Tag: Marshall-Gradisnik

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

Medial prefrontal cortex deficits correlate with unrefreshing sleep in patients with chronic fatigue syndrome

Abstract:

Unrefreshing sleep is a hallmark of chronic fatigue syndrome/myalgic encephalomyelitis (CFS). This study examined brain structure variations associated with sleep quality in patients with CFS. 38 patients with CFS (34.8 ± 10.1 years old) and 14 normal controls (NCs) (34.7 ± 8.4 years old) were recruited. All subjects completed the Hospital Anxiety and Depression Scale, Pittsburgh Sleep Quality Index (PSQI), and Chalder Fatigue Scale (CFQ) questionnaires. Brain MRI measures included global and regional grey and white matter volumes, magnetization transfer T1 weighted (MT-T1w) intensities, and T1 weighted (T1w) and T2 weighted spin echo signal intensities.

We performed voxel based group comparisons of these regional brain MRI measures and regressions of these measures with the PSQI and CFQ scales adjusted for age, anxiety and depression, and the appropriate global measure. In CFS patients, negative correlations were observed in the medial prefrontal cortex (mPFC) between PSQI and MT-T1w intensities (family-wise error corrected cluster, PFWE < 0.05) and between PSQI and T1w intensities (PFWE < 0.05). In the same mPFC location, both MT and T1w intensities were lower in CFS patients compared with NCs (uncorrected voxel P < 0.001).

This study is the first to report that brain structural differences are associated with unrefreshing sleep in CFS. This result refutes the suggestion that unrefreshing sleep is a misperception in CFS patients and further investigation of this symptom is warranted.

Source: Shan ZY, Kwiatek R, Burnet R, Del Fante P, Staines DR, Marshall-Gradisnik SM, Barnden LR. Medial prefrontal cortex deficits correlate with unrefreshing sleep in patients with chronic fatigue syndrome. NMR Biomed. 2017 Jun 29. doi: 10.1002/nbm.3757. [Epub ahead of print] http://onlinelibrary.wiley.com/doi/10.1002/nbm.3757/full

Further clues in the fight against chronic fatigue syndrome

New findings regarding the pathology of Chronic Fatigue Syndrome (CFS) are bringing Griffith University researchers closer to identifying the cause of this disabling illness.

This is the news from a team at the National Centre for Neuroimmunology and Emerging Diseases at the Menzies Health Institute Queensland.

Professors Marshall-Gradisnik and Don Staines and their research team have identified significant impairments in cellular function of people with CFS.

CFS — sometimes known as ME (myalgic encephalomyelitis) — is a complex illness characterized 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.

“While the patho-mechanism of CFS/ME is unknown, these recent findings by NCNED researchers provide further evidence for the pathology of this illness,” says Professor Sonya Marshall-Gradisnik, who speaks as we approach International CFS Awareness Day on Thursday May 12.

Published in the Journal of Translational Medicine, the results report significant differences in intracellular signalling of cells with CFS patients.

“In this group, we see that dysfunctional signalling may contribute to impaired cell activity. These findings are consistent with our previous findings and align with the presentation of symptoms in patients,” says Professor Staines.

The current research findings build upon recent discoveries including novel identification of key genetic changes in cells of the immune system.

The NCNED — internationally recognised for research into CFS/ME — will present a seminar on current research findings on this disease on International CFS/ME Awareness Day, Thursday May 12 at Griffith University, Gold Coast Campus, commencing 1pm, location G17, Lecture theatre 3.

Griffith University will also be illuminating the Griffith Health Centre in blue to further help raise awareness for CFS/ME.

Journal Reference: Teilah Kathryn Huth, Donald Staines, Sonya Marshall-Gradisnik. ERK1/2, MEK1/2 and p38 downstream signalling molecules impaired in CD56dimCD16 and CD56brightCD16dim/− natural killer cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis patients. Journal of Translational Medicine, 2016; 14 (1) DOI: 10.1186/s12967-016-0859-z

 

Source: Griffith University. “Further clues in the fight against chronic fatigue syndrome.” ScienceDaily. ScienceDaily, 10 May 2016. https://www.sciencedaily.com/releases/2016/05/160510093906.htm

 

New light shed on cause of chronic fatigue syndrome

New research findings may shed new light on the potential cause of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME).

Researchers from Griffith University’s National Centre for Neuroimmunology and Emerging Diseases (NCNED) — part of the new Menzies Health Institute Queensland — have uncovered significant factors contributing to the pathology of this illness.

The results reveal genetic changes in important receptors associated with immunological and cellular function and contribute to the development of this complex illness.

“These findings have been achieved through a team effort involving researchers, patients, funding bodies, clinicians and the support of Griffith University and the Queensland Government,” say chief investigators Professor Sonya Marshall-Gradisnik and Professor Donald Staines.

Co-researcher and consultant immunologist Professor Pete Smith said that important signalling mechanisms are disrupted as a result of these genetic changes involving the detection and response to threats.

“These are primitive genes that are involved in many cellular signals in the brain, gut, cardiovascular and immune systems, as well as in the mediation of pain.”

These research findings coincide with International Neuroimmune Awareness week commencing Monday 11 May.

The Griffith Health Centre on the university’s Gold Coast campus is being lit up each evening from 10 -12 May to raise awareness of neurological conditions such as CFS/ME as well as other conditions such as Fibromyalgia and Gulf War Syndrome.

“The lighting up of the Griffith Health Centre signifies Griffith’s commitment to the CFS patient community and our team approach to this research,” says Pro-Vice Chancellor (Health) Professor Allan Cripps.

CFS/ME is a highly debilitating disorder characterized by profound fatigue, muscle and joint pain, cerebral symptoms of impaired memory and concentration, impaired cardiovascular function, gut disorder and sensory dysfunction such as noise intolerance and balance disturbance. Many cases can continue for months or years. It is believed to affect around 250,000 Australians.

The research findings are to be presented at an international conference in London later this month.

Journal Reference: Sonya Marshall-Gradisnik, Donald Staines, Pete Smith, Bernd Nilius, Ekua Brenu, Sandra Ramos. Examination of Single Nucleotide Polymorphisms (SNPs) in Transient Receptor Potential (TRP) Ion Channels in Chronic Fatigue Syndrome Patients. Immunology and Immunogenetics Insights, 2015; 1 DOI: 10.4137/III.S25147

 

Source: Griffith University. “New light shed on cause of chronic fatigue syndrome.” ScienceDaily. ScienceDaily, 11 May 2015. https://www.sciencedaily.com/releases/2015/05/150511172755.htm 

 

A targeted genome association study examining transient receptor potential ion channels, acetylcholine receptors, and adrenergic receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Abstract:

BACKGROUND: Chronic Fatigue Syndrome, also known as Myalgic Encephalomyelitis (CFS/ME) is a debilitating condition of unknown aetiology. It is characterized by a range of physiological effects including neurological, sensory and motor disturbances. This study examined candidate genes for the above clinical manifestations to identify single nucleotide polymorphism (SNP) alleles associated with CFS/ME compared with healthy controls.

METHODS: DNA was extracted and whole genome genotyping was performed using the HumanOmniExpress BeadChip array. Gene families for transient receptor potential ion channels, acetylcholine receptors, and adrenergic receptors, and acetylcholinesterase were targeted. The frequency of each SNP and their association between CFS/ME and healthy controls was examined using Fisher’s exact test, and to adjust for multiple testing, False Detection Rate (FDR) and Bonferroni corrections were applied (p < 0.05).

RESULTS: The study included 172 participants, consisting of 95 Fukuda defined CFS/ME patients (45.8 ± 8.9; 69 % female) and 77 healthy controls (42.3 ± 10.3; 63 % female). A total of 950 SNPs were included for analysis. 60 significant SNPs were associated with CFS/ME compared with healthy controls. After applying FDR and Bonferroni corrections, SNP rs2322333 in adrenergic receptor α1 (ADRA1A) was higher in CFS/ME compared with healthy controls (45.3 % vs. 23.4 %; p = 0.059). The genotype class that was homozygous minor (AA) was substantially lower in CFS/ME compared with healthy controls (4.2 % vs. 24.7 %).

CONCLUSIONS: This study reports for the first time the identification of ADRA1A and a possible association between CFS/ME and genotype classes. Further examination of the functional role of this class of adrenergic receptors may elucidate the cause of particular clinical manifestations observed in CFS/ME

 

Source: Johnston S, Staines D, Klein A, Marshall-Gradisnik S. A targeted genome association study examining transient receptor potential ion channels, acetylcholine receptors, and adrenergic receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis. BMC Med Genet. 2016 Nov 11;17(1):79. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5105265/ (Full article)

 

Single nucleotide polymorphisms and genotypes of transient receptor potential ion channel and acetylcholine receptor genes from isolated B lymphocytes in myalgic encephalomyelitis/chronic fatigue syndrome patients

Abstract:

OBJECTIVE: The pathomechanism of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is unknown; however, a small subgroup of patients has shown muscarinic antibody positivity and reduced symptom presentation following anti-CD20 intervention. Given the important roles of calcium (Ca2+) and acetylcholine (ACh) signalling in B cell activation and potential antibody development, we aimed to identify relevant single nucleotide polymorphisms (SNPs) and genotypes in isolated B cells from CFS/ME patients.

METHODS: A total of 11 CFS/ME patients (aged 31.82 ± 5.50 years) and 11 non-fatigued controls (aged 33.91 ± 5.06 years) were included. Flow cytometric protocols were used to determine B cell purity, followed by SNP and genotype analysis for 21 mammalian TRP ion channel genes and nine mammalian ACh receptor genes. SNP association and genotyping analysis were performed using ANOVA and PLINK analysis software.

RESULTS: Seventy-eight SNPs were identified in nicotinic and muscarinic acetylcholine receptor genes in the CFS/ME group, of which 35 were in mAChM3. The remaining SNPs were identified in nAChR delta (n = 12), nAChR alpha 9 (n = 5), TRPV2 (n = 7), TRPM3 (n = 4), TRPM4 (n = 1) mAChRM3 2 (n = 2), and mAChRM5 (n = 3) genes. Nine genotypes were identified from SNPs in TRPM3 (n = 1), TRPC6 (n = 1), mAChRM3 (n = 2), nAChR alpha 4 (n = 1), and nAChR beta 1 (n = 4) genes, and were located in introns and 3′ untranslated regions. Odds ratios for these specific genotypes ranged between 7.11 and 26.67 for CFS/ME compared with the non-fatigued control group.

CONCLUSION: This preliminary investigation identified a number of SNPs and genotypes in genes encoding TRP ion channels and AChRs from B cells in patients with CFS/ME. These may be involved in B cell functional changes, and suggest a role for Ca2+ dysregulation in AChR and TRP ion channel signalling in the pathomechanism of CFS/ME.

© The Author(s) 2016.

 

Source: Marshall-Gradisnik S, Johnston S, Chacko A, Nguyen T, Smith P, Staines D. Single nucleotide polymorphisms and genotypes of transient receptor potential ion channel and acetylcholine receptor genes from isolated B lymphocytes in myalgic encephalomyelitis/chronic fatigue syndrome patients. J Int Med Res. 2016 Nov 10. pii: 0300060516671622. [Epub ahead of print] https://www.ncbi.nlm.nih.gov/pubmed/27834303

 

Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels

Abstract:

Transient receptor potential melastatin subfamily 3 (TRPM3) ion channels play a role in calcium (Ca2+ ) cell signalling. Reduced TRPM3 protein expression has been identified in chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) patients. However, the significance of TRPM3 and association with intracellular Ca2+ mobilization has yet to be determined.

Fifteen CFS/ME patients (mean age 48·82 ± 9·83 years) and 25 healthy controls (mean age 39·2 ± 12·12 years) were examined. Isolated natural killer (NK) cells were labelled with fluorescent antibodies to determine TRPM3, CD107a and CD69 receptors on CD56dim CD16+ NK cells and CD56bright CD16dim/- NK cells. Ca2+ flux and NK cytotoxicity activity was measured under various stimulants, including pregnenolone sulphate (PregS), thapsigargin (TG), 2-aminoethoxydiphenyl borate (2APB) and ionomycin.

Unstimulated CD56bright CD16dim/- NK cells showed significantly reduced TRPM3 receptors in CFS/ME compared with healthy controls (HC). Ca2+ flux showed no significant difference between groups. Moreover, PregS-stimulated CD56bright CD16dim/- NK cells showed a significant increase in Ca2+ flux in CFS/ME patients compared with HC. By comparison, unstimulated CD56dim CD16+ NK cells showed no significant difference in both Ca2+ flux and TRPM3 expression. PregS-stimulated CD56dim CD16+ NK cells increased TRPM3 expression significantly in CFS/ME, but this was not associated with a significant increase in Ca2+ flux.

Furthermore, TG-stimulated CD56dim CD16+ NK cells increased K562 cell lysis prior to PregS stimulation in CFS/ME patients compared with HC. Differential expression of TRPM3 and Ca2+ flux between NK cell subtypes may provide evidence for their role in the pathomechanism involving NK cell cytotoxicity activity in CFS/ME.

© 2016 The Authors. Clinical & Experimental Immunology published by John Wiley & Sons Ltd on behalf of British Society for Immunology.

 

Source: Nguyen T, Johnston S, Clarke L, Smith P, Staines D, Marshall-Gradisnik S. Impaired calcium mobilization in natural killer cells from chronic fatigue syndrome/myalgic encephalomyelitis patients is associated with transient receptor potential melastatin 3 ion channels. Clin Exp Immunol. 2017 Feb;187(2):284-293. doi: 10.1111/cei.12882. Epub 2016 Nov 23. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5217865/ (Full article)