Tag: 2018

Pitfalls in cytokine measurements – Plasma TGF-β1 in chronic fatigue syndrome

Abstract:

BACKGROUND: Serum TGF-β1 concentrations are reported to be elevated in chronic fatigue syndrome (CFS). However, measurement of circulating cytokines is a complex procedure and control of pre-analytical procedures is essential. The objective of the current study was to measure circulating TGF-β1 concentrations in CFS patients compared to healthy controls, taking into account differences in pre-analytical procedures.

METHODS: Two cohorts of female CFS patients were included. In both studies patients were asked to bring a healthy, age-matched control. At baseline, TGF-β1 levels were measured in plasma and additionally P-selectin, a marker of platelet activity, was determined in a subgroup of participants.

RESULTS: 50 patients and 48 controls were included in cohort I, and 90 patients and 29 controls in cohort II. Within the cohorts there were no differences in TGF-β1 concentrations. However, between the cohorts there was a large discrepancy, which appeared to be caused by differences in g-force of the centrifuges used. The lower g-force used in cohort II (1361 g) caused more platelet activation, reflected by higher p-selectin concentrations, compared to cohort I (p < 0.0001), which was confirmed in a second independent experiment. There was a correlation between TGF-β1 and p-selectin concentrations (r 0.79, p < 0.0001).

CONCLUSION: These results demonstrate that control of pre-analytical procedures is an essential aspect when measuring circulating cytokines. No evidence for enhanced TGF-β1 in patients with CFS was found.

Source: Roerink ME, van der Schaaf ME, Hawinkels LJAC, Raijmakers RPH, Knoop H, Joosten LAB, van der Meer JWM. Pitfalls in cytokine measurements – Plasma TGF-β1 in chronic fatigue syndrome. Neth J Med. 2018 Sep;76(7):310-313. https://www.ncbi.nlm.nih.gov/pubmed/30220655

Why do some ME/CFS patients benefit from treatment with sodium dichloroacetate, but others do not?

Abstract:

Myalgic Encephalopathy/Chronic Fatigue Syndrome (ME/CFS) is an enigmatic disease the pathogenesis of which remains elusive. Pragmatic proof-of-principle of the hypothetical mechanisms causing the clinical symptoms has been delivered, but it is hard to explain why some patients do respond favourably to treatment with sodium dichloroacetate (DCA), which enhances the activity of the mitochondrial enzyme pyruvate dehydrogenase, but other patients experience no benefit from this substance.

In a prospective trial including 35 ME/CFS patients, logistic regression analysis with stepwise elimination has identified 6 pre-treatment characteristics allowing for the differentiation between responders (n = 13) and non-reponders (n = 22) with high accuracy (P < 0.0001; area under the ROC-curve = 0.92). A formula was derived generating the probability of belonging to the group of responders. This finding may assist in selecting ME/CFS patients suitable for treatment with DCA, but requires further studies as to the predictive capacity of the derived formula.

Source: Comhaire F. Why do some ME/CFS patients benefit from treatment with sodium dichloroacetate, but others do not? Med Hypotheses. 2018 Nov;120:65-67. doi: 10.1016/j.mehy.2018.08.014. Epub 2018 Aug 25. https://www.ncbi.nlm.nih.gov/pubmed/30220343

The effects of warm water immersion on blood pressure, heart rate and heart rate variability in people with chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is a central sensitisation syndrome with abnormalities in autonomic regulation of blood pressure (BP), heart rate (HR) and heart rate variability (HRV). Prior to exploring the effects of hydrotherapy as a treatment for this population, changes in BP, HR and HRV during warm water immersion need to be established.

OBJECTIVES: The study aimed to determine the effects of warm water immersion on BP, HR and HRV in adults with CFS compared to matched-pair healthy adults.

METHOD: A quasi-experimental, single-blinded study design was used with nine CFS participants and nine matched controls. Participants’ BP, HR and HRV were measured before, after 5 minutes and post warm water immersion at the depth of the fourth intercostal space, using the Ithlete® System and Dräger BP monitor.

RESULTS: There was a significant difference between groups in HRV prior to immersion (control group: 73 [55-74] vs. chronic fatigue syndrome group: 63 [50-70]; p = 0.04). There was no difference in HRV post-immersion. A significant difference in HR after immersion was recorded with the control group having a lower HR than those with CFS (78 [60-86] vs. 86 [65-112]; p = 0.03). The low HRV present in the CFS group prior to immersion suggests autonomic dysregulation. Individuals with CFS may have reduced vagal nerve activation post-immersion. During immersion, HRV of the CFS participants improved similar to that of the healthy controls.

CONCLUSION: Prior to immersion, differences were present in the HRV of the participants with CFS compared to healthy controls. These differences were no longer present post-immersion.

CLINICAL IMPLICATIONS: Warm water immersion appears safe and may be beneficial in the management of individuals with CFS.

Source: Parker R, Higgins Z, Mlombile ZNP, Mohr MJ, Wagner TL. The effects of warm water immersion on blood pressure, heart rate and heart rate variability in people with chronic fatigue syndrome. S Afr J Physiother. 2018 Aug 28;74(1):442. doi: 10.4102/sajp.v74i1.442. eCollection 2018. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6131699/ (Full article)

Successful treatment of postural orthostatic tachycardia and mast cell activation syndromes using naltrexone, immunoglobulin and antibiotic treatment

Abstract:

A patient with severe postural orthostatic tachycardia syndrome (POTS) and mast cell activation syndrome (MCAS) received immunotherapy with low-dose naltrexone (LDN) and intravenous immunoglobulin (IVIg) and antibiotic therapy for small intestinal bacterial overgrowth (SIBO). A dramatic and sustained response was documented. The utility of IVIg in autoimmune neuromuscular diseases has been published, but clinical experience with POTS is relatively unknown and has not been reported in MCAS. As a short-acting mu-opioid antagonist, LDN paradoxically increases endorphins which then bind to regulatory T cells which regulate T-lymphocyte and B-lymphocyte production and this reduces cytokine and antibody production. IVIg is emerging as a promising therapy for POTS. Diagnosis and treatment of SIBO in POTS is a new concept and appears to play an important role.

Source: Leonard B Weinstock, Jill B Brook, Trisha L Myers, Brent Goodman. Successful treatment of postural orthostatic tachycardia and mast cell activation syndromes using naltrexone, immunoglobulin and antibiotic treatment. Case Report. BMJ Case Rep. 2018; 2018: bcr2017221405. Published online 2018 Jan 11. doi: 10.1136/bcr-2017-221405 PMCID: PMC5778345 PMID: 29326369. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778345/ (Full article)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – Evidence for an autoimmune disease

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent and severe chronic disease drastically impairing life quality. The underlying pathomechanism is incompletely understood yet but there is convincing evidence that in at least a subset of patients ME/CFS has an autoimmune etiology. In this review, we will discuss current autoimmune aspects for ME/CFS. Immune dysregulation in ME/CFS has been frequently described including changes in cytokine profiles and immunoglobulin levels, T- and B-cell phenotype and a decrease of natural killer cell cytotoxicity.

Moreover, autoantibodies against various antigens including neurotransmitter receptors have been recently identified in ME/CFS individuals by several groups. Consistently, clinical trials from Norway have shown that B-cell depletion with rituximab results in clinical benefits in about half of ME/CFS patients.

Furthermore, recent studies have provided evidence for severe metabolic disturbances presumably mediated by serum autoantibodies in ME/CFS. Therefore, further efforts are required to delineate the role of autoantibodies in the onset and pathomechanisms of ME/CFS in order to better understand and properly treat this disease.

Source: Sotzny F, Blanco J, Capelli E, Castro-Marrero J, Steiner S, Murovska M, Scheibenbogen C; European Network on ME/CFS (EUROMENE). Myalgic Encephalomyelitis/Chronic Fatigue Syndrome – Evidence for an autoimmune disease. Autoimmun Rev. 2018 Jun;17(6):601-609. doi: 10.1016/j.autrev.2018.01.009. Epub 2018 Apr 7. https://www.sciencedirect.com/science/article/pii/S1568997218300880 (Full article)

Near-Infrared Spectroscopy Screening to Allow Detection of Pathogenic Mitochondrial DNA Variants in Individuals with Unexplained Abnormal Fatigue: A Preliminary Study

Abstract:

Unexplained abnormal fatigue is characterized by chronic fatigue persisting for at least six months and not sufficiently explained by any recognized medical condition. In this pilot study, twelve individuals with abnormal fatigue remaining unexplained after thorough screening were investigated using a near-infrared (NIR) spectroscopy handgrip test.

Four of them were found to have an abnormal oxygen extraction pattern similar to participants with documented mitochondrial myopathy. In three of the four individuals, diverse mitochondrial abnormalities were documented by spectrophotometric, immunocytological, fluorescent, and morphological analyses performed in skeletal muscle and in cultured skin fibroblasts. Three of the four participants with decreased muscular oxygen extraction were each shown to harbor a different homoplasmic pathogenic mitochondrial DNA point mutation (m.961T > C, m.1555A > G, m.14484T > C). In the fourth participant, the presence of multiple large mitochondrial DNA deletions was suspected in muscle tissue. In contrast, none of the eight abnormally fatigued participants with normal NIR spectroscopy results harbored either a pathogenic mitochondrial DNA point mutation or large deletions ( P < 0.001).

This pilot study shows that NIR spectroscopy may serve as a noninvasive screening tool to delineate a subgroup (of participants) with mitochondrial dysfunction among the large group of individuals with unexplained abnormal fatigue.

Source: Celie BM, Mariman A, Boone J, Delesie L, Tobback E, Seneca S, De Paepe B, Vogelaers D, Van Coster RN, Bourgois JG. Near-Infrared Spectroscopy Screening to Allow Detection of Pathogenic Mitochondrial DNA Variants in Individuals with Unexplained Abnormal Fatigue: A Preliminary Study. Appl Spectrosc. 2018 May;72(5):715-724. doi: 10.1177/0003702818756647. Epub 2018 Feb 13.  https://www.ncbi.nlm.nih.gov/pubmed/29336589

Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Background: Concise methodological directions for administration of serial cardiopulmonary exercise testing (CPET) are needed for testing of patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Maximal CPET is used to evaluate the coordinated metabolic, muscular, respiratory and cardiac contributions to energy production in patients with ME/CFS. In this patient population, CPET also elicits a robust post-exertional symptom flare (termed, post-exertional malaise); a cardinal symptom of the disease. CPET measures are highly reliable and reproducible in both healthy and diseased populations. However, evidence to date indicates that ME/CFS patients are uniquely unable to reproduce CPET measures during a second test, despite giving maximal effort during both tests, due to the effects of PEM on energy production.

Methodology: To document and assess functional impairment due to the effects of post-exertional malaise in ME/CFS, a 2-day CPET procedure (2-day CPET) has been used to first measure baseline functional capacity (CPET1) and provoke post-exertional malaise, then assess changes in CPET variables 24 h later with a second CPET to assess the effects of post-exertional malaise on functional capacity. The second CPET measures changes in energy production and physiological function, objectively documenting the effects of post-exertional malaise. Use of CPET as a standardized stressor to induce post-exertional malaise and quantify impairment associated with post-exertional malaise has been employed to examine ME/CFS pathology in several studies. This article discusses the results of those studies, as well as the standardized techniques and procedures for use of the 2-day CPET in ME/CFS patients, and potentially other fatiguing illnesses.

Conclusions: Basic concepts of CPET are summarized, and special considerations for performing CPET on ME/CFS patients are detailed to ensure a valid outcome. The 2-day CPET methodology is outlined, and the utility of the procedure is discussed for assessment of functional capacity and exertion intolerance in ME/CFS.

Source: Staci Stevens, Chris Snell, Jared Stevens, Betsy Keller and J. Mark VanNess.  Cardiopulmonary Exercise Test Methodology for Assessing Exertion Intolerance in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front. Pediatr., 04 September 2018 | https://doi.org/10.3389/fped.2018.00242 https://www.frontiersin.org/articles/10.3389/fped.2018.00242/full  (Full article)

VIDEO: Ronald W. Davis, PhD’s presentation at the IIMEC13

Dr. Ron Davis presented a research update at the International Invest in ME Conference 13 (IIMEC13) in London. His presentation reviewed the latest progress on research funded by OMF. View Dr. Davis’s full presentation here. 

(Gratefully shared with permission from Invest in ME Research.)

The full IIMEC13 conference DVD can be ordered here.

To hear a research update and meet our amazing scientists in person, join us for the Community Symposium on the Molecular Basis of ME/CFS at Stanford University sponsored by OMF on Saturday, September 29. In-person registration has been extended until Tuesday, September 18. If you are able to join us in person, please register here.

To watch the Community Symposium on the free Livestream. Register here.

A Brief Questionnaire to Assess Post-Exertional Malaise

Abstract:

Post-exertional malaise (PEM) is a key symptom of myalgic encephalomyelitis (ME) and chronic fatigue syndrome (CFS). Currently, five PEM-items from the DePaul Symptom Questionnaire (DSQ) were recommended as a first step in measuring this symptom for patients with ME and CFS by the National Institutes of Health/Centers for Disease Control and Prevention (NIH/CDC) Common Data Elements’ (CDE) working group.

The second step in this process, as recommended by the NIH/CDC CDE working group, involves assembling information from various sources to confirm the presence of PEM. There have not been any efforts, to date, to standardize this second-step process in the assessment of PEM.

The current study examined whether five supplementary items on the DSQ could be used to operationalize the second step of the recommendations made by the NIH/CDC CDE working group. The five supplementary DSQ PEM duration items correctly categorized patients with ME or CFS 81.7% of the time, while incorrectly categorizing multiple sclerosis (MS) and post-polio syndrome (PPS) as ME or CFS only 16.6% of the time. The findings suggested that a PEM second-step process could be operationalized using supplementary DSQ items.

Source: Cotler J, Holtzman C, Dudun C, Jason LA. A Brief Questionnaire to Assess Post-Exertional Malaise. Diagnostics (Basel). 2018 Sep 11;8(3). pii: E66. doi: 10.3390/diagnostics8030066.