Pathophysiology of chronic fatigue syndrome

From Wikipedia, the free encyclopedia
Jump to: navigation, search

The pathophysiology of chronic fatigue syndrome is unknown. Several potential causes for the development of chronic fatigue syndrome have been proposed, including neurological factors, psychological or psychosocial factors or influences, infections, immunological factors, endocrinal factors and genetic factors. Other, less-common theories have also been articulated. No clinically meaningful risk factor has been identified.[1]

Nervous system factors[edit]

Neurological abnormalities[edit]

CFS may involve neurological abnormalities, revealed by MRI and SPECT scans,[2] blood flow measurements,[3] studies of the serotonin signalling pathways,[4][5] and gene expression.[6] Levels of beta-endorphin, a natural pain killer, are low in some CFS patients.[7] Some of these findings resemble viral infection[8] and clinical depression, while others do not.[9]

Dysautonomia is the disruption of the function of the autonomic nervous system (ANS) which controls many aspects of homeostasis. In CFS this is mostly orthostatic intolerance - the inability to stand up without feeling dizzy, faint, or nauseated.[10] Research on CFS orthostatic intolerance shows associations with neurally mediated hypotension and postural orthostatic tachycardia syndrome,[11][12][13] as well as hypocapnia.[14] These conditions may cause blood to pool in the lower body when a person stands, reducing blood flow to the heart and brain. Many CFS patients report symptoms of orthostatic intolerance and low or lowered blood pressure.[15][16]

Psychoneuroimmunological interactions[edit]

The brain and immune system influence each other, especially in the HPA axis and sympathetic nervous system. Mental stress causes suppression of the immune system by hormones such as cortisol and epinepherine. Release of stress hormones, caused by diseases outside the brain, can result in neurological symptoms due to the influence of stress hormones on neurotransmitters. Neuropsychiatric disorders present in CFS may be related to autoantibodies to neuronal or endothelial (interior surface of blood vessels) targets,[17][18] or disordered cytokine production by glial cells within the central nervous system.[19]

Psychological and psychosocial[edit]

The possible involvement of psychological factors within CFS is both unclear and contentious,[20][21] with several psychological and psychosocial factors having been theorized. Some individuals with CFS firmly reject any psychological involvement and believe strongly that their condition has a physical cause.[22]

Behavioral[edit]

High levels of "action-proneness" may play a predisposing, initiating and/or perpetuating role in CFS.[23][24] It has been hypothesized that in CFS the health threat is no longer the illness, but rather anything that threatens to disrupt a precarious accommodation to it. Due to established vicious circles, attempts at threat regulation may become inadvertently self-defeating, promoting the threats they attempt to diminish.[25]

Neuroticism and introversion have previously been reported as risk factors for developing CFS.[26] A systematic review of personality and CFS found an association with neuroticism, but stated that it was often accounted for by co-morbid depression and levels were similar to those in patients with other chronic diseases. It found no firm evidence for introversion.[27]

Cognitive behavioural model[edit]

According to the cognitive-behavioural model of illness, the patient's interpretation of symptoms plays an important role in perpetuating the illness. Catastrophic interpretations of symptoms, the belief that symptoms are beyond the patient's control and excessive emotional reactions may accentuate the physiological changes giving rise to symptoms. The cognitive-behavioural model differs from the extreme psychological model which proposes that illness symptoms are exclusively mental.[28] In response to a version of the cognitive behavioural model described in the book "Chronic Fatigue and Its Syndromes", the authors of a status report on CFS state, "Although this model may explain continued illness in some CFS patients, it certainly does not pertain to all CFS patients and is thus not too satisfactory."[29]

Fixation[edit]

Some research suggests that CFS may be perpetuated when patients fixate on a physical cause for their symptoms or when exercise is avoided.[26][30]

Illness behavior[edit]

A lack of support, or the reinforcement of illness behavior by social networks, may be associated with delayed recovery for some patients.[26]

Mood disorders[edit]

There are clinical overlaps and differences between CFS and clinical depression. Current mood disorders occur in 18.9% of CFS patients compared to 3.9% of the general population.[31] Previous psychiatric disorders or shared risk factors for psychiatric disorders may have an etiological role in some cases of CFS.[32] The presence of multiple comorbid disorders could be a marker for psychological influences on etiology.[33] Neuropsychological impairments could be involved in CFS,[34] and neuroendocrine studies and brain imaging have confirmed the occurrence of neurobiological abnormalities in most patients with CFS.[35] Findings of increased autoimmune antibodies against phospholipids (phosphatidyl inositol) in CFS and depression may underpin the similarities and comorbity between the two disorders.[36]

Sensitization[edit]

Central sensitization could be responsible for the sustaining pain complaints in CFS. Elevated concentrations of nitric oxide are present in the blood of CFS patients, and brain imaging shows brain abnormalities. Catastrophizing, avoidance behaviour, and somatization may result in, or are initiated by, sensitization of the central nervous system.[37]

Stress and trauma[edit]

The majority of people who experience stress or trauma do not develop CFS, but these factors may increase the likelihood of acquiring CFS.[38][39][40] A systematic scoping review included one retrospective study which reported that childhood trauma was significantly associated with the development of adult CFS, one prospective study which reported that genetics and self-reported stress sensitivity could contribute to CFS-like illness 25 years later, and one prospective study on fatigued employees which took measurements of current psychological distress and recent "shocking life events" (within last 12 months) at baseline and 12/24 month followup but did not find these to predict CFS-like caseness at 44 month followup.[1] Anxiety disorders may be associated with CFS in 5- to 15-year-olds.[41] CDC studies found gene mutation and abnormal gene activity levels in CFS patients that may relate to the function of the hypothalamic-pituitary-adrenal (HPA) axis, which helps regulate the body's stress response.[42]

Infections[edit]

Many viral and bacterial infections have been proposed to cause or associate with CFS, but no infectious influence on pathophysiology has been proven. A reportedly higher winter onset of CFS has led some to hypothesise that symptom onset is precipitated by a viral infection in some people.[43][44] However, although symptoms of CFS can occur after severe infection, strong data do not yet exist to support an infectious process in disease maintenance.[29]

Bacteria[edit]

Q Fever, caused by Coxiella burnetii, can cause a post infectious fatigue syndrome resembling CFS.[45][46][47] CFS patients reportedly have higher rates of Chlamydia pneumoniae infection than controls.[45][48] The possible influence of mycoplasma is disputed, with reports for[49][50][51][52] and against.[53] A review concludes the role of mycoplasma as causal agents, cofactors, or opportunistic infections is not clear.[54] Gram-negative enterobacteria and increased intestinal permeability may be associated with severity of CFS symptoms.[55] Associations of multiple bacterial and/or viral co-infections (mycoplasma, Chlamydia, HHV-6) with increased severity of signs and symptoms have also been proposed.[48]

Viruses[edit]

Enteroviruses like the Coxsackie virus[56] and Polio virus have been associated with symptoms resembling CFS. A number of studies have investigated enterovirus infections in CFS patients, but the results are contradictory and no causal relationship has been demonstrated.[57] Epstein-Barr virus (EBV) is present in 90% of the general population and sometimes causes infectious mononucleosis (glandular fever). EBV was once the principal suspect in chronic fatigue illnesses,[58][59] but mixed study results[60][61][62] have led to the current view of EBV in some patients as either a post infectious causal factor[45][63] or a factor in reactivation.[64] Other viruses implicated by some researchers include Ross river virus;[65] Borna disease;[66] Parvovirus B19;[45] and herpes viruses Cytomegalovirus (HHV-5),[67] Human Herpesvirus Six (HHV-6), and HHV-7.[68][69] A role for herpes viruses in CFS is controversial.[70][71]

In 1991, retrovirus sequences similar to human T-lymphotropic virus (HTLV) type II were reportedly found in the blood of a subset of CFS patients and not in healthy controls.[72] This finding was not replicated, and no evidence of infection with human retroviruses was found.[72]

In 2009, another retrovirus, xenotropic murine leukemia virus-related virus (XMRV), was reportedly detected in the blood of 67% of CFS patients but in only 3.7% of healthy controls by a team led by Judy Mikovits of the Whittemore Peterson Institute.[73] Follow-up studies detected no XMRV in CFS patients, patients with other conditions, or healthy controls in experiments using one or more methods including polymerase chain reaction, antibody-based detection and viral culture.[74][75][76][77][78][79][80][81][82] Several studies indicated that contamination contributed to the initial XMRV positive findings.[82][83][84][85][86][87][88][89][90][91][83] A study with samples from the patient group used in the only positive study found no XMRV, but reported that reagents used by the Mikovits group contained mouse DNA contamination.[82] These reagents were also used by another group that found mouse viruses (but not XMRV) in CFS samples.[92] The authors stated, however, that this contamination did not explain the striking differences between disease and control samples in the initial report, and stressed the importance of blinding samples to avoid introduction of inadvertent bias.[82] The editors of Science, in which the 2009 report was published, have attached an "Editorial Expression of Concern" to the report indicating that the validity of the study "is now seriously in question".[93] In September 2011, the original authors published a "Partial Retraction" of their 2009 findings, in which they acknowledged that "some of the CFS peripheral blood mononuclear cell (PBMC) DNA preparations are contaminated with XMRV plasmid DNA."[94]

In December 2011, Science and Proceedings of the National Academy of Science, withdrew published papers claiming sufferers carried the virus. Don Staines, from ME/CFS Australia says, "That area of research is pretty well dead and buried".[95][96][97]

Immunological dysfunction[edit]

Immunological factors including a chronic activation or suppression of the immune system may contribute to symptoms of CFS,[98] but they may not represent the entire picture[99] and some CFS experts doubt they are responsible.[29] A 2009 review into the immunological aspects of CFS reported that patients do seem to have a specific immune dysfunction profile involving an enhanced baseline activation of lymphoid subsets but a suppression of certain immune responses, particularly Th1-driven ones such as the anti-viral and anti-tumour responses. Reported findings from various studies include an alteration in cytokine profile (high level of pro-inflammatory cytokines and dysregulation of anti-inflammatory cytokines), decreased function of natural killer (NK) cells, the presence of autoantibodies, reduced responses of T cells and abnormal activation of T lymphocyte subsets. The authors note that the immune alteration pattern of CFS "has a striking resemblance to the one caused by developmental immune toxicology", perhaps due to a combination of factors such as xenobiotics, infections and stress.[100]

A systematic literature review published in 2014 concluded persons diagnosed with the illness have an abnormal immune response to exercise. Specifically, complement products are increased, larger oxidative stress is generated along with reduced anti-oxidant immune response, and larger interleukin-10 and toll-like receptor 4 gene expression are seen verses healthy controls. Many of these immune responses correlate with the symptom of post-exertional malaise.[101]

Allergies or food intolerance[102] have been reported in CFS sufferers. Gene expression changes have been reported in the white blood cells of CFS patients. This is consistent with the theory of abnormal types of antiviral protein RNase L and are postulated to affect sleep-wake cycles and exercise capacity.[103] High levels of Th2-type cytokines and the cells that make them are also found in CFS.[98][104][105][106] Therapeutic alterations of cytokine expression patterns are being investigated.[104][107]

In contrast, immunodeficiency disorders characterized by abnormal T-cell subset ratios, levels of immunoglobulins, and hypoallergic responses on the French Multitest have been reported in CFS.[104]

HPA axis[edit]

The hypothalamic-pituitary-adrenal axis (HPA axis) controls levels of hormones such as cortisol and is activated in a circadian rhythm and modulated by factors such as stress, digestion or illness. It is important in regulating energy metabolism, the immune system, stress responses and inflammation in the body.

A substantial body of evidence points to the following findings in CFS patients: mild hypocortisolism, an attenuated diurnal variation in cortisol, enhanced cortisol negative feedback, and a blunted HPA axis responsiveness. Women are more likely to exhibit hypocortisolism than men, as well as those who are depressed, inactive or not taking medication. The findings are similar to those seen in atypical depression. Glucocorticoid and mineralocorticoid receptor hypersensitivity appears to be the most probable explanation for the enhanced HPA axis negative feedback. Patients who undergo treatment such as CBT show reversal of the HPA axis changes. Steroid replacement therapy is not recommended due to lack of evidence and possible adverse effects.[108]

It has been debated whether these disturbances would play a primary role in the pathogenesis of CFS, but prospective evidence suggests that the HPA axis is not an important factor during the early stages of CFS, although it has been hypothesized that it might play a role in exacerbating or perpetuating symptoms later on in the course of the illness.[109][110][111] A 2011 meta-analysis reported a small but statistically significant hypocortisolism in CFS.[112] A study of cognitive behavioural therapy for CFS, which also measured cortisol levels, had observed that hypocortisolism was associated with a poorer response to CBT.[113]

A 2006 update in the journal Current Opinion in Psychiatry stated, "Recent advances in understanding the pathophysiology of chronic fatigue syndrome continue to demonstrate the involvement of the central nervous system. Hyperserotonergic state and hypoactivity of the hypothalamic-pituitary-adrenal axis (HPA axis) constitute other findings, but the question of whether these alterations are a cause or consequence of chronic fatigue syndrome still remains unanswered."[99]

Serotonin signaling[edit]

Hyperactivity of the serotonergic system has been implicated in CFS. Alterations in serotonin signaling can lead to physiologic and behavioral changes. Polymorphisms in genes related to serotonin pathways may indicate genetic predisposition in the pathophysiology of CFS.[114]

Gene expression and polymorphisms[edit]

CFS-related abnormalities in gene expression have been studied.[42][115] Changes in genes involved in transport (both vesicle-mediated and protein transport),[116] metabolism,[117] immune regulation, neuronal function, mitochondrial function, apoptosis and other processes have been reported.[118][119][120] The CDC has said these changes could be involved in CFS.[42] Some of the symptoms of gene expression differences may be treatable with existing drugs.[121] Some researchers think gene expression studies could make possible better categorization of CFS[122][123] and even help with differential diagnosis.[124]

An abnormally large and rapid mRNA activation of sensory, immune/cytokine and adrenergic receptors have been implicated in the post-exertional symptoms experienced by CFS patients after exercise.[125]

A 2007 review stated that certain genetic polymorphisms might be regarded as predisposing factors.[126] Studies have shown genetic differences in genes of CFS patients and healthy controls in the central nervous,[114][127] endocrine,[6][128][129] immune [130][131] and cardiovascular systems.[132]

Other hypotheses[edit]

Oxidative stress[edit]

Oxidative stress, an imbalance between the production of reactive oxygen and a biological system's ability to readily detoxify the reactive intermediates or easily repair the resulting damage, occurs in CFS and helps to explain the muscle pain, postexertional malaise, and the decrease in pain threshold following graded exercise.[133] Gene expression studies suggest a common link between oxidative stress, immune system dysfunction and potassium imbalance in CFS patients leading to impaired nerve balance, reflected in abnormal heart rate variability.[134]

Metabolic disorders[edit]

Metabolic disorders and mitochondrial disorders can cause symptoms that resemble CFS.[135] Mitochondrial disturbances have been discovered in patients diagnosed with post-viral fatigue syndrome.[136] Folate deficiency may also mimic CFS symptoms.[137][138]

Essential fatty acid deficiencies[edit]

Essential fatty acid levels: Several studies published between 1990 and 2005 reported finding reduced levels of Omega-6 or Omega-3 essential fatty acids in cell membranes or serum in patients diagnosed with post-viral fatigue syndrome or CDC-defined CFS.[139][140][141][142] One study conducted in 1999 on Oxford-criteria-defined CFS patients (Warren et al.) found no significant differences in fatty acid levels between treatment and placebo groups.[143] A review of CFS treatments compared two studies of essential fatty acids, concluding that there is insufficient evidence to recommend it as a treatment for CFS.[144]

Toxic agents[edit]

Insecticides have a possible effect on the cause and/or course of CFS.[45] Chronic exposure to organophosphates, a pesticide, has neurophsychiatric effects including cognitive impairment and chronic fatigue,[145] and according to a paper by Davies, the CDC includes organophosphates as a cause of (CFS). The authors, however, state that a diagnosis of CFS may be unhelpful and misleading in people with organophosphate toxicity.[146]

Exercise findings[edit]

In a large national birth cohort study, the risk of developing CFS as an adult was inversely correlated with childhood exercise, but no association was found for other childhood or maternal factors such as psychological problems, academic ability, allergic tendencies, birth weight, birth order or obesity.[147] However, a similar study found that an increased level of exercise in childhood and early-adulthood is a risk factor.[148]

Abnormal lactic acid responses to exercise in some CFS patients[149][150][151] have been suggested to be a factor in CFS because it is commonly believed to be responsible for muscle fatigue.[152] However, some scientists have found that lactic acid may actually help prevent muscle fatigue rather than cause it, by keeping muscles properly responding to nerve signals.[153]

Other findings[edit]

Children and teenagers with CFS are several times more likely than healthy controls to have some hyperflexible joints[154] in an association with Ehlers-Danlos syndrome.

References[edit]

  1. ^ a b Hempel S, Chambers D, Bagnall AM, Forbes C (July 2008). "Risk factors for chronic fatigue syndrome/myalgic encephalomyelitis: a systematic scoping review of multiple predictor studies". Psychol Med 38 (7): 915–26. doi:10.1017/S0033291707001602. PMID 17892624. 
  2. ^ Schwartz RB; Garada BM; Komaroff AL et al. (1994). "Detection of intracranial abnormalities in patients with chronic fatigue syndrome: comparison of MR imaging and SPECT". AJR. American journal of roentgenology 162 (4): 935–41. doi:10.2214/ajr.162.4.8141020. PMID 8141020. 
  3. ^ Abu-Judeh HH; Levine S; Kumar M et al. (1998). "Comparison of SPET brain perfusion and 18F-FDG brain metabolism in patients with chronic fatigue syndrome". Nuclear medicine communications 19 (11): 1065–71. doi:10.1097/00006231-199811000-00006. PMID 9861623. 
  4. ^ Demitrack MA, Gold PW, Dale JK, Krahn DD, Kling MA, Straus SE (1992). "Plasma and cerebrospinal fluid monoamine metabolism in patients with chronic fatigue syndrome: preliminary findings". Biol. Psychiatry 32 (12): 1065–77. doi:10.1016/0006-3223(92)90187-5. PMID 1282370. 
  5. ^ Cleare AJ, Messa C, Rabiner EA, Grasby PM (2005). "Brain 5-HT1A receptor binding in chronic fatigue syndrome measured using positron emission tomography and [11C]WAY-100635". Biol. Psychiatry 57 (3): 239–46. doi:10.1016/j.biopsych.2004.10.031. PMID 15691524. 
  6. ^ a b Goertzel BN, Pennachin C, de Souza Coelho L, Gurbaxani B, Maloney EM, Jones JF (2006). "Combinations of single nucleotide polymorphisms in neuroendocrine effector and receptor genes predict chronic fatigue syndrome". Pharmacogenomics 7 (3): 475–83. doi:10.2217/14622416.7.3.475. PMID 16610957. 
  7. ^ Conti F, Pittoni V, Sacerdote P, Priori R, Meroni PL, Valesini G (1998). "Decreased immunoreactive beta-endorphin in mononuclear leucocytes from patients with chronic fatigue syndrome". Clin. Exp. Rheumatol. 16 (6): 729–32. PMID 9844768. 
  8. ^ Schwartz RB; Komaroff AL; Garada BM et al. (1994). "SPECT imaging of the brain: comparison of findings in patients with chronic fatigue syndrome, AIDS dementia complex, and major unipolar depression". AJR. American journal of roentgenology 162 (4): 943–51. doi:10.2214/ajr.162.4.8141022. PMID 8141022. 
  9. ^ MacHale SM; Lawŕie SM; Cavanagh JT et al. (2000). "Cerebral perfusion in chronic fatigue syndrome and depression". The British Journal of Psychiatry : the journal of mental science 176 (6): 550–6. doi:10.1192/bjp.176.6.550. PMID 10974961. 
  10. ^ Goldstein DS, Robertson D, Esler M, Straus SE, Eisenhofer G (2002). "Dysautonomias: clinical disorders of the autonomic nervous system". Annals of Internal Medicine 137 (9): 753–63. doi:10.7326/0003-4819-137-9-200211050-00011. PMID 12416949. 
  11. ^ Galland BC, Jackson PM, Sayers RM, Taylor BJ (2008). "A matched case control study of orthostatic intolerance in children/adolescents with chronic fatigue syndrome". Pediatr. Res. 63 (2): 196–202. doi:10.1203/PDR.0b013e31815ed612. PMID 18091356. 
  12. ^ Tolan R, Stewart J. "Chronic Fatigue Syndrome", eMedicine, August 17, 2006, retrieved November 9, 2006.
  13. ^ Rowe, PC. "General Information Brochure on Orthostatic Intolerance and its Treatment", Chronic Fatigue Clinic, Johns Hopkins Children's Center, February 2003, retrieved November 9, 2006.
  14. ^ Natelson BH, Intriligator R, Cherniack NS, Chandler HK, Stewart JM (2007). "Hypocapnia is a biological marker for orthostatic intolerance in some patients with chronic fatigue syndrome". Dyn Med 6: 2. doi:10.1186/1476-5918-6-2. PMC 1796865. PMID 17263876. 
  15. ^ Newton JL, Okonkwo O, Sutcliffe K, Seth A, Shin J, Jones DE (2007). "Symptoms of autonomic dysfunction in chronic fatigue syndrome". QJM 100 (8): 519–26. doi:10.1093/qjmed/hcm057. PMID 17617647. 
  16. ^ Stewart JM, Gewitz MH, Weldon A, Arlievsky N, Li K, Munoz J (1999). "Orthostatic intolerance in adolescent chronic fatigue syndrome". Pediatrics 103 (1): 116–21. doi:10.1542/peds.103.1.116. PMID 9917448. 
  17. ^ Margutti P, Delunardo F, Ortona E (2006). "Autoantibodies associated with psychiatric disorders". Curr Neurovasc Res 3 (2): 149–57. doi:10.2174/156720206776875894. PMID 16719797. 
  18. ^ Tanaka S, Kuratsune H, Hidaka Y, Hakariya Y, Tatsumi KI, Takano T, Kanakura Y, Amino N (2003). "Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome". Int J Mol Med 12 (2): 225–30. doi:10.3892/ijmm.12.2.225. PMID 12851722. 
  19. ^ Vollmer-Conna U, Lloyd A, Hickie I, Wakefield D (1998). "Chronic fatigue syndrome: an immunological perspective". Aust N Z J Psychiatry 32 (4): 523–7. doi:10.3109/00048679809068326. PMID 9711366. 
  20. ^ "Chronic Fatigue Syndrome Basic Facts". Centers for Disease Control and Prevention. May 9, 2006. Retrieved 2008-02-07. 
  21. ^ Prior, Lindsay (2003). Using Documents in Social Research. SAGE Publications. p. 120. ISBN 978-0-7619-5747-8. Retrieved 2009-08-19. 
  22. ^ Cho HJ, Hotopf M, Wessely S (2005). "The placebo response in the treatment of chronic fatigue syndrome: A systematic review and meta-analysis". Psychosom Med 67 (2): 301–13. doi:10.1097/01.psy.0000156969.76986.e0. PMID 15784798. Retrieved 2008-12-12. 
  23. ^ Van Houdenhove B, Neerinckx E, Onghena P, Lysens R, Vertommen H (2001). "Premorbid "overactive" lifestyle in chronic fatigue syndrome and fibromyalgia. An etiological factor or proof of good citizenship?". J Psychosom Res 51 (4): 571–6. doi:10.1016/S0022-3999(01)00247-1. PMID 11595245. 
  24. ^ Van Houdenhove B, Onghena P, Neerinckx E, Hellin J (1995). "Does high 'action-proneness' make people more vulnerable to chronic fatigue syndrome? A controlled psychometric study". J Psychosom Res 39 (5): 633–40. doi:10.1016/0022-3999(95)00008-9. PMID 7490698. 
  25. ^ Deary V (2008). "A precarious balance: Using a self-regulation model to conceptualize and treat chronic fatigue syndrome". Br J Health Psychol 13 (Pt 2): 231–6. doi:10.1348/135910708X283760. PMID 18267050. 
  26. ^ a b c Prins JB, van der Meer JW, Bleijenberg G (2006). "Chronic fatigue syndrome". Lancet 367 (9507): 346–55. doi:10.1016/S0140-6736(06)68073-2. PMID 16443043. 
  27. ^ van Geelen SM, Sinnema G, Hermans HJ, Kuis W (January 2007). "Personality and chronic fatigue syndrome: Methodological and conceptual issues" (PDF). Clin Psychol Rev 27 (8): 885–903. doi:10.1016/j.cpr.2007.01.010. PMID 17350740. 
  28. ^ Mark A. Demitrack, Susan E. Abbey (1999). Chronic Fatigue Syndrome: An Integrative Approach to Evaluation and Treatment. Guilford Press. p. 241. ISBN 9781572304994. 
  29. ^ a b c Natelson BH, Lange G (2002). "A status report on chronic fatigue syndrome". Environ. Health Perspect. 110 Suppl 4 (Suppl 4): 673–7. doi:10.1289/ehp.02110s4673. PMC 1241224. PMID 12194905. 
  30. ^ Deary V, Chalder T, Sharpe M (October 2007). "The cognitive behavioural model of medically unexplained symptoms: a theoretical and empirical review". Clin Psychol Rev 27 (7): 781–97. doi:10.1016/j.cpr.2007.07.002. PMID 17822818. 
  31. ^ Prins J, Bleijenberg G, Rouweler EK, van der Meer J. (2005). "Effect of psychiatric disorders on outcome of cognitive-behavioural therapy for chronic fatigue syndrome". Br J Psychiatry 187 (2): 184–5. doi:10.1192/bjp.187.2.184. PMID 16055833. 
  32. ^ Harvey SB, Wadsworth M, Wessely S, Hotopf M (2007). "The relationship between prior psychiatric disorder and chronic fatigue: evidence from a national birth cohort study". Psychol Med 38 (7): 1–8. doi:10.1017/S0033291707001900. PMC 3196526. PMID 17976252. 
  33. ^ Whitehead WE, Palsson O, Jones KR (2002). "Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications?". Gastroenterology 122 (4): 1140–56. doi:10.1053/gast.2002.32392. PMID 11910364. 
  34. ^ Deluca J, Johnson SK, Natelson BH (1994). "Neuropsychiatric status of patients with chronic fatigue syndrome: an overview". Toxicol Ind Health 10 (4–5): 513–22. PMID 7778111. 
  35. ^ Gonzalez MB, Cousins JC, Doraiswamy PM (1996). "Neurobiology of chronic fatigue syndrome". Prog. Neuropsychopharmacol. Biol. Psychiatry 20 (5): 749–59. doi:10.1016/0278-5846(96)00057-7. PMID 8870062. 
  36. ^ Maes M, Mihaylova I, Leunis JC (2007). "Increased serum IgM antibodies directed against phosphatidyl inositol (Pi) in chronic fatigue syndrome (CFS) and major depression: evidence that an IgM-mediated immune response against Pi is one factor underpinning the comorbidity between both CFS and depression". Neuro Endocrinol. Lett. 28 (6): 861–7. PMID 18063934. 
  37. ^ Nijs J, Van de Velde B, De Meirleir K (2005). "Pain in patients with chronic fatigue syndrome: does nitric oxide trigger central sensitization?". Med. Hypotheses 64 (3): 558–62. doi:10.1016/j.mehy.2004.07.037. PMID 15617866. 
  38. ^ Hatcher S, House A (2003). "Life events, difficulties and dilemmas in the onset of chronic fatigue syndrome: a case-control study" (PDF). Psychol Med 33 (7): 1185–92. doi:10.1017/S0033291703008274. PMID 14580073. 
  39. ^ Theorell T, Blomkvist V, Lindh G, Evengard B (1999). "Critical life events, infections, and symptoms during the year preceding chronic fatigue syndrome (CFS): an examination of CFS patients and subjects with a nonspecific life crisis". Psychosom Med. 61 (3): 304–10. doi:10.1097/00006842-199905000-00009. PMID 10367610. 
  40. ^ Salit IE (1997). "Precipitating factors for the chronic fatigue syndrome". J Psychiatr Res 31 (1): 59–65. doi:10.1016/S0022-3956(96)00050-7. PMID 9201648. 
  41. ^ T Chalder, R Goodman, S Wessely, M Hotopf, H Meltzer (2003). "Epidemiology of chronic fatigue syndrome and self reported myalgic encephalomyelitis in 5-15 year olds: cross sectional study". BMJ 327 (7416): 654–655. doi:10.1136/bmj.327.7416.654. PMC 196393. PMID 14500438. 
  42. ^ a b c Reeves W; Vernon S (April 20, 2006). "Press Briefing on Chronic Fatigue Syndrome". Centers for Disease Control and Prevention. Archived from the original on 2007-12-20. Retrieved 2008-01-27. 
  43. ^ Jason LA, Taylor RR, Carrico AW (2001). "A community-based study of seasonal variation in the onset of chronic fatigue syndrome and idiopathic chronic fatigue". Chronobiol. Int. 18 (2): 315–9. doi:10.1081/CBI-100103194. PMID 11379670. 
  44. ^ Zhang QW; Natelson BH; Ottenweller JE et al. (2000). "Chronic fatigue syndrome beginning suddenly occurs seasonally over the year". Chronobiol. Int. 17 (1): 95–9. doi:10.1081/CBI-100101035. PMID 10672437. 
  45. ^ a b c d e Devanur LD, Kerr JR (November 2006). "Chronic fatigue syndrome". J. Clin. Virol. 37 (3): 139–50. doi:10.1016/j.jcv.2006.08.013. PMID 16978917. 
  46. ^ Parker NR, Barralet JH, Bell AM (February 2006). "Q fever". Lancet 367 (9511): 679–88. doi:10.1016/S0140-6736(06)68266-4. PMID 16503466. 
  47. ^ Madariaga MG, Rezai K, Trenholme GM, Weinstein RA (November 2003). "Q fever: a biological weapon in your backyard". Lancet Infect Dis 3 (11): 709–21. doi:10.1016/S1473-3099(03)00804-1. PMID 14592601. 
  48. ^ a b Nicolson GL, Gan R, Haier J (May 2003). "Multiple co-infections (Mycoplasma, Chlamydia, human herpes virus-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms". APMIS 111 (5): 557–66. doi:10.1034/j.1600-0463.2003.1110504.x. PMID 12887507. 
  49. ^ Nijs J, Nicolson GL, De Becker P, Coomans D, De Meirleir K (November 2002). "High prevalence of mycoplasma infections among European chronic fatigue syndrome patients. Examination of four mycoplasma species in blood of chronic fatigue syndrome patients". FEMS Immunol. Med. Microbiol. 34 (3): 209–14. doi:10.1111/j.1574-695X.2002.tb00626.x. PMID 12423773. 
  50. ^ Nasralla M, Haier J, Nicolson GL (December 1999). "Multiple mycoplasmal infections detected in blood of patients with chronic fatigue syndrome and/or fibromyalgia syndrome". Eur. J. Clin. Microbiol. Infect. Dis. 18 (12): 859–65. doi:10.1007/s100960050420. PMID 10691196. 
  51. ^ Choppa PC, Vojdani A, Tagle C, Andrin R, Magtoto L (October 1998). "Multiplex PCR for the detection of Mycoplasma fermentans, M. hominis and M. penetrans in cell cultures and blood samples of patients with chronic fatigue syndrome". Mol. Cell. Probes 12 (5): 301–8. doi:10.1006/mcpr.1998.0186. PMID 9778455. 
  52. ^ Vojdani A, Choppa PC, Tagle C, Andrin R, Samimi B, Lapp CW (December 1998). "Detection of Mycoplasma genus and Mycoplasma fermentans by PCR in patients with Chronic Fatigue Syndrome". FEMS Immunol. Med. Microbiol. 22 (4): 355–65. doi:10.1111/j.1574-695X.1998.tb01226.x. PMID 9879928. 
  53. ^ Vernon SD, Shukla SK, Reeves WC (November 2003). "Absence of Mycoplasma species DNA in chronic fatigue syndrome". J. Med. Microbiol. 52 (Pt 11): 1027–8. doi:10.1099/jmm.0.05316-0. PMID 14532349. 
  54. ^ Endresen GK (September 2003). "Mycoplasma blood infection in chronic fatigue and fibromyalgia syndromes". Rheumatol. Int. 23 (5): 211–5. doi:10.1007/s00296-003-0355-7. PMID 12879275. 
  55. ^ Maes M, Mihaylova I, Leunis JC (April 2007). "Increased serum IgA and IgM against LPS of enterobacteria in chronic fatigue syndrome (CFS): indication for the involvement of gram-negative enterobacteria in the etiology of CFS and for the presence of an increased gut-intestinal permeability". J Affect Disord 99 (1–3): 237–40. doi:10.1016/j.jad.2006.08.021. PMID 17007934. 
  56. ^ Ramsay MA (1986), "Postviral Fatigue Syndrome. The saga of Royal Free disease", Londen, ISBN 0-906923-96-4
  57. ^ Dalakas MC (October 2003). "Enteroviruses in chronic fatigue syndrome: "now you see them, now you don't"". J. Neurol. Neurosurg. Psychiatr. 74 (10): 1361–2. doi:10.1136/jnnp.74.10.1361. PMC 1757390. PMID 14570825. 
  58. ^ Jones J, Ray C, Minnich L, Hicks M, Kibler R, Lucas D (1985). "Evidence for active Epstein-Barr virus infection in patients with persistent, unexplained illnesses: elevated anti-early antigen antibodies". Annals of Internal Medicine 102 (1): 1–7. doi:10.7326/0003-4819-102-1-. PMID 2578266. 
  59. ^ Straus S, Tosato G, Armstrong G, Lawley T, Preble O, Henle W, Davey R, Pearson G, Epstein J, Brus I (1985). "Persisting illness and fatigue in adults with evidence of Epstein-Barr virus infection". Annals of Internal Medicine 102 (1): 7–16. doi:10.7326/0003-4819-102-1-7. PMID 2578268. 
  60. ^ Holmes GP, Kaplan JE, Stewart JA, Hunt B, Pinsky PF, Schonberger LB (1987). "A cluster of patients with a chronic mononucleosis-like syndrome. Is Epstein-Barr virus the cause?". JAMA 257 (17): 2297–302. doi:10.1001/jama.257.17.2297. PMID 3033337. 
  61. ^ Kawai K, Kawai A (1992). "Studies on the relationship between chronic fatigue syndrome and Epstein-Barr virus in Japan". Intern Med 31 (3): 313–8. doi:10.2169/internalmedicine.31.313. PMID 1319246. 
  62. ^ Lerner A, Beqaj S, Deeter R, Fitzgerald J (2004). "IgM serum antibodies to Epstein-Barr virus are uniquely present in a subset of patients with the chronic fatigue syndrome". In Vivo 18 (2): 101–6. PMID 15113035. 
  63. ^ Glaser R; Padgett DA; Litsky ML et al. (March 2005). "Stress-associated changes in the steady-state expression of latent Epstein-Barr virus: implications for chronic fatigue syndrome and cancer". Brain Behav. Immun. 19 (2): 91–103. doi:10.1016/j.bbi.2004.09.001. PMID 15664781. 
  64. ^ Klimas NG, Koneru AO (December 2007). "Chronic fatigue syndrome: inflammation, immune function, and neuroendocrine interactions". Curr Rheumatol Rep 9 (6): 482–7. doi:10.1007/s11926-007-0078-y. PMID 18177602. 
  65. ^ Hickie I Davenport T (2006). "Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study". BMJ 333 (7568): 575. doi:10.1136/bmj.38933.585764.AE. PMC 1569956. PMID 16950834. 
  66. ^ Kitani T; Kuratsune H; Fuke I et al. (1996). "Possible correlation between Borna disease virus infection and Japanese patients with chronic fatigue syndrome". Microbiol. Immunol. 40 (6): 459–62. doi:10.1111/j.1348-0421.1996.tb01094.x. PMID 8839433. 
  67. ^ Beqaj SH, Lerner AM, Fitzgerald JT (2007). "Immunoassay with cytomegalovirus early antigens from gene products p52 and CM2 (UL44 and UL57) detect active infection in patients with chronic fatigue syndrome". J Clin Pathol 61 (5): 623–6. doi:10.1136/jcp.2007.050633. PMID 18037660. 
  68. ^ Chapenko S; Krumina A; Kozireva S et al. (2006). "Activation of human herpesviruses 6 and 7 in patients with chronic fatigue syndrome". J. Clin. Virol. 37 Suppl 1: S47–51. doi:10.1016/S1386-6532(06)70011-7. PMID 17276369. 
  69. ^ De Bolle L, Naesens L, De Clercq E (2005). "Update on Human Herpesvirus 6 Biology, Clinical Features, and Therapy". Clin. Microbiol. Rev. 18 (1): 217–45. doi:10.1128/CMR.18.1.217-245.2005. PMC 544175. PMID 15653828. 
  70. ^ Soto, NE; Straus, SE (2000). "Chronic Fatigue Syndrome and Herpesviruses: the Fading Evidence". Herpes 7 (2): 46–50. PMID 11867001. 
  71. ^ Komaroff AL (2006). "Is human herpesvirus-6 a trigger for chronic fatigue syndrome?". J. Clin. Virol. 37 Suppl 1: S39–46. doi:10.1016/S1386-6532(06)70010-5. PMID 17276367. 
  72. ^ a b Ablashi DV (January 1994). "Viral studies of chronic fatigue syndrome". Clin. Infect. Dis. 18 Suppl 1: S130–3. doi:10.1093/clinids/18.supplement_1.s130. JSTOR 4457622. PMID 8148440. 
  73. ^ Lombardi VC; Ruscetti FW; Das Gupta J et al. (October 2009). "Detection of an infectious retrovirus, XMRV, in blood cells of patients with chronic fatigue syndrome". Science 326 (5952): 585–9. Bibcode:2009Sci...326..585L. doi:10.1126/science.1179052. PMID 19815723.  (Retracted, see PMID 22194552)
  74. ^ Erlwein, O et al. (2010). Nixon, Douglas F., ed. "Failure to Detect the Novel Retrovirus XMRV in Chronic Fatigue Syndrome". PLoS ONE 5 (1): e8519. Bibcode:2010PLoSO...5.8519E. doi:10.1371/journal.pone.0008519. PMC 2795199. PMID 20066031. 
  75. ^ Harriet C T Groom, Virginie C Boucherit, Kerry Makinson, Edward Randal, Sarah Baptista, Suzanne Hagan, John W Gow, Frank M Mattes, Judith Breuer, Jonathan R Kerr, Jonathan P Stoye, Kate N Bishop (2010). "Absence of xenotropic murine leukaemia virus-related virus in UK patients with chronic fatigue syndrome". Retrovirology 7 (1): 10. doi:10.1186/1742-4690-7-10. PMC 2839973. PMID 20156349. 
  76. ^ van Kuppeveld FJ; Jong AS; Lanke KH et al. (2010). "Prevalence of xenotropic murine leukaemia virus-related virus in patients with chronic fatigue syndrome in the Netherlands: retrospective analysis of samples from an established cohort". BMJ 340: c1018. doi:10.1136/bmj.c1018. PMC 2829122. PMID 20185493. 
  77. ^ Switzer, W. M.; Jia, H.; Hohn, O.; Zheng, H.; Tang, S.; Shankar, A.; Bannert, N.; Simmons, G.; Hendry, R. M.; Falkenberg, V. R.; Reeves, W. C.; Heneine, W. (2010). "Absence of evidence of Xenotropic Murine Leukemia Virus-related virus infection in persons with Chronic Fatigue Syndrome and healthy controls in the United States". Retrovirology 7 (1): 57. doi:10.1186/1742-4690-7-57. PMC 2908559. PMID 20594299.  edit
  78. ^ Hong, P.; Li, J.; Li, Y. (2010). "Failure to detect Xenotropic murine leukaemia virus-related virus in Chinese patients with chronic fatigue syndrome". Virology Journal 7: 224. doi:10.1186/1743-422X-7-224. PMC 2945957. PMID 20836869.  edit
  79. ^ Digard, P.; Strohschein, O.; Brandt, K.; Seeher, A. U.; Klein, S.; Kurth, S.; Paul, R.; Meisel, F.; Scheibenbogen, C.; Bannert, N. (2010). Digard, Paul, ed. "No Evidence for XMRV in German CFS and MS Patients with Fatigue Despite the Ability of the Virus to Infect Human Blood Cells in Vitro". PLoS ONE 5 (12): e15632. Bibcode:2010PLoSO...515632H. doi:10.1371/journal.pone.0015632. PMC 3008728. PMID 21203514.  edit
  80. ^ Schutzer SE, Rounds MA, Natelson BH, Ecker DJ, Eshoo MW (2011). "Analysis of cerebrospinal fluid from chronic fatigue patients for multiple human ubiquitous viruses and XMRV". Ann Neurol 69 (4): 735–8. doi:10.1002/ana.22389. PMID 21472770. 
  81. ^ Satterfield BC, Garcia RA, Jia H, Tang S, Zheng H, Switzer WM (2011). "Serologic and PCR testing of persons with chronic fatigue syndrome in the United States shows no association with xenotropic or polytropic murine leukemia virus-related viruses". Retrovirology 8 (1): 12. doi:10.1186/1742-4690-8-12. PMC 3050813. PMID 21342521. 
  82. ^ a b c d Shin, C. H.; Bateman, L.; Schlaberg, R.; Bunker, A. M.; Leonard, C. J.; Hughen, R. W.; Light, A. R.; Light, K. C.; Singh, I. R. (2011). "Absence of XMRV and other MLV-related viruses in patients with Chronic Fatigue Syndrome". Journal of Virology 85 (14): 7195–7202. doi:10.1128/JVI.00693-11. PMC 3126563. PMID 21543496.   edit
  83. ^ a b Garson, JA; Kellam, P; Towers, GJ (2011). "Analysis of XMRV integration sites from human prostate cancer tissues suggests PCR contamination rather than genuine human infection". Retrovirology 8: 13. doi:10.1186/1742-4690-8-13. PMC 3050814. PMID 21352548. 
  84. ^ Menéndez-Arias, L (2011). "Evidence and controversies on the role of XMRV in prostate cancer and chronic fatigue syndrome". Reviews in medical virology 21 (1): 3–17. doi:10.1002/rmv.673. PMID 21294212. 
  85. ^ Shan, H (2011). "What is XMRV and should we be worried about it?". Transfusion 51 (3): 450–3. doi:10.1111/j.1537-2995.2011.03070.x. PMID 21388387. 
  86. ^ Kaiser, J (2011). "Chronic fatigue syndrome. Studies point to possible contamination in XMRV findings". Science 331 (6013): 17. Bibcode:2011Sci...331...17K. doi:10.1126/science.331.6013.17. PMID 21212329. 
  87. ^ Cohen, J. (2011). "More Negative Data for Link Between Mouse Virus and Human Disease". Science 331 (6022): 1253–1254. doi:10.1126/science.331.6022.1253. PMID 21393520. 
  88. ^ Carlowe, J (2010). "Chronic fatigue syndrome is not caused by XMRV virus, study shows". BMJ (Clinical research ed.) 341: c7358. doi:10.1136/bmj.c7358. PMID 21177733. 
  89. ^ Sato, E; Furuta, RA; Miyazawa, T (2010). "An Endogenous Murine Leukemia Viral Genome Contaminant in a Commercial RT-PCR Kit is Amplified Using Standard Primers for XMRV". Retrovirology 7: 110. doi:10.1186/1742-4690-7-110. PMC 3024226. PMID 21171978. 
  90. ^ Robinson, MJ; Erlwein, OW; Kaye, S; Weber, J; Cingoz, O; Patel, A; Walker, MM; Kim, WJ; Uiprasertkul, M; Coffin, John M; McClure, Myra O (2010). "Mouse DNA contamination in human tissue tested for XMRV". Retrovirology 7: 108. doi:10.1186/1742-4690-7-108. PMC 3019155. PMID 21171966. 
  91. ^ Oakes, B; Tai, AK; Cingöz, O; Henefield, MH; Levine, S; Coffin, JM; Huber, BT (2010). "Contamination of human DNA samples with mouse DNA can lead to false detection of XMRV-like sequences". Retrovirology 7: 109. doi:10.1186/1742-4690-7-109. PMC 3022687. PMID 21171973. 
  92. ^ http://www.pnas.org/content/early/2010/08/16/1006901107.full.pdf
  93. ^ Alberts, B. (2011). "Editorial Expression of Concern". Science 333 (6038): 35. Bibcode:2011Sci...333...35A. doi:10.1126/science.1208542. PMID 21628391. 
  94. ^ Silverman, R.; Das Gupta, J.; Lombardi, V. C.; Ruscetti, F. W.; Pfost, M. A.; Hagen, K. S.; Peterson, D. L.; Ruscetti, S. K.; Bagni, R. K.; Petrow-Sadowski, C.; Gold, B.; Dean, M.; Mikovits, J. A. (2011). "Partial Retraction". Science 334 (6053): 176. Bibcode:2011Sci...334..176S. doi:10.1126/science.1212182. PMID 21940859. 
  95. ^ Virus theory for chronic fatigue dismissed - By Nonee Walsh - (6 Jan 2012) - Australian Broadcasting Corporation - Retrieved 6 Jan 2012.
  96. ^ Alberts B (December 2011). "Retraction". Science 334 (6063): 1636. Bibcode:2011Sci...334.1636A. doi:10.1126/science.334.6063.1636-a. PMID 22194552. 
  97. ^ Lo SC; Pripuzova N; Li B et al. (January 2012). "Retraction for Lo et al., Detection of MLV-related virus gene sequences in blood of patients with chronic fatigue syndrome and healthy blood donors". Proceedings of the National Academy of Sciences 109 (1): 346. Bibcode:2012PNAS..109..346.. doi:10.1073/pnas.1119641109. PMC 3252929. PMID 22203980.  - Retrieved 7 Jan 2012
  98. ^ a b Appel S, Chapman J, Shoenfeld Y (2007). "Infection and vaccination in chronic fatigue syndrome: myth or reality?". Autoimmunity 40 (1): 48–53. doi:10.1080/08916930701197273. PMID 17364497. 
  99. ^ a b Cho HJ, Skowera A, Cleare A, Wessely S (2006). "Chronic fatigue syndrome: an update focusing on phenomenology and pathophysiology". Current Opinion in Psychiatry 19 (1): 67–73. doi:10.1097/01.yco.0000194370.40062.b0. PMID 16612182. 
  100. ^ Lorusso L, Mikhaylova SV, Capelli E, Ferrari D, Ngonga GK, Ricevuti G (February 2009). "Immunological aspects of chronic fatigue syndrome". Autoimmun Rev 8 (4): 287–91. doi:10.1016/j.autrev.2008.08.003. PMID 18801465. 
  101. ^ Nijs J, Nees A, Paul L, De Kooning M, Ickmans K, Meeus M, Van Oosterwijck J (2014). "Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review" (PDF). Exerc Immunol Rev 20: 94–116. PMID 24974723. Retrieved 2015-06-19. 
  102. ^ Logan AC, Wong C (2001). "Chronic fatigue syndrome: oxidative stress and dietary modifications". Alternative medicine review : a journal of clinical therapeutic 6 (5): 450–9. PMID 11703165. 
  103. ^ Nijs J, De Meirleir K (2005). "Impairments of the 2-5A synthetase/RNase L pathway in chronic fatigue syndrome". In Vivo 19 (6): 1013–21. PMID 16277015. 
  104. ^ a b c Patarca R (2001). "Cytokines and chronic fatigue syndrome". Annals of the New York Academy of Sciences 933: 185–200. Bibcode:2001NYASA.933..185P. doi:10.1111/j.1749-6632.2001.tb05824.x. PMID 12000020. 
  105. ^ Visser JT, De Kloet ER, Nagelkerken L; Kloet; Nagelkerken (2000). "Altered glucocorticoid regulation of the immune response in the chronic fatigue syndrome". Annals of the New York Academy of Sciences 917: 868–75. Bibcode:2000NYASA.917..868V. doi:10.1111/j.1749-6632.2000.tb05453.x. PMID 11268418. 
  106. ^ Patarca-Montero R, Antoni M, Fletcher MA, Klimas NG (2001). "Cytokine and other immunologic markers in chronic fatigue syndrome and their relation to neuropsychological factors". Appl Neuropsychol 8 (1): 51–64. doi:10.1207/S15324826AN0801_7. PMID 11388124. 
  107. ^ Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES (2000). "The sympathetic nerve--an integrative interface between two supersystems: the brain and the immune system". Pharmacol. Rev. 52 (4): 595–638. PMID 11121511. 
  108. ^ Papadopoulos, Andrew S.; Cleare, Anthony J. (27 September 2011). "Hypothalamic–pituitary–adrenal axis dysfunction in chronic fatigue syndrome". Nature Reviews Endocrinology 8 (1): 22–32. doi:10.1038/nrendo.2011.153. PMID 21946893. 
  109. ^ Cleare AJ (April 2003). "The neuroendocrinology of chronic fatigue syndrome.". Endocr Rev 24 (2): 236–52. PMID 12700181. 
  110. ^ Cleare AJ (March 2004). "The HPA axis and the genesis of chronic fatigue syndrome.". Trends Endocrinol Metab 15 (2): 55–9. doi:10.1016/j.tem.2003.12.002. PMID 15036250. 
  111. ^ Van Den Eede F, Moorkens G, Van Houdenhove B, Cosyns P, Claes SJ (2007). "Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome." (PDF). Neuropsychobiology 55 (2): 112–20. doi:10.1159/000104468. PMID 17596739. 
  112. ^ Tak LM, Cleare AJ, Ormel J, Manoharan A, Kok IC, Wessely S, Rosmalen JG (May 2011). "Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis activity in functional somatic disorders.". Biol Psychol 87 (2): 183–94. doi:10.1016/j.biopsycho.2011.02.002. PMID 21315796. 
  113. ^ Roberts AD, Charler ML, Papadopoulos A, Wessely S, Chalder T, Cleare AJ (March 2010). "Does hypocortisolism predict a poor response to cognitive behavioural therapy in chronic fatigue syndrome?". Psychol Med 40 (3): 515–22. doi:10.1017/S0033291709990390. PMID 19607750. 
  114. ^ a b Smith AK; Dimulescu I; Falkenberg VR et al. (2008). "Genetic evaluation of the serotonergic system in chronic fatigue syndrome". Psychoneuroendocrinology 33 (2): 188–97. doi:10.1016/j.psyneuen.2007.11.001. PMID 18079067. 
  115. ^ "Molecular Epidemiology Program". National Center for Infectious Diseases. 2005-07-25. 
  116. ^ Whistler T, Jones JF, Unger ER, Vernon SD (2005). "Exercise responsive genes measured in peripheral blood of women with Chronic Fatigue Syndrome and matched control subjects". BMC Physiol 5 (1): 5. doi:10.1186/1472-6793-5-5. PMC 1079885. PMID 15790422. 
  117. ^ Whistler T, Unger ER, Nisenbaum R, Vernon SD (2003). "Integration of gene expression, clinical, and epidemiologic data to characterize Chronic Fatigue Syndrome". J Transl Med 1 (1): 10. doi:10.1186/1479-5876-1-10. PMC 305360. PMID 14641939. 
  118. ^ Vernon SD, Unger ER, Dimulescu IM, Rajeevan M, Reeves WC (2002). "Utility of the blood for gene expression profiling and biomarker discovery in chronic fatigue syndrome". Dis Markers 18 (4): 193–9. doi:10.1155/2002/892374. PMID 12590173. 
  119. ^ Kaushik N, Fear D, Richards SC, McDermott CR, Nuwaysir EF, Kellam P, Harrison TJ, Wilkinson RJ, Tyrrell DA, Holgate ST, Kerr JR (2005). "Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome". J Clin Pathol 58 (8): 826–32. doi:10.1136/jcp.2005.025718. PMC 1770875. PMID 16049284. 
  120. ^ Fang H, Xie Q, Boneva R, Fostel J, Perkins R, Tong W (2006). "Gene expression profile exploration of a large dataset on chronic fatigue syndrome". Pharmacogenomics 7 (3): 429–40. doi:10.2217/14622416.7.3.429. PMID 16610953. 
  121. ^ BBC News (28 May 2005) - Scientists 'unlock ME genetics' (study still in its early stages)
  122. ^ Kerr J; Burke B; Petty R et al. (2007). "Seven genomic subtypes of Chronic Fatigue Syndrome / Myalgic Encephalomyelitis (CFS/ME): a detailed analysis of gene networks and clinical phenotypes". J Clin Pathol 61 (6): 730–9. doi:10.1136/jcp.2007.053553. PMID 18057078. 
  123. ^ Kerr JR; Petty R; Burke B et al. (April 2008). "Gene expression subtypes in patients with chronic fatigue syndrome/myalgic encephalomyelitis". J. Infect. Dis. 197 (8): 1171–84. doi:10.1086/533453. PMID 18462164. 
  124. ^ Saiki T; Kawai T; Morita K et al. (July 2008). "Identification of Marker Genes for Differential Diagnosis of Chronic Fatigue Syndrome". Mol. Med. 14 (9–10): 599–607. doi:10.2119/2007-00059.Saiki. PMC 2442021. PMID 18596870. 
  125. ^ Light, A. R.; Vierck, C. J.; Light, K. C.; Kruger, L.; Light, A. R. (2010). "Myalgia and Fatigue: Translation from Mouse Sensory Neurons to Fibromyalgia and Chronic Fatigue Syndromes". PMID 21882454.  edit
  126. ^ Wyller VB (2007). "The chronic fatigue syndrome--an update". Acta Neurol. Scand., Suppl. 187: 7–14. doi:10.1111/j.1600-0404.2007.00840.x. PMID 17419822. 
  127. ^ Narita M, Nishigami N, Narita N, Yamaguti K, Okado N, Watanabe Y, Kuratsune H (2003). "Association between serotonin transporter gene polymorphism and chronic fatigue syndrome". Biochem. Biophys. Res. Commun. 311 (2): 264–6. doi:10.1016/j.bbrc.2003.09.207. PMID 14592408. 
  128. ^ Smith AK, White PD, Aslakson E, Vollmer-Conna U, Rajeevan MS (2006). "Polymorphisms in genes regulating the HPA axis associated with empirically delineated classes of unexplained chronic fatigue". Pharmacogenomics 7 (3): 387–94. doi:10.2217/14622416.7.3.387. PMID 16610949. 
  129. ^ Torpy DJ, Bachmann AW, Gartside M, Grice JE, Harris JM, Clifton P, Easteal S, Jackson RV, Whitworth JA (2004). "Association between chronic fatigue syndrome and the corticosteroid-binding globulin gene ALA SER224 polymorphism". Endocr. Res. 30 (3): 417–29. doi:10.1081/ERC-200035599. PMID 15554358. 
  130. ^ Kerr JR (2005). "Pathogenesis of parvovirus B19 infection: host gene variability, and possible means and effects of virus persistence". J. Vet. Med. B Infect. Dis. Vet. Public Health 52 (7–8): 335–9. doi:10.1111/j.1439-0450.2005.00859.x. PMID 16316396. 
  131. ^ Carlo-Stella N, Badulli C, De Silvestri A, Bazzichi L, Martinetti M, Lorusso L, Bombardieri S, Salvaneschi L, Cuccia M (2006). "A first study of cytokine genomic polymorphisms in CFS: Positive association of TNF-857 and IFNgamma 874 rare alleles". Clin. Exp. Rheumatol. 24 (2): 179–82. PMID 16762155. 
  132. ^ Vladutiu GD, Natelson BH (2004). "Association of medically unexplained fatigue with ACE insertion/deletion polymorphism in Gulf War veterans". Muscle Nerve 30 (1): 38–43. doi:10.1002/mus.20055. PMID 15221876. 
  133. ^ Nijs J, Meeus M, De Meirleir K (2006). "Chronic musculoskeletal pain in chronic fatigue syndrome: recent developments and therapeutic implications". Man Ther 11 (3): 187–91. doi:10.1016/j.math.2006.03.008. PMID 16781183. 
  134. ^ Broderick G, Craddock RC, Whistler T, Taylor R, Klimas N, Unger ER (2006). "Identifying illness parameters in fatiguing syndromes using classical projection methods". Pharmacogenomics 7 (3): 407–19. doi:10.2217/14622416.7.3.407. PMID 16610951. 
  135. ^ van de Glind G, de Vries M, Rodenburg R, Hol F, Smeitink J, Morava E (2007). "Resting muscle pain as the first clinical symptom in children carrying the MTTK A8344G mutation". Eur. J. Paediatr. Neurol. 11 (4): 243–6. doi:10.1016/j.ejpn.2007.01.004. PMID 17293137. 
  136. ^ Behan WM, More IA, Behan PO (1991). "Mitochondrial abnormalities in the postviral fatigue syndrome". Acta Neuropathol. 83 (1): 61–5. doi:10.1007/BF00294431. PMID 1792865. 
  137. ^ Lundell K, Qazi S, Eddy L, Uckun FM (2006). "Clinical activity of folinic acid in patients with chronic fatigue syndrome". Arzneimittelforschung 56 (6): 399–404. doi:10.1055/s-0031-1296741. PMID 16889122. 
  138. ^ Jacobson W, Saich T, Borysiewicz LK, Behan WM, Behan PO, Wreghitt TG (December 1993). "Serum folate and chronic fatigue syndrome". Neurology 43 (12): 2645–7. doi:10.1212/wnl.43.12.2645. PMID 8255470. 
  139. ^ Behan PO, Behan WM, Horrobin D (1990). "Effect of high doses of essential fatty acids on the postviral fatigue syndrome". Acta Neurol. Scand. 82 (3): 209–16. doi:10.1111/j.1600-0404.1990.tb04490.x. PMID 2270749. 
  140. ^ Ogawa R, Toyama S, Matsumoto H. (1992). "Chronic fatigue syndrome--cases in the Kanebo Memorial Hospital". Nippon Rinsho. 50 (11): 2648–52. PMID 1337561. 
  141. ^ Liu Z; Wang D; Xue Q et al. (2003). "Determination of fatty acid levels in erythrocyte membranes of patients with chronic fatigue syndrome". Nutritional neuroscience 6 (6): 389–92. doi:10.1080/10284150310001640356. PMID 14744043. 
  142. ^ Maes M, Mihaylova I, Leunis JC (2005). "In chronic fatigue syndrome, the decreased levels of omega-3 poly-unsaturated fatty acids are related to lowered serum zinc and defects in T cell activation". Neuro Endocrinol. Lett. 26 (6): 745–51. PMID 16380690. 
  143. ^ Warren G, McKendrick M, Peet M (1999). "The role of essential fatty acids in chronic fatigue syndrome. A case-controlled study of red-cell membrane essential fatty acids (EFA) and a placebo-controlled treatment study with high dose of EFA". Acta Neurol. Scand. 99 (2): 112–6. doi:10.1111/j.1600-0404.1999.tb00667.x. PMID 10071170. 
  144. ^ Chronic fatigue syndrome - Musculoskeletal disorders - BMJ Clinical Evidence
  145. ^ Tahmaz N, Soutar A, Cherrie JW (June 2003). "Chronic fatigue and organophosphate pesticides in sheep farming: a retrospective study amongst people reporting to a UK pharmacovigilance scheme". Ann Occup Hyg 47 (4): 261–7. doi:10.1093/annhyg/meg042. PMID 12765866. 
  146. ^ Robert Davies, Ghouse Ahmed and Tegwedd Freer (2000). "Chronic exposure to organophosphates: background and clinical picture". Advances in Psychiatric Treatment 6 (3): 187–192. doi:10.1192/apt.6.3.187. 
  147. ^ Viner R, Hotopf M (2003). "Childhood predictors of self reported chronic fatigue syndrome/myalgic encephalomyelitis in adults: national birth cohort study". BMJ 329 (7472): 941. doi:10.1136/bmj.38258.507928.55. PMC 524102. PMID 15469945. 
  148. ^ Harvey SB, Wadsworth M, Wessely S, Hotopf M (2008). "Etiology of chronic fatigue syndrome: testing popular hypotheses using a national birth cohort study". Psychosom Med 70 (4): 488–95. doi:10.1097/PSY.0b013e31816a8dbc. PMID 18378866. 
  149. ^ Lane RJ, Barrett MC, Taylor DJ, Kemp GJ, Lodi R (1998). "Heterogeneity in chronic fatigue syndrome: evidence from magnetic resonance spectroscopy of muscle". Neuromuscul. Disord. 8 (3–4): 204–9. doi:10.1016/S0960-8966(98)00021-2. PMID 9631403. 
  150. ^ Lane RJ, Barrett MC, Woodrow D, Moss J, Fletcher R, Archard LC (1998). "Muscle fibre characteristics and lactate responses to exercise in chronic fatigue syndrome". J. Neurol. Neurosurg. Psychiatr. 64 (3): 362–7. doi:10.1136/jnnp.64.3.362. PMC 2169994. PMID 9527150. 
  151. ^ Lane RJ, Soteriou BA, Zhang H, Archard LC (2003). "Enterovirus related metabolic myopathy: a postviral fatigue syndrome". J. Neurol. Neurosurg. Psychiatr. 74 (10): 1382–6. doi:10.1136/jnnp.74.10.1382. PMC 1757378. PMID 14570830. 
  152. ^ Lamb GD, Stephenson DG (2006). "Point: lactic acid accumulation is an advantage during muscle activity". J. Appl. Physiol. 100 (4): 1410–2; discussion 1414. doi:10.1152/japplphysiol.00023.2006. PMID 16540714. 
  153. ^ Pedersen TH, Nielsen OB, Lamb GD, Stephenson DG; Nielsen; Lamb; Stephenson (2004). "Intracellular acidosis enhances the excitability of working muscle". Science 305 (5687): 1144–7. Bibcode:2004Sci...305.1144P. doi:10.1126/science.1101141. PMID 15326352. 
  154. ^ Barron DF, Cohen BA, Geraghty MT, Violand R, Rowe PC (2002). "Joint hypermobility is more common in children with chronic fatigue syndrome than in healthy controls". J Pediatr 141 (3): 421–5. doi:10.1067/mpd.2002.127496. PMID 12219066.