differences in actual and perceived physical functioning between active and passive patients with CFS were evaluated.

METHODS: Sixty patients, who received CBT during the FatiGo trial were included. Based on the expert opinion and using the definitions of subgroups defined in the CBT protocols, the therapist categorized the patient. Data from an activity monitor was used to calculate actual physical functioning, physical activity, daily uptime, activity fluctuations and duration of rest during daily life. Perceived physical functioning was assessed by measuring physical activity, physical functioning and functional impairment with the Checklist Individual Strength, Short Form-36 and Sickness-Impact Profile 8.

RESULTS: Relatively active patients have a significantly higher daily uptime and show significantly less fluctuations in activities between days. Passive patients experience a significantly lower level of physical functioning and feel more functionally impaired in their mobility. However, no significant differences were found in the other actual or perceived physical functioning indices.

CONCLUSIONS: A clear difference in actual and perceived physical functioning between relatively active and passive patients with CFS as judged by their therapists could not be found. Future research is needed to form a consensus on how to categorize subgroups of patients with CFS.

Copyright © 2013 Elsevier Inc. All rights reserved.

 

Source: Vos-Vromans DC, Huijnen IP, Köke AJ, Seelen HA, Knottnerus JA, Smeets RJ. Differences in physical functioning between relatively active and passive patients with Chronic Fatigue Syndrome. J Psychosom Res. 2013 Sep;75(3):249-54. doi: 10.1016/j.jpsychores.2013.05.001. Epub 2013 Jun 2. https://www.ncbi.nlm.nih.gov/pubmed/23972414