Tag: Staines

A systematic review of cytokines in chronic fatigue syndrome/myalgic encephalomyelitis/systemic exertion intolerance disease (CFS/ME/SEID)

Abstract:

BACKGROUND: Cytokines in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis/Systemic Exertion Intolerance Disease (CFS/ME/SEID) patients compared with healthy controls have been extensively studied. However, the evidence regarding whether a baseline difference between CFS/ME/SEID patients and the normal population remains unclear. The aim of this study was to conduct a systematic review of the literature regarding cytokines in CFS/ME/SEID and whether there is a significant difference in cytokine levels between this patient group and the normal population.

METHODS: Pubmed, Scopus, Medline (EBSCOHost), and EMBASE databases were searched to source relevant studies for CFS/ME/SEID. The review included any studies examining cytokines in CFS/ME/SEID patients compared with healthy controls. Results of the literature search were summarised according to aspects of their study design and outcome measures, namely, cytokines. Quality assessment was also completed to summarise the level of evidence available.

RESULTS: A total of 16,702 publications were returned using our search terms. After screening of papers according to our inclusion and exclusion criteria, 15 studies were included in the review. All the included studies were observational case control studies. Ten of the studies identified measured serum cytokines in CFS/ME/SEID patients, and four measured cytokines in other physiological fluids of CFS/ME/SEID patients. The overall quality assessment revealed most papers included in this systematic review to be consistent.

CONCLUSIONS: Despite the availability of moderate quality studies, the findings of this review are inconclusive as to whether cytokines play any definitive role in CFS/ME/SEID, and consequently, they would not serve as reliable biomarkers. Therefore, in light of these results, it is recommended that further efforts toward a diagnostic test and treatment for CFS/ME/SEID continue to be developed in a range of research fields.

Source: Corbitt M, Eaton-Fitch N, Staines D, Cabanas H, Marshall-Gradisnik S. A systematic review of cytokines in chronic fatigue syndrome/myalgic encephalomyelitis/systemic exertion intolerance disease (CFS/ME/SEID). BMC Neurol. 2019 Aug 24;19(1):207. doi: 10.1186/s12883-019-1433-0. https://bmcneurol.biomedcentral.com/articles/10.1186/s12883-019-1433-0 (Full article)

Prevalence and characteristics of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) in Poland: a cross-sectional study

Abstract:

OBJECTIVES: The aim of this study was to estimate the prevalence of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and describe illness characteristics in a community population in Poland.

DESIGN: cross-sectional study.

SETTING: Poland.

PARTICIPANTS: Of the cohort of 1400 who self-presented with fatigue only 69 subsequently were confirmed as having CFS/ME using the Fukuda criteria.

MAIN OUTCOME MEASURES: Participants completed the following screening symptom assessment tools: Chalder Fatigue Scale, Hospital Anxiety and Depression Scale (HADS), Epworth Sleepiness Scale (ESS), Composite Autonomic Symptom Score 31 (COMPASS 31), Quality of Life Scale (QOLS). Haemodynamic and autonomic parameters were automatically measured at rest with a Task Force Monitor.

RESULTS: In 1308, from 1400 (93%) individuals who identified themselves as fatigued, recognised chronic conditions were identified, for example, neurological (n=280, 21.5%), neurodegenerative (n=200, 15%), psychiatric (n=654, 50%) and immunologic (n=174, 13.5%) disorders. The remaining 69 participants (mean age 38.3±8.5) met the Fukuda defintion for CFS/ME and had baseline objective assessment. The majority had experienced symptoms for over 2 years with 37% having symptoms for 2-5 years and 21.7% for more than 10 years. The COMPASS 31 indicated that 50% have symptoms consistent with orthostatic intolerance. About 43/69 (62%) had Epworth sleepiness scores ≥10, ie, consistent with excessive daytime sleepiness, 26/69 (38%) had significant anxiety and 22/69 (32%) depression measured by HADS A & D. Quality of life is significantly impaired in those with Fukuda criteria CFS (QLS score 64±11) with significant negative relationships between quality of life and fatigue (p<0.0001), anxiety (p=0.0009), depression (p<0.0001) and autonomic symptoms (p=0.04).

CONCLUSION: This is the first study to summarise illness characteristics of Polish CFS/ME patients. Our study has confirmed that fatigue is a common and under-recognised symptom affecting the Polish population.

Source: Słomko J, Newton JL, Kujawski S, Tafil-Klawe M, Klawe J, Staines D, Marshall-Gradisnik S, Zalewski P. Prevalence and characteristics of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) in Poland: a cross-sectional study. BMJ Open. 2019 Mar 7;9(3):e023955. doi: 10.1136/bmjopen-2018-023955. https://bmjopen.bmj.com/content/9/3/e023955.long (Full study)

A systematic review of enteric dysbiosis in chronic fatigue syndrome/myalgic encephalomyelitis

Abstract:

BACKGROUND: Chronic fatigue syndrome or myalgic encephalomyelitis (CFS/ME) is an illness characterised by profound and pervasive fatigue in addition to a heterogeneous constellation of symptoms. The aetiology of this condition remains unknown; however, it has been previously suggested that enteric dysbiosis is implicated in the pathogenesis of CFS/ME. This review examines the evidence currently available for the presence of abnormal microbial ecology in CFS/ME in comparison to healthy controls, with one exception being probiotic-supplemented CFS/ME patients, and whether the composition of the microbiome plays a role in symptom causation.

METHODS: EMBASE, Medline (via EBSCOhost), Pubmed and Scopus were systematically searched from 1994 to March 2018. All studies that investigated the gut microbiome composition of CFS/ME patients were initially included prior to the application of specific exclusion criteria. The association between these findings and patient-centred outcomes (fatigue, quality of life, gastrointestinal symptoms, psychological wellbeing) are also reported.

RESULTS: Seven studies that met the inclusion criteria were included in the review. The microbiome composition of CFS/ME patients was compared with healthy controls, with the exception of one study that compared to probiotic-supplemented CFS/ME patients. Differences were reported in each study; however, only three were considered statistically significant, and the findings across all studies were inconsistent. The quality of the studies included in this review scored between poor (< 54%), fair (54-72%) and good (94-100%) using the Downs and Black checklist.

CONCLUSIONS: There is currently insufficient evidence for enteric dysbiosis playing a significant role in the pathomechanism of CFS/ME. Recommendations for future research in this field include the use of consistent criteria for the diagnosis of CFS/ME, reduction of confounding variables by controlling factors that influence microbiome composition prior to sample collection and including more severe cases of CFS/ME.

Source: Du Preez S, Corbitt M, Cabanas H, Eaton N, Staines D, Marshall-Gradisnik S. A systematic review of enteric dysbiosis in chronic fatigue syndrome/myalgic encephalomyelitis. Syst Rev. 2018 Dec 20;7(1):241. doi: 10.1186/s13643-018-0909-0. https://systematicreviewsjournal.biomedcentral.com/articles/10.1186/s13643-018-0909-0 (Full article)

Brain function characteristics of chronic fatigue syndrome: A task fMRI study

Abstract:

The mechanism underlying neurological dysfunction in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is yet to be established. This study investigated the temporal complexity of blood oxygenation level dependent (BOLD) changes in response to the Stroop task in CFS patients. 43 CFS patients (47.4 ± 11.8 yrs) and 26 normal controls (NCs, 43.4 ± 13.9 yrs) were included in this study. Their mental component summary (MCS) and physical component summary (PCS) from the 36-item Short Form Health Survey (SF-36) questionnaire were recorded. Their Stroop colour-word task performance was measured by accuracy and response time (RT). The BOLD changes associated with the Stroop task were evaluated using a 2-level general linear model approach. The temporal complexity of the BOLD responses, a measure of information capacity and thus adaptability to a challenging environment, in each activated region was measured by sample entropy (SampEn).

The CFS patients showed significantly longer RTs than the NCs (P < 0.05) but no significant difference in accuracy. One sample t-tests for the two groups (Family wise error adjusted PFWE < 0.05) showed more BOLD activation regions in the CFS, although a two sample group comparison did not show significant difference. BOLD SampEns in ten regions were significantly lower (FDR-q < 0.05) in CFS patients. BOLD SampEns in 15 regions were significantly associated with PCS (FDR-q < 0.05) and in 9 regions were associated with MCS (FDR-q < 0.05) across all subjects. SampEn of the BOLD signal in the medioventral occipital cortex could explain 40% and 31% of the variance in the SF-36 PCS and MCS scores, and those in the precentral gyrus could explain an additional 16% and 7% across all subjects.

This is the first study to investigate BOLD signal SampEn in response to tasks in CFS. The results suggest the brain responds differently to a cognitive challenge in patients with CFS, with recruitment of wider regions to compensate for lower information capacity.

Source: Shan ZY, Finegan K, Bhuta S, Ireland T, Staines DR, Marshall-Gradisnik SM, Barnden LR. Brain function characteristics of chronic fatigue syndrome: A task fMRI study. Neuroimage Clin. 2018 Apr 25;19:279-286. doi: 10.1016/j.nicl.2018.04.025. eCollection 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6051500/ (Full study)

Reduced glycolytic reserve in isolated natural killer cells from Myalgic encephalomyelitis/chronic fatigue syndrome patients: A preliminary investigation

Abstract:

BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is medically unexplained post-exertional fatigue associated with significant reduction in natural killer cell (NK) cytotoxicity activity. Cytotoxic activity relies on glycolytic flux and mitochondrial respiration to fulfill energetic cellular demands. While mitochondrial dysfunction has been reported in ME/CFS patients, no previous investigation has examined the bioenergetic profile of isolated NK cells from ME/CFS patients.

OBJECTIVE: This study was to determine the metabolic function in resting NK cells from ME/CFS patients.

METHOD: Six ME/CFS patients (aged 50.33±4.95) were age and sex-matched with non-fatigued healthy controls (aged 50.00±5.04). Mitochondrial stress tests measured parameters of mitochondrial function in the NK cells including basal respiration, ATP production, proton leak, maximal respiration, spare respiratory capacity and bioenergetic health index. Glycolytic stress tests measured parameters of glycolytic function such as glycolytic reserve, glycolysis and glycolytic capacity in isolated NK cells from ME/CFS patients and healthy controls using an extracellular flux analyzer, Seahorse XFp.

RESULT: There was a significant reduction of glycolytic reserve in resting NK cells from ME/CFS patients (0.6±0.07 mpH/ min) compared with healthy control (2.25±1.3 mpH/min). Mitochondrial respiration in resting NK cells did not approach statistical significance between ME/CFS patients and healthy controls.

CONCLUSION: These findings suggest resting NK cells from ME/CFS patients have reduced ability to increase glycolytic flux to respond to high energetic demands for ATP production. Hence, the reduced glycolytic reserves we have identified in isolated resting isolated NK cells should be further investigated to assist in understanding ME/CFS pathogenesis.

Source: Nguyen T, Staines D, Johnston S, Marshall-Gradisnik S. Reduced glycolytic reserve in isolated natural killer cells from Myalgic encephalomyelitis/chronic fatigue syndrome patients: A preliminary investigation. Asian Pac J Allergy Immunol. 2018 Jul 8. doi: 10.12932/AP-011117-0188. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29981562

Transient Receptor Potential Ion Channels in the Etiology and Pathomechanism of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Abstract:

Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a disabling condition of unknown cause having multi-system manifestations. Our group has investigated the potential role of transient receptor potential (TRP) ion channels in the etiology and pathomechanism of this illness. Store-operated calcium entry (SOCE) signaling is the primary intracellular calcium signaling mechanism in non-excitable cells and is associated with TRP ion channels. While the sub-family (Canonical) TRPC has been traditionally associated with this important cellular mechanism, a member of the TRPM sub-family group (Melastatin), TRPM3, has also been recently identified as participating in SOCE in white matter of the central nervous system. We have identified single nucleotide polymorphisms (SNPs) in TRP genes in natural killer (NK) cells and peripheral blood mononuclear cells (PBMCs) in CFS/ME patients. We also describe biochemical pathway changes and calcium signaling perturbations in blood cells from patients. The ubiquitous distribution of TRP ion channels and specific locations of sub-family group members such as TRPM3 suggest a contribution to systemic pathology in CFS/ME.

Source: D. Staines, S. Du Preez, H. Cabanas, C. Balinas, N. Eaton, R. Passmore, R. Maksoud, J. Redmayne, S. Marshall-Gradisnik. Transient Receptor Potential Ion Channels in the Etiology and Pathomechanism of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. IJCM, Vol.9 No.5, May 2018. DOI: 10.4236/ijcm.2018.95038 

Rituximab impedes natural killer cell function in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients: A pilot in vitro investigation

Abstract:

BACKGROUND: A recent in vitro pilot investigation reported Rituximab significantly reduced natural killer (NK) cell cytotoxicity in healthy donors. Chronic fatigue syndrome/Myalgic encephalomyelitis (CFS/ME) is a debilitating disorder of unknown etiology. A consistent finding is a significant reduction in NK cell cytotoxicity. Rituximab has been reported having questionable potential therapeutic benefits for the treatment of CFS/ME, however, the potential effects of Rituximab on NK cell cytotoxicity in CFS/ME patients are yet to be determined.

METHODS: A total of eight CFS/ME patients (48.63 ± 15.69 years) and nine non-fatigued controls (NFC) (37.56 ± 11.06 years) were included using the Fukuda case definition. Apoptotic function, lytic proteins and degranulation markers were measured on isolated NK cells using flow cytometry following overnight incubation with Rituximab at 10 μg/ml and 100 μg/ml.

RESULTS: There was a significant reduction in NK cell lysis between CFS/ME patients and NFC following incubation with Rituximab at 100 μg/ml at 12.5:1 and 6.25:1 effecter-target (E:T) ratios (p < 0.05). However, there was no significant difference for NFC following incubation with Rituximab at 10 μg/ml and 100 μg/ml. There was no significant difference between CFS/ME patients and NFC for granzyme A and granzyme B prior to incubation with Rituximab and following overnight incubation with Rituximab at 10 μg/ml. There was a significant decrease in granzyme B in CFS/ME patients compared to NFC with 100 μg/ml of Rituximab prior to K562 cells stimulation (p < 0.05). There was a significant increase in CD107a (p < 0.05) and CD107b expression (p < 0.01) in NFC after stimulation with K562 cells prior to incubation with Rituximab. There was a significant increase in CD107b expression between CFS/ME patients and NFC prior to incubation with Rituximab and without stimulation of K562 cells (p < 0.01). Importantly, there was a significant increase in CD107b following overnight incubation with 100 μg/ml of Rituximab in NFC prior to K562 cells stimulation (p < 0.01).

CONCLUSION: This study reports significant decreases in NK cell lysis and a significant increase in NK cell degranulation following Rituximab incubation in vitro in CFS/ME patients, suggesting Rituximab may be toxic for NK cells. Caution should be observed in clinical trials until further investigations in a safe and controlled in vitro setting are completed.

Source: Eaton N, Cabanas H, Balinas C, Klein A, Staines D, Marshall-Gradisnik S. Rituximab impedes natural killer cell function in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients: A pilot in vitro investigation.BMC Pharmacol Toxicol. 2018 Mar 27;19(1):12. doi: 10.1186/s40360-018-0203-8.   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5870391/ (Full article)

Drug hoped to treat CFS causes impaired immune function, Griffith study says

Reports that a drug used to treat autoimmune diseases and cancer could also treat Chronic Fatigue Syndrome (CFS) have been refuted by a new Griffith University study.

To be published in BMC Pharmacology and Toxicology, the study by Griffith’s National Centre for Neuroimmunology and Emerging Diseases(NCNED) concluded that the use of Rituximab in CFS patients could incur problems with their immune cells and is not beneficial as a potential treatment.

The Natural Killer (NK) cells have vital functions in fighting viruses, bacteria and tumours.

“We found that these functions were significantly impaired when exposed to Rituximab in CFS patients,” says Scientific Co-Director of NCNED, Professor Sonya Marshall-Gradisnik.

CFS – sometimes known as ME (myalgic encephalomyelitis) – is a complex illness characterised by impaired memory and concentration, metabolic, cardiac, gut and immune dysfunction and debilitating muscle pain and fatigue on exertion (also known as neuroimmune exhaustion).

It is estimated that the prevalence rate of CFS/ME worldwide is between 1 and 2 per cent.

Related to the ion channels

The Gold Coast NCNED team has discovered the illness is related to problems in the ion channels that allow calcium into the body’s cells. Calcium is required by almost every cell in the human body and is vital in helping the immune system destroy a virus or infection.

The team has proven that patients with CFS/ME have lower levels of calcium coming into their cells, that their cells store less calcium and that this is the basis of their illness.

Professor Don Staines, Clinical Co-Director of NCNED, says: “These results are important as NK cells are already known to have impaired function in CFS patients, suggesting certain doses of Rituximab may not be beneficial for the treatment of this condition.”

“Undertaking an initial study has enabled us to secure additional research funding from the national competitive grants process from the Mason Foundation where we can now undertake a larger study using this drug in vitro to validate our novel findings,” says Professor Staines.

First author for these world-first scientific findings was PhD student, Ms Natalie Eaton.  She will be presenting the study at an NCNED-sponsored conference later this year.  The focus of the conference will be promoting greater understanding of pathology and pharmacothereapeutics for CFS, through a Research, Innovation, Discovery, Learning and Education (RIDLE) model.

Source: Press Release: Griffith University, March 27, 2018.

A Systematic Review of Probiotic Interventions for Gastrointestinal Symptoms and Irritable Bowel Syndrome in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)

Abstract:

Gastrointestinal (GI) symptoms and irritable bowel (IB) symptoms have been associated with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME). The aim of this study was to conduct a systematic review of these symptoms in CFS/ME, along with any evidence for probiotics as treatment. Pubmed, Scopus, Medline (EBSCOHost) and EMBASE databases were searched to source relevant studies for CFS/ME. The review included any studies examining GI symptoms, irritable bowel syndrome (IBS) and/or probiotic use.

Studies were required to report criteria for CFS/ME and study design, intervention and outcome measures. Quality assessment was also completed to summarise the level of evidence available. A total of 3381 publications were returned using our search terms. Twenty-five studies were included in the review. Randomised control trials were the predominant study type (n = 24). Most of the studies identified examined the effect of probiotic supplementation on the improvement of IB symptoms in IBS patients, or IB symptoms in CFS/ME patients, as well as some other significant secondary outcomes (e.g. quality of life, other gastrointestinal symptoms, psychological symptoms).

The level of evidence identified for the use of probiotics in IBS was excellent in quality; however, the evidence available for the use of probiotic interventions in CFS/ME was poor and limited. There is currently insufficient evidence for the use of probiotics in CFS/ME patients, despite probiotic interventions being useful in IBS. The studies pertaining to probiotic interventions in CFS/ME patients were limited and of poor quality overall. Standardisation of protocols and methodology in these studies is required.

Source: Corbitt M, Campagnolo N, Staines D, Marshall-Gradisnik S. A Systematic Review of Probiotic Interventions for Gastrointestinal Symptoms and Irritable Bowel Syndrome in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). Probiotics Antimicrob Proteins. 2018 Feb 20. doi: 10.1007/s12602-018-9397-8. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29464501

Decreased connectivity and increased BOLD complexity in the default mode network in individuals with chronic fatigue syndrome

Abstract:

The chronic fatigue syndrome / myalgic encephalomyelitis (CFS) is a debilitating disease with unknown pathophysiology and no diagnostic test. This study investigated the default mode network (DMN) in order to understand the pathophysiology of CFS and to identify potential biomarkers.

Using functional MRI (fMRI) collected from 72 subjects (45 CFS and 27 controls) with a temporal resolution of 0.798s, we evaluated the default mode network using static functional connectivity (FC), dynamic functional connectivity (DFC) and DFC complexity, blood oxygenation level dependent (BOLD) activation maps and complexity of activity. General linear model (GLM) univariate analysis was used for inter group comparison to account for age and gender differences. Hierarchical regression analysis was used to test whether fMRI measures could be used to explain variances of health scores.

BOLD signals in the posterior cingulate cortex (PCC), the driving hub in the DMN, were more complex in CFS in both resting state and task (P < 0.05). The FCs between medial prefrontal cortex (mPFC) and both inferior parietal lobules (IPLs) were weaker (P < 0.05) during resting state, while during task mPFC – left IPL and mPFC – PCC were weaker (P < 0.05). The DFCs between the DMN hubs were more complex in CFS (P < 0.05) during task. Each of these differences accounted for 7 – 11% variability of health scores. This study showed that DMN activity is more complex and less coordinated in CFS, suggesting brain network analysis could be potential used as a diagnostic biomarker for CFS.

Source: Shan ZY, Finegan K, Bhuta S, Ireland T, Staines DR, Marshall-Gradisnik SM, Barnden LR. Decreased connectivity and increased BOLD complexity in the default mode network in individuals with chronic fatigue syndrome. Brain Connect. 2017 Nov 20. doi: 10.1089/brain.2017.0549. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/29152994