Category: Biomarker

CFSUM1 and CFSUM2 in urine from patients with chronic fatigue syndrome are methodological artefacts

Abstract:

McGregor et al. reported increased levels of an unidentified urinary compound (CFSUM1) in patients with chronic fatigue syndrome (CFS), with reduced excretion of another unidentified compound (CFSUM2), and suggested the possibility of chemical or metabolic ‘markers’ for CFS. The identity of CFSUM1 as reported was erroneous and the identities of these compounds have remained unknown until now.

Urine samples were obtained from 30 patients with ME/CFS, 30 age- and sex-matched healthy controls, 20 control patients with depression and 22 control patients with rheumatoid arthritis. Samples were prepared using the published methods of McGregor et al. to produce heptafluorobutyryl-isobutyl derivatives of urinary metabolites. Alternative preparations utilised isopropyl, n-butyl and trifluoroacetyl derivatives. These were separated and identified using gas chromatography-mass spectrometry.

CFSUM2 was identified as being partially derivatised [isobutyl ester-mono-heptafluorobutyryl (HFB)] serine. CFSUM1 was identified as partially derivatised pyroglutamic acid, being the isobutyl ester without formation of a HFB derivative.

Both CFSUM1 and CFSUM2 are artefacts of the sample preparation procedure and previously reported quantitative abnormalities of CFSUM1 and CFSUM2 in urine from patients with ME/CFS are also artefactual. Pyroglutamic acid may be of primarily dietary origin. The methods used cannot provide reliable qualitative or quantitative data on urinary metabolites. No clinical or biochemical significance can be drawn between these compounds in ME/CFS or any other clinical conditions.

 

Source: Chalmers RA, Jones MG, Goodwin CS, Amjad S. CFSUM1 and CFSUM2 in urine from patients with chronic fatigue syndrome are methodological artefacts. Clin Chim Acta. 2006 Feb;364(1-2):148-58. Epub 2005 Aug 10. http://www.ncbi.nlm.nih.gov/pubmed/16095585

 

Urinary and plasma organic acids and amino acids in chronic fatigue syndrome

Abstract:

Previous work by others have suggested the occurrence of one or more chemical or metabolic ‘markers’ for ME/CFS including specific amino acids and organic acids and a number of unidentified compounds (CFSUM1, CFSUM2). We have shown elsewhere that CFSUM1 is partially derivatised pyroglutamic acid and CFSUM2 partially derivatised serine and have suggested and demonstrated that the analytical methods used were unsuitable to identify or to accurately quantify urinary metabolites. We have now made a detailed analysis of plasma and urinary amino acids and of urinary organic acids from patients with ME/CFS and from three control groups.

Fasting blood plasma and timed urine samples were obtained from 31 patients with CFS, 31 age and sex-matched healthy controls, 15 patients with depression and 22 patients with rheumatoid arthritis. Plasma and urinary amino acids and urinary organic acids were determined using established and validated methods and data compared by statistical analysis. None of the previously reported abnormalities in urinary amino acids or of organic acids could be confirmed.

Results however provide some evidence in patients with ME/CFS for underlying inflammatory disease and for reduced intramuscular collagen with a lowered threshold for muscle micro-injury. These factors in combination may provide a basis for the fatigue and muscle pain that are the major symptoms in these patients.

 

Source: Jones MG, Cooper E, Amjad S, Goodwin CS, Barron JL, Chalmers RA. Urinary and plasma organic acids and amino acids in chronic fatigue syndrome. Clin Chim Acta. 2005 Nov;361(1-2):150-8. http://www.ncbi.nlm.nih.gov/pubmed/15992788

 

Exercise capacity and immune function in male and female patients with chronic fatigue syndrome (CFS)

Abstract:

Hyperactivition of an unwanted cellular cascade by the immune-related protein RNase L has been linked to reduced exercise capacity in persons with chronic fatigue syndrome (CFS). This investigation compares exercise capacities of CFS patients with deregulation of the RNase L pathway and CFS patients with normal regulation, while controlling for potentially confounding gender effects.

Thirty-five male and seventy-one female CFS patients performed graded exercise tests to voluntary exhaustion. Measures of peak VO2, peak heart rate, body mass index, perceived exertion, and respiratory quotient were entered into a two-way factorial analysis with gender and immune status as independent variables. A significant multivariate main effect was found for immune status (p < 0.01), with no gender effect or interaction.

Follow-up analyses identified VO2(peak) as contributing most to the difference. These results implicate abnormal immune activity in the pathology of exercise intolerance in CFS and are consistent with a channelopathy involving oxidative stress and nitric oxide-related toxicity.

 

Source: Snell CR, Vanness JM, Strayer DR, Stevens SR. Exercise capacity and immune function in male and female patients with chronic fatigue syndrome (CFS). In Vivo. 2005 Mar-Apr;19(2):387-90. http://iv.iiarjournals.org/content/19/2/387.long (Full article)

 

Variability of the RNase L isoform ratio (37 kiloDaltons/83 kiloDaltons) in diagnosis of chronic fatigue syndrome

Chronic fatigue syndrome (CFS) is a disorder characterized by debilitating fatigue whose etiology and pathophysiology remain unclear. Previous studies showed abnormalities of the RNase L pathway in peripheral blood mononuclear cells (PBMC) from patients with CFS (1, 2). The ratio of RNase L isoforms (37 kDa/83 kDa ratio [37/83 R]) has therefore been proposed as a potential biochemical marker of CFS, with a sensitivity of 91% and a specificity of 71% when the cutoff ratio was 0.4 (3).

You can read the rest of this article here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC549313/

 

Source: Tiev KP, Briant M, Ziani M, Cabane J, Demettre E, Lebleu B. Variability of the RNase L isoform ratio (37 kiloDaltons/83 kiloDaltons) in diagnosis of chronic fatigue syndrome. Clin Diagn Lab Immunol. 2005 Feb;12(2):366. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC549313/ (Full article)

 

Urinary electrophoretic profiles from chronic fatigue syndrome and chronic fatigue syndrome/fibromyalgia patients: a pilot study for achieving their normalization

Abstract:

Aim of our study was to determine if there were distinct, disease-related patterns of urinary analytes in chronic fatigue syndrome (CFS) and chronic fatigue syndrome/fibromyalgia (CFS/FM) compared to normal controls (NC).

Urine was collected from these subjects for two consecutive 24 h periods and aliquots were submitted to micellar electrokinetic chromatography (MEKC). To compensate for the differences in peak migration times, these were normalized from the 35 min duration of run to a 100-point scale, and each peak was assigned its normalized time measure. Peak heights were also normalized by dividing the mAU by that of the internal standard (creatinine) and multiplying by 100. MEKC with normalization for peak height and migration time generated comparable results within each of the patient groups.

CFS/FM and CFS had significant differences in peaks compared to NC that may be of significance as biomarkers of illnesses.

 

Source: Casado B, Zanone C, Annovazzi L, Iadarola P, Whalen G, Baraniuk JN. Urinary electrophoretic profiles from chronic fatigue syndrome and chronic fatigue syndrome/fibromyalgia patients: a pilot study for achieving their normalization. J Chromatogr B Analyt Technol Biomed Life Sci. 2005 Jan 5;814(1):43-51. http://www.ncbi.nlm.nih.gov/pubmed/15607706

 

Differential-display PCR of peripheral blood for biomarker discovery in chronic fatigue syndrome

Abstract:

We used differential-display PCR of peripheral blood mononuclear cells (PBMCs) to search for candidate biomarkers for chronic fatigue syndrome(CFS). PBMCs were collected from a subject with CFS and an age- and sex-matched control before and 24 h after exercise. RNA expression profiles were generated using 46 primer combinations, and the similarity between the individuals was striking.

Differentially expressed bands were excised, reamplified, and sequenced, yielding 95 nonredundant sequences, of which 50 matched to known gene transcripts, 38 matched to genes with unknown functions, and 7 had no similarity to any database entry. Most (86%) of the differences between the two subjects were present at baseline.

Differential expression of ten genes was verified by real-time reverse-transcription PCR: five (cystatin F, MHC class II, platelet factor 4, fetal brain expressed sequence tag, and perforin) were downregulated, and the remaining five genes (cathepsin B, DNA polymerase epsilon4, novel EST PBMC191MSt, heparanase precursor, and ORF2/L1 element) were upregulated in the subject with CFS. Many of these genes have known functions in defense and immunity, thus supporting prior suggestions of immune dysregulation in the pathogenesis of CFS.

Differential-display PCR is a powerful tool for identification of candidate biomarkers. Investigation of these markers in samples from well-designed epidemiological studies of CFS will be required to determine the validity of these candidate biomarkers. The real-time reverse-transcription PCR assays that we developed for assay of these biomarkers will facilitate high-throughput testing of these additional samples.

 

Source: Steinau M, Unger ER, Vernon SD, Jones JF, Rajeevan MS. Differential-display PCR of peripheral blood for biomarker discovery in chronic fatigue syndrome. J Mol Med (Berl). 2004 Nov;82(11):750-5. Epub 2004 Oct 14. http://www.ncbi.nlm.nih.gov/pubmed/15490094

 

Altered central nervous system signal during motor performance in chronic fatigue syndrome

Abstract:

OBJECTIVE: The purpose of this study was to determine whether brain activity of chronic fatigue syndrome (CFS) patients during voluntary motor actions differs from that of healthy individuals.

METHODS: Eight CFS patients and 8 age- and gender-matched healthy volunteers performed isometric handgrip contractions at 50% maximal voluntary contraction level. They first performed 50 contractions with a 10 s rest between adjacent trials–‘Non-Fatigue’ (NFT) task. Subsequently, the same number of contractions was performed with only a 5 s rest between trials–‘Fatigue’ (FT) task. Fifty-eight channels of surface EEG were recorded simultaneously from the scalp. Spectrum analysis was performed to estimate power of EEG frequency in different tasks. Motor activity-related cortical potential (MRCP) was derived by triggered averaging of EEG signals associated with the muscle contractions.

RESULTS: Major findings include: (i) Motor performance of the CFS patients was poorer than the controls. (ii) Relative power of EEG theta frequency band (4-8 Hz) during performing the NFT and FT tasks was significantly greater in the CFS than control group (P < 0.05). (iii) The amplitude of MRCP negative potential (NP) for the combined NFT and FT tasks was higher in the CFS than control group (P < 0.05) (iv) Within the CFS group, the NP was greater for the FT than NFT task (P<0.01), whereas no such difference between the two tasks was found in the control group.

CONCLUSIONS: These results clearly show that CFS involves altered central nervous system signals in controlling voluntary muscle activities, especially when the activities induce fatigue.

SIGNIFICANCE: Physical activity-induced EEG signal changes may serve as physiological markers for more objective diagnosis of CFS.

 

Source: Siemionow V, Fang Y, Calabrese L, Sahgal V, Yue GH. Altered central nervous system signal during motor performance in chronic fatigue syndrome. Clin Neurophysiol. 2004 Oct;115(10):2372-81. http://www.ncbi.nlm.nih.gov/pubmed/15351380

 

Patterns of cardiovascular reactivity in disease diagnosis

Abstract:

BACKGROUND: Aberrations of cardiovascular reactivity (CVR), an expression of autonomic function, occur in a number of clinical conditions, but lack specificity for a particular disorder. Recently, a CVR pattern particular to chronic fatigue syndrome was observed.

AIM: To assess whether specific CVR patterns can be described for other clinical conditions.

METHODS: Six groups of patients, matched for age and gender, were evaluated with a shortened head-up tilt test: patients with chronic fatigue syndrome (CFS) (n = 20), non-CFS fatigue (F) (n = 15), neurally-mediated syncope (SY) (n = 21), familial Mediterranean fever (FMF) (n = 17), psoriatic arthritis (PSOR) (n = 19) and healthy subjects (H) (n = 20). A 10-min supine phase was followed by recording 600 cardiac cycles on tilt (5-10 min). Beat-to-beat heart rate (HR) and pulse transit time (PTT) were measured. Results were analysed using conventional statistics, recurrence plot analysis and fractal analysis.

RESULTS: Multivariate analysis evaluated independent predictors of the CVR in each patient group vs. all other groups. Based on these predictors, equations were determined for a linear discriminant score (DS) for each group. The best sensitivities and specificities of the DS, consistent with disease-related phenotypes of CVR, were noted in the following groups: CFS, 90.0% and 60%; SY, 93.3% and 62.5%; FMF, 90.1% and 75.4%, respectively.

DISCUSSION: Pathological disturbances may alter cardiovascular reactivity. Our data support the existence of disease-related CVR phenotypes, with implications for pathogenesis and differential diagnosis.

 

Source: Naschitz JE, Rosner I, Rozenbaum M, Fields M, Isseroff H, Babich JP, Zuckerman E, Elias N, Yeshurun D, Naschitz S, Sabo E. Patterns of cardiovascular reactivity in disease diagnosis. QJM. 2004 Mar;97(3):141-51. http://qjmed.oxfordjournals.org/content/97/3/141.long (Full article)

 

Dysautonomia in chronic fatigue syndrome: facts, hypotheses, implications

Abstract:

The diagnosis of chronic fatigue syndrome (CFS) is based on patient history and treatment on cognitive behavior therapy and graded exercise. There is increasing evidence that dysautonomia occurs in CFS manifest primarily as disordered regulation of cardiovascular responses to stress. We impart our experience relating to diagnosis, monitoring, and treatment of CFS based on identification and management of dysautonomia.

Recently proposed methods for assessment of the cardiovascular reactivity, the ‘hemodynamic instability score’ (HIS) and the ‘Fractal and Recurrence Analysis-based Score’ (FRAS), served for this purpose. On HUTT, a particular dysautonomia is revealed in CFS patients that differ from dysautonomia in several other disorders. This distinct abnormality in CFS can be identified by HIS >-0.98 (sensitivity 84.5% and specificity 85.1%) and FRAS > +0.22 (sensitivity 70% and specificity 88%). Therefore, the HIS and FRAS may be used, in the appropriate clinical context, to support the diagnosis of CFS, which until now, could only be subjectively inferred.

A pilot study suggested that midodrine treatment, directed at the autonomic nervous system in CFS, results first in correction of dysautonomia followed by improvement of fatigue. This finding implies that dysautonomia is pivotal in the pathophysiology CFS, at least in a large part of the patients, and that manipulating the autonomic nervous system may be effective in the treatment of CFS.

 

Source: Naschitz JE, Yeshurun D, Rosner I. Dysautonomia in chronic fatigue syndrome: facts, hypotheses, implications. Med Hypotheses. 2004;62(2):203-6. http://www.ncbi.nlm.nih.gov/pubmed/14962627

 

The head-up tilt test in the diagnosis and management of chronic fatigue syndrome

Fatigue, as a symptom, refers to a sense of lethargy or loss of energy. Fatigue is common in infections, endocrine disorders, heart failure, chronic diseases of the lungs, liver or kidneys, malignancies, anemia, nutritional deficits, inflammatory arthritis, Parkinson’s disease, depression, anxiety states, effect of certain medications, or drug withdrawal [1]. Population-based studies show that fatigue is one of the most common somatic symptoms, with as much as 20± 30% of the population complaining of chronic fatigue [2]. Only a small fraction of these satisfy the clinical definition criteria for chronic fatigue syndrome [1].

You can read the rest of this article here: https://www.ima.org.il/FilesUpload/IMAJ/0/54/27402.pdf

 

Source: Naschitz JE, Sabo E, Dreyfuss D, Yeshurun D, Rosner I. The head-up tilt test in the diagnosis and management of chronic fatigue syndrome. Isr Med Assoc J. 2003 Nov;5(11):807-11. https://www.ima.org.il/FilesUpload/IMAJ/0/54/27402.pdf (Full article)