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Central sensitization
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=== Other findings === In 2015 Staud et al. found indirect evidence for sensitized fatigue pathways in ME/CFS. Patients underwent exhausting handgrip-exercises and showed higher increased fatigue ratings than healthy controls after muscle metabolites were trapped in forearm tissues. The fact that fatigue ratings returned to baseline rapidly after removing the forearm occlusion suggests that ME/CFS patients display an increased sensitivity to exercise metabolites.<ref>{{Cite journal | last = Staud | first = Roland | last2 = Mokthech | first2 = Meriem | last3 = Price | first3 = Donald D. | last4 = Robinson | first4 = Michael E. | date = Apr 2015 | title = Evidence for sensitized fatigue pathways in patients with chronic fatigue syndrome | url =http://dx.doi.org/10.1097/j.pain.0000000000000110 | journal = PAIN | volume = 156 | issue = 4 | pages = 750–759|doi=10.1097/j.pain.0000000000000110|issn=0304-3959}}</ref> In 2009 Light et al. found an increase in metabolite detecting receptors in the white blood cells of ME/CFS patients after an exercise test - an increase that was not seen in controls.<ref name="Light2009">{{Cite journal | last = Light | first = Alan R. | last2 = White | first2 = Andrea T. | last3 = Hughen | first3 = Ronald W. | last4 = Light | first4 = Kathleen C. | date = Oct 2009 | title = Moderate exercise increases expression for sensory, adrenergic, and immune genes in chronic fatigue syndrome patients but not in normal subjects |url =https://www.ncbi.nlm.nih.gov/pubmed/19647494 | journal = The Journal of Pain: Official Journal of the American Pain Society | volume = 10 | issue = 10 | pages = 1099–1112|doi=10.1016/j.jpain.2009.06.003|issn=1528-8447|pmc=2757484|pmid=19647494|quote= | authorlink = Alan Light | author-link2 = | author-link3 = | author-link4 = Kathleen Light | author-link5 = |via=}}</ref> Results were confirmed by three other studies.<ref>{{Cite journal | last = Light | first = A.R. | last2 = Bateman | first2 = L. | last3 = Jo | first3 = D. | last4 = Hughen | first4 = R.W. | last5 = Vanhaitsma | first5 = T.A. |last6 = White | first6 = A.T. | last7 = Light | first7 = K.C. | date = Jan 2012 | title = Gene expression alterations at baseline and following moderate exercise in patients with Chronic Fatigue Syndrome and Fibromyalgia Syndrome | url =https://www.ncbi.nlm.nih.gov/pubmed/21615807 | journal = Journal of Internal Medicine | volume = 271 | issue = 1 | pages = 64–81|doi=10.1111/j.1365-2796.2011.02405.x|issn=1365-2796|pmc=3175315|pmid=21615807|quote= | authorlink = Alan Light | author-link2 = Lucinda Bateman|via= | author-link8 = Kathleen Light}}</ref><ref>{{Cite journal | last = Meyer | first = Jacob D. | last2 = Light | first2 = Alan R. | last3 = Shukla | first3 = Sanjay K. | last4 = Clevidence | first4 = Derek | last5 = Yale | first5 = Steven | last6 = Stegner | first6 = Aaron J. | last7 = Cook | first7 = Dane B. | date = Oct 2013 | title = Post-exertion malaise in chronic fatigue syndrome: symptoms and gene expression | url =https://www.tandfonline.com/doi/abs/10.1080/21641846.2013.838444|journal = Fatigue: Biomedicine, Health & Behavior |language=en | volume = 1 | issue = 4 | pages = 190–209|doi=10.1080/21641846.2013.838444|issn=2164-1846|quote= | authorlink = | author-link2 = Alan Light|via= | author-link8 = Dane Cook}}</ref><ref>{{Cite journal | last = White | first = Andrea T. | last2 = Light | first2 = Alan R. | last3 = Hughen | first3 = Ronald W. | last4 = Vanhaitsma | first4 = Timothy A. | last5 = Light | first5 = Kathleen C. | date = Jan 2012 | title = Differences in metabolite-detecting, adrenergic, and immune gene expression after moderate exercise in patients with chronic fatigue syndrome, patients with multiple sclerosis, and healthy controls |url =https://www.ncbi.nlm.nih.gov/pubmed/22210239 | journal = Psychosomatic Medicine | volume = 74 | issue = 1 | pages = 46–54|doi=10.1097/PSY.0b013e31824152ed|issn=1534-7796|pmc=3256093|pmid=22210239|quote= | authorlink = | author-link2 = Alan Light | author-link3 = | author-link4 = | author-link5 = Kathleen Light|via=}}</ref> The authors speculate this might reflect an increased sensitivity to fatigue pathways in ME/CFS: <blockquote>“If these receptors are increased in CFS patients, it is possible that low levels of metabolites can activate leukocytes, and moderate exercise could increase the signal, thereby increasing cytokine levels that sensitize muscle sensory fatigue signaling afferents.”<ref name="Light2009" /></blockquote>In 2002 Nijs et al. reported bronchial hyperesponsiveness (BHR) after a histamine provocation test in 77 ME/CFS patients out of a sample of 137. Further research into immune factors failed to show a link with IGE-mediated activation of mast cells and eosinophils as is seen in asthma patients, but there was a connection with increased [[cytotoxic T-cell]] count and BHR.<ref>{{Cite journal | last = Nijs | first = Jo | last2 = De Becker | first2 = Pascale | last3 = De Meirleir | first3 = Kenny | last4 = Demanet | first4 = Christian | last5 = Vincken | first5 = Walter | last6 = Schuermans | first6 = Daniel | last7 = McGregor | first7 = Neil | date = Apr 2003 | title = Associations Between Bronchial Hyperresponsiveness and Immune Cell Parameters in Patients With Chronic Fatigue Syndrome | url =http://dx.doi.org/10.1378/chest.123.4.998 | journal = Chest | volume = 123 | issue = 4 | pages = 998–1007|doi=10.1378/chest.123.4.998|issn=0012-3692|quote= | authorlink = Jo Nijs | author-link2 = Pascale De Becker | author-link3 = Kenny De Meirleir | author-link4 = | author-link5 = |via=}}</ref> According to Nijs “the high prevalence of bronchial hyperresponsiveness can be viewed as another piece of evidence in support of central sensitisation in at least a large subset of the CFS population.”<ref name="Nijs2011a" /> The research group of Jo Nijs was initially drawn to exploring central sensitization in ME/CFS because of increased nitric oxide (NO) levels in these patients, as reported by Kurup & Kurup in 2003.<ref>{{Cite journal | last = Nijs | first = Jo | last2 = Van de Velde | first2 = Bart | last3 = De Meirleir | first3 = Kenny | date = Jan 2005 | title = Pain in patients with chronic fatigue syndrome: Does nitric oxide trigger central sensitisation? | url = http://dx.doi.org/10.1016/j.mehy.2004.07.037 | journal = Medical Hypotheses | volume = 64 | issue = 3 | pages = 558–562|doi=10.1016/j.mehy.2004.07.037|issn=0306-9877|quote= | authorlink = Jo Nijs | author-link2 = | author-link3 = Kenny De Meirleir | author-link4 = | author-link5 = |via=}}</ref> Subsequent research however showed that NO concentrations were normal and unrelated to activity levels in 30 ME/CFS patients.<ref>{{Cite journal | last = Meeus | first = Mira | last2 = Van Eupen | first2 = Inge | last3 = Hondequin | first3 = Jasmien | last4 = DE Hauwere | first4 = Lieve | last5 = Kos | first5 = Daphne | last6 = Nijs | first6 = Jo | date = Nov 2010 | title = Nitric oxide concentrations are normal and unrelated to activity level in chronic fatigue syndrome: a case-control study | url = https://www.ncbi.nlm.nih.gov/pubmed/21164046 | journal = In Vivo (Athens, Greece) | volume = 24 | issue = 6 | pages = 865–869|issn=1791-7549|pmid=21164046|quote= | authorlink = Mira Meeus|via= | author-link6 = Jo Nijs}}</ref> Substance P is another element believed to be involved in central sensitization. Increased levels of [[Substance P]] in [[cerebrospinal fluid]] have been reported in patients with [[fibromyalgia]]<ref>{{Cite journal | last = Russell | first = I. Jon | last2 = Orr | first2 = Malcolm D. | last3 = Littman | first3 = Bruce | last4 = Vipraio | first4 = Gilbert A. | last5 = Alboukrek | first5 = David | last6 = Michalek | first6 = Joel E. | last7 = Lopez | first7 = Yolanda | last8 = Mackillip | first8 = Fane | date = Nov 1994 | title = Elevated cerebrospinal fluid levels of substance p in patients with the fibromyalgia syndrome | url =http://dx.doi.org/10.1002/art.1780371106 | journal = Arthritis & Rheumatism | volume = 37 | issue = 11 | pages = 1593–1601|doi=10.1002/art.1780371106|issn=0004-3591}}</ref><ref>{{Cite journal | last = Vaerøy | first = Henning | last2 = Helle | first2 = Robert | last3 = Førre | first3 = Øystein | last4 = Kåss | first4 = Erik | last5 = Terenius | first5 = Lars | date = Jan 1988 | title = Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis |url =http://dx.doi.org/10.1016/0304-3959(88)90019-x | journal = Pain | volume = 32 | issue = 1 | pages = 21–26|doi=10.1016/0304-3959(88)90019-x|issn=0304-3959}}</ref> – the prototype of central sensitivity syndromes. A small Swedish study involving 15 patients found values of Substance P to be in the normal range in ME/CFS.<ref>{{Cite journal | last = Evengard | first = B. | last2 = Nilsson | first2 = C.G. | last3 = Lindh | first3 = G. | last4 = Lindquist | first4 = L. | last5 = Eneroth | first5 = P. | last6 = Fredrikson | first6 = S. | last7 = Terenius | first7 = L. | last8 = Henriksson | first8 = K.G. | date = Nov 1998 | title = Chronic fatigue syndrome differs from fibromyalgia. No evidence for elevated substance P levels in cerebrospinal fluid of patients with chronic fatigue syndrome | url =https://www.ncbi.nlm.nih.gov/pubmed/9839828 | journal = Pain | volume = 78 | issue = 2 | pages = 153–155|issn=0304-3959|pmid=9839828|quote=|via=}}</ref>
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