Category: Pathophysiology

Detection of mycotoxins in patients with chronic fatigue syndrome

Abstract:

Over the past 20 years, exposure to mycotoxin producing mold has been recognized as a significant health risk. Scientific literature has demonstrated mycotoxins as possible causes of human disease in water-damaged buildings (WDB). This study was conducted to determine if selected mycotoxins could be identified in human urine from patients suffering from chronic fatigue syndrome (CFS).

Patients (n = 112) with a prior diagnosis of CFS were evaluated for mold exposure and the presence of mycotoxins in their urine. Urine was tested for aflatoxins (AT), ochratoxin A (OTA) and macrocyclic trichothecenes (MT) using Enzyme Linked Immunosorbent Assays (ELISA). Urine specimens from 104 of 112 patients (93%) were positive for at least one mycotoxin (one in the equivocal range).

Almost 30% of the cases had more than one mycotoxin present. OTA was the most prevalent mycotoxin detected (83%) with MT as the next most common (44%). Exposure histories indicated current and/or past exposure to WDB in over 90% of cases. Environmental testing was performed in the WDB from a subset of these patients.

This testing revealed the presence of potentially mycotoxin producing mold species and mycotoxins in the environment of the WDB. Prior testing in a healthy control population with no history of exposure to a WDB or moldy environment (n = 55) by the same laboratory, utilizing the same methods, revealed no positive cases at the limits of detection.

 

Source: Brewer JH, Thrasher JD, Straus DC, Madison RA, Hooper D. Detection of mycotoxins in patients with chronic fatigue syndrome. Toxins (Basel). 2013 Apr 11;5(4):605-17. doi: 10.3390/toxins5040605. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3705282/ (Full article)

 

Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology

Abstract:

BACKGROUND: Chronic fatigue syndrome (CFS) is a debilitating disorder characterized by persistent fatigue that is not alleviated by rest. The lack of a clearly identified underlying mechanism has hindered the development of effective treatments. Studies have demonstrated elevated levels of inflammatory factors in patients with CFS, but findings are contradictory across studies and no biomarkers have been consistently supported. Single time-point approaches potentially overlook important features of CFS, such as fluctuations in fatigue severity. We have observed that individuals with CFS demonstrate significant day-to-day variability in their fatigue severity.

METHODS: Therefore, to complement previous studies, we implemented a novel longitudinal study design to investigate the role of cytokines in CFS pathophysiology. Ten women meeting the Fukuda diagnostic criteria for CFS and ten healthy age- and body mass index (BMI)-matched women underwent 25 consecutive days of blood draws and self-reporting of symptom severity. A 51-plex cytokine panel via Luminex was performed for each of the 500 serum samples collected. Our primary hypothesis was that daily fatigue severity would be significantly correlated with the inflammatory adipokine leptin, in the women with CFS and not in the healthy control women. As a post-hoc analysis, a machine learning algorithm using all 51 cytokines was implemented to determine whether immune factors could distinguish high from low fatigue days.

RESULTS: Self-reported fatigue severity was significantly correlated with leptin levels in six of the participants with CFS and one healthy control, supporting our primary hypothesis. The machine learning algorithm distinguished high from low fatigue days in the CFS group with 78.3% accuracy.

CONCLUSIONS: Our results support the role of cytokines in the pathophysiology of CFS.

 

Source: Stringer EA, Baker KS, Carroll IR, Montoya JG, Chu L, Maecker HT, Younger JW. Daily cytokine fluctuations, driven by leptin, are associated with fatigue severity in chronic fatigue syndrome: evidence of inflammatory pathology. J Transl Med. 2013 Apr 9;11:93. doi: 10.1186/1479-5876-11-93. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3637529/ (Full article)

 

Inflammatory and oxidative and nitrosative stress cascades as new drug targets in myalgic encephalomyelitis and chronic fatigue syndrome

Abstract:

Myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS) and chronic fatigue (CF) are distinct diagnostic categories with regard to clinical symptoms, severity of illness and biomarkers. Patients with ME and CFS show higher scores on fatigue, neurocognitive disorders, hyperalgesia, autonomic symptoms, postexertional malaise and a subjective feeling of infection than patients with CF. ME is characterized by increased postexertional malaise, a subjective feeling of infection and neurocognitive disorders and is a more severe variant than CFS.

Fukuda’s 1994 CDC criteria are adequate to make a distinction between patients with ME/CFS and CF, while ME/CFS patients should be subdivided into those with and without postexertional malaise into ME and CFS, respectively. Different interrelated pathophysiological mechanisms play a role in ME/CFS, i.e. (1) inflammation and immune activation, (2) oxidative and nitrosative stress and lowered antioxidant defenses, (3) activation of cell signaling networks, e.g. nuclear factor ĸβ, the 2 9 ,5 9 -oligoadenylate/RNase-L and/or protein kinase R pathway, (4) a transition towards autoimmune reactions, and (5) bacterial translocation.

The inflammatory biomarkers are higher in ME/CFS than in CF and higher in ME than in CFS. The above-mentioned pathways may explain the onset of characteristic ME/CFS symptoms, such as fatigue, malaise, autonomic symptoms, hyperalgesia, and neurocognitive symptoms. Different etiological factors may trigger ME/CFS/CF, e.g. viral and bacterial infections, and (auto)immune and inflammatory disorders, while psychosocial and physical stressors act as modulating factors. New pathophysiologically driven drug candidates for ME and CFS are discussed which target the pathways that play a role in ME/CFS.

Copyright © 2013 S. Karger AG, Basel.

 

Source: Maes M. Inflammatory and oxidative and nitrosative stress cascades as new drug targets in myalgic encephalomyelitis and chronic fatigue syndrome. Mod Trends Pharmacopsychiatri. 2013;28:162-74. doi: 10.1159/000343982. Epub 2013 Feb 27. https://www.ncbi.nlm.nih.gov/pubmed/25224898

 

Targeting mitochondrial dysfunction in the treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) – a clinical audit

Abstract:

We report on an audit of 138 ME/CFS patients who attended a private practice and took the ATP Profile biomedical test. The results revealed that all of these patients had measureable mitochondrial dysfunction. A basic treatment regime, based on 1) eating the evolutionary correct stone-age diet, 2) ensuring optimum hours of good quality sleep, 3) taking a standard package of nutritional supplements, and 4) getting the right balance between work and rest, was recommended for all patients. Additions to the basic regime were tailored for each patient according to the results of the ATP Profile and additional nutritional tests and clues from the clinical history.

Mitochondrial function is typically impaired in two ways: substrate or co-factor deficiency, and inhibition by chemicals, exogenous or endogenous. For the former, additional nutrients are recommended where there is a deficiency, and for the latter, improvement of anti-oxidant status and selective chelation therapy or far-infrared saunas are appropriate. We show case histories of nine patients who have taken the ATP Profile on three or four occasions, and a before-and-after treatment summary of the 34 patients who have had at least two ATP Profile tests separated by some months.

Finally, we summarize the results for the 30 patients who followed all aspects of the treatment regime and compare them with the 4 patients who were lax on two or more aspects of the treatment regime. All patients who followed the treatment regime improved in mitochondrial function by on average a factor of 4.

 

Source: Myhill S, Booth NE, McLaren-Howard J. Targeting mitochondrial dysfunction in the treatment of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) – a clinical audit. Int J Clin Exp Med. 2013;6(1):1-15. Epub 2012 Nov 20. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3515971/ (Full article)

 

Clinical characteristics of a novel subgroup of chronic fatigue syndrome patients with postural orthostatic tachycardia syndrome

Abstract:

OBJECTIVES: A significant proportion of patients with chronic fatigue syndrome (CFS) also have postural orthostatic tachycardia syndrome (POTS). We aimed to characterize these patients and differentiate them from CFS patients without POTS in terms of clinical and autonomic features.

METHODS: A total of 179 patients with CFS (1994 Centers for Disease Control and Prevention criteria) attending one of the largest Department of Health-funded CFS clinical services were included in this study. Outcome measures were as follows: (i) symptom assessment tools including the fatigue impact scale, Chalder fatigue scale, Epworth sleepiness scale (ESS), orthostatic grading scale (OGS) and hospital anxiety and depression scale (HADS-A and -D, respectively), (ii) autonomic function analysis including heart rate variability and (iii) haemodynamic responses including left ventricular ejection time and systolic blood pressure drop upon standing.

RESULTS: CFS patients with POTS (13%, n = 24) were younger (29 ± 12 vs. 42 ± 13 years, P < 0.0001), less fatigued (Chalder fatigue scale, 8 ± 4 vs. 10 ± 2, P = 0.002), less depressed (HADS-D, 6 ± 4 vs. 9 ± 4, P = 0.01) and had reduced daytime hypersomnolence (ESS, 7 ± 6 vs. 10 ± 5, P = 0.02), compared with patients without POTS. In addition, they exhibited greater orthostatic intolerance (OGS, 11 ± 5; P < 0.0001) and autonomic dysfunction. A combined clinical assessment tool of ESS ≤9 and OGS ≥9 identifies accurately CFS patients with POTS with 100% positive and negative predictive values.

CONCLUSIONS: The presence of POTS marks a distinct clinical group of CFS patents, with phenotypic features differentiating them from those without POTS. A combination of validated clinical assessment tools can determine which CFS patients have POTS with a high degree of accuracy, and thus potentially identify those who require further investigation and consideration for therapy to control heart rate.

© 2013 The Association for the Publication of the Journal of Internal Medicine.

Comment in: Postural orthostatic tachycardia syndrome as a clinically important subgroup of chronic fatigue syndrome: further evidence for central nervous system dysfunctioning. [J Intern Med. 2013]

 

Source: Lewis I, Pairman J, Spickett G, Newton JL. Clinical characteristics of a novel subgroup of chronic fatigue syndrome patients with postural orthostatic tachycardia syndrome. J Intern Med. 2013 May;273(5):501-10. doi: 10.1111/joim.12022. Epub 2013 Jan 7. http://onlinelibrary.wiley.com/doi/10.1111/joim.12022/full (Full article)

 

Lipid and protein oxidation in female patients with chronic fatigue syndrome

Abstract:

INTRODUCTION: Chronic fatigue syndrome (CFS) is a widely recognized problem, characterized by prolonged, debilitating fatigue and a characteristic group of accompanying symptoms, that occurs four times more frequently in women than in men. The aim of the study was to determine the existence of oxidative stress and its possible consequences in female patients with CFS.

MATERIAL AND METHODS: Twenty-four women aged 15-45 who fulfilled the diagnostic criteria for CFS with no comorbidities were recruited and were age matched to a control group of 19 healthy women. After conducting the routine laboratory tests, levels of the lipid oxidation product malondialdehyde (MDA) and protein oxidation protein carbonyl (CO) were determined.

RESULTS: The CFS group had higher levels of triglycerides (p = 0.03), MDA (p = 0.03) and CO (p = 0.002) and lower levels of HDL cholesterol (p = 0.001) than the control group. There were no significant differences in the levels of total protein, total cholesterol or LDL cholesterol.

CONCLUSIONS: The CFS group had an unfavorable lipid profile and signs of oxidative stress induced damage to lipids and proteins. These results might be indicative of early proatherogenic processes in this group of patients who are otherwise at low risk for atherosclerosis. Antioxidant treatment and life style changes are indicated for women with CFS, as well as closer observation in order to assess the degree of atherosclerosis.

 

Source: Tomic S, Brkic S, Maric D, Mikic AN. Lipid and protein oxidation in female patients with chronic fatigue syndrome. Arch Med Sci. 2012 Nov 9;8(5):886-91. doi: 10.5114/aoms.2012.31620. Epub 2012 Nov 7. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3506242/ (Full article)

 

Increased nuclear factor-κB and loss of p53 are key mechanisms in Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Fukuda’s criteria are adequate to make a distinction between Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS) and chronic fatigue (CF), but ME/CFS patients should be subdivided into those with (termed ME) and without (termed CFS) post exertional malaise [Maes et al. 2012].

ME/CFS is considered to be a neuro-immune disease. ME/CFS is characterized by activated immuno-inflammatory pathways, including increased levels of pro-inflammatory cytokines, nuclear factor κB (NF-κB) and aberrations in mitochondrial functions, including lowered ATP. These processes may explain typical symptoms of ME/CFS, e.g. fatigue, malaise, hyperalgesia, and neurologic and autonomic symptoms.

Here we hypothesize that increased NF-κB together with a loss of p53 are key phenomena in ME/CFS that further explain ME/CFS symptoms, such as fatigue and neurocognitive dysfunction, and explain ME symptoms, such as post-exertional malaise following mental and physical activities. Inactivation of p53 impairs aerobic mitochondrial functions and causes greater dependence on anaerobic glycolysis, elevates lactate levels, reduces mitochondrial density in skeletal muscle and reduces endurance during physical exercise. Lowered p53 and increased NF-κB are associated with elevated reactive oxygen species. Increased NF-κB induces the production of pro-inflammatory cytokines, which increase glycolysis and further compromise mitochondrial functions.

All these factors together may contribute to mitochondrial exhaustion and indicate that the demand for extra ATP upon the commencement of increased activity cannot be met. In conditions of chronic inflammation and oxidative stress, high NF-κB and low p53 may conspire to promote neuron and glial cell survival at a price of severely compromised metabolic brain function. Future research should examine p53 signaling in ME/CFS.

Copyright © 2012. Published by Elsevier Ltd.

 

Source: Morris G, Maes M. Increased nuclear factor-κB and loss of p53 are key mechanisms in Myalgic Encephalomyelitis/chronic fatigue syndrome (ME/CFS). Med Hypotheses. 2012 Nov;79(5):607-13. doi: 10.1016/j.mehy.2012.07.034. Epub 2012 Aug 27. https://www.ncbi.nlm.nih.gov/pubmed/22951418

 

Orthostatic tolerance testing in a prospective cohort of adolescents with chronic fatigue syndrome and recovered controls following infectious mononucleosis

Abstract:

Chronic fatigue syndrome (CFS) is a complex condition responsible for marked functional impairment. The authors recently reported that 6 months following acute infectious mononucleosis (IM), 13%, of adolescents met criteria for CFS. The authors’ objective was to assess standing orthostatic tolerance (SOT) in adolescents with CFS and in controls 6 months following IM.

In all, 36 of 39 adolescents diagnosed with CFS 6 months following IM and 43 of 50 recovered controls had SOT testing (SOTT) performed. χ(2) Analysis was performed to study the relationships between SOTT and the diagnosis of CFS. Adolescents diagnosed with CFS and recovered controls did not differ significantly in age, weight, or body mass index. The authors found that 9 of 36 adolescents with CFS (25%) versus 9 of 43 recovered controls (21%) had an abnormal SOTT, which was not a statistically significant difference. Adolescents who meet criteria for CFS 6 months following IM do not have, as a group, more standing orthostatic intolerance than recovered controls.

 

Source: Katz BZ, Stewart JM, Shiraishi Y, Mears CJ, Taylor R. Orthostatic tolerance testing in a prospective cohort of adolescents with chronic fatigue syndrome and recovered controls following infectious mononucleosis. Clin Pediatr (Phila). 2012 Sep;51(9):835-9. doi: 10.1177/0009922812455094. Epub 2012 Jul 31. https://www.ncbi.nlm.nih.gov/pubmed/22850676

 

Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

The objectives of this study are to test the hypothesis that the fatigue and accompanying symptoms of Chronic Myalgic Encephalomyelitis/Fatigue Syndrome are in part due to defects in energy provision at the cellular level, and to understand the pathophysiology of the defects so that effective medical intervention can be implemented.

We performed an audit of 138 patients (ages 18-65) diagnosed with ME/CFS and attending a private practice. The patients and 53 normal, healthy controls had the ATP Profile test carried out on neutrophils from a 3-ml venous blood sample. This test yields 6 numerical factors that describe the availability of ATP and the efficiency of oxidative phosphorylation in mitochondria. Other biomedical measurements, including the concentration of cell-free DNA in plasma, were made. The results of the audit are compared with the controls and a previous cohort of 61 patients. We find that all patients tested have measureable mitochondrial dysfunction which correlates with the severity of the illness.

The patients divide into two main groups differentiated by how cellular metabolism attempts to compensate for the dysfunction. Comparisons with exercise studies suggest that the dysfunction in neutrophils also occurs in other cells. This is confirmed by the cell-free DNA measurements which indicate levels of tissue damage up to 3.5 times the normal reference range. The major immediate causes of the dysfunction are lack of essential substrates and partial blocking of the translocator protein sites in mitochondria. The ATP Profile is a valuable diagnostic tool for the clinical management of ME/CFS.

 

Source: Booth NE, Myhill S, McLaren-Howard J. Mitochondrial dysfunction and the pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Int J Clin Exp Med. 2012;5(3):208-20. Epub 2012 Jun 15. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3403556/ (Full article)

 

A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome

Abstract:

This paper proposes a neuro-immune model for Myalgic Encephalomyelitis/Chronic fatigue syndrome (ME/CFS). A wide range of immunological and neurological abnormalities have been reported in people suffering from ME/CFS. They include abnormalities in proinflammatory cytokines, raised production of nuclear factor-κB, mitochondrial dysfunctions, autoimmune responses, autonomic disturbances and brain pathology. Raised levels of oxidative and nitrosative stress (O&NS), together with reduced levels of antioxidants are indicative of an immuno-inflammatory pathology. A number of different pathogens have been reported either as triggering or maintaining factors.

Our model proposes that initial infection and immune activation caused by a number of possible pathogens leads to a state of chronic peripheral immune activation driven by activated O&NS pathways that lead to progressive damage of self epitopes even when the initial infection has been cleared. Subsequent activation of autoreactive T cells conspiring with O&NS pathways cause further damage and provoke chronic activation of immuno-inflammatory pathways. The subsequent upregulation of proinflammatory compounds may activate microglia via the vagus nerve.

Elevated proinflammatory cytokines together with raised O&NS conspire to produce mitochondrial damage. The subsequent ATP deficit together with inflammation and O&NS are responsible for the landmark symptoms of ME/CFS, including post-exertional malaise. Raised levels of O&NS subsequently cause progressive elevation of autoimmune activity facilitated by molecular mimicry, bystander activation or epitope spreading. These processes provoke central nervous system (CNS) activation in an attempt to restore immune homeostatsis.

This model proposes that the antagonistic activities of the CNS response to peripheral inflammation, O&NS and chronic immune activation are responsible for the remitting-relapsing nature of ME/CFS. Leads for future research are suggested based on this neuro-immune model.

 

Source: Morris G, Maes M. A neuro-immune model of Myalgic Encephalomyelitis/Chronic fatigue syndrome. Metab Brain Dis. 2013 Dec;28(4):523-40. doi: 10.1007/s11011-012-9324-8. Epub 2012 Jun 21. https://www.ncbi.nlm.nih.gov/pubmed/22718491