Important Research
2023
Brainstem volume changes in ME/CFS and long COVID patients
Thapaliya, Marshall-Gradisnik, Barth, Eaton-Fitch & Barnden (Australia) 02 March 2023 -“We observed a larger volume for the whole brainstem and pons in ME/CFS patients compared with Healthy Controls. … The brainstem contains the nuclei of the reticular activation system which control arousal, the sleep/wake cycle, gait, and memory via cortical connections and cardio-respiratory function (Costa et al., 1995; Garcia-Rill et al., 2013, 2016). Therefore, brainstem dysfunction is consistent with the symptoms experienced by ME/CFS patients including cognitive dysfunction, sleep disturbance, orthostatic intolerance, and dyspnea. … The brainstem regulates respiratory, cardiovascular, gastrointestinal, and neurological processes and its impairment can explain the overlapping symptoms of ME/CFS and long COVID.”
Symptom-based clusters in people with ME/CFS: an illustration of clinical variety in a cross-sectional cohort
Vaes, Ban Herck, Deng, Delbressine, Jason & Spruit (Netherlands & US) 10 February 2023 – “This study demonstrated that in ME/CFS there are subgroups of patients displaying a similar pattern of symptoms. These symptom-based clusters were confirmed in an independent ME/CFS sample. Classification of ME/CFS patients according to severity and symptom patterns might be useful to develop tailored treatment options. … “
Developing a blood cell-based diagnostic test for myalgic encephalomyelitis/chronic fatigue syndrome using peripheral blood mononuclear cells (preprint)
Xu, Lodge, Kingdon … & Morten (U.K.) -23 March 2023 – “In this study, we utilized a single-cell Raman platform and artificial intelligence to analyze blood cells from 98 human subjects, including 61 ME/CFS patients of varying disease severity and 37 healthy and disease controls. Our results demonstrate that Raman profiles of blood cells can distinguish between healthy individuals, disease controls, and ME/CFS patients with high accuracy (91%), and can further differentiate between mild, moderate, and severe ME/CFS patients (84%).”
ME/CFS and fibromyalgia: PR3-versus MPO-ANCA-associated vasculitis, an exploratory cross-sectional study
van Eeden, Mohazab, Redmond, … & Tervaert (Canada) -27 February 2023 – “We believe this to be the first manuscript investigating the presence of both ME/CFS and fibromyalgia in AAV patients. All our AAV patients had inactive disease (BVAS = 0), yet we found that over half of [them] fulfil the diagnostic criteria for ME/CFS, and that a third of those patients suffered from fibromyalgia.”
MEI ~ ANCA vasculitis is a type of autoimmune disease that causes swelling or inflammation of small blood vessels.
Urine Metabolomics Exposes Anomalous Recovery after Maximal Exertion in Female ME/CFS Patients
Glass, Germain, Huang & Hanson (US) – CCC – 12 February 2023 – “Using a linear mixed effects model, pathway enrichment analysis, topology analysis, and correlations between urine and plasma metabolite levels, significant differences were discovered between controls and ME/CFS patients in many lipid (steroids, acyl carnitines and acyl glycines) and amino acid subpathways (cysteine, methionine, SAM, and taurine; leucine, isoleucine, and valine; polyamine; tryptophan; and urea cycle, arginine and proline). Our most unanticipated discovery is the lack of changes in the urine metabolome of ME/CFS patients during recovery while significant changes are induced in controls after CPET, potentially demonstrating the lack of adaptation to a severe stress in ME/CFS patients.”
Symptom-based clusters in people with ME/CFS: an illustration of clinical variety in a cross-sectional cohort
Vaes, Ban Herck, Deng, Delbressine, Jason & Spruit (Netherlands & US) 10 February 2023 – “This study demonstrated that in ME/CFS there are subgroups of patients displaying a similar pattern of symptoms. These symptom-based clusters were confirmed in an independent ME/CFS sample. Classification of ME/CFS patients according to severity and symptom patterns might be useful to develop tailored treatment options.
Deficient butyrate-producing capacity in the gut microbiome is associated with bacterial network disturbances and fatigue symptoms in ME/CFS
Guo, Che, Briese, … & Williams (US) – 08 February 2023 – “The study included stool samples from 106 ME/CFS cases who met both the 1994 CDC and the 2003 Canadian Consensus criteria for ME/CFS”
- ME/CFS patients have substantial gut microbiome dysbiosis
- Bacterial abundances, functions, SCFAs and species interactions deviate in ME/CFS
- Reduced F. Prausnitzii and E. rectale in ME/CFS may contribute to butyrate deficiency
- Low F. Prausnitzii abundance correlates with more severe fatigue symptoms in ME/CFS
Endothelial dysfunction in ME/CFS patients
Sandvik, Sørland, Leirgul, … & Fluge (Norway) -02 February 2023 – “The study was a substudy of the RituxME trial, a national, multicenter, randomized, double-blind, placebo-controlled phase III study on the effect of rituximab vs. placebo in ME/CFS patients in Norway. … ME/CFS patients had reduced macro- and microvascular endothelial function, indicating that vascular homeostasis may play a role in the clinical presentation of this disease.”
Circulating microRNA expression signatures accurately discriminate ME from FM comorbid conditions
Nepotchatykh, Caraus, Elremaly, … & Moreau (Canada) – 02 February 2023 – “The results of this study demonstrate that ME/CFS and FM are two distinct illnesses, and we highlight the comorbidity between the two conditions. Proper diagnosis of patients suffering from ME/CFS, FM or ME/CFS + FM is crucial to elucidate the pathophysiology of both diseases, determine preventive measures, and establish more effective treatments.”
Stress-Induced Transcriptomic Changes in Females with ME/CFS Reveal Disrupted Immune Signatures
Van Booven, Gamer, Joseph, Perez, Zarnowski, Pandya, Collado, Klimas, Oltra & Nathanson (USA & Spain) 25 January 2023 – “During recovery, ME/CFS immune cells have dysfunctional cytokine signaling networks and are vulnerable to cell death due to poor defense systems and dysregulated epigenetic regulation of apoptotic pathways.”
Altered Fatty Acid Oxidation in Lymphocyte Populations of ME/CFS
Maya, Leddy, Gottschalk, Peterson and Hanson (USA) -16 January 2023 – “These findings provide support for metabolic dysfunction in ME/CFS immune cells. We further hypothesize about the consequences that these altered fuel dependencies may have on T and NK cell effector function, which may shed light on the illness’s mechanism of action.”
2022
Connectivity between Salience and Default Mode Networks and subcortical nodes distinguishes between two classes of ME/CFS
Su, Thapaliza, Eaton-Fitch, Marshall-Gradisnik and Barnden (Australia) 13 December 2022 – “In this study, we acquired resting state and task fMRI with an advanced scanner for improved subject numbers: 24 healthy controls (HC) and 42 ME/CFS patients, … Different regulatory connections are consistent with the impaired cognitive performance and sleep-wake cycle of ME/CFS. This is the first objective medical evidence that the questionnaire-based diagnosis does indeed differentiate between two different disease states. This facilitates a clearer understanding of ME/CFS and can better direct research and therapy development.”
The occurrence of hyperactivated platelets and fibrinaloid microclots in ME/CFS
Nunes, Kruger, Proal, Kell & Pretorius (US, UK, South Africa & Denmark) This offers insight into abnormalities found in the blood of #pwME. The paper entitled “The occurrence of hyperactivated platelets and fibrinaloid microclots in ME/CFS” used patients recruited via the ME/CFS Foundation of South Africa and were asked to complete the International Consensus Criteria (ICC) questionnaire to gain an understanding of their perspective of disease severity.
The study showed “The presence of fibrinaloid microclots and associated coagulation issues are present in ME/CFS, and point to a systemic vascular pathology and endothelial inflammation.”.
This paper follows-up on findings in patients with Long Covid and showed a comparison of results stated as: “However, it is important to note that the fibrinaloid burden in ME/CFS seems to be less than that present in LongCovid/PASC”
Ensuring the Voice of the Very Severely Affected ME/CFS Patient Is Heard in Research – A Research Model
Helen Baxter (UK) – ME-I: 08 July 2022 – “By making the necessary reasonable adjustments, such as direct outreach and the option to complete the questionnaire by telephone or texting, very severely affected patients were enabled to participate and provided invaluable contributions. This study aimed to act as a model for future researchers.”
The higher resting heart rate in ME/CFS patients compared to healthy controls: relation with stroke volumes
van Campen & Visser (Neatherlands) – “Already at rest heart rate in patients developing POTS [postural orthostatic tachycardia syndrome] during tilt-testing were higher compared to the patients with a normal heart rate and blood pressure response per unit of SVI [stroke volume index], but the heart rate of the majority of all patients fell within the limits of normal of healthy controls. The difference of patients with heart rate above the upper limit versus between the upper limit and lower limit deserves further investigation and may have therapeutic implications.”
Animal Models for Neuroinflammation and Potential Treatment Methods
Tamura, Yamato & Kataoka (Japan) – 27 June 2022 – “The pathogenesis of ME/CFS is linked with viral or bacterial infection-induced neuroinflammation…. Neuroinflammation is thought to be mitigated by suppressing immune response in the central nervous system as well as in the periphery. Herein, we reviewed the anti-inflammatory effects of three compounds using animal models and highlight the potential of these anti-inflammatory drugs to alleviate symptoms in patients with ME/CFS.”
Alteration of Cortical Volume and Thickness in ME/CFS
Thapaliya, Staines, Marshall-Gradisnik, Su & Barnden (Australia) – 22 April 2022 – “Our study detected significantly reduced cortical volume and thickness in ME/CFS patients compared with HC. We found that amygdala volume was significantly higher in ME/CFS patients. We also observed that cortical volume and thickness relationships were abnormal in regressions with clinical and autonomic measures. Overall, our findings suggest altered cortical volume and thickness in ME/CFS patients relative to heathy controls.”
Impaired TRPM3-dependent calcium influx and restoration using Naltrexone in natural killer cells of ME/CFS patients
Eaton-Fitch, Du Preez, Cabanas, Muraki, Staines & Marshall-Gradisnik (Australia, France & Japan) – 16 February 2022 – “TRPM3-dependent Ca2+ influx was restored in ME/CFS patients following overnight treatment of isolated NK cells with NTX in vitro. Collectively, these findings validate that TRPM3 loss of function results in altered Ca2+ influx supporting the growing evidence that ME/CFS is a TRP ion channel disorder and that NTX provides a potential therapeutic intervention for ME/CFS”
For more info see this video by researchers explaining their TRPM research at https://www.youtube.
Psychogenic Pseudosyncope: Real or Imaginary? Results from a Case-Control Study in ME/CFS Patients
van Campen & Visser (The Netherlands) -09 January 2022 “Furthermore, we speculate that the misperceptions that ME/CFS has a behavioral or psychiatric origin may have contributed to the long delay before the proper diagnosis was reached. … The abnormal cerebral blood flow reduction while being upright makes it clear, that the origin of the attacks might not be behavioral or psychogenic, but have a clear somatic pathophysiologic background. This must be taken into consideration in patients with frequent syncopal spells and the extracranial Doppler measurements before and at end-tilt have the potential to improve the evaluation of recurrent syncope and presyncope, and might avoid misdiagnosis of a behavioral origin.”
Muscle sodium content in patients with ME/CFS
Patient selection -Petter, Scheibenbogen, Linz, Stehning, Wirth, Kuehne and Kelm (Germany) – 09 December 2022 – “Muscle sodium content before and after exercise was higher in ME/CFS than in healthy controls. Furthermore, our findings indicate an inverse correlation between muscle sodium content and handgrip strength. These findings provide evidence that sodium overload may play a role in the pathophysiology of ME/CFS and may allow for potential therapeutic targeting.”
Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome
Patient selection Apostolou, Rizwan, Moustardas, Sjorgen, Bertilson, Bragee, Polo and Rosen (Sweden) – 20 October 2022 – “Reactivation of human herpesviruses 1-6 (HSV1, HSV2, VZV, EBV, CMV, HHV6), and human endogenous retrovirus K (HERV-K) was detected by anti-viral antibody fingerprints in saliva… Our results denote an altered and chronically aroused anti-viral profile against latent viruses in ME/CFS. … This has not been shown before because the antibody elevation is not detected systemically in the circulation/plasma.”
A prospective observational study of post-COVID-19 chronic fatigue syndrome following the first pandemic wave in Germany and biomarkers associated with symptom severity
Patient selection –
Kedor, Freitag, Meyer-Arndt … Bellmann-Strobl & Scheibenbogen (Germany) – 30 August 2022 – “19 post-COVID-19 syndrome patients [out of 42] fulfill the 2003 Canadian Consensus Criteria for ME/CFS. Disease severity and symptom burden is similar in post-COVID-19 syndrome-ME/CFS and non-COVID-19- ME/CFS patients.”
“Hand grip strength is diminished in most patients compared to normal values in healthy. Association of hand grip strength with hemoglobin, interleukin 8 and C-reactive protein in post-COVID-19 syndrome/non-myalgic encephalomyelitis/chronic fatigue syndrome and with hemoglobin, N-terminal prohormone of brain natriuretic peptide, bilirubin, and ferritin in post-COVID-19 syndrome/myalgic encephalomyelitis/chronic fatigue syndrome may indicate low level inflammation and hypoperfusion as potential pathomechanisms.”
Metabolic Evidence for Peroxisomal Dysfunction in ME/CFS
Che, Brydges, Yu, Price, Joshi, Roy, Lee, Barupal, Cheng, Palmer, Levine, Peterson, Vernon, Bateman, Hornig, Montoya, Komaroff, Fiehn & Lipkin (USA) – 18 July 2022 – “Our findings indicate a series of interconnected metabolic alterations in people with ME/CFS that may contribute to the pathogenesis of ME/CFS: (i) reduced levels of plasmalogens, unsaturated phospholipid ethers, and carnitines suggest peroxisomal dysfunction; (ii) reductions in levels of PCs indicate dysregulation of CDP-choline pathway, and (iii) elevations in the levels of dicarboxylic acids, particularly the TCA cycle intermediates alpha-ketoglutarate and succinate, consistent with an impairment in the TCA cycle that may contribute to physical and cognitive fatigue.”
Revisiting IgG Reactivity to Epstein-Barr Virus in ME/CFS and Its Potential Application to Disease Diagnosis
Sepulveda, Malato, Sotzny, Grabowska, Fonseca, Cordeiro, Graca, Biecek, Behrends, Mautner, Westermeier, Lacerda & Scheibenbogen (Poland, Portugal, Germany, Austria, Chile, UK) – 24 June 2022 – “Thus, given the heterogeneous nature of ME/CFS, it is pivotal to stratify patients adequately, based on age, gender, and disease trigger for biomarker discovery…. An implication of having a different antibody profiling between men and women is that analysis of each gender should be performed separately. … In conclusion, this study identified two candidate antigens whose antibodies could be used to identify ME/CFS patients with an infectious trigger. To strengthen our findings, two other cohorts of patients are currently studied, including the well-characterized ME/CFS patients with different disease triggers and healthy controls from the United Kingdom ME/CFS biobank.”
Survey of Anti-Pathogen Antibody Levels in ME/CFS
O’Neal, Glass, Emig, Vitug, Henry, Shungu, Mao, Levine & Hanson (USA) – 10 June 2022 – “While most of the differences were not significant, the opposite trends between male and female antibody levels indicate it is inappropriate to combine data from the two sexes. … Age-based cohort stratification provides additional insight into humoral immune biology, with a large number of antigens identified with significantly different antibody levels between subjects under 50 and those over 50. … The subtle serological alterations between healthy controls and ME/CFS subjects found here should be interpreted cautiously, but these findings do contribute to the growing body of evidence that the immune system of ME/CFS patients is dysregulated.”
The Pathobiology of ME/CFS: The Case for Neuroglial Failure
Renz-Polster, Tremblay, Bienzle & Fischer (Germany & Canada) – 09 May 2022 – “From this review we conclude that the multifaceted pathobiology of ME/CFS may be attributable in a unifying manner to neuroglial dysfunction. Because the two key features – post exertional malaise and decreased cerebral blood flow – are also recognized in a subset of patients with post-acute sequelae COVID, we suggest that our findings may also be pertinent to this entity.”
Diagnosis of ME/CFS Syndrome With Partial Least Squares Discriminant Analysis: Relevance of Blood Extracellular Vesicles
Gonzalez-Cebrian, Almenar-Perez, Xu, Y, Huang, Gimenez-Orenga, Hutchinson, Lodge, Nathanson, Morten, Ferrer & Oltra (Spain, U.K. & U.S.) – 01 April 2022 – Possible biomarker using extracellular vesicles (EV) – “Strikingly, EV physical features, including EV size and z-potential measures were detected by this model as relevant features for the effective diagnosis of patients indicating a potential important role of EVs in ME/CFS.”
Decreased NO production in endothelial cells exposed to plasma from ME/CFS patients
Rayhan and Baraniuk (Chile, Canada, Austria & Poland) – April 2022 – “In conclusion, this study in vitro shows a decreased NO production in HUVECs exposed to plasma from ME/CFS patients, suggesting an unreported role of eNOS in the pathophysiology of this disease. … Study references indicates the following patient selection:
Plasma metabolomics reveals disrupted response and recovery following maximal exercise in ME/CFS
Germain, Giloteaux, Moore, Levine, Chia, Keller, Stevens, Franconi, Mao, Shungu, Grimson and Hanson (U.S.) – 31 March 2022 – “The effects of exertion in the ME/CFS cohort predominantly highlighted lipid-related as well as energy-related pathways and chemical structure clusters, which were disparately affected by the first and second exercise sessions. The 24-hour recovery period was distinct in the ME/CFS cohort, with over a quarter of the identified pathways statistically different from the controls. The pathways that are uniquely different 24 hours after an exercise challenge provide clues to metabolic disruptions that lead to PEM. Numerous altered pathways were observed to depend on glutamate metabolism, a crucial component of the homeostasis of many organs in the body, including the brain.”
IgG stimulated β2 adrenergic receptor activation is attenuated in patients with ME/CFS
Hartwig, Sotzny, Bauer, Heidecke, Riemekasten, Dragun, Meisel, Dames, Grabowski and Scheibenbogen (Germany) – 05 February 2022 – “There is emerging evidence of a network of natural autoantibodies against GPCR [G-protein coupled receptors] which is dysregulated in various diseases. β2 adrenergic and M3 and M4 cholinergic receptor (β2 AdR and M3/4 mAChR) antibodies were found to be elevated in a subset of ME/CFS patients. … We provide evidence that IgG can activate β2 AdR. The β2 AdR activation by IgG is attenuated in ME/CFS patients. A dysregulation of β2 AdR function could explain many symptoms of ME/CFS.”
2021
The maintained attention assessment in patients affected by ME/CFS: a reliable biomarker?
Murga, Aranburu, Gargiulo, Gomex-Esteban & Lafuente (Spain & Argentina) – 04 December 2021 – “There were no significant differences between genders in GIAP or fatigue for CFS/ME; however, sick women perceive cognitive effort higher than men. Deficits in sustained attention and the perception of fatigue, so effort after performing the proposed test are a sensitive and reliable indicator that allows us to substantiate a clinical suspicion and refer patients for further studies in order to confirm or rule out CFS/ME.”
Characterization of IL-2 Stimulation and TRPM7 Pharmacomodulation in NK Cell Cytotoxicity and Channel Co-Localization with PIP2 in ME/CFS Patients
Du Preez, Eaton-Fitch, Cabanas, Staines & Marshall-Gradisnik (Australia & France) -12 November 2021 – “Importantly, these current data, along with previous studies reporting TRP dysfunction and altered expression patterns in the NK cells of ME/CFS patients provide evidence for potential channelopathy as the pathomechanism for ME/CFS. Prospective Ca2+ influx assays, isotyping, and patch-clamp electrophysiology provide additional avenues for further characterizing TRPM7 in the pathomechanism of this illness for possible targeted pharmacotherapeutic interventions for the treatment of ME/CFS.”
Limbic Perfusion Is Reduced in Patients with ME/CFS
Xia Li, Per Julin & Tie-Qiang Li (Sweden & China) – 01 November 2021 – “The differences in the rCBF [regional cerebral blood flow] between the ME/CSF patients and healthy controls were statistically assessed with voxel-wise and AAL ROI-based two-sample t-tests. Linear regression analysis was also performed on the rCBF data by using the symptom severity score as the main regressor. In comparison with the healthy controls, the patient group showed significant hypoperfusion (uncorrected voxel wise p ≤ 0.001, FWE p ≤ 0.01) in several brain regions of the limbic system, including the anterior cingulate cortex, putamen, pallidum, and anterior ventral insular area. For the ME/CFS patients, the overall symptom severity score at rest was significantly associated with a reduced rCBF in the anterior cingulate cortex. The results of this study show that brain blood flow abnormalities in the limbic system may contribute to ME/CFS pathogenesis.”
Cerebral blood flow remains reduced after tilt testing in ME/CFS patients
van Campen, Rowe & Visser (The Netherlands & U.S.) – October 2021 – “The finding that orthostatic stress elicits a post-stress cerebral blood flow reduction and that disease severity greatly influences the cerebral blood flow reduction may have implications on the advice of energy management after a stressor and on the advice of lying down after a stressor in these ME/CFS patients.”
Potential Implications of Mammalian Transient Receptor Potential Melastatin 7 in the Pathophysiology of ME/CFS: A Review
Du Preez, Cabanas, Staines, & Marshall-Gradisnik (Australia & France) – 12 October 2021 – “In this review, we present TRPM7 as a potential candidate in the pathomechanism of ME/CFS, as TRPM7 is increasingly recognized as a key mediator of physiological and pathophysiological mechanisms affecting neurological, immunological, cardiovascular, and metabolic processes. A focused examination of the biochemistry of TRPM7, the role of this protein in the aforementioned systems, and the potential of TRPM7 as a molecular mechanism in the pathophysiology of ME/CFS will be discussed in this review. TRPM7 is a compelling candidate to examine in the pathobiology of ME/CFS as TRPM7 fulfils several key roles in multiple organ systems, and there is a paucity of literature reporting on its role in ME/CFS.”
Diffusion Tensor Imaging Reveals Neuronal Microstructural Changes in ME/CFS
Thapaliya, Marshall-Gradisnik, Staines & Barnden (Australia) – 06 August 2021 – “In this study, we evaluated [Diffusion Tensor Imaging] DTI parameters to investigate microstructural abnormalities in ME/CFS patients. Our study demonstrated that DTI parameters are sensitive to microstructural changes in ME/CFS-ICC and could potentially act as an imaging biomarker of abnormal pathophysiology in ME/CFS. The group analysis using a voxel-based method detected differences in diffusion metrics in ascending and descending tracts in the medulla, pons and midbrain of the brainstem in ME/CFS patients.”
Evaluating Routine Blood Tests According to Clinical Symptoms and Diagnostic Criteria in Individuals with ME/CFS
Baklund, Dammen, Moum, Kristiansen, Duarte, Castro-Marrero, Helland & Strand
(Norway, Spain) 14 July 2021 – Results of several routine blood tests of ME/CFS patients differed from those healthy controls. Our findings particularly highlight that decreased creatinine and CK levels may indicate greater muscle damage and metabolic disturbances in ME/CFS patients and is worthy of future studies. This is also true of results that may indicate a possible low-grade inflammation in ME/CFS patients.”
Elements of Suffering in ME/CFS: The Experience of Loss, Grief, Stigma, and Trauma in the Severely and Very Severely Affected
Fennell, Dorr & George (USA) — 09 May 2021 – “This review article examines the suffering of patients with ME/CFS through the lens of the Fennell Four-Phase Model of chronic illness. Using a systems approach, this phase framework illustrates the effects of suffering on the patient and can be utilized to help the clinician, patient, family, and caregivers understand and respond to the patient’s experiences. We highlight the constructs of severity, uncertainty, ambiguity, and chronicity and their role in the suffering endured by patients with ME/CFS.”
Deconditioning does not explain orthostatic intolerance in ME/CFS
van Campen, Rowe & Visser (Netherlands, USA) 04 May 2021 – This study shows that in ME/CFS patients orthostatic intolerance is not caused by deconditioning as defined on cardiopulmonary exercise testing. An abnormal high decline in cerebral blood flow during orthostatic stress was present in all ME/CFS patients regardless of their %peak VO2 results on cardiopulmonary exercise testing.
Effects of Post-Exertional Malaise on Markers of Arterial Stiffness in Individuals with ME/CFS
Bond, Nielsen, and Hodges
(New Zealand) March 2021 – “The current study builds upon the growing evidence that patients with ME/CFS may suffer from impaired vascular function which remains unchanged following exercise. We have shown that ME/CFS patients may experience altered vascular responses following aerobic exercise, contrary to what is seen in healthy populations. This is thought to be a result of the increased presence of oxidative stress and low-grade vascular inflammation, which may be exacerbated by exercise and contribute to the onset of PEM.”
Skewing of the B cell receptor repertoire in ME/CFS
Sato, Ono, Matsutani, Nakamura, Shin, Amano, Suzuki & Yamamura
(Japan) – 27 March 2021 – Conclusion: “… we revealed a biased usage of several IGHV genes in peripheral blood B cells from ME/CFS patients. Results of receiver operating characteristic (ROC) analysis further indicated a possibility of distinguishing patients from healthy controls, based on the skewed B cell repertoire.”
Open-label study with the monoamine stabilizer (-)-OSU6162 in ME/CFS
Haghighi, Forsmark, Zachrisson, Carlsson, Nilsson, Carlsson, Schuit & Gottfries
(Sweden, The Netherlands) -02 February 2021 – Conclusion: “‐OSU6162 is well tolerated in ME/CFS patients and shows promise as a novel treatment to mitigate fatigue and improve mood and health‐related quality of life in ME/CFS. Obviously, the present results need to be confirmed in future placebo‐controlled double‐blind trials.”
2020
Deep phenotyping of ME/CFS in Japanese population
Kitami, Fukuda, Kato, Yamaguti, Nakatomi, Yamano, Kataoka, Mizuno, Tsuboi, Kogo, Suzuki, Itoh, Morioka, Kawaji, Koseki, Kikuchi, Hayashizaki, Ohno, Kuratsune & Watanabe (Japan) 16 November 2020 – Conclusion: “Our study points to a cluster of sleep-related molecular changes as a prominent feature of ME/CFS in our Japanese cohort.”
The Economic Impacts of ME/CFS in an Australian Cohort
Close, Marshall-Gradisnik, Byrnes, Smith, Nghiem & Staines (Australia) – 21 August 2020 – Conclusion: The economic impacts of ME/CFS in Australia are significant. Improved understanding of the illness pathology, diagnosis, and management, may reduce costs, improve patient prognosis and decrease the burden of ME/CFS in Australia.
Validation of the Severity of ME/CFS by Other Measures than History: Activity Bracelet, Cardiopulmonary Exercise Testing and a Validated Activity Questionnaire: SF-36
van Campen, Rowe & Visser (Netherlands, USA) – 14 August 2020 – This study confirms the validity of the ICC severity grading.
Review of case definitions for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
Lim & Son (Republic of Korea) – 29 July 2020 – Conclusions: “In this review, we found three key factors that have affected ME/CFS case definitions: etiology, pathophysiology, and exclusionary disorders. These factors have impacted the specification of the main symptoms, required conditions, and range of inclusive and exclusive symptoms/disorders in the development of case definitions.”
Altered Structural Brain Networks Related to Adrenergic/Muscarinic Receptor Autoantibodies in CFS
Fujii, Sato, Kimura, Matsuda, Ota, Maikusa, Suzuki, Amano, Shin, Yamamura, Mori and Sato (Japan) – 01 July 2020 – Conclusion: “Our findings suggest that β1 AdR‐Ab and β2 AdR‐Ab are potential markers of ME/CFS.”
Cognitive Function Declines Following Orthostatic Stress in Adults With ME/CFS
van Campen, Rowe, Verheught and Visser (Netherlands, USA) – 26 June 2020 – Conclusion: “As measured by the N-back test, working memory remains impaired in adults with ME/CFS following a 30-min head-up tilt test.”
Epidemiological and Clinical Factors Associated With Post-Exertional Malaise Severity in Patients With ME/CFS
Ghali, Richa, Lacout, Gury, Beucher, Homedan, Lavigne & Urbanski (France) – 22 June 2020 – Conclusion: “We identified some epidemiological and clinical features, which were positively associated with PEM severity in subsets of ME/CFS patients. This could help improving disease management and patients’ quality of life.”
Cerebral Blood Flow Is Reduced in Severe ME/CFS Patients During Mild Orthostatic Stress Testing: An Exploratory Study at 20 Degrees of Head-Up Tilt Testing
van Campen, Rowe & Visser (Netherlands, USA) – 13 June 2020 – Conclusions: “Using a less demanding 20 degree tilt test for 15 min in severe ME/CFS patients resulted in a mean CBF decline of 27%. This is comparable to the mean 26% decline previously noted in less severely affected patients studied during a 30-min 70 degree head-up tilt. These observations have implications for the evaluation and treatment of severely affected individuals with ME/CFS.”
A Unifying Hypothesis of the Pathophysiology of ME/CFS: Recognitions from the finding of autoantibodies against ß2-adrenergic receptors
Wirth & Scheibenbogen (Germany) – 01 April 2020 – This is a compilation of many studies.
Changes in DNA methylation profiles of ME/CFS patients reflect systemic dysfunctions
Helliwell, Sweetman, Stockwell, Edgar, Chatterjee & Ta (New Zealand) – 04 November 2020 – Major differences were identified in the DNA methylation patterns of ME/CFS patients that clearly distinguished them from the healthy controls.
A SWATH-MS analysis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction
Sweetman, Kleffmann, Edgar, de Lange, Vallings and Tate (New Zealand) – 24 September 2020
A systematic review of neurological impairments in myalgic encephalomyelitis/ chronic fatigue syndrome using neuroimaging techniques
Maksoud, du Preez, Eaton-Fitch, Thapaliya, Barnden, Cabanas, Staines, and Marshall-Gradisnik (Australia) – 30 April 2020
Intravenous Cyclophosphamide in ME/CFS. An Open-Label Phase II Study
Rekeland, Fosså, Lande, Ktoridou-Valen, Sørland, Holsen, Tronstad, Risa, Alme, Viken, Lie, Dahl, Mella and Fluge (Norway) – 29 April 2020
The effect of ME/CFS severity on cellular bioenergetic function
Thomas, Elson, Straasheim, Newton and Walker (UK, USA) – 10 April 2020
Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in ME/CFS
Schreiner, Harrer, Scheibenbogen, Lamer, Schlosser, Naviaux and Prusty (Germany, USA) – 23 April 2020
Assessing diagnostic value of microRNAs from peripheral blood mononuclear cells and extracellular vesicles in ME/CFS
Almenar-Pérez, Sarría, Nathanson & Oltra (Spain, USA) – 07 February 2020
An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients
Missailidis, Annesley, Allan, Sanislav, Lidbury, Lewis, and Fisher (Australia) – 06 February 2020
Cell-Based Blood Biomarkers for ME/CFS
Missailidis, Sanislav, Allan, Annesley and Fisher (Australia) – 03 February 2020
2019
Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with ME/CFS
Ghali, Lacout, Ghali, Gury, Beucher, Lozac’h, Lavigne & Urbanski (France) –
11 December 2019
Reduced glycolytic reserve in isolated natural killer cells from ME/CFS patients: A preliminary investigation
Nguyen, Staines, Johnston & Marshall-Gradisnik (Australia) – June 2019
Diagnostic sensitivity of 2-day cardiopulmonary exercise testing in ME/CFS
Nelson, Buckley, Thomson, Clark, Kwiatek & Davison (Australia) – 14 March 2019
ME/CFS patients exhibit altered T cell metabolism and cytokine associations
Mandarano, Maya, Giloteaux, Peterson, Maynard, Gottschalk & Hanson (U.S.) – 12 December 2019 – “… To investigate immune metabolism in ME/CFS, we isolated CD4+ and CD8+ T cells from 53 patients with ME/CFS and 45 healthy controls. We analyzed glycolysis and mitochondrial respiration in resting and activated T cells, along with markers related to cellular metabolism and plasma cytokines. We found that ME/CFS CD8+ T cells had reduced mitochondrial membrane potential compared with those from healthy controls. Both CD4+ and CD8+ T cells from patients with ME/CFS had reduced glycolysis at rest, whereas CD8+ T cells also had reduced glycolysis following activation. Patients with ME/CFS had significant correlations between measures of T cell metabolism and plasma cytokine abundance that differed from correlations seen in healthy control subjects. Our data indicate that patients have impaired T cell metabolism consistent with ongoing immune alterations in ME/CFS that may illuminate the mechanism behind this disease.”
Transient receptor potential melastatin 2 channels are overexpressed in ME/CFS patients
Balinas, Cabanas, Staines and Marshall-Gradisnik (Australia) – 03 December 2019
Naltrexone [NTX] Restores Impaired Transient Receptor Potential Melestatin 3 Ion Channel Function in Natural Killer Cells From ME/CFS Patients Cabanas, Muraki, Staines and Marshall-Gradisnik (Australia & Japan) – 31 October 2019 – “… we demonstrated that NTX does not act as an agonist by directly coupling on the TRPM3 ion channel gating. The opioid antagonist NTX has the potential to negate the inhibitory function of opioid receptors on TRPM3 in NK cells from ME/CFS patients, resulting in calcium signals remodeling, which will in turn affect cell functions, supporting the hypothesis that NTX may have potential for use as a treatment for ME/CFS. Our results demonstrate, for the first time, and based on novel patch clamp electrophysiology, potential pharmaco-therapeutic interventions in ME/CFS.”
Evidence of altered cardiac autonomic regulation in ME/CFS
Patient selection – CCC
M.Nelson, J.Bahl, J.Buckley, R.Thomson & K.Davison (Australia) “… Meta-analysis revealed significant differences between patients and controls in a number of parameters, including patients having: higher RHR, HRtilt, orthostatic HR response, and LF/HF ratio; and lower HRmax, HRthreshold, HFP and RMSSD. These differences suggest an altered regulation of HR in ME/CFS patients that is suggestive of reduced vagal and increased sympathetic modulation of heart rate. … However, the results of this review suggest that there are quantifiable differences in autonomic HR regulation in ME/CFS patients, and future research in ME/CFS populations should therefore focus on determining if there are additional HR parameters which have diagnostic utility in this group.”
HFP = high frequency power of heart rate variability, HRmax = maximal heart rate, HRmentaltask = heart rate during mental task, HRtilt = heart rate during head-up tilt testing, LF/HF = ratio between low frequency and high frequency power of heart rate variability analysis, RHR = resting heart rate, RMSSD = root mean of the sum of squares of beat to beat deviations
Abnormal blood lactate accumulation during repeated exercise testing in ME/CFS
Patient selection
Lien, Johansen, Veierød, Haslestad, Bøhn, Melsom, Kardel and Iversen (Norway) – 03 June 2019
2018
Blood Volume Status in ME/CFS Correlates With the Presence or Absence of Orthostatic Symptoms: Preliminary Results
M.C. van Campen, Rowe & Visser (Netherlands, USA) – 15 November 2018
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – Evidence for an autoimmune disease
F.Sotzny, J.Blanco, E.Capelli, J.Castro-Marrero, S.Steiner, M.Murovska & C.Scheibenbogen on behalf of EUROMENE (Germany, Spain, Italy & Latvia) – June 2018
Decreased Expression of TRPM3 and mAChRM3 in the Small Intestine in CFS/ME
S. Marshall-Gradisnik, M. Fretel, N. Eaton, H. Cabanas, C. Balinas, V. Gopalan, D. Petersen, R. Passmore, K. Tang, M. Haque, A. Lam, & D. Staines (Australia) – May 2018
Transient Receptor Potential Ion Channels in the Etiology and Pathomechanism of CFS/ME
Staines, Du Preez, Cabanas, Balinas, Eaton, Passmore, Maksoud, Redmayne & Marshall-Gradisnik (Australia) – 22 May 2018
The etiologic relation between disequilibrium and orthostatic intolerance in patients with ME (CFS)
Miwa & Inoue (Japan) – 26 March 2018
2017
Novel characterisation of mast cell phenotypes from peripheral blood mononuclear cells in CFS/ME patients
Nguyen, Johnston, Chacko, Gibson, Cepon, Smith, Staines & Marshall-Gradisnik (Australia) – June 2017 – Conclusions: “This preliminary study investigates mast cell phenotypes from PBMCs in healthy controls. We report significant increase of naïve MCs in moderate and severe CFS/ME patients compared with healthy controls. Moreover, a significant increase in CD40 ligand and MHC-II receptors on differentiated mast cells in severe CFS/ME patients. Peripheral MCs may be present in CFS/ME pathology however, further investigation to determine their role is required.”
Exercise – induced changes in cerebrospinal fluid miRNAs in Gulf War Illness, CFS and sedentary control subjects
Baraniuk & Shivapurkar (US) – 10 November 2017
Cytokine signature associated with disease severity in CFS patients
Montoya, Holmes, Anderson, Maecker, Rosenberg-Hasson, Valencia, Chu, Younger, Tato & Davis (US) – 28 June 2017
2016
Autonomic correlations with MRI are abnormal in the brainstem vasomotor centre in CFS
Barndena, Kwiatekc, Croucha, Burnet & Del Fante (Australia) – 2016
A Preliminary Comparative Assessment of the Role of CD8+ T Cells in CFS/ME and MS
Brenu, Broadley, Nguyen, Johnston, Ramos, Staines & Marshall-Gradisnik (Australia) – 04 January 2016
Epidemiological characteristics of CFS/ME in Australian patients
Johnston, Staines & Marshall-Gradisnik (Australia) – 17 May 2016
Dysregulation of Protein Kinase Gene Expression in NK Cells from CFS/ME Patients
Chacko, Staines, Johnston & Marshall-Gradisnik (Australia) – 28 August 2016
Metabolic profiling indicates impaired pyruvate dehydrogenase function in ME/CFS
Fluge, Melle, Bruland, Risa, Dyrstad, … Dahl & Tronstad (Norway) – 22 December 2016
Impaired calcium mobilization in natural killer cells from CFS/ME patients is associated with transient receptor potential melastatin 3 ion channels
Nguyen, Johnston, Clarke, Smith, Staines & Marshall-Gradisnik (Australia) – 11 October 2016
Extended B cell phenotype in patients with ME/CFS: a cross-sectional study
Mensah, Bansal, Berkovitz, Sharma, Reddy, Leandro & Cambridge (England) – May 2016
2015
A Comparison of Cytokine Profiles of CFS/ME and Multiple Sclerosis Patients
Wong, Nguyen, Brenu, Broadley, Staines & Marshall-Gradisnik (Australia) – 29 October 2015
Antibodies to β adrenergic and muscarinic cholinergic receptors in patients with CFS
Loebel, Grabowski, Heidecke, Bauer, Hanitsch, Wittke, Meisel, Reinke, Volk, Fluge, Mella & Scheibenbogen (Germany, Norway) – 19 September 2015 – Results: “We found significantly higher autoantibody levels against M3 and M4 AChR and β2 AdR in CFS patients compared to controls. Crossreactivity between all 5 M and β1 and β2 AdR but also between M and β receptor was seen in a substantial portion of CFS patients as shown for M4 in Fig. 1C. The highest correlation was found between M3 and M4 receptor antibodies (r = 0.87), the lowest for M1 and M4 receptor antibodies (r = 0.59).”
Pilot Study of Natural Killer Cells in CFS/ME and Multiple Sclerosis
Huth, Brenu, Ramos, Nguyen, Broadley, Staines & Marshall‐Gradisnik (Australia) – 18 September 2015
Metabolic profiling reveals anomalous energy metabolism and oxidative stress pathways in CFS patients
=Armstrong, McGregor, Lewis, Butt & Gooley (Australia) – 30 May 2015
Characterisation of cell functions and receptors in CFS/ME
Hardcastle, Brenu, Johnston, Nguyen, Huth, Wong, Ramos, Staines & Marshall-Gradisnik (Australia) – 02 June 2015
2014
Neuroinflammation in Patients with CFS/ME: An ¹¹C-(R)-PK11195 PET Study
Nakatomi, Mizuno, Wada, Tanaka, Tazawa, Onoe, Fukuda, Kawabe, Takahashi, Kataoka, Shiomi, Yamaguti, Inaba, Kuratsune & Watanabe (Japan) – 24 March 2014
Evidence in CFS for severity-dependent upregulation of prefrontal myelination that is independent of anxiety and depression
Barnden, Crouch, Kwiatek, Burnet & Del Fante (Australia) – 18 December 2014
Oxidative and Nitrosative Stress and Immune-Inflammatory Pathways in Patients with ME/CFS
Morris & Maes (UK & Australia) – March 2014
Mitochondrial dysfunctions in ME/CFS explained by activated immuno-inflammatory, oxidative and nitrosative stress pathways
Morris & Maes (UK) – March 2014
2013
Immune Abnormalities in Patients Meeting New Diagnostic Criteria for CFS/ME
Brenu, Johnston, Hardcastle, Huth, Fuller, Ramos, Staines and Marshall-Gradisnik (Australia) – 14 November 2013