Articles sorted by topic: General M.E. articles and research overviews, The outbreaks (and infectious nature) of M.E., The severity of M.E. and M.E. fatalities. Click here to read the full list of topics available.
Before reading the research/advocacy information given in the links below, please be aware of the following facts: 2. The research referred to on this website varies considerably in quality. Some is of a high scientific standard and relates wholly to M.E. and uses the correct terminology. Other studies are included which may only have partial or minor possible relevance to M.E., use unscientific terms/concepts such as ‘CFS,’ ‘ME/CFS,’ ‘CFS/ME,’ ‘CFIDS’ or Myalgic ‘Encephalopathy’ and also include a significant amount of misinformation. Before reading this research it is also essential that the reader be aware of the most commonly used ‘CFS’ propaganda, as explained in A warning on ‘CFS’ and ‘ME/CFS’ research and advocacy and in more detail in Putting research and articles on Myalgic Encephalomyelitis into context.
1. Myalgic Encephalomyelitis and ‘Chronic Fatigue Syndrome’ are not synonymous terms. The overwhelming majority of research on ‘CFS’ or ‘CFIDS’ or ‘ME/CFS’ or ‘CFS/ME’ or ‘ICD-CFS’ does not involve M.E. patients and is not relevant in any way to M.E. patients. If the M.E. community were to reject all ‘CFS’ labelled research as ‘only relating to ‘CFS’ patients’ (including research which describes those abnormalities/characteristics unique to M.E. patients), however, this would seem to support the myth that ‘CFS’ is just a ‘watered down’ definition of M.E. and that M.E. and ‘CFS’ are virtually the same thing and share many characteristics.
A very small number of ‘CFS’ studies refer in part to people with M.E. but it may not always be clear which parts refer to M.E. The A warning on ‘CFS’ and ‘ME/CFS’ research and advocacy paper is recommended reading and includes a checklist to help readers assess the relevance of individual ‘CFS’ studies to M.E. (if any) and explains some of the problems with this heterogeneous and skewed research.
In future, it is essential that M.E. research again be conducted using only M.E. defined patients and using only the term M.E. The bogus, financially-motivated disease category of ‘CFS’ must be abandoned.
2. The research referred to on this website varies considerably in quality. Some is of a high scientific standard and relates wholly to M.E. and uses the correct terminology. Other studies are included which may only have partial or minor possible relevance to M.E., use unscientific terms/concepts such as ‘CFS,’ ‘ME/CFS,’ ‘CFS/ME,’ ‘CFIDS’ or Myalgic ‘Encephalopathy’ and also include a significant amount of misinformation. Before reading this research it is also essential that the reader be aware of the most commonly used ‘CFS’ propaganda, as explained in A warning on ‘CFS’ and ‘ME/CFS’ research and advocacy and in more detail in Putting research and articles on Myalgic Encephalomyelitis into context.
Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome Narendra Kaushik, David Fear, Selwyn CM Richards, Clare R McDermott, Emile F Nuwaysir, Paul Kellam, Tim J Harrison, Robert J Wilkinson, David AJ Tyrrell, Stephen T Holgate, Jonathan R Kerr J Clin Path 2005;58:826-832
BACKGROUND: Chronic fatigue syndrome (CFS) is a multisystem disease, the pathogenesis of which remains undetermined. AIMS: To test the hypothesis that there are reproducible abnormalities of gene expression in patients with CFS compared with normal healthy persons. METHODS: To gain further insight into the pathogenesis of this disease, gene expression was analysed in peripheral blood mononuclear cells from 25 patients with CFS diagnosed according to the Centers for Disease Control criteria and 25 normal blood donors matched for age, sex, and geographical location, using a single colour microarray representing 9522 human genes. After normalisation, average difference values for each gene were compared between test and control groups using a cutoff fold difference of expression >/= 1.5 and a p value of 0.001. Genes showing differential expression were further analysed using Taqman real time polymerase chain reaction (PCR) in fresh samples. RESULTS: Analysis of microarray data revealed differential expression of 35 genes. Real time PCR confirmed differential expression in the same direction as array results for 16 of these genes, 15 of which were upregulated (ABCD4, PRKCL1, MRPL23, CD2BP2, GSN, NTE, POLR2G, PEX16, EIF2B4, EIF4G1, ANAPC11, PDCD2, KHSRP, BRMS1, and GABARAPL1) and one of which was downregulated (IL-10RA). This profile suggests T cell activation and perturbation of neuronal and mitochondrial function. Upregulation of neuropathy target esterase and eukaryotic translation initiation factor 4G1 may suggest links with organophosphate exposure and virus infection, respectively. CONCLUSION: These results suggest that patients with CFS have reproducible alterations in gene regulation.
Exercise responsive genes measured in peripheral blood of women with Chronic Fatigue Syndrome and matched control subjects. Whistler T, Jones JF, Unger ER, Vernon SD. Submission date 13 Sep 2004 - Acceptance date 24 Mar 2005 - Publication date 24 Mar 2005
Abstract :BACKGROUND: Chronic fatigue syndrome (CFS) is defined by debilitating fatigue that is exacerbated by physical or mental exertion. To search for markers of CFS-associated post-exertional fatigue, we measured peripheral blood gene expression profiles of women with CFS and matched controls before and after exercise challenge.METHODS: Women with CFS and healthy, age-matched, sedentary controls were exercised on a stationary bicycle at 70% of their predicted maximum workload. Blood was obtained before and after the challenge, total RNA was extracted from mononuclear cells, and signal intensity of the labeled cDNA hybridized to a 3800-gene oligonucleotide microarray was measured. We identified differences in gene expression among and between subject groups before and after exercise challenge, and evaluated differences in terms of Gene Ontology categories.RESULTS: Exercise-responsive genes differed between CFS cases and controls. These were in genes classified in chromatin and nucleosome assembly, cytoplasmic vesicles, membrane transport, and G protein-coupled receptor ontologies. Differences in ion transport activity/ion channel activity were evident at baseline and were exaggerated after exercise as evidenced by greater numbers of differentially genes in these molecular functions.CONCLUSIONS: These results highlight the potential use of an exercise challenge combined with microarray gene expression analysis in identifying gene ontologies associated with CFS.
Differential-display PCR of peripheral blood for biomarker discovery in chronic fatigue syndrome. Steinau M, Unger ER, Vernon SD, Jones JF, Rajeevan MS. Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, 1600 Clifton Rd., MSG-41, Atlanta, GA 30333, USA.
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.
Integration of gene expression, clinical, and epidemiologic data to characterize Chronic Fatigue Syndrome. Toni Whistler , Elizabeth R Unger , Rosane Nisenbaum and Suzanne D Vernon ISSN 1479-5876. Submission date 30 Oct 2003 - Acceptance date 01 Dec 2003 - Publication date 01 Dec 2003
Article URL http://www.translational-medicine.com/content/1/1/10
© 2003 Whistler et al, licensee BioMed Central Ltd. BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original URL.
Background: Chronic fatigue syndrome (CFS) has no diagnostic clinical signs or diagnostic laboratory abnormalities and it is unclear if it represents a single illness. The CFS research case definition recommends stratifying subjects by co-morbid conditions, fatigue level and duration, or functional impairment. But to date, this analysis approach has not yielded any further insight into CFS pathogenesis. This study used the integration of peripheral blood gene expression results with epidemiologic and clinical data to determine whether CFS is a single or heterogeneous illness. Results: CFS subjects were grouped by several clinical and epidemiological variables thought to be important in defining the illness. Statistical tests and cluster analysis were used to distinguish CFS subjects and identify differentially expressed genes. These genes were identified only when CFS subjects were grouped according to illness onset and the majority of genes were involved in pathways of purine and pyrimidine metabolism, glycolysis, oxidative phosphorylation, and glucose metabolism. Conclusion: These results provide a physiologic basis that suggests CFS is a heterogeneous illness. The differentially expressed genes imply fundamental metabolic perturbations that will be further investigated and illustrates the power of microarray technology for furthering our understanding CFS.
Utility of the blood for gene expression profiling and biomarker discovery in chronic fatigue syndrome. Suzanne D Vernon, Elizabeth R Unger, Irina M Dimulescu, Mangalathu Rajeevan, William C Reeves. Division of Viral and Rickettsial Diseases, National Center for Infectious Diseases, Centers for Disease Control and Prevention, Atlanta, GA. Source: Disease Markers 2002; 18(4):193-199.
Abstract: Chronic fatigue syndrome (CFS) is a debilitating illness lacking consistent anatomic lesions and eluding conventional laboratory diagnosis. Demonstration of the utility of the blood for gene expression profiling and biomarker discovery would have implications into the pathophysiology of CFS. The objective of this study was to determine if gene expression profiles of peripheral blood mononuclear cells (PMBCs) could distinguish between subjects with CFS and healthy controls. Total RNA from PBMCs of five CFS cases and seventeen controls was labeled and hybridized to 1764 genes on filter arrays. Gene intensity values were analyzed by various classification algorithms and nonparametric statistical methods. The classification algorithms grouped the majority of the CFS cases together, and distinguished them from the healthy controls. Eight genes were differentially expressed in both an age-matched case-control analysis and when comparing all CFS cases to all controls. Several of the deferentially expressed genes are associated with immunologic functions (e.g., CMRF35 antigen, IL-8, HD protein) and implicate immune dysfunction in the pathophysiology of CFS. These results successfully demonstrate the utility of the blood for gene expression profiling to distinguish subjects with CFS from healthy controls and for identifying genes that could serve as CFS biomarkers.
Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome Stefania Fulle (a), Patrizia Mecocci (b), Giorgio Fano (c), Iacopo Vecchiet (d), Alba Vecchini (e), Delia Racciotti (d), Antonio Cherubini (b), Eligio Pizzigallo (d), Leonardo Vecchiet (c), Umberto Senin (b) and M. Flint Beal (f). Address correspondence to: Dr. M. Flint Beal, Chairman, Neurology Department, New York Hospital-Cornell Medical Center, 525 East 68th Street, New York, NY 10021, USA; Tel: (212) 746-6575; Fax: (212) 746-8532; email: email@example.com Free Radical Biology and Medicine Dec 15, 2000, Vol. 29, No. 12, 1252-59
Chronic fatigue syndrome (CFS) is a poorly understood disease characterized by mental and physical fatigue, most often observed in young white females. Muscle pain at rest, exacerbated by exercise, is a common symptom. Although a specific defect in muscle metabolism has not been clearly defined, yet several studies report altered oxidative metabolism. In this study, we detected oxidative damage to DNA and lipids in muscle specimens of CFS patients as compared to age-matched controls, as well as increased activity of the antioxidant enzymes catalase, glutathione peroxidase, and transferase, and increases in total glutathione plasma levels. From these results we hypothesize that in CFS there is oxidative stress in muscle, which results in an increase in antioxidant defenses. Furthermore, in muscle membranes, fluidity and fatty acid composition are significantly different in specimens from CFS patients as compared to controls and to patients suffering from fibromyalgia. These data support an organic origin of CFS, in which muscle suffers oxidative damage.
Alterations in muscles of CFS patients at morphological, biochemical and molecular level. Pizzigallo E, Di Girolamo A, Montanari G, Dragani L, Vecchiet J, Calella G. Journal of Chronic Fatigue Syndrome 1996; 2(2/3) 76-77.
Abstract: OBJECTIVES. The peripheral origin of symptoms related to CFS has been hypothesized from various AA and is still under investigation to determine if symptoms can be related to muscular damage. Our studies aimed to look for specific alterations in muscles of CFS patients, followed in our Clinic and enrolled according to the 1988 CDC criteria (Holmes et al.) revised in 1994 by Fukuda et al. (CDC). METHODS. Fourteen CFS patients, 3 male and 11 females, 17 to 60 years old (mean 34.6), mean illness duration 49.9 months, post viral onset in 10 cases, underwent muscular biopsy of the vastus lateralis according to Edwards, et al., using a UCH needle. We analyzed the specimens by electron (EM) and light (LM) microscopy. Moreover, we performed histochemical and quantitative analysis of enzymatic activities and studies of mitochondrial DNA (mtDNA) deletions. RESULTS. All specimens showed: hypotrophy, especially of the type 11 (a and b) fibres; fibres fragmentation, red ragged fibres and fusion events with nuclei centralisation; and fatty and fibrous degeneration. EM observations confirmed these alterations, showed degenerative changes in the I band, and allowed us to detect the poli/pleiomorphism and cristae thickening of the mitochondia. The alterations of the fibres always began from an I band of a sarcomere. The histochemical and quantitative determination of the enzymatic activities showed important reduction, in particular of the cytochrome-oxydase and citrate-synthetase. Finally, the "common deletion" of 4977 bp of the mtdna was increased as high as 3,000 times the normal values in 3 patients. CONCLUSIONS. Our results agree with those of other AA (Behan et al., 1991; Gow et al., 1994). The alterations are compatible with a myopathy of probable mitochondrial origin. This could explain the drop in the functional capability of the muscle as a reduction in potency but, above all, as a reduction in resistance. In conclusion, even if CFS seems to be attributable to mitochondrial and/or muscular alterations, a damage in the central nervous system cannot be excluded. This could explain the neurophychological, behavioral, and neuroendocrinological alterations often found in these patients.
Biochemical and muscle studies in patients with acute onset post-viral fatigue syndrome. Preedy VR, Smith DG, Salisbury JR, Peters TJ. Journal of Clinical Pathology 1993; 46(8): 722-6.
Abstract:AIMS-To investigate in detail various biochemical and pathophysiological indices of muscle pathology in acute onset post-viral fatigue syndrome (PVFS). METHODS-Twenty three patients with PVFS (of mean duration 4.6 years) were subjected to needle biopsy for histomorphometry and total RNA contents. Plasma analysis included serology and creatine kinase activities. Indices of whole body mass were also measured-namely, whole body potassium content and plasma carnosinase activities. RESULTS-About 80% of the patients had serology indicative of persistent enteroviral infection as determined by VP1 antigen assay. Only about 10% of that same group of patients had serological indications of current enterovirus infection by IgM assay; a separate subset of 10% showed antibody changes suggestive of reactivation of Epstein-Barr virus. Quantitative morphometric analysis of skeletal muscle fibres indicated that the quadriceps muscle was normal or displayed only minor abnormalities in 22 patients. The Quetelet's Index (body mass index) and whole-body potassium values (index of lean body mass) were not affected in PVFS. The mean plasma carnosinase and creatinine kinase activities were also generally normal in these patients. The mean muscle RNA composition-mg RNA/mg DNA-was significantly reduced in acute onset PVFS by about 15%. The protein:DNA ratio was not significantly affected. CONCLUSIONS-Patients with acute onset PVFS, therefore, lose muscle protein synthetic potential, but not muscle bulk. Histopathology is consistent with these observations. These perturbations may contribute to the apparent feature of perceived muscle weakness associated with the persistent viral infection in the muscle themselves.
Sensory characterization of somatic parietal tissues in humans with chronic fatigue syndrome. Vecchiet L, Montanari G, Pizzigallo E, Iezzi S, de Bigontina P, Dragani L, Vecchiet J, Giamberardino MA. Institute of Medical Pathophysiology, 'G. D'Annunzio' University of Chieti, Italy.
Patients with chronic fatigue syndrome (CFS) mainly complain of symptoms in the musculoskeletal domain (myalgias, fatigue). In 21 CFS patients the deep (muscle) versus superficial (skin, subcutis) sensitivity to pain was explored by measuring pain thresholds to electrical stimulation unilaterally in the deltoid, trapezius and quadriceps and overlying skin and subcutis in comparison with normal subjects. Thresholds in patients were normal in skin and subcutis but significantly lower than normal (hyperalgesia) in muscles (P < 0.001) in all sites. The selective muscle hypersensitivity corresponded also to fiber abnormalities at muscle biopsy (quadriceps) performed in nine patients which were absent in normal subjects (four cases): morphostructural alterations of the sarchomere, fatty degeneration and fibrous regeneration, inversion of the cytochrome oxidase/succinate dehydrogenase ratio, pleio/polymorphism and monstruosity of mitochondria, reduction of some mitochondrial enzymatic activities and increments of common deletion of 4977 bp of mitochondrial DNA 150-3000 times the normal values. By showing both sensory (diffuse hyperalgesia) and anatomical (degenerative picture) changes at muscle level, the results suggest a role played by peripberal mechanisms in the genesis of CFS symptoms. They would exclude the heightened perception of physiological signals from all districts hypothesized by some authors, especially as the hyperalgesia is absent in skin/subcutis.
*O* The role of mitochondria in the pathogenesis of neurodegenerative diseases.
Manfredi G, Beal MF Department of Neurology and Neuroscience, Weill Medical College of Cornell University and the New York Hospital, Cornell Medical Center, New York 10021, USA. firstname.lastname@example.org Brain Pathol 2000 Jul;10(3):462-72
A growing body of evidence indicates that mitochondrial dysfunction may play an important role in the pathogenesis of many neurodegenerative disorders. Because mitochondrial metabolism is not only the principal source of high energy intermediates, but also of free radicals, it has been suggested that inherited or acquired mitochondrial defects could be the cause of neuronal degeneration as a consequence of energy defects and oxidative damage. Mitochondrial respiratory chain dysfunction has been reported in association with primary mitochondrial DNA abnormalities, and also as a consequence of mutations in nuclear genes directly involved in mitochondrial functions, such as SURF1, frataxin, and paraplegin. Defects of oxidative phosphorylation and increased free radical production have also been observed in diseases that are not due to primary mitochondrial abnormalities. In these cases, the mitochondrial dysfunction is likely to be an epiphenomenon, which, nevertheless, could be of importance in precipitating a cascade of events leading to cell death. In either case, understanding the role of mitochondria in the pathogenesis of neurodegenerative diseases could be important for the development of therapeutic strategies in these disorders.
*O* Evidence Based Psychiatry Eileen Marshall and Margaret Williams, 11th June 2005
In as yet unpublished work, bona fide research has indicated that in those with ME/ICD-CFS there are more gene abnormalities present than are found in cancer sufferers.
The validity of this remains to be established, but there can no longer be any doubt from both US and UK research that in ME/ICD-CFS there are proven abnormalities in numerous genes and that such abnormalities are acquired as a result of interactions with the environment as opposed to being hereditary.
Gene expression describes the behaviour of certain genes when attacked by an infection or other insult: some genes become over-active and produce chemicals that cause symptoms seen in ME/ICD-CFS, while other genes become under-active or shut down (The Chronic Fatigue Syndrome Research Foundation Newsletter 10, November 2004).
In the UK, Jonathan Kerr of Imperial College, London, is leading the CFS Research Foundation’s work in this area: using micro arrays and Taqman PCR techniques, his team has found no fewer than 15 genes to be abnormal and these genes showed problems in various body systems including the immune system, in neurological function and in mitochondrial metabolism (ie. in the production of cellular energy). As the CFSRF Newsletter makes plain: "It is clear that in ME/ICD-CFS patients the gene function has changed and these changes can be detected and measured".
In the US Suzanne Vernon and her team have shown that differentially expressed genes are related to energy metabolism, muscle and immune response (T-cell associated chemokines and receptors) and that several of these genes are involved in transcriptional regulation, metabolism and the immune response; Vernon et al have put forward mechanisms possibly associated with exacerbation of symptoms in ME/ICD-CFS and with differences in how patients cope with stress compared with controls (Co-Cure 14th March 2005: http://www.co-cure.org ).
The key question associated with genetic abnormalities is whether or not the detected abnormalities are associated with changes in the function of the gene that would lead to changes in the gene product(s), so it is the functional changes that are critical to understanding the relevance of these observations. It is necessary to understand how the biochemical changes relate to the gene changes because it is the genetic changes that drive the biochemical processes associated with the gene product(s) --- in other words, biochemical abnormalities are a reflection of gene abnormalities.
Diagnostic Marker for CFS? The poker game going on in our genes This article is based on a taped conversation with Dr. Cheney and has been reviewed and edited by him.
More research is needed to confirm that this segment of RNA is a diagnostic marker, but Dr. Cheney believes this is by far the best candidate yet. He also notes that while it would be a genetic marker, it is not one we are born with. It is one our body creates in response to this illness.
Lyndonville News - Information and Support for the ME/CFS Community. David S. Bell MD, FAAP, Editor
Volume 2, Number 2: May 2005
Genes that may play an important role in ME/CFS, partial listing:
1. Polymorphism in PON1 gene encoding paraoxonase/arylesterase, an enzyme that hydrolyzes organophosphate poisons to harmless products (Haley R, Billecke S, La Du B. Association of low PON1 type Q (Type A) arylesterase activity with neurologic symptom complexes in Gulf War veterans. Toxicol Appl Pharmacol 1999;157:2129-2137).
2. Familial corticosteroid-binding globulin deficiency, due to null mutation in globulin gene (Torpy D, Bachmann A, Grice J, Fitzgerald S, Phillips P, Whitworth J, et al. Familial corticosteroid-binding globulin deficiency due to a novel null mutation: association with fatigue and relative hypotension. J Clin Endocrinol Metab 2001;86:3692-3700.
3. Hypofunction of 5-HT system due to long allelic variants in the serotonin transporter (5-HTT) gene promoter (Narita M, Nishigami N, Narita N, Yamaguti K, Okado N, Watanabe Y, et al. Association between serotonin transporter gene polymorphism and chronic fatigue syndrome. Biochemical and Biophysical Research Communications 2003;311:264-266.
4. Myoadenylate deaminase (AMPD1) mutation cause of myopathy.
5. Carnitine palmitoyltransferase (CPT2) gene mutation causing myopathy.
6. I/D polymorphism in ACE gene (DCP1) (Vladutiu G, Natelson B. Association of medically unexplained fatigue with ACE insertion/deletion polymorphism in Gulf War verterans. Muscle Nerve 2004;30:38-43.)
7. Polymorphism of the corticosteroid binding globulin Ser/Ala 224 (Torpy D, Bachmann A, Gartside M, Grice J, Harris J, Clifton P, et al. Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER 224 polymorphism. Endocrine Research 2004;30(3):417-429.