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=== In ME/CFS === Several findings in [[Myalgic encephalomyelitis]] suggest that patients might be experiencing local or global hypoxia. For example, many studies have found reduced blood flow to the [[heart]]<ref>{{Cite journal | last = Patrick Neary|first = J. | last2 = Roberts | first2 = Andy D.W. | last3 = Leavins | first3 = Nina | last4 = Harrison | first4 = Michael F. | last5 = Croll | first5 = James C. | last6 = Sexsmith | first6 = James R. | date = Nov 2008 | title = Prefrontal cortex oxygenation during incremental exercise in chronic fatigue syndrome|url=https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1475-097X.2008.00822.x|journal=Clinical Physiology and Functional Imaging|volume=28|issue=6 | pages = 364–372|doi=10.1111/j.1475-097x.2008.00822.x|issn=1475-0961}}</ref><ref>{{Cite journal | last = Peterson | first = PK | last2 = Sirr | first2 = SA | last3 = Grammith | first3 = FC | last4 = Schenck | first4 = CH | last5 = Pheley | first5 = AM | 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/pmc/articles/PMC368231/|journal=Clinical and Diagnostic Laboratory Immunology|volume=1|issue=2|pages=222–226|issn=1071-412X|pmid=7496949}}</ref>, [[Cerebral hypoperfusion]] (reduced blood flow to the brain) in ME/CFS,<ref name="Natelson, 2017">{{Cite journal | last1 = Natelson | first1 =Benjamin | author-link1 = Benjamin Natelson | last2 = Mao | first2 = Xiangling | author-link2 = | last3 = Stegner | first3 = Aaron J | author-link3 = | last4 = Lange | first4 = Gudrun | author-link4 = Gudrun Lange | last5 = Vu | first5 = Diana| author-link5 = | last6 = Blate | first6 = Michelle| author-link6 = | last7 = Kang | first7 = Guoxin | author-link7 = | last8 = Soto | first8 = Eli | author-link8 = | last9 = Kapusuz | first9 = Tolga| author-link9 = | last10 = Shungu | first10 = Dikoma C | author-link10 = | title = Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity | journal = Journal of the Neurological Sciences | volume = 375 | issue = | page = 411-416 | date = 2017 | pmid = | pmc = PMC5393352 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5393352/ | doi = 10.1016/j.jns.2017.02.046}}</ref><ref name="Costa1995">{{Cite journal | last = Costa | first = D.C. | last2 = Tannock | first2 = C. | last3 = Brostoff | first3 = J. | date = Nov 1995 | title = Brainstem perfusion is impaired in chronic fatigue syndrome | url =https://www.ncbi.nlm.nih.gov/pubmed/8542261 | journal = QJM: monthly journal of the Association of Physicians | volume = 88 | issue = 11 | pages = 767–773|issn=1460-2725|pmid=8542261}}</ref><ref name="Barnden2011">{{Cite journal | last = Barnden | first = Leighton R. | last2 = Crouch | first2 = Benjamin | last3 = Kwiatek | first3 = Richard | last4 = Burnet | first4 = Richard | last5 = Mernone | first5 = Anacleto | last6 = Chryssidis | first6 = Steve | last7 = Scroop | first7 = Garry | last8 = Fante | first8 = Peter Del | date = 2011 | title = A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis |url =https://onlinelibrary.wiley.com/doi/abs/10.1002/nbm.1692 | journal = NMR in Biomedicine|language=en | volume = 24 | issue = 10 | pages = 1302–1312|doi=10.1002/nbm.1692|issn=1099-1492|pmc=4369126|pmid=21560176}}</ref><ref name="Biswal2011">{{Cite journal | last = Biswal | first = Bharat | last2 = Kunwar | first2 = Pratap | last3 = Natelson | first3 = Benjamin H. | date = 2011-02-15 | title = Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling | url =http://www.sciencedirect.com/science/article/pii/S0022510X10005666 | journal = Journal of the Neurological Sciences | volume = 301 | issue = 1 | pages = 9–11|doi=10.1016/j.jns.2010.11.018|issn=0022-510X}}</ref><ref name="Yoshiuchi2006">{{Cite journal | last = Yoshiuchi | first = Kazuhiro | last2 = Farkas | first2 = Jeffrey | last3 = Natelson | first3 = Benjamin H. | date = 2006 | title = Patients with chronic fatigue syndrome have reduced absolute cortical blood flow | url =https://onlinelibrary.wiley.com/doi/abs/10.1111/j.1475-097X.2006.00649.x | journal = Clinical Physiology and Functional Imaging|language=en | volume = 26 | issue = 2 | pages = 83–86|doi=10.1111/j.1475-097X.2006.00649.x|issn=1475-097X}}</ref><ref>{{Cite journal | last = Freedman | first = M. | last2 = Kirsh | first2 = J.C. | last3 = Gray | first3 = B. | last4 = Chung | first4 = D.G. | last5 = Abbey | first5 = S.E. | last6 = Salit | first6 = I.E. | last7 = Ichise | first7 = M. | date = Oct 1992 | title = Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome. | url = http://europepmc.org/abstract/med/1491843 | journal = Nuclear medicine communications | volume = 13 | issue = 10 | pages = 767–772|issn=0143-3636|pmid=1491843}}</ref><ref>{{Cite journal | last = Chao | first = C.C. | last2 = Hu | first2 = S. | last3 = Pheley | first3 = A.M. | last4 = Schenck | first4 = C.H. | last5 = Grammith | first5 = F.C. | last6 = Sirr | first6 = S.A. | last7 = Peterson | first7 = P.K. | date = 1994-03-01 | title = Effects of mild exercise on cytokines and cerebral blood flow in chronic fatigue syndrome patients. | url = https://cvi.asm.org/content/1/2/222 | journal = Clinical and Diagnostic Laboratory Immunology|language=en | volume = 1 | issue = 2 | pages = 222–226|issn=1071-412X|pmid=7496949}}</ref><ref>{{Cite journal | last = Lange | first = Gudrun | last2 = Wang | first2 = Samuel | last3 = DeLuca | first3 = John | last4 = Natelson | first4 = Benjamin H. | date = 1998-09-28 | title = Neuroimaging in chronic fatigue syndrome | url =http://www.sciencedirect.com/science/article/pii/S0002934398001752 | journal = The American Journal of Medicine | volume = 105 | issue = 3, Supplement 1 | pages = 50S–53S|doi=10.1016/S0002-9343(98)00175-2|issn=0002-9343}}</ref>, even in the absence of [[postural orthostatic tachycardia]] or [[Neurally mediated hypotension|neurally-mediated hypotension]]; cerebral hypo-metabolism (reduced metabolic activity in the brain)<ref>{{Cite journal | title = Observer independent analysis of cerebral glucose metabolism in patients with chronic fatigue syndrome | url =https://jnnp.bmj.com/content/74/7/922 | journal = Journal of Neurology, Neurosurgery & Psychiatry | date = 2003-07-01|issn=0022-3050|pmid=12810781 | pages = 922–928 | volume = 74 | issue = 7|doi=10.1136/jnnp.74.7.922|language=en | first = P. | last = Bartenstein | first2 = U.T. | last2 = Egle | first3 = M. | last3 = Schreckenberger | first4 = J. | last4 = Hardt | first5 = W.A. | last5 = Nix | first6 = T. | last6 = Siessmeier}}</ref><ref>{{Cite journal | last = Tirelli | first = Umberto | last2 = Chierichetti | first2 = Franca | last3 = Tavio | first3 = Marcello | last4 = Simonelli | first4 = Cecilia | last5 = Bianchin | first5 = Gianluigi | last6 = Zanco | first6 = Pierluigi | last7 = Ferlin | first7 = Giorgio | date = 1998-09-28 | title = Brain positron emission tomography (PET) in chronic fatigue syndrome: preliminary data | url = http://www.sciencedirect.com/science/article/pii/S000293439800179X | journal = The American Journal of Medicine | volume = 105 | issue = 3, Supplement 1 | pages = 54S–58S|doi=10.1016/S0002-9343(98)00179-X|issn=0002-9343}}</ref>; as well as elevated [[Lactic acid]] in the brain<ref name="Natelson, 20172">{{Cite journal | last1 = Natelson | first1 =Benjamin | author-link1 = Benjamin Natelson | last2 = Mao | first2 = Xiangling | author-link2 = | last3 = Stegner | first3 = Aaron J | author-link3 = | last4 = Lange | first4 = Gudrun | author-link4 = Gudrun Lange | last5 = Vu | first5 = Diana| author-link5 = | last6 = Blate | first6 = Michelle| author-link6 = | last7 = Kang | first7 = Guoxin | author-link7 = | last8 = Soto | first8 = Eli | author-link8 = | last9 = Kapusuz | first9 = Tolga| author-link9 = | last10 = Shungu | first10 = Dikoma C | author-link10 = | title = Multimodal and simultaneous assessments of brain and spinal fluid abnormalities in chronic fatigue syndrome and the effects of psychiatric comorbidity | journal = Journal of the Neurological Sciences | volume = 375 | issue = | page = 411-416 | date = 2017 | pmid = | pmc = PMC5393352 | url = https://www.ncbi.nlm.nih.gov/pmc/articles/pmc5393352/ | doi = 10.1016/j.jns.2017.02.046}}</ref> and blood<ref name=":0">{{Cite journal | last = Ghali | first = Alaa | last2 = Lacout | first2 = Carole | last3 = Ghali | first3 = Maria | last4 = Gury | first4 = Aline | last5 = Beucher | first5 = Anne-Berengere | last6 = Lozac’h | first6 = Pierre | last7 = Lavigne | first7 = Christian | last8 = Urbanski | first8 = Geoffrey | date = 2019-12-11 | title = Elevated blood lactate in resting conditions correlate with post-exertional malaise severity in patients with Myalgic encephalomyelitis/Chronic fatigue syndrome|url=https://www.nature.com/articles/s41598-019-55473-4|journal=Scientific Reports|language=en|volume=9|issue=1|pages=1–9|doi=10.1038/s41598-019-55473-4|issn=2045-2322}}</ref>. Peripheral endothelial dysfunction has also been found.<ref name="endothelial2020">{{Cite journal | last = Scherbakov|first = Nadja | authorlink = | last2 = Szklarski | first2 = Marvin | author-link2 = | last3 = Hartwig | first3 = Jelka | author-link3 = | last4 = Sotzny | first4 = Franziska | author-link4 = Franziska Sotzny | last5 = Lorenz | first5 = Sebastian | author-link5 = | last6 = Meyer | first6 = Antje | authorlink6 = Antje Meyer | last7 = Grabowski | first7 = Patricia | last8 = Doehner | first8 = Wolfram | last9 = Scheibenbogen | first9 = Carmen | authorlink9 = Carmen Scheibenbogen | date = 2020 | title=Peripheral endothelial dysfunction in myalgic encephalomyelitis/chronic fatigue syndrome|url=https://onlinelibrary.wiley.com/doi/abs/10.1002/ehf2.12633|journal=ESC Heart Failure|language=en|volume=7|issue=3|pages=1064–1071|doi=10.1002/ehf2.12633|issn=2055-5822|pmc = 7261521|pmid=32154656|access-date=|quote=|via=}}</ref> Elevated [[WASF3]] was found in one case study. WASF3 can be elevated in other conditions where hypoxia is a mechanism, such as cancer<ref>{{Cite journal|title=HIF1A induces expression of the WASF3 metastasis-associated gene under hypoxic conditions|date=2012-09-15|url=https://onlinelibrary.wiley.com/doi/10.1002/ijc.27631|journal=International Journal of Cancer|volume=131|issue=6|pages=E905–E915|last=Ghoshal|first=Pushpankur|last2=Teng|first2=Yong|last3=Lesoon|first3=Leslie Ann|last4=Cowell|first4=John K.|language=en|doi=10.1002/ijc.27631|pmc=PMC3629704|pmid=22581642}}</ref><ref>{{Cite journal|title=Targeting WASF3 Signaling in Metastatic Cancer|date=2021-01|url=https://www.mdpi.com/1422-0067/22/2/836|journal=International Journal of Molecular Sciences|volume=22|issue=2|pages=836|last=Loveless|first=Reid|last2=Teng|first2=Yong|language=en|doi=10.3390/ijms22020836|pmc=7830529|pmid=33467681|issn=1422-0067}}</ref>, and in animal models<ref>{{Cite journal|title=Comparative transcriptome analysis of the swimbladder reveals expression signatures in response to low oxygen stress in channel catfish, Ictalurus punctatus|date=2018-08-01|url=https://www.physiology.org/doi/10.1152/physiolgenomics.00125.2017|journal=Physiological Genomics|volume=50|issue=8|pages=636–647|last=Yang|first=Yujia|last2=Fu|first2=Qiang|last3=Wang|first3=Xiaozhu|last4=Liu|first4=Yang|last5=Zeng|first5=Qifan|last6=Li|first6=Yun|last7=Gao|first7=Sen|last8=Bao|first8=Lisui|last9=Liu|first9=Shikai|last10=Gao|first10=Dongya|last11=Dunham|first11=Rex|language=en|doi=10.1152/physiolgenomics.00125.2017|issn=1094-8341}}</ref><ref>{{Cite journal|title=Hypoxia-related gene expression in porcine skeletal muscle tissues at different altitude|date=2015-09-01|url=https://doi.org/10.4238/2015.September.28.10|journal=Genetics and molecular research|volume=14|issue=3|pages=11587–11593|last=Zhang|first=J|last2=Chen|first2=L|last3=Long|first3=K R|last4=Mu|first4=Z P|doi=10.4238/2015.september.28.10|pmid=26436399|issn=1676-5680}}</ref>. [[Natural killer cell]] function<ref name="Barker1994">{{Cite journal | last1 = Barker | first1 = Edward | authorlink1 = | last2 = Fujimura | first2 = Sue F. | authorlink2 = | last3 = Fadem | first3 = Mitchell B. | authorlink3 = | last4 = Landay | first4 = Alan L. | authorlink4 = | last5 = Levy | first5 = Jay A. | authorlink5 = Jay Levy | title = Immunologic Abnormalities Associated with Chronic Fatigue Syndrome | journal = Clin Infect Dis. | date = 1994 | volume = 18 | issue = Suppl 1 | pages = S136-S141 | doi = 10.1093/clinids/18.Supplement_1.S136 | url = http://cid.oxfordjournals.org/content/18/Supplement_1/S136.short }}</ref><ref name="WhitesideTL1998">{{citation | last1 = Whiteside | first1 = TL | last2 = Friberg | first2 = D | title = Natural killer cells and natural killer cell activity in chronic fatigue syndrome. | journal = Am J Med | date = 1998 | volume= 105 | issue= 3A | pages = 27S-34S | pmid = 9790479 | doi= }}</ref><ref name="BrenuEW2014">{{Cite journal | last1 = Brenu | first1 = EW | authorlink1 = Ekua Brenu | last2 = Huth | first2 = TK | authorlink2 = Teilah Huth | last3 = Hardcastle | first3 = SL | authorlink3 = Sharni Hardcastle | last4 = Fuller | first4 = K | authorlink4 = | last5 = Kaur | first5 = M | authorlink5 = | last6 = Johnston | first6 = S | authorlink6 = | last7 = Ramos | first7 = S | authorlink7 = Sandra Ramos | last8 = Staines | first8 = D | authorlink8 = Donald Staines | last9 =Marshall-Gradisnik | first9 = S | authorlink9 = Sonya Marshall-Gradisnik | title = The Role of adaptive and innate immune cells in chronic fatigue syndrome/myalgic encephalomyelitis | journal = International Immunology | date = 2014 | volume = 26 | issue = 4 | pages = 233-42 | pmid = 24343819 | doi = 10.1093/intimm/dxt068 }}</ref><ref name="FletcherMA2002">{{citation | last1 = Fletcher | first1 = Mary Ann | authorlink1 = Mary Ann Fletcher | last2 = Maher | first2 = Kevin J | authorlink2 = | last3 = Klimas | first3 = Nancy | authorlink3 = Nancy Klimas | title = Natural killer cell function in chronic fatigue syndrome | journal = Clinical and Applied Immunology Reviews | volume = 2 | issue = 2 | date = April 2002 | pages = 129–139 | doi = 10.1016/S1529-1049(01)00047-2 | url = http://www.sciencedirect.com/science/article/pii/S1529104901000472 }}</ref><ref name="BrenuEW2012">{{citation | last1 = Brenu | first1 = Ekua W | authorlink1 = Ekua Brenu | last2 = van Driel | first2 = Mieke L | authorlink2 = | last3 = Staines | first3 = Donald R | authorlink3 = Donald Staines | last4 = Ashton | first4 = Kevin J | authorlink4 = | last5 = Hardcastle | first5 = Sharni L | authorlink5 = Sharni Hardcastle | last6 = Keane | first6 = James | authorlink6 = | last7 = Tajouri | first7 = Lotti | authorlink7 = | last8 = Peterson | first8 = Daniel | authorlink8 = Daniel Peterson | last9 =Ramos | first9 = Sandra B | authorlink9 = Sandra Ramos | last10 = Marshall-Gradisnik | first10 = Sonya M | authorlink10 = Sonya Marshall-Gradisnik | title = Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/myalgic encephalomyelitis | journal = Journal of Translational Medicine | date = 2012 | volume = 10 | issue = | pages = 88 | doi = 10.1186/1479-5876-10-88 | url = http://www.translational-medicine.com/content/10/1/88 }}</ref>, lower in ME/CFS patients, is also reduced in conditions of hypoxia.<ref>{{Cite journal|title=NK Cells Under Hypoxia: The Two Faces of Vascularization in Tumor and Pregnancy|date=2022|url=https://www.frontiersin.org/articles/10.3389/fimmu.2022.924775|journal=Frontiers in Immunology|volume=13|last=Garcés-Lázaro|first=Irene|last2=Kotzur|first2=Rebecca|last3=Cerwenka|first3=Adelheid|last4=Mandelboim|first4=Ofer|doi=10.3389/fimmu.2022.924775/full|issn=1664-3224}}</ref> [[Mast cell|Mast cells]], increased in ME/CFS patients, can create conditions similar to hypoxia while conversely, systemic hypoxia causes mast cell deganulation.<ref>{{Cite journal|title=Mast cells mediate the microvascular inflammatory response to systemic hypoxia|date=2003-01-01|url=https://www.physiology.org/doi/10.1152/japplphysiol.00637.2002|journal=Journal of Applied Physiology|volume=94|issue=1|pages=325–334|last=Steiner|first=Dawn R. S.|last2=Gonzalez|first2=Norberto C.|last3=Wood|first3=John G.|language=en|doi=10.1152/japplphysiol.00637.2002|issn=8750-7587}}</ref> Preliminary data from the [[UK ME/CFS biobank]] show an association between increased risk of ME/CFS and a gene variant that encodes for a subunit of [[prolyl 4-hydroxylase]] subunit alpha 1 (P4HA1), which encodes for [[procollagen-proline dioxygenase]], an enzyme involved in the production of collagen. P4HA1 also plays a role in the regulation of [[energy metabolism]] via downregulation of [[pyruvate dehydrogenase]] during [[hypoxia]].<ref>{{Cite journal|title=Therapeutic inhibition of prolyl hydroxylase domain-containing enzymes in surgery: putative applications and challenges|date=Jan 2015|url=https://www.dovepress.com/therapeutic-inhibition-of-prolyl-hydroxylase-domain-containing-enzymes-peer-reviewed-fulltext-article-HP|journal=Hypoxia|volume=3|pages=1|last=Schneider|first=Martin|last2=Harnoss|first2=Jonathan Michael|last3=Strowitzki|first3=Moritz J.|last4=Radhakrishnan|first4=Praveen|last5=Platzer|first5=Lisa|last6=Harnoss|first6=Julian Camill|last7=Hank|first7=Thomas|last8=Cai|first8=Jun|last9=Ulrich|first9=Alexis|language=English|doi=10.2147/HP.S60872|issn=2324-1128}}</ref> [[Creatine]], elevated in #MECFS patients<ref>{{Cite journal | last = Albrecht | first = Robert | date = March 21, 1964 | title = Epidemic Neuromyasthenia Outbreak in a Convent in New York State|url=https://www.ncbi.nlm.nih.gov/pubmed/14100144|journal=Journal of the American Medical Association|volume=187 | pages = 904-907|via=}}</ref>, is protective against hypoxia<ref>{{Cite journal|title=Exogenous creatine delays anoxic depolarization and protects from hypoxic damage: dose–effect relationship|date=1999-01-16|url=https://www.sciencedirect.com/science/article/pii/S0006899398011317|journal=Brain Research|volume=816|issue=1|pages=124–130|last=Balestrino|first=Maurizio|last2=Rebaudo|first2=Renata|last3=Lunardi|first3=Gianluigi|doi=10.1016/S0006-8993(98)01131-7|issn=0006-8993}}</ref>. Hypoxia can induce mitochondrial damage and dysfunction<ref>{{Cite journal|title=Hypoxia–reoxygenation-induced mitochondrial damage and apoptosis in human endothelial cells are inhibited by vitamin C|date=2005-05-15|url=https://www.sciencedirect.com/science/article/pii/S0891584905000353|journal=Free Radical Biology and Medicine|volume=38|issue=10|pages=1311–1322|last=Dhar-Mascareño|first=Manya|last2=Cárcamo|first2=Juan M.|last3=Golde|first3=David W.|doi=10.1016/j.freeradbiomed.2005.01.017|issn=0891-5849}}</ref>, which has been found in ME/CFS patients<ref>{{Cite journal | last = Behan | first = W. M.H. | last2 = More | first2 = I.A.R. | last3 = Behan | first3 = P.O. | date = Dec 1991 | title = Mitochondrial abnormalities in the postviral fatigue syndrome|url=https://link.springer.com/article/10.1007/BF00294431|journal=Acta Neuropathologica|language=en|volume=83|issue=1 | pages = 61–65|doi=10.1007/bf00294431|issn=0001-6322}}</ref><ref name=":02">{{Cite journal | date = 1996-04-19 | title = Sensory characterization of somatic parietal tissues in humans with chronic fatigue syndrome|url=https://www.sciencedirect.com/science/article/abs/pii/0304394096125593|journal=Neuroscience Letters|language=en|volume=208|issue=2|pages=117–120|doi=10.1016/0304-3940(96)12559-3|issn=0304-3940}}</ref>.
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