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Post-exertional malaise
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== Objective findings after exertion: == In the 1980s Melvin A. Ramsay stressed the use of assessing ME patients after exertion. Regarding muscle weakness – what he regarded as the hallmark symptom of the disease –he noted: <blockquote>"If muscle power is found to be satisfactory, a re-examination should be made after exercise; a walk of half a mile is sufficient, as very few ME case can manage more. […] It is most important to stress the fact that cases of ME of mild or even moderate severity may have normal muscle power in a remission. In such cases, test for muscle power should be repeated after exercise."<ref name="Ramsay1988" /> </blockquote>Though the definition of PEM has been expended far beyond muscle weakness, modern day research has confirmed the utility of testing ME/CFS after exertion. Many markers that are normal in resting state in ME/CFS patients turn out to be abnormal after a physical or cognitive stressor.<ref name="IOM2015" /> A fairly small study of ME/CFS patients who met the widely used [[Fukuda criteria]] found different brain activation patterns in particular areas of the brain in ME/CFS patients after exercise compared to before exercise; these changes in brain activation was not found in healthy controls after exercise.<ref name="Washington2020" /> === Gene expression === <embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''72. Gene-expression and exercise / Gen-expressie en inspanning – Dr. Lucinda Bateman'' (2015) By Dr. Lucinda Bateman/Wetenschap voor Patienten - ME/cvs Vereniging">https://www.youtube.com/watch?v=F1PP21TmUPs</embedvideo> One example is gene expression. In a 2009 study Light et al. showed that after a moderate exercise test, the [[leukocyte]]s of ME/CFS patients showed an increase in expression of [[Adrenergic receptor|adrenergic]], metabolite detecting and immune-related genes that was not seen in healthy controls. Before the exercise test there were no abnormalities in the expression of these genes of ME/CFS patients. The authors speculated this to be evidence for sensitization of fatigue pathways in ME/CFS.<ref name="Light2009" /> The research team was able to confirm their results in a subsequent study using a larger sample of 48 patients.<ref name="Light2011" /> In a 2012 comparison MS patients also displayed an increase in post-exercise gene expression, but only ME/CFS patients showed increases in metabolite-detecting sensory receptors. According to the authors:<blockquote>"Because only the CFS patients showed increases in these metabolite-detecting receptors, the sensory receptor elements of this gene profile seem particularly specific to CFS and may reflect dysregulated pathways that directly contribute to increased effort sense during exercise and postexertional malaise."<ref name="White2011" /></blockquote>Attempts at replication by other research teams have produced contradictory results. Meyer et al. were unable to confirm most of the post-exertional increases in gene expression, except for some in the adrenergic and glucocorticoid pathway.<ref name="Meyer2013" /> An [[Australia|Australian]] team under the guidance of [[Andrew Lloyd]] failed to find any significant exercise-induced changes in leucocyte gene expression, though the patient sample used (n = 10) was rather small and did not include any patients with severe disability.<ref name="Keech2016">{{Cite journal | last = Keech | first = Andrew | last2 = Vollmer-Conna | first2 = Ute | last3 = Barry | first3 = Benjamin K. | last4 = Lloyd | first4 = Andrew R. | date = 2016 | title=Gene Expression in Response to Exercise in Patients with Chronic Fatigue Syndrome: A Pilot Study|url=https://www.ncbi.nlm.nih.gov/pubmed/27713703|journal=Frontiers in Physiology|volume=7 | pages = 421|doi=10.3389/fphys.2016.00421|issn=1664-042X|pmc=5031769|pmid=27713703}}</ref> === Immune activation === <embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Inducing Post-Exertional Malaise in ME/CFS: A Look at the Research Evidence'' (2015) By Dr. Peter Rowe/Solve CFS">https://www.youtube.com/watch?v=ux93w7yGQ5g</embedvideo> There are many studies demonstrating exercise-induced immunological abnormalities in ME/CFS patients.<ref name="Nijs2014" /> Most findings however still have to be replicated by other research groups, using larger samples. ==== Oxidative stress ==== <embedvideo service="youtube" dimensions="400" alignment="right" container="frame" description="''Post-Exertion Malaise: The Intersection of Biology and Behavior'' (2015) By Dr. Dane B. Cook/Solve CFS">https://www.youtube.com/watch?v=vfmrPd4-rIE</embedvideo> In 2005 the French team Jammes et al. found a lengthened and accentuated oxidative stress response in ME/CFS patients after a cycling exercise until exhaustion. At baseline markers of [[oxidative stress]] (thiobarbituric acidreactiv substances and ascorbic acid) did not differ significantly from healthy controls. After the exercise challenge however, the oxidative stress response occurred sooner and lasted longer in the ME/CFS group. This was associated with alterations in muscle excitability (lengthened M-wave duration) in ME/CFS-patients, which were not seen in controls.<ref>{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Mambrini | first3 = O. | last4 = Brégeon | first4 = F. | last5 = Delliaux | first5 = S. | date = Mar 2005 | title = Chronic fatigue syndrome: assessment of increased oxidative stress and altered muscle excitability in response to incremental exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/15715687|journal=Journal of Internal Medicine|volume=257|issue=3|pages=299–310|doi=10.1111/j.1365-2796.2005.01452.x|issn=0954-6820|pmid=15715687}}</ref> A small 2009 follow-up study confirmed these results and associated it with a post-exertional reduction of [[Heat shock protein|heat shock proteins]] HSP 27 and HSP 70 after exercise.<ref name="Jammes2009">{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Delliaux | first3 = S. | last4 = Brégeon | first4 = F. | date = Aug 2009 | title = Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses|url=https://www.ncbi.nlm.nih.gov/pubmed/19457057|journal=Journal of Internal Medicine|volume=266|issue=2|pages=196–206|doi=10.1111/j.1365-2796.2009.02079.x|issn=1365-2796|pmid=19457057}}</ref> According to the authors, this is another indication of an impaired redox status in ME/CFS patients. A 2011 study confirmed most of these results in a larger cohort of 43 ME/CFS patients and 23 healthy controls. Again the data indicated an increased exercise-induced oxidative stress and a reduced Hsp response. Though it is know that deconditioning can increase oxidative stress, the authors argued this to be unlikely in their study population, for several reasons: <blockquote>“…deconditioning can be ruled out in our study because (i) it induces carbohydrate and lipid disorders that were not observed during routine biochemical check-up in these CFS patients, (ii) CFS patients did not have reduced maximal exercise performance or an accentuated lactic acid response and (iii) we found no correlation between the duration of CFS symptoms […] and the resting levels of oxidant–antioxidant status and HSPs.”<ref>{{Cite journal | last= Jammes | first = Y. | last2 = Steinberg | first2 = J.G. | last3 = Delliaux | first3 = S. | date = Jul 2012 | title = Chronic fatigue syndrome: acute infection and history of physical activity affect resting levels and response to exercise of plasma oxidant/antioxidant status and heat shock proteins|url=https://www.ncbi.nlm.nih.gov/pubmed/22112145|journal=Journal of Internal Medicine|volume=272|issue=1 | pages = 74–84|doi=10.1111/j.1365-2796.2011.02488.x|issn=1365-2796|pmid=22112145}}</ref></blockquote>A [[Canada|Canadian]] research team had already reported a marked decline of HSP 27 during the post-exercise period of six ME/CFS patients in 2002.<ref>{{Cite journal | last = Thambirajah | first = Anita A. | last2 = Sleigh | first2 = Kenna | last3 = Stiver | first3 = H. Grant | last4 = Chow | first4 = Anthony W. | date = 2008-12-01 | title = Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls|url=https://www.ncbi.nlm.nih.gov/pubmed/19032901|journal=Clinical and Investigative Medicine. Medecine Clinique Et Experimentale|volume=31|issue=6| pages = E319–327|issn=1488-2353|pmid=19032901}}</ref> ==== Complement C4a ==== In 2003 Sorensen et al. found that the [[Complement C4a|complement split product C4a]] was increased after exercise in the 20 ME/CFS patients, but not in controls. Furthermore a significant correlation was found between the increase in C4a and total symptom score.<ref>{{Cite journal | last = Sorensen | first=Bristol | last2 = Streib | first2 = Joanne E. | last3 = Strand | first3 = Matthew | last4 = Make | first4 = Barry | last5 = Giclas | first5 = Patricia C. | last6 = Fleshner | first6 = Monika | last7 = Jones | first7 = James F. | date = Aug 2003 | title = Complement activation in a model of chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12897748|journal=The Journal of Allergy and Clinical Immunology|volume=112|issue=2|pages=397–403|issn=0091-6749|pmid=12897748}}</ref> C4a is generated from the cleavage of the native complement protein C4 via the classical and lectin pathways. A follow up study, published in 2009, found that other elements of the lectin pathway also responded differently to an exercise challenge in ME/CFS patients compared to controls. Both C4 and mannan-binding lectin serine protease 2 (MASP2) were observed at higher levels in ME/CFS subjects 1 hour post-exercise.<ref>{{Cite journal | last = Sorensen | first=Bristol | author-link = | last2 = Jones | first2 = James F | authorlink2 = | last3 = Vernon | first3 = Suzanne D | authorlink3 = Suzanne Vernon | last4 = Rajeevan | first4 = Mangalathu S | authorlink4 = Mangalathu Rajeevan | author-link5 = | date = Jan 2009 | title = Transcriptional Control of Complement Activation in an Exercise Model of Chronic Fatigue Syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2583111/|journal=Molecular Medicine|volume=15|issue=1-2|pages=34–42|doi=10.2119/molmed.2008.00098|pmc=2583111|pmid=19015737|quote=|via=}}</ref> The authors speculated this to contribute to the increased C4a split product 6 hours after the exercise challenge. In a 2010 study by Nijs et al. there was no increase in C4a after exercise in ME/CFS patients, though a significant correlation with post-exertional pain and fatigue was found.<ref>{{Cite journal | last = Nijs | first = J. | last2 = Van Oosterwijck | first2 = J. | last3 = Meeus | first3 = M. | last4 = Lambrecht | first4 = L. | last5 = Metzger | first5 = K. | last6 = Frémont | first6 = M. | last7 = Paul | first7 = L. | date = Apr 2010 | title = Unravelling the nature of postexertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome: the role of elastase, complement C4a and interleukin-1β|url=https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2796.2009.02178.x|journal=Journal of Internal Medicine|volume=267|issue=4 | pages = 418–435|doi=10.1111/j.1365-2796.2009.02178.x|issn=0954-6820}}</ref> ==== Cytokines ==== The expression of cytokines after physical exercise has been researched in ME/CFS patients since the mid-1990s. Most of these studies have found negative results (see table below). {| class="wikitable" |<small>Study</small> |<small>Number of participants</small> |<small>Exercise challenge</small> |<small>Cytokines tested:</small> |<small>Results:</small> |- |<small>[[Daniel Peterson|Peterson]] et al. (1994)</small><ref name="Peterson1994">{{Cite journal | last = Peterson | first=P. K. | last2 = Sirr | first2 = S.A. | last3 = Grammith | first3 = F.C. | last4 = Schenck | first4 = C.H. | last5 = Pheley | first5 = A.M. | last6 = Hu | first6 = S. | last7 = Chao | first7 = C.C. | date = Mar 1994 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients|url=https://www.ncbi.nlm.nih.gov/pubmed/7496949|journal=Clinical and Diagnostic Laboratory Immunology|volume=1|issue=2|pages=222–226|issn=1071-412X|pmid=7496949}}</ref> |<small>10 ([[Holmes criteria]], all cases were post-infectious)</small> |<small>Walking 1 mile per hour for 30 min</small> |<small>[[Interleukin 1 beta|IL-1 β]], [[Interleukin 6|IL-6]], and [[TNF-alpha|TNF-α]], [[TGF-beta|TGF-β]]</small> |<small>Negative results</small> |- |<small>[[Andrew Lloyd|Lloyd]] et al. (1994)</small><ref name="Lloyd1994">{{Cite journal | last = Lloyd | first=A. | last2 = Gandevia | first2 = S. | last3 = Brockman | first3 = A. | last4 = Hales | first4 = J. | last5 = Wakefield | first5 = D. | date = Jan 1994 | title = Cytokine production and fatigue in patients with chronic fatigue syndrome and healthy control subjects in response to exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/8148442|journal=Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America|volume=18 | issue = Suppl 1|pages=S142–146|issn=1058-4838|pmid=8148442}}</ref> |<small>12 ([[Australian criteria]])</small> |<small>30 min hand grip exercises</small> |<small>[[Interferon gamma|IFN-γ]], [[Interferon alpha|IFN-α]], [[Interleukin 1-beta|IL-1 β]], [[TNF-alpha|TNF-α]]</small> |<small>Negative results</small> |- |<small>La Manca et al. (1999)</small><ref name="LaManca1999">{{Cite journal | last = LaManca | first=J.J. | last2 = Sisto | first2 = S.A. | last3 = Zhou | first3 = X. D. | last4 = Ottenweller | first4 = J.E. | last5 = Cook | first5 = S. | last6 = Peckerman | first6 = A. | last7 = Zhang | first7 = Q. | last8 = Denny | first8 = T.N. | last9 = Gause | first9 = W.C. | date = Mar 1999 | title = Immunological response in chronic fatigue syndrome following a graded exercise test to exhaustion|url=https://www.ncbi.nlm.nih.gov/pubmed/10226888|journal=Journal of Clinical Immunology|volume=19|issue=2|pages=135–142|issn=0271-9142|pmid=10226888}}</ref> |<small>20 ([[Fukuda criteria]]) "only patients with an illness duration of less than 6 years, who reported at least substantial intensity on symptom severity scales in the month prior to recruitment and who had no major psychiatric diagnosis in the 5 years prior to illness onset" were included</small> |<small>An exhaustive treadmill exercise test</small> |<small>[[Interleukin 2|IL-2]], [[Interleukin 4|IL-4]], [[Interleukin 10|IL-10]], [[Interferon gamma|IFN-γ]], [[TNF-alpha|TNF-α]]</small> |<small>Negative results</small> |- |<small>Cannon et al. (1997)</small><ref name="Cannon1997">{{Cite journal | last = Cannon | first=J. G. | last2 = Angel | first2 = J.B. | last3 = Abad | first3 = L.W. | last4 = Vannier | first4 = E. | last5 = Mileno | first5 = M. D. | last6 = Fagioli | first6 = L. | last7 = Wolff | first7 = S.M. | last8 = Komaroff | first8 = A.L. | date=May 1997 | title = Interleukin-1 beta, interleukin-1 receptor antagonist, and soluble interleukin-1 receptor type II secretion in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9168406|journal=Journal of Clinical Immunology|volume=17|issue=3|pages=253–261|issn=0271-9142|pmid=9168406}}</ref> |<small>8 (Holmes criteria) “their chronic illness began abruptly with a "flu-like" condition, (c) they had been ill for less than 3 years, and (d) they regularly experienced postexertional malaise”</small> |<small>Stepping up and down on a platform for 15 min</small> |<small>[[Interleukin 1 beta |IL-1 β]], [[interleukin 1 receptor antagonist]] (IL-1Ra), and [[soluble interleukin 1 receptor type II]] (IL-1sRII).</small> |<small>Negative results</small> |- |<small>Gupta et al. (1998)</small><ref name="Gupta1998">{{Cite journal | last = Gupta | first = S. | last2 = Aggarwal | first2 = S. | last3 = Starr | first3 = A. | date = Feb 1999 | title = Increased production of interleukin-6 by adherent and non-adherent mononuclear cells during 'natural fatigue' but not following 'experimental fatigue' in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9917531|journal=International Journal of Molecular Medicine|volume=3|issue=2|pages=209–213|issn=1107-3756|pmid=9917531}}</ref> |<small>5 (Holmes criteria)</small> |<small>30 min hand grip exercises</small> |<small>[[Interleukin 6|IL-6]]</small> |<small>Negative results</small> |- |<small>Cannon et al. (1999)</small><ref name="Cannon1999">{{Cite journal | last = Cannon | first=J. G. | last2 = Angel | first2 = J.B. | last3 = Ball | first3 = R.W. | last4 = Abad | first4 = L.W. | last5 = Fagioli | first5 = L. | last6 = Komaroff | first6 = A.L. | date=Nov 1999 | title = Acute phase responses and cytokine secretion in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10634215|journal=Journal of Clinical Immunology|volume=19|issue=6 | pages = 414–421|issn=0271-9142|pmid=10634215}}</ref> |<small>10 (Holmes criteria) their chronic illness began abruptly with a "flu-like" condition, (c) they had been ill for less than 3 years, and (d) they regularly experienced postexertional malaise”</small> |<small>Stepping up and down on a platform for 15 min</small> |<small>[[Interleukin 1 beta |IL-1 β]], [[interleukin 6|IL-6]]</small> |<small>Negative results</small> |- |<small>Jammes et al. (2009)</small><ref name="Jammes2009" /> |<small>9 ([[Fukuda criteria]]) 6/9 had practiced sport at high level, for more than 4 years before the symptoms occurred.</small> |<small>Cycling test until maximal work load</small> |<small>[[interleukin 6|IL-6]], [[TNF-alpha|TNF-a]]</small> |<small>Negative results</small> |- |<small>Robinson et al (2010)</small><ref name="Robinson2010">{{Cite journal | last = Robinson | first = M. | last2 = Gray | first2 = S.R. | last3 = Watson | first3 = M.S. | last4 = Kennedy | first4 = G. | last5 = Hill | first5 = A. | last6 = Belch | first6 = J.J.F. |last7 = Nimmo | first7 = M.A. | date = Apr 2010 | title = Plasma IL-6, its soluble receptors and F2-isoprostanes at rest and during exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/19422646|journal=Scandinavian Journal of Medicine & Science in Sports|volume=20|issue=2|pages=282–290|doi=10.1111/j.1600-0838.2009.00895.x|issn=1600-0838|pmid=19422646}}</ref> |<small>6 (Fukuda criteria)</small> |<small>Incremental exercise test to exhaustion</small> |<small>[[Interleukin 6|IL-6]], [[sIL-6R]] and [[sgp130]]</small> |<small>Negative results</small> |- |<small>Andrea White et al. (2010)</small><ref name="WhiteA2010">{{Cite journal | last = White | first = Andrea T. | author-link = Andrea White | last2 = Light | first2 = Alan R. | authorlink2 = Alan Light | last3 = Hughen | first3 = Ronald W. | authorlink3 = Ronald Hughen | last4 = Bateman | first4 = Lucinda | authorlink4 = Lucinda Bateman | last5 = Martins | first5 = Thomas B. | last6 = Hill | first6 = Harry R. | last7 = Light | first7 = Kathleen C. | authorlink7 = Kathleen Light | date = 2010-07-01 | title = Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/20230500|journal=Psychophysiology|volume=47|issue=4 | pages = 615–624|doi=10.1111/j.1469-8986.2010.00978.x|issn=1540-5958|pmc=4378647|pmid=20230500}}</ref> |<small>19 (Fukuda criteria)</small> |<small>The authors used "a moderate whole-body exercise task (working both arms and legs) for 25 min that was mild enough that all CFS patients were able to complete it successfully but did induce a flare of fatigue and pain symptoms that remained above pre-exercise levels for 48 h post-exercise in the majority of patients."</small> |<small>[[Interleukin 1 beta|IL-1β]], [[Interleukin 2|IL-2]], [[Interleukin 12|IL-12]], [[TNF-alpha|TNF-α]], soluble [[CD40L]], [[Interferon gamma|IFN-γ]], [[Interleukin 4|IL-4]], [[Interleukin 10 |IL-10]], [[Interleukin 13|IL-13]], [[Interleukin 6|IL-6]] and [[Interleukin 8|IL-8]]</small> <small> </small> |<small>Positive results for a subgroup (11/19) of patients with high PEM</small> <small> </small> |- |<small>Andrew Lloyd et al. (2018)</small><ref name="Lloyd2018">{{Cite journal | last = Moneghetti | first = Kegan J. | last2 = Skhiri | first2 = Mehdi | last3 = Contrepois | first3 = Kévin | last4 = Kobayashi | first4 = Yukari | last5 = Maecker | first5 = Holden | last6 = Davis | first6 = Mark | last7 = Snyder | first7 = Michael | last8 = Haddad | first8 = Francois | last9 = Montoya | first9 = Jose G. | date = 2018-02-09 | title = Value of Circulating Cytokine Profiling During Submaximal Exercise Testing in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.nature.com/articles/s41598-018-20941-w|journal=Scientific Reports|language=en|volume=8|issue=1|doi=10.1038/s41598-018-20941-w|issn=2045-2322}}</ref> |<small>24 ([[Fukuda criteria]]) "we used the 1994 Centers for Disease Control (CDC)/Fukuda international diagnostic criteria for ME/CFS, but required participants to have post exertional malaise. Terefore, in labeling our patients this refers to the revised [[International Consensus Criteria|international consensus criteria]] from 2011"</small> |<small>Symptom limited exercise on an ergocycle.</small> |<small>Growth factors: [[FGF beta|FGF-β]], [[HGF]], [[NGF]], [[PDGF-BB]], [[TGF alpha|TGFα]], [[TGF beta 1|TGF-β1]], [[Vascular endothelial growth factor|VEGF]]</small> <small> </small> <small>[[Colony stimulating factors]] and [[stem cell factors]]: [[G-CSF]], [[GM-CSF]], [[M-CSF]], [[SCF]]</small> <small> </small> <small>Interleukins: [[Interleukin 1 alpha|IL-1α]], [[Interleukin 1 beta|IL-1β]], [[Interleukin 1RA|IL-1RA]], [[Interleukin 2|IL-2]], [[Interleukin 4|IL-4]], [[Interleukin 5|IL-5]], [[Interleukin 6|IL-6]], [[Interleukin 7|IL-7]], [[Interleukin 8|IL-8]], [[Interleukin 10|IL-10]], [[Interleukin 12p40|IL-12p40]], [[Interleukin 12p70|IL-12p70]], [[Interleukin 13|IL-13]], [[Interleukin 15|IL-15]], [[Interleukin 17|IL-17]], [[Interleukin 17f|IL-17F]], [[Interleukin 18|IL-18]] and [[LIF]]</small> <small> </small> <small>[[Chemokine]]s: [[CCL2]] ([[MCP-1]]), [[CCL3]] ([[MIP-1α]]), [[CCL4]] ([[MIP-1β]]), [[Regulated upon activation, normally T-expressed, and presumably secreted|CCL5 (RANTES)]] ([[RANTES]]) [[CCL7]] ([[MCP-3]]), [[CXCL1]] ([[Gro alpha|Gro-α]]), [[CXCL5]] ([[ENA78]]), [[CXCL9]] ([[MIG]]), [[CXCL10]] ([[IP-10]]), [[CCL11]] ([[Eotaxin]])</small> <small> </small> <small>[[Interferon|Interferons]]: [[Interferon alpha|INF-α]], [[Interferon beta|INF-β]], [[Interferon gamma|INF-γ]]</small> <small> </small> <small>[[Adhesion Molecule|Adhesion Molecules]] : [[ICAM-1]], [[VCAM-1]]</small> <small> </small> <small>Other factors: [[CD40L]], [[FASL]], [[leptin]], [[PAI-1]], [[resistin]], [[TNF-alpha|TNF-α]], [[TNF-beta|TNF-β]], [[TRAIL]]</small> |<small>Positive results: ME/CFS had a distinct cytokine profile post-exercise.</small> |} Moneghetti et al. took a different approach and looked at the cytokine profiling after exercise, as this may differentiate patients with ME/CFS from sedentary controls. Of the 51 [[cytokine]]s and growth factors tested, 10 significantly changed after exercise in both groups, a further 7 only changed in controls and five only changed in ME/CFS (namely, [[CXCL10]], [[interleukin 8|IL-8]], [[CCL4]], [[TNF-β]] and [[ICAM-1]]). This suggests a distinct [[cytokine]] inflammatory signature in ME/CFS.<ref name="Lloyd2018" /> White et al. (2010) differentiated their 19 ME/CFS patients with a high or low post-exertional malaise (called symptom flare in the study). While the cytokine expression after exercise of patients with low PEM was similar to those of healthy controls, patients with high PEM showed opposite results. As the authors noted:<blockquote>"In sum, low SF [symptom flare] patients and controls showed a pattern of post-exercise decreases in both pro and anti-inflammatory cytokines (with the exception of increases in [[Interleukin 8|IL-8]]), whereas the high SF [symptom flare] patients showed a pattern of increases in both cytokine types at 8h and no decreases at any time."<ref name="WhiteA2010" /></blockquote> === Autonomic response === Several research teams have noted post-exertional abnormalities in the [[Autonomic nervous system|autonomic]] function of ME/CFS patients, though the exact meaning of these results is not yet clear. A Canadian team under the guidance of Terrence Montague noted that during a maximal exercise test, ME/CFS patients have a lower maximal heart rate than controls. The authors noted that: <blockquote>"...patients with chronic fatigue syndrome have normal resting cardiac function but a markedly abbreviated exercise capacity characterized by slow acceleration of heart rate and fatigue of exercising muscles long before peak heart rate is achieved."<ref name="Montague1979">{{Cite journal | last = Montague | first = T.J. | last2 = Marrie | first2 = T.J. | last3 = Klassen | first3 = G.A. | last4 = Bewick | first4 = D.J. | last5 = Horacek | first5 = B.M. | date = Apr 1989 | title = Cardiac function at rest and with exercise in the chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/2924607|journal=Chest|volume=95|issue=4 | pages = 779–784|issn=0012-3692|pmid=2924607}}</ref> </blockquote>A significantly lower peak heart rate has been repeatedly observed in CPET-studies with ME/CFS patients.<ref name="Gibson1993">{{Cite journal | last = Gibson | first=H | last2 = Carroll | first2 = N | last3 = Clague | first3 = J E | last4 = Edwards | first4 = R H | date = Sep 1993 | title = Exercise performance and fatiguability in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC489735/|journal=Journal of Neurology, Neurosurgery, and Psychiatry|volume=56|issue=9 | pages = 993–998|issn=0022-3050|pmid=8410041}}</ref><ref name="LaManca1996">{{Cite journal | last = Sisto | first = Sue Ann | last2 = LaManca | first2 = John | last3 = Cordero | first3 = Douglas L. | last4 = Bergen | first4 = Michael T. | last5 = Ellis | first5 = Steven P. | last6 = Drastal | first6 = Susan | last7 = Boda | first7 = Wanda L. | last8 = Tapp | first8 = Walter N. | last9 = Natelson | first9 = Benjamin H. | date = Jun 1996 | title = Metabolic and cardiovascular effects of a progressive exercise test in patients with chronic fatigue syndrome|url=https://www.amjmed.com/article/S0002-9343(96)00041-1/pdf|journal=The American Journal of Medicine|language=English|volume=100|issue=6 | pages = 634–640|doi=10.1016/S0002-9343(96)00041-1|issn=0002-9343}}</ref><ref name="Rowbottom1998">{{Cite journal | last = Rowbottom | first = David | last2 = Keast | first2 = David | last3 = Pervan | first3 = Zhukov | last4 = Morton | first4 = Alan | date = Jan 1998 | title = The Physiological Response to Exercise in Chronic Fatigue Syndrome|url=https://www.tandfonline.com/doi/abs/10.1300/J092v04n02_04|journal=Journal of Chronic Fatigue Syndrome|language=en|volume=4|issue=2|pages=33–49|doi=10.1300/j092v04n02_04|issn=1057-3321}}</ref> In one of the largest of these into exercise performance, the authors noted the same phenomenon as Montague et al. <blockquote>“The resting heart rate of the patient group was higher, but the maximal heart rate at exhaustion was lower, relative to the control subjects.”<ref name="deBecker2000">{{Cite journal | last = De Becker | first=P. | last2 = Roeykens | first2 = J. | last3 = Reynders | first3 = M. | last4 = McGregor | first4 = N. | last5 = De Meirleir | first5 = K. | date = 2000-11-27 | title = Exercise capacity in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/11088089|journal=Archives of Internal Medicine|volume=160|issue=21|pages=3270–3277|issn=0003-9926|pmid=11088089}}</ref></blockquote>The Belgium team Van Oosterwijck et al. (2015) reported an impaired heart rate recovery in 20 female ME/CFS patients following exercise.<ref name="VanOosterwijck2015">{{Cite journal | last = Van Oosterwijck | first = J. | author-link = Jessica Van Oosterwijck | last2 = Marusic | first2 = U. | last3 = De Wandele | first3 = I. | last4 = Meeus | first4 = M. | last5 = Paul | first5 = L. | last6 = Lambrecht | first6 = L. | last7 = Moorkens | first7 = G. | last8 = Nijs | first8 = J. | authorlink8 = Jo Nijs | date = May 2015 | title = Reduced parasympathetic reactivation during recovery from exercise in myalgic encephalomyelitis (ME)/chronic fatigue syndrome (CFS)|url=https://www.physiotherapyjournal.com/article/S0031-9406(15)02014-3/fulltext|journal=Physiotherapy|language=English|volume=101| pages = e1091–e1092|doi=10.1016/j.physio.2015.03.1984|issn=0031-9406|issue=|quote=|via=}}</ref> In other disease groups this is associated with risk for cardiac events and sudden death. Cordero et al. (1986) did not find a significant difference in mean heart rate between 11 ME/CFS patients and six healthy controls after walking on a treadmill, but they did find patients to have significantly less 'vagal power', a measure for respiratory-related parasympathetic contributions to heart rate.<ref name="Cordero1996">{{Cite journal | last = Cordero | first = D. L. | last2 = Sisto | first2 = S.A. | last3 = Tapp | first3 = W.N. | last4 = LaManca | first4 = J.J. | last5 = Pareja | first5 = J.G. |last6 = Natelson | first6 = B.H. | date = Dec 1996 | title = Decreased vagal power during treadmill walking in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/8985621|journal=Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society|volume=6|issue=6|pages=329–333|issn=0959-9851|pmid=8985621}}</ref> Soetekouw et al. (1999) noted that during a handgrip exercise, the hemodynamics response was lower in the ME/CFS group than in the control group, although this could be attributed to the lower level of muscle exertion in the ME/CFS group.<ref name="Soetekouw1999">{{Cite journal | last = Soetekouw | first = P. M. | last2 = Lenders | first2 = J.W. | last3 = Bleijenberg | first3 = G. | last4 = Thien | first4 = T. | last5 = van der Meer | first5 = J.W. | date = Dec 1999 | title = Autonomic function in patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/10638807|journal=Clinical Autonomic Research: Official Journal of the Clinical Autonomic Research Society|volume=9|issue=6|pages=334–340|issn=0959-9851|pmid=10638807}}</ref> LaManca et al. studied 19 ME/CFS (Holmes criteria) and found that they had a diminished heart rate and blood pressure in response to a cognitive test compared to healthy controls, though exercise did not magnify this effect.<ref name="LaManca2001">{{Cite journal | last = LaManca | first=J.J. | last2 = Peckerman | first2 = A. | last3 = Sisto | first3 = S.A. | last4 = DeLuca | first4 = J. | last5 = Cook | first5 = S. | last6 = Natelson | first6 = B.H. | date = Sep 2001 | title = Cardiovascular responses of women with chronic fatigue syndrome to stressful cognitive testing before and after strenuous exercise|url=https://www.ncbi.nlm.nih.gov/pubmed/11573024|journal=Psychosomatic Medicine|volume=63|issue=5 | pages = 756–764|issn=0033-3174|pmid=11573024}}</ref> Similar results were found by a Norwegian research group. They studied 13 adolescents with ME/CFS and 53 age-matched controls after a mental stress test (arithmetic questions). Though heart rate was significantly higher in patients at baseline, there were no meaningful differences during the arithmetic challenge.<ref name="Egge2010">{{Cite journal | last = Egge | first = Caroline | last2 = Wyller | first2 = Vegard Bruun | date = 2010-12-14 | title = No differences in cardiovascular autonomic responses to mental stress in chronic fatigue syndrome adolescents as compared to healthy controls|url=https://www.ncbi.nlm.nih.gov/pubmed/21156045|journal=BioPsychoSocial Medicine|volume=4|pages=22|doi=10.1186/1751-0759-4-22|issn=1751-0759|pmc=3012010|pmid=21156045}}</ref> Finally, Ocon et al. (2012) studied 16 patients with both the diagnosis of ME/CFS and POTS after increased orthostatic stress and a cognitive challenge. An impairment of the neurocognitive abilities was noted, that was not seen in healthy controls.<ref name="Ocon2012">{{Cite journal | last = Ocon | first=Anthony J. | last2 = Messer | first2 = Zachary R. | last3 = Medow | first3 = Marvin S. | last4 = Stewart | first4 = Julian M. | date = Mar 2012 | title = Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/21919887|journal=Clinical Science (London, England: 1979)|volume=122|issue=5|pages=227–238|doi=10.1042/CS20110241|issn=1470-8736|pmc=3368269|pmid=21919887}}</ref> === Sleep === A first study into the effects of exercise on sleep in ME/CFS found a beneficial effect: approximately half the patients slept better after exercise.<ref name="Togo2010">{{Cite journal | last = Togo | first = Fumiharu | last2 = Natelson | first2 = Benjamin H. | last3 = Cherniack | first3 = Neil S. | last4 = Klapholz | first4 = Marc | last5 = Rapoport | first5 = David M. | last6 = Cook | first6 = Dane B. | date = Jan 2010 | title = Sleep is not disrupted by exercise in patients with chronic fatigue syndromes|url=https://www.ncbi.nlm.nih.gov/pubmed/20010134|journal=Medicine and Science in Sports and Exercise|volume=42|issue=1|pages=16–22|doi=10.1249/MSS.0b013e3181b11bc7|issn=1530-0315|pmc=2796587|pmid=20010134}}</ref> A follow-up study by the same research team (under the guidance of Benjamin Natelson) found more post-exercise improvement (transitions to deeper sleep stages) of sleep in ME/CFS patients than in controls. The patients, however, reported more fatigue in the morning after exercise while healthy controls showed significant improvement in sleepiness and fatigue. The authors speculated this to be due to a disruption of the REM sleep: ME/CFS showed, both at baseline and post-exercise, an increased rate of transition from REM to wake compared to controls and this correlated with symptoms of fatigue, pain and sleepiness.<ref name="Kishi2013">{{Cite journal | last = Kishi | first = Akifumi | last2 = Togo | first2 = Fumiharu | last3 = Cook | first3 = Dane B | last4 = Klapholz | first4 = Marc | last5 = Yamamoto | first5 = Yoshiharu | last6 = Rapoport | first6 = David M | last7 = Natelson | first7 = Benjamin H | date = Nov 2013 | title = The effects of exercise on dynamic sleep morphology in healthy controls and patients with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871467/|journal=Physiological Reports|volume=1|issue=6|doi=10.1002/phy2.152|issn=2051-817X|pmc=3871467|pmid=24400154}}</ref> An Australian study followed up on 35 ME/CFS patients after performing a physical (stationary cycling) or cognitive (stimulated driving) challenge. While patients spent a greater proportion of wakeful hours lying down, they did not report significant changes in sleep quality or sleep duration. The authors did however note that the expected increase in [[heart rate variability]] (HRV) between wake and sleep, was significantly reduced in ME/CFS patients after completing the challenges. These changes in HRV have been associated with the falling asleep, and might be related to the unfreshed sleep of ME/CFS patients.<ref name="Cvejic2017">{{Cite journal | last = Cvejic | first = Erin | last2 = Sandler | first2 = Carolina X. | last3 = Keech | first3 = Andrew | last4 = Barry | first4 = Benjamin K. | last5 = Lloyd | first5 = Andrew R. | last6 = Vollmer-Conna | first6 = Uté | date = Dec 2017 | title = Autonomic nervous system function, activity patterns, and sleep after physical or cognitive challenge in people with chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/29167053|journal=Journal of Psychosomatic Research|volume=103 | pages = 91–94|doi=10.1016/j.jpsychores.2017.10.010|issn=1879-1360|pmid=29167053}}</ref> Finally, Ohashi et al. (2002) recorded physical activity for 6-days in 10 patients with ME/CFS and 6 controls before and after performing a maximal treadmill test. Their results indicate an increase in circadian rest-activity in ME/CFS patients after exercise as the activity pattern of patients shifted toward later hours in the day.<ref name="Ohashi2002">{{Cite journal | last = Ohashi | first = Kyoko | last2 = Yamamoto | first2 = Yoshiharu | last3 = Natelson | first3 = Benjamin H. | date = Sep 2002 | title = Activity rhythm degrades after strenuous exercise in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/12213500|journal=Physiology & Behavior|volume=77|issue=1|pages=39–44|issn=0031-9384|pmid=12213500}}</ref> === Cognitive performance === While some studies have found a decreased cognitive performance after exercise in ME/CFS, others have not (see table below).<ref name="IOM2015" /> This difference may be due to heterogeneity of the patient sample and methods used. {| class="wikitable" |<small>Study</small> |<small>Number of ME/CFS subjects</small> |<small>Neurocognitive tests</small> |<small>Results</small> |- |<small>[[Sonya Marshall]] et al. (1997)</small><ref name="Marshall1997">{{Cite journal | last = Marshall | first = P. S. | last2 = Forstot | first2 = M. | last3 = Callies | first3 = A. | last4 = Peterson | first4 = P.K. | last5 = Schenck | first5 = C.H. | date = Jan 1997 | title = Cognitive slowing and working memory difficulties in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9021867|journal=Psychosomatic Medicine|volume=59|issue=1 | pages = 58–66|issn=0033-3174|pmid=9021867}}</ref> |<small>8</small> |<small>Buschke Selective Reminding Test, Continuous-Performance Test-Identical Pairs Version (CPTIP), Paced Auditory Serial Addition Task (PASAT), Stroop Color Word Test, Reaction-Time Tests, Salthouse Reading Span Task (SRST), Verbal Scholastic Aptitude Test (SAT).</small> |<small>Negative</small> |- |<small>Blackwood et al. (1998)</small><ref name="Blackwood1998" /> |<small>10</small> |<small>"The following aspects of cognitive function were examined (in order): working memory/auditory attention (digit span, from WAIS-R); psychomotor speed (digit symbol, also from WAIS-R); word fluency (FAS test, using the letters F and S only); and selective attention and sustained attention (telephone search and lottery tasks respectively, both from the test of everyday attention)”</small> |<small>Positive</small> |- |<small>La Manca et al. (1998)</small><ref name="LaManca1998">{{Cite journal | last = LaManca | first=J.J. | last2 = Sisto | first2 = S.A. | last3 = DeLuca | first3 = J. | last4 = Johnson | first4 = S.K. | last5 = Lange | first5 = G. | last6 = Pareja | first6 = J. | last7 = Cook | first7 = S. | last8 = Natelson | first8 = B.H. | date = 1998-09-28 | title = Influence of exhaustive treadmill exercise on cognitive functioning in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/9790484|journal=The American Journal of Medicine|volume=105|issue=3A | pages = 59S–65S|issn=0002-9343|pmid=9790484}}</ref> |<small>19</small> |<small>The Stroop Color and Word Test, the Symbol Digit Modalities Test (SDMT), an oral version of the Trail Making Test (TMT) and the Serial 13s Test (STT)</small> |<small>Positive</small> |- |<small>Claypoole et al. (2001)</small><ref name="Claypoole2001">{{Cite journal | last = Claypoole | first = Keith | last2 = Mahurin | first2 = Roderick | last3 = Fischer | first3 = Mary E. | last4 = Goldberg | first4 = Jack | last5 = Schmaling | first5 = Karen B. | last6 = Schoene | first6 = Robert B. | last7 = Ashton | first7 = Suzanne | last8 = Buchwald | first8 = Dedra | date = Mar 2001 | title = Cognitive Compromise Following Exercise in Monozygotic Twins Discordant for Chronic Fatigue Syndrome: Fact or Artifact?|url=http://dx.doi.org/10.1207/s15324826an0801_5|journal=Applied Neuropsychology|volume=8|issue=1|pages=31–40|doi=10.1207/s15324826an0801_5|issn=0908-4282}}</ref> |<small>21</small> |<small>The Wechsler Adult Intelligence Scale–Revised, Digit Span Forward and Backward subtests, The Hopkins Verbal Learning Test, The Digit Vigilance Test, the Lafayette Clinic Repeatable Neuropsychological Test Battery, Controlled Oral Word Association Test (COWAT)</small> |<small>Negative</small> |- |<small>[[Dane Cook|Cook]] et al. (2005)</small><ref name="Cook2005">{{Cite journal | last = Cook | first = Dane B. | last2 = Nagelkirk | first2 = Paul R. | last3 = Peckerman | first3 = Arnold | last4 = Poluri | first4 = Ashok | last5 = Mores | first5 = John | last6 = Natelson | first6 = Benjamin H. | date = Sep 2005 | title = Exercise and cognitive performance in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/16177595|journal=Medicine and Science in Sports and Exercise|volume=37|issue=9|pages=1460–1467|issn=0195-9131|pmid=16177595}}</ref> |<small>20 ME/CFS only and 19 ME/CFS with comorbid fibromyalgia</small> |<small>Participants completed cognitive testing using the automated neuropsychological assessment matrices (ANAM)</small> |<small>Negative</small> |- |<small>Yoshiuchi et al. (2007)</small><ref name="Yoshiuchi2007" /> |<small>9</small> |<small>A one-back memory task</small> |<small>Negative</small> |- |<small>Cook et al. (2017)</small><ref name="Cook2017">{{Cite journal | date = 2017-05-01 | first1 = Dane B | last = Cook | first2 =Suzanne D. | last2 = Vernon | authorlink = Dane Cook | authorlink2 = Suzanne Vernon | title = Neural consequences of post-exertion malaise in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome|url=https://www.sciencedirect.com/science/article/pii/S088915911730051X|journal=Brain, Behavior, and Immunity|language=en|volume=62 | pages = 87–99|doi=10.1016/j.bbi.2017.02.009|issn=0889-1591}}</ref> |<small>15</small> |<small>The Paced Auditory Serial Addition Task (PASAT) and a simple number recognition task</small> |<small>Positive</small> |} === Pain modulation === Another post-exertional abnormality reported in ME/CFS is pain modulation. When healthy people exercise, their brain produces [[endorphins]] that increase pain thresholds. In some chronic pain patients like [[fibromyalgia]] and whiplash associated disorders, this endogenous pain inhibition response is defect and pain thresholds decrease shortly after exercise (i.e. they experience more pain while they should be feeling less). In 2004 Whiteside et al. first showed this defect in ME/CFS patients.<ref name="Whiteside2004" /> These results were confirmed by two studies by the Belgium pain in motion team: while pain thresholds increased in normal controls they decreased in the ME/CFS patient group.<ref name="Meeus2010" /><ref name="VanOosterwijck2010" /> As a caveat, one must note that these studies only included ME/CFS patients that were suffering from chronic pain, while comorbid FM was not assessed. So it remains unclear if these results will also show up in ME/CFS patients that do not have comorbid FM.<ref name="Yunus2015">{{Cite journal | last = Yunus | first = Muhammad | date = 2015-07-02 | title = Editorial Review (Thematic Issue: An Update on Central Sensitivity Syndromes and the Issues of Nosology and Psychobiology)|url=http://dx.doi.org/10.2174/157339711102150702112236|journal=Current Rheumatology Reviews|language=en|volume=11|issue=2 | pages = 70–85|doi=10.2174/157339711102150702112236|issn=1573-3971}}</ref> === Other === ==== The gut microbiome ==== Shukla et al. (2015) found post-exertional changes in the gut microbiome in ME/CFS patients that were not seen in healthy controls. Increased clearance of bacteria in the blood was also noted, which made the authors speculate that exercise induced a bacterial translocation in ME/CFS patients.<ref name="Shukla2015">{{Cite journal | last = Shukla | first = Sanjay K. | last2 = Cook | first2 = Dane | last3 = Meyer | first3 = Jacob | last4 = Vernon | first4 = Suzanne D. | last5 = Le | first5 = Thao | last6 = Clevidence | first6 = Derek | last7 = Robertson | first7 = Charles E. | last8 = Schrodi | first8 = Steven J. | last9 = Yale | first9 = Steven | date = 2015-12-18 | title = Changes in Gut and Plasma Microbiome following Exercise Challenge in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)|url=http://dx.doi.org/10.1371/journal.pone.0145453|journal=PLOS ONE|volume=10|issue=12| pages = e0145453|doi=10.1371/journal.pone.0145453|issn=1932-6203}}</ref> ==== Catecholaminergic hyporeactivity ==== Strahler et al. found that ME/CFS patients showed an attenuated response (lower increases) of epinephrine to an exercise challenge, compared to heathy controls. This ‘catecholaminergic hyporeactivity’ was however subtle and short-lived.<ref name="Strahler2013">{{Cite journal | last = Strahler | first=Jana | last2 = Fischer | first2 = Susanne | last3 = Nater | first3 = Urs M. | last4 = Ehlert | first4 = Ulrike | last5 = Gaab | first5 = Jens | date = Sep 2013 | title = Norepinephrine and epinephrine responses to physiological and pharmacological stimulation in chronic fatigue syndrome|url=https://www.ncbi.nlm.nih.gov/pubmed/23770415|journal=Biological Psychology|volume=94|issue=1|pages=160–166|doi=10.1016/j.biopsycho.2013.06.002|issn=1873-6246|pmid=23770415}}</ref> ==== Nitric oxide metabolites ==== A [[Spain|Spanish]] research team found much higher increases of nitric oxide metabolites (nitrates) after a maximal exercise test in 44 ME/CFS patients compared to 25 healthy controls while there were no differences between the groups at baseline.<ref name="Suarez2010">{{Cite journal | last = Suárez | first = Andrea | last2 = Guillamó | first2 = Elisabet | last3 = Roig | first3 = Teresa | last4 = Blázquez | first4 = Alicia | last5 = Alegre | first5 = José | last6 = Bermúdez | first6 = Jordi | last7 = Ventura | first7 = José Luis | last8 = García-Quintana | first8 = Ana María | last9 = Comella | first9 = Agustí | date = Jun 2010 | title = Nitric Oxide Metabolite Production During Exercise in Chronic Fatigue Syndrome: A Case-Control Study|url=http://dx.doi.org/10.1089/jwh.2008.1255|journal=Journal of Women's Health|volume=19|issue=6|pages=1073–1077|doi=10.1089/jwh.2008.1255|issn=1540-9996}}</ref>
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