The 4I Hypothesis: A Neuro-Immunological Explanation for Characteristic Symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome



Frank NM Twisk


Frank NM Twisk, ME-de-patiënten Foundation, Zonnedauw 15, 1906 HB, Limmen, The Netherlands

Correspondence to: Frank NM Twisk, ME-de-patiënten Foundation, Zonnedauw 15, 1906 HB, Limmen, The Netherlands


Telephone: +31-72-505 477      

Received: February 4, 2015            Revised: March 22, 2015

Accepted: March 28, 2015

Published online: May 13, 2015



Characteristic symptoms of Myalgic Encephalomyelitis (ME) are (muscle) weakness, muscle pain, cognitive deficits, neurological abnormalities, but above all post-exertional malaise: a long-lasting increase of symptoms after a minor exertion. In contrast, Chronic Fatigue Syndrome (CFS) is primarily defined by chronic fatigue. Since chronic fatigue is not mandatory for the diagnosis ME, and post-exertional malaise and cognitive deficits are not obligatory for the diagnosis CFS, the case criteria for ME and CFS define two distinct, partly overlapping nosological entities. ME and CFS are considered to be enigmatic diseases, qualified by some authors as medically unexplained syndromes of functional syndromes. However, specific abnormalities consistently observed over the years and their direct and indirect sequels can plausibly explain characteristic symptoms, e.g. exhaustion and pain. Abnormalities established repetitively incorporate immunological aberrations (inflammation, immune activation, immunosuppression, and immune dysfunction), persistent and/or reactivating infections, gastro-intestinal dysbiosis, oxidative and nitrosative stress, mitochondrial dysfunction, a (prolonged) deviant response to exertion and orthostatic stress, circulatory deficits, and neurological abnormalities.This article depicts the 4I hypothesis, an explanatory model for ME (CFS) with a central role for four types of immunological abnormalities: inflammation, (Th2-predominated) immune activation, immunosuppression, and immune dysfunction. The potential direct sequels of these abnormalities, e.g. increased oxidative and nitrosative stress, (reactivating or chronic) infections, and their possible indirect consequences, e.g. mitochondrial dysfunction, hypothalamic-pituitary-adrenal axis (HPA) axis hypofunction, and cardiovascular dysregulation, can plausibly explain various distinctive symptoms of ME/CFS, e.g. exhaustion, (muscle) weakness, pain, cognitive deficits, a flu-like feeling, and post-exertional malaise.


© 2015 ACT. All rights reserved.


Key words: Myalgic Encephalomyelitis; Chronic fatigue syndrome; Immunology; Neurology; Oxidative stress; Nitrosative stress; Pathophysiology; Hypothesis; Post-exertional malaise


Twisk FNM. The 4I Hypothesis: A Neuro-Immunological Explanation for Characteristic Symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. International Journal of Neurology Research 2015; 1(2): 20-38 Available from: URL:



ME and CFS are two distinct, partially overlapping diagnostic entities.

    More consistent findings in ME and/or CFS relate to four types of immunological abnormalities: inflammation (I1), (Th2-dominated) immune activation (I2), immunosuppression (I3), and immune dysfunction (I4).

    The potential sequels of these abnormalities encompass oxidative/nitrosative stress and infections.

    The possible indirect consequences of the immunological aberrations and increased oxidative/nitrosative stress include neurological abnormalities, mitochondrial dysfunction and cardiovascular disturbances.

    The direct and indirect sequels of the immunological abnormalities can plausibly explain distinctive symptoms of ME/CFS, e.g. cognitive deficits, and post-exertional malaise: a prolonged aggravation of characteristic symptoms, e.g. cognitive impairments and pain, after a minor exertion.



Although ME and CFS are often used interchangeably, the case criteria for ME[1] and CFS[2] define two distinct, partially overlapping diagnostic entities[3]. The diagnosis ME requires specific neurological/neurocognitive and immunological symptoms and energy production and/or transport impairment, but the distinctive feature of ME is post-exertional malaise or neuro-immune exhaustion: a pathological inability to produce sufficient energy on demand resulting into symptom exacerbation, e.g. flu-like symptoms and pain, after minor exertion[1]. The distinctive feature of CFS[2] on the other hand is (unexplained) chronic fatigue, which should be accompanied by at least four out of a eight symptoms, e.g. sore throat, unrefreshing sleep, and headaches. While post-exertional malaise is not obligatory for CFS[2], fatigue is not mandatory for the diagnosis ME[1]. The distinction between patients with post-exertional malaise and without post-exertional malaise seems to be reflected by specific immunological differences[4,5]. Although ME and CFS criteria select partially overlapping, partially disjoint patient groups, the majority of the research into ME/CFS in the last decades has been conducted in patients selected by CFS criteria[2]. However, since many optional symptoms of CFS are mandatory for the diagnosis ME, the CFS criteria also apply to a substantial ME patient subgroup reporting fatigue (Figure 1). In conclusion, while ME is a neuro-immunological disease in nature[1], the CFS criteria[2] select a heterogeneous patient population of people with self-reported chronic fatigue.




Notwithstanding the debate about the distinction between ME and CFS[6-8] and definitional criteria of ME and CFS[9], including obligatory symptoms, many patients with ME/CFS experience a plethora of symptoms[3], which differ inter-individually and seem to fluctuate in number and severity within an individual over time as a consequence of daily activity[10]. Symptoms experienced by substantial patient subgroups are: post-exertional malaise, fatigue/lack of energy, muscle weakness, (muscle/joint) pain, cognitive impairment (brain fog), a flu-like feeling, sleep dysfunction (unrefreshing sleep), hypersensitivity to food, light, sound and odours (central sensitisation), stress intolerance, orthostatic intolerance and depression[9] (Table 1). Various characteristic symptoms can be assessed objectively using well-accepted methods[3], e.g. neurocognitive tests, while other symptoms due to their nature, e.g. (muscle) pain, cannot be assessed objectively.




Partly due to the heterogeneity[32] of the CFS[2] patient population and the variety of methods employed and samples investigated, research into ME/CFS has yielded contradictory results. However, various typical aberrations (Table 2) have been observed repetitively in the ME/CFS patient population or subgroups thereof[1,33], Several abnormalities are confirmed by differential gene expression[34-37].




Contrary to gradual onset ME/CFS, sudden-onset ME/CFS is often preceded by a (viral) infection/flu-like illness[94,95]. The onset is reflected by distinctive immunological aberrations[96,97] and other abnormalities[98,99]. Several pathogens have been reported to initiate ME/CFS, e.g. Epstein-Barr virus[100], parvovirus B19[101], and enteroviruses[48]. For example, 10-15% of individuals do not recover from infectious mononucleosis and fulfil the criteria for CFS[2] after six months[100,102]. The severity of the acute infection seems to predict the clinical outcome, rather than demographic, psychological, or microbiological factors[102,103].



Although contradicted by some studies, applying various methods various studies have found (multiple) infections or related antigens in patient subgroups (Table 3).

Intestinal dysbiosis and hyperpermeability

Some studies have observed intestinal dysbiosis[49,51], intestinal inflammation and immune activation[52,130] and intestinal hyperpermeability, conceivably resulting into translocation of enterobacteria to the blood stream, thereby inducing systemic inflammation[50]. Inflammation and immune activation observed in ME/CFS have been associated with these gastro-intestinal abnormalities[53,54]. Bacteriotherapy (transcolonoscopic infusion of non-pathogenic enteric bacteria) showed long-term positive effects (15-20 year) in a substantial subgroup of ME/CFS patients with gastrointestinal complaints in a retrospective follow-up study[131].


Immunological abnormalities

Consistent findings in ME/CFS relate to immunological aberrations: (a) inflammation[41,132,133]; (b) (Th2-predominant) immune activation[48,134-136]; (c) immunosuppression, especially low NK cell activity (NKCA)[43,137,138], blunted responses to mitogens[38,139,140], and IgG deficiencies, most often Igg1 and IgG3[141,142]; and d) immune dysfunction, e.g. predominance of the humoral (Th2) immune response accompanied by suppression of the cellular (Th1) immune system, possibly due to altered glucocorticoid regulation of the immune response[143,144], and dysregulation of the RNase-L pathway, likely due to cleavage of the native 83-kDa RNase L[145,146].


Increased oxidative and nitrosative stress

Elevated oxidative and nitrosative stress[36,88], increased levels of superoxide (O2-), nitric oxide (NO) and peroxynitrite (ONOO-), oxidative and nitrosative damage to DNA, proteins, lipids etc.[147-149], and antioxidant depletion / increased antioxidant activity, e.g. vitamin A[150], B[151], C[56], D[152], E[56], glutathione[153], super oxide dismutase[62] and zinc[154], have been observed repetitively.


Mitochondrial dysfunction and damage

Some studies have found structural mitochondrial damage, e.g. branching and fusion of mitochondrial cristae /mitochondrial degeneration[63], substantially higher rates of deletion of common 4977 bp of mitochondrial DNA[155] and unusual patterns of mitochondrial DNA deletions in skeletal muscle[59], while other studies implicate mitochondrial dysfunction[60,61,156]. Future research should provide clarity whether hypometabolism[157] and low oxygen uptake[75,78] and extraction[158] in ME/CFS is due to mitochondrial dysfunction and/or mitochondrial damage, circulatory deficits (see next paragraph) or other causes.


Low blood volume, cardiac output and/or blood and oxygen supply

Several studies have established markedly reduced blood volume[64,65,75] and impaired cardiac function, indicated by decreased cardiac index/output and stroke volume[65,66,74], when compared to healthy sedentary controls. Post-exertional malaise, flu-like symptoms and cognitive deficits seem to differentiate those with severe CFS from those with less severe CFS and to predict lower cardiac output[74]. In addition, some studies indicate low cardiac mass[66,159]. So, low cardiac output in ME/CFS could be due to reduced cardiac mass (a small heart)[160] and/or hypovolemia[65]. Low cardiac output and/or blood/oxygen supply to muscles[69] and brain[67] and/or mitochondrial abnormalities could explain the low exercise capacity/oxygen uptake[75,161] and elevated (ventricular) lactate levels[68].


Orthostatic abnormalities

Orthostatic intolerance, (delayed) orthostatic hypotension and/or tachycardia (POTS), in patient subgroups has been implicated by various studies[73,162,163]. Orthostatic stress seems to induce cognitive deficits[24,164] and reduced angle-related mental task-activated cerebral blood flow velocity[164]. According to some authors[165], POTS marks a distinct group of patents with distinct phenotypical features. Some studies have also observed abnormalities in (parasympathetic and sympathetic) heart rate variability at rest and on standing[166].


Neurological abnormalities

Over time various researchers have observed various neurological aberrations in ME/CFS patient subgroups[79,81], e.g. diminished grey[82,167] and white matter[82,168], reduced blood flow and hypoperfusion[169,170], glucose hypometabolism in specific regions of the cerebrum and the brain stem[171], an increased number of defects on SPECT cans, predominantly in the frontal and temporal lobes[172], intracranial abnormalities on MRI and SPECT scans[173], neuro-inflammation in various brain areas[174], cerebrospinal fluid anomalies suggesting inflammation and immune activation[175,176], and elevated ventricular lactate levels[68].


HPA axis dysfunction

HPA axis hypofunction in ME/CFS[83,177] can potentially manifest itself in (a) low basal levels and diurnal production levels (total production, variation during the day) of stress hormones, especially cortisol (hypocortisolism)[178,179]; (b) hyporesponsiveness of the HPA axis: blunted responses of the pituitary and the adrenal glands to provocation, e.g. reduced cortisol response to ACTH[85,180]; (c) diminished HPA axis responses to stress and exercise[181,182] and (d) enhanced sensitivity of the HPA axis to negative feedback to cortisol[183,184] and increased sensitivity of the cellular immune system to the immunosuppressive effects of cortisol[143,144].


Abnormal responses to exercise

Several studies have established (long-lasting) deviant responses to physical exertion in ME/CFS, when compared to sedentary controls, e.g. substantially lower values for oxygen uptake and workload at peak exercise and at the ventilatory or anaerobic threshold at a second exercise test 24 hours later[77,91,185]; a long-term increase of gene expression of metabolite-detecting receptors after sustained moderate exercise[31]; decreased prefrontal oxygenation during exercise and recovery[71]; (prolonged) severe oxidative stress[93] and (long-lasting) suppression of protective heat shock proteins[92] in response to exercise, especially when a history of high level physical activity and infection is present[150], cognitive deficits induced by exercise[186]; and substantially higher increments of NO metabolites in relation to workload during exercise[187]. Post-exertional malaise in ME/CFS seems to be related to exercise-induced inflammation and immune activation[188,189].



Figure 2, the 4I hypothesis: a key role for four types of immunological abnormalities

Four immunological abnormalities underpin the 4I hypothesis for ME/CFS (Figure 2): inflammation (I1), (Th2-predominant) immune activation (I2), immunosuppression (I3) and immune dysfunction (I4).



Potential immunological stimuli in ME/CFS

The immune system seems to face three potential stimuli in ME/CFS: pathogens and associated antigens, due to acute, chronic and/or reactivated infections (Figure 2, A, B1 and B2), gastro-intestinal inflammation and hyperpermeability of the intestines, possibly resulting into translocation of enterobacteria to the blood stream (Figure 2, D), and auto-epitopes, due to oxidative and nitrosative damage to proteins, lipids etc. (Figure 3, K).

    ME/CFS is often precipitated by infections, the severity of which seems to predict the clinical outcome[102,103]. Some studies implicate persistency of the pathogens[48] or antigens related to the pathogen[190] that instigated ME/CFS. Various infectious agents linked to ME/CFS are able to produce a persistent active infection, thereby establishing a constant incitement to the immune system[45]. In addition, some pathogens associated with ME/CFS, e.g. EBV[191] and HHV-6A/B[192], are known to induce a life-long latent infection. Several studies suggest reactivation of these pathogens[111,193], possible due to immunosuppression and immune dysfunction, e.g. a deficient EBV-specific B- and T-cell response[191]. The chronic or reactivated infection-hypothesis is contested[194]. However, as summarized, many studies have observed active infections in substantial patient subgroups. Infections would explain inflammation and immune activation in ME/CFS (Figure 2, A). It is also known that certain pathogens evade the immune system by immune modulation (Figure 2, B1 and B2), e.g. inhibiting the innate immune response, disrupting of T-cell function, and inducing a Th1->Th2 switch[195,196].

    Another possible immunological challenge relates to intestinal dysbiosis[49,51] and inflammation[130] and increased permeability of the intestinal barrier, thereby allowing enterobacteria to enter the blood stream, as indicated by elevated serum IgA levels against lipopolysaccharides (LPS) of gram-negative enterobacteria[50]. Intestinal dysbiosis and inflammation[54] and increased IgA responses to the LPS of commensal bacteria[53] have been associated with systemic inflammation and immune activation (Figure 2, D). It is known the gastro-intestinal tract can modulate the central nervous system by various blood-brain-barrier mediated mechanisms, e.g. through the secretion of NO and cytokines, thereby influencing behaviour[197].

    Finally, auto-epitopes, originating from oxidative and nitrosative damage to proteins and lipids (Figure 3, J), can induce autoimmune responses[198,199] (Figure 3, K). Although insufficiently explained, elevated levels of auto-antibodies have frequently been observed in ME/CFS, e.g. against serotonin[200,201], gangliosides[200], phospholipids[200], including mitochondrial cardiolipins[202,203], antinuclear antibodies[47,204], muscarinic cholinergic receptor[204] and ssDNA[205].



A vicious cycle of oxidative and nitrosative stress induced by inflammation

Oxidative and nitrosative stress play an important intermediate role in the 4I hypothesis. Inflammation will generate oxidative and nitrosative stress[206,207] (Figure 3, E), while oxidative and nitrosative stress can induce or amplify inflammation[208,209] (Figure 3, F). NO and reactive oxygen species (ROS) exert multiple immune-modulating effects[210,211]. ROS and reactive nitrogen species (RNS), including NO, can suppress NK[212,213] and T[214,215] cell cytotoxicity, which could contribute to immunosuppression (Figure 3, G). High levels of NO, produced by cytotoxic activated macrophages[216] may also play an important role in the shift from a Th1 to Th2 response[217,218] (Figure 3, H). While NO seems to suppress both Th1- and Th2-cell-mediated immunity at the early proliferation stage, high levels of NO appear to inhibit the Th1-cell differentiation of mature T helper (Th) cells[219]. Through several feedback loops oxidative and nitrosative stress can induce a self-perpetuating cycle of elevated oxidative and nitrosative stress, inflammation, elevated N-methyl-D-aspartate (NMDA) receptor activity, and ATP depletion, which is mediated by O2-, NO and ONOO-[220] (Figure 3, I).


HPA axis hypofunction as a potential sequel of inflammation, immune activation and oxidative stress

The HPA axis and the immune system are bidirectionally interconnected[221]. Some authors have suggested that the immunological abnormalities in ME/CFS, e.g. inflammation, are secondary to HPA axis hypofunction[177], possibly due to a stress crash: a switch from HPA axis hyper- to hypofunction[26]. However looking at various observations this doesnt seem very likely. Hypocortisolism is only present in a minority of the patients[222], HPA axis dysfunction is not present during the early stages of ME/CFS[223] and seems to develop gradually and to be more pronounced the longer ME/CFS exists[224], whereas immune activation and inflammation are often already present at the onset of the illness[102]. In contrast, chronic inflammation and immune activation can induce adrenal exhaustion gradually through various pathways (figure 4, L1): (a) (synergistic) suppression of cortisol release and the cortisol response to adrenocorticotropic hormone (ACTH) by tumor necrosis factor alpha (TNF)[225,226], possibly mediated by NO[227], and interleukin (IL)-1[228]; (b) HPA axis desensitizing[229], resulting into a long-lasting state of LPS tolerance to a second exposure of LPS, affecting the response of plasma TNF and HPA-hormones to LPS[230]; (c) reduced adrenal response to ACTH as a consequence of elevated levels of interleukin-10[231], associated with Th2 and Treg immune responses. Adrenal responses can also be inhibited by oxidative[232,233] and nitrosative stress/NO[234,235] (Figure 4, L2). A typical endocrine abnormality in ME/CFS relates to increased sensitivity of the cellular immune system[143,144] and HPA axis[183,184] to glucocorticoids (Figure 4, M1 and M2), plausibly explaining the paradoxical combination of hypocortisolism and Th2 predominance in ME/CFS.



Mitochondrial dysfunction induced by oxidative and nitrosative stress

In addition to causing damage to lipids, proteins and DNA, inducing neo-epitopes, oxidative and nitrosative stress can have various other negative effects (Figure 5).

    ROS and RNS, including ONOO-, exert multiple effects on mitochondria, including mitochondrial dysfunction, damage, and apoptosis[236,237] (Figure 5, N). NO and RNS inhibit the respiratory chain, leading to elevated O2 production, and, after reaction with NO, to increased ONOO- levels, further impeding mitochondrial respiration[238] (Figure 5, O).


Cardiovascular abnormalities due to oxidative and nitrosative stress

NO plays an important role in the cardiovascular system and increased levels of NO can have various adverse cardiovascular effects[239] (Figure 5, P). NO is a potent vasodilator[240,241] and seems essential in autoregulation of blood flow, both in large arteries and at the microcirculatory level, thereby determining the distribution of flow among the various vascular networks[239]. Therefore elevated basal NO levels in ME/CFS could explain decreased peripheral resistance and low blood pressure (hypotension)[242]. Although possibly mediated by other pathways, these phenomena are induced in healthy subjects by exercise[243]. Exercise-induced NO, added to elevated basal levels, might partially account for post-exertional hypotension and delayed recovery in ME/CFS[242]. Furthermore, elevated NO levels could also be involved in reduced myocardial contractility, disrupted autonomic modulation of myocardial function and abnormalities in heart rate variability[239,244,245]. The cardiovascular aberrations and/or mitochondrial dysfunction/damage could plausibly explain reduced oxygen uptake[158] and oxygenation[71] during exercise in ME/CFS (Figure 5, Q).



Neurological aberrations as potential consequences of inflammation, oxidative and nitrosative stress, cardiovascular abnormalities and reduced oxygen uptake

Various neurological abnormalities could be induced by the abnormalities in ME/CFS. First, systemic inflammation can induce neuroinflammation and sickness behavior[246] (Figure 5, R). Pro-inflammatory cytokines, induced by peripheral inflammation, can access the central nervous system through various pathways, and induce cytokines, amplify cytokine signals and release secondary messengers, e.g. NO, in the brain thereby influencing virtually every aspect of brain function[247]. Peripheral inflammation affects neuroendocrine function, NMDA receptor activity, neurotransmitter metabolism, and neurogenesis[248]. The behavorial effects of peripheral inflammation include depression, fatigue, psychomotor slowing, cognitive dysfunction and sleep disruption[247]. In addition to systemic inflammation-induced sickness behaviour, other mechanisms by which immunological aberrations affect the nervous system in ME/CFS have been suggested, e.g. an elevated release of cytokines by glial cells[249], auto-immune pathways, involving vasoactive neuropeptides damaging the blood-brain barrier and blood-spinal barrier[250], and infections of the nervous system by neurotropic viruses[45]. A recent study established evidence for brain glial activation in patients with chronic pain, a phenomenon repetitively observed in animal models[251]. Activation of microglia or astrocytes, related to neuro-inflammation, in widespread brain areas[174] could account for the chronic pain experienced by many patients with ME/CFS.

    Second, increased levels of NO-stimulated glutamate release and hypersensitivity of NMDA receptors[252,253] could account for central sensitisation, manifesting itself in enhanced sensitivity of the central nervous system to various stimuli, e.g. sound, and hyperalgesia (Figure 5, S). Others have proposed an NO-independent O2-mediated pathway to induce hyperalgesia[254,255]. Third, cardiovascular abnormalities, resulting into reduced cerebral blood flow[70] (Figure 5, T1) and cerebral oxygenation[256] (Figure 5, T2), induced or intensified by exertion[71], would account for reduced ATP synthesis in the central nervous system, as implicated by increased ventricular lactate levels[68].

The physiological effects of exercise and stress can explain post-exertional malaise

Exercise and psychological stress could amplify pre-existing immunological abnormalities, oxidative and nitrosative stress, and intestinal hyperpermeability (Figure 6). Since these anomalies can plausibly explain various typical symptoms of ME and CFS (next paragraph), the physiological effects of exercise and psychological stress would intensify abnormalities already present in rest. This could explain a (prolonged) aggravation of symptoms after a minor exertion: post-exertional malaise.

    Exercise has well-known beneficial effects[257,258]. Strenous exercise induces an increase in the pro-inflammatory cytokines TNF, IL-1, and IL-8 and the inflammatory cytokine IL-6, produced locally in the skeletal muscle in response to exercise[259,260]. This release is counterbalanced by the release of IL1 and TNF inhibitors and IL-10[259]. In chronic inflammatory diseases, exercise could have adverse effects through a combination of exercise-induced stimulation of immune signals with leukocytes previously affected by other stress, inflammatory, or immune mediators[261]. Deviant effects of exercise on inflammation and immune activation in ME/CFS (Figure 6, X1) are illustrated by the observations that the severity of symptom flare after moderate exercise is directly linked to increased levels of IL-1, IL-12, IL-6, IL-8, IL-10, and IL-13 8 hours post-exercise[188], that travelling from home to the hospital is sufficient for significantly elevated TGF- levels[262], that exercise induces a sustained increase in plasma TNF- in patients, not in controls[262], and that moderate exercise induces a larger 48 hours post-exercise area under the curve for IL-10[15]. In addition, since acute[263] and chronic[264] stress can induce inflammation[264], psychological stress could amplify pre-existing (low-grade) inflammation in ME/CFS.

    Exercise can also have immunosuppressive effects. While moderate exercise seems to stimulate immunity, prolonged strenuous exercise seem to suppress immune function, e.g. NK cell activity and antibody synthesis[265,266]. Since the aerobic threshold seems (profoundly) decreased in ME/CFS, low-level anaerobic exercise can amplify immunosuppression, e.g. diminished NK cell cytotoxicity and antibody levels, observed in ME/CFS (Figure 6, X2).

    In addition, eccentric exercise could induce and/or intensify immune dysfunction in ME/CFS (Figure 6, X3), e.g. inducing or amplifying a Th2-predominance[267,268]. Acute, subacute or chronic stress can suppress cellular (Th1) immunity and boost humoral (Th2) immunity, due to a differential effect of glucocorticoids and catecholamines on Th1/Th2 cells and type 1/type 2 cytokine synthesis[263]. In general, physiological and psychological stress may cause a selective suppression of Th1 functions and a shift towards a Th2 response, protecting the host from systemic 'overshooting' with pro-inflammatory cytokines[269].

    Another mechanism by which exercise can amplify pre-existing abnormalities is intestinal hyperpermeability[270,271] (Figure 6, X4). Psychological and physiological stress can compromise the intestinal barrier function[272,273]. Intestinal hyperpermeability could result in translocation of enterobacteria to the blood stream, instigating inflammation in response to endotoxins.

    An additional pathway by which exercise can amplify pre-existing aberrations is oxidative[274,275] and nitrosative[274,276] stress as a result of exercise (Figure 6, X5). ME/CFS seems to be associated with a prolonged accentuated oxidative stress and reduced heat shock proteins responses to incremental exercise[93]. Several observations suggest an abnormal adaptive response to exercise in ME/CFS[92], the severity of which seems to be related with premorbid physical activity and severe acute infections[150]. Through elevated glutamate release and subsequent NMDA receptor activation and induction of nuclear factor kappa-B (NF-kB), psychological distress enhances levels of NO and pro-oxidants in various brain areas[277,278].




The abnormalities observed in ME/CFS patients or substantial subgroups could explain the presence and variability of various characteristic symptoms (Figure 7 and Table 4). As explained in the previous paragraph the physiological effects of exercise in general and in ME/CFS in particular could account for the post-exertional malaise: exercise-induced intensification of symptoms[279].





The subjective and ambiguous criteria for CFS define a heterogeneous population of patients with chronic fatigue[32]. While chronic fatigue is obligatory for the diagnosis CFS[2], easy muscle fatigability and cognitive impairment, but above all, post-exertional malaise are mandatory for the diagnosis ME, whether defined by the original criteria[304] or the recently proposed new[1] criteria. ME and CFS are two distinct, partially overlapping clinical entities[8]. Based upon observations, it is estimated that 30-60% of people fulfilling the criteria for CFS[2] meet the more strict criteria for ME.

Fatigue is not obligatory for the diagnosis ME, and since the majority of the research in the last decades have used the CFS criteria for patient selection, it is unknown how many patients fulfilling the ME criteria dont meet the case definition for CFS. Despite the confusion created by the use of the CFS criteria, various studies have observed typical abnormalities in the ME/CFS patient group or significant ME/CFS patient subgroups.

    More consistent findings relate to four types of immunological abnormalities in ME/CFS: inflammation (I1), (Th2-predominated) immune activation and counteractive immunoregulatory responses (I2), immunosuppression (I3), and immune dysfunction (I4). These immunological abnormalities and their direct and indirect sequels can account for various abnormalities observed in ME/CFS and several typical symptoms, including post-exertional malaise and weakness. ME/CFS often has an sudden, flu-like onset. Whether the original infection persists and perpetuates the illness or is only a hit-and-run infection remains subject to debate. However, using different methods and samples, various infections have been observed in substantial ME/CFS patient subgroups. Immunosuppression (I3) and immune dysfunction (I4), either due to pathogens modulating and evading the immune system (as an effect) or enabling chronic/reactivating infections (as a cause) or both, seem to play a key role in the etiology. (Chronic) inflammation (I1) and immune activation (I2), both observed repetitively in ME/CFS, can induce and sustain a vicious circle of reactive oxygen and nitrogen species and peroxynitrite. Elevated oxidative/nitrosative stress has various detrimental effects: inflammation (I1), immunosuppression (I3), immune dysfunction (I4), the generation of auto-epitopes (due to oxidative and nitrosative damage to proteins, mitochondria etc.), mitochondrial dysfunction, cardiovascular deficits, et cetera-. Gastro-intestinal dysbiosis and inflammation and intestinal hyperpermeability, found by some studies, could result into translocation of enterobacteria into the blood stream, thereby inducing a third potential immunological stimulus in ME/CFS (i.e. LPS). HPA axis dysfunction, especially hypocortisolism and HPA axis hyporesponsiveness, can explain some immunological abnormalities, but seem to arise at a later stage of the disease. On the other hand, inflammation, immune activation and oxidative and nitrosative stress can induce hypocortisolism and a blunted adrenal response to ACTH through various pathways gradually. The endocrine and immunological anomalies in ME/CFS reflect a paradox: reduced adrenal output (cortisol) combined with suppression of the (cellular) immune system, (possibly) due to enhanced glucocorticoid sensitivity of the Th1 arm of the immune system. Finally, inflammation/immune activation, cardiovascular impairment and low oxygenation/oxygen uptake could account for various neurocognitive and neuropsychological abnormalities found in ME/CFS.

    Other authors have proposed alternative explanatory models for ME/CFS. The ONOO-model, with a key role for the self-perpetuating vicious circle of elevated oxidative and nitrosative stress, resulting into peroxynitrite (ONOO-), proposed by Pall et al[305] is incorporated within the 4I explanatory model. The 4I explanatory model is also in line with the NO-induced central sensitisation-model of Meeus et al[306]. The 4I model has commonalities with the neuro-immunological (NI) model for ME/CFS, put forward by Morris and Maes[307]. However, there also some relevant differences. In essence, the NI model is a linear model in which a non-persistent infection induces a vicious circle of oxidative and nitrosative stress and inflammation, neo-epitopes (induced by oxidative and nitrosative damage to proteins) and autoimmunity. The 4I hypothesis embodies key roles for reactivating and chronic infections, immune dysfunction and Th2-dominated immune activation (next to inflammation), HPA axis dysfunction, e.g. hypocortisolism and blunted adrenal responses, enhanced sensitivity of the HPA axis and the (cellular) immune system to the suppressive effects of cortisol, and circulatory deficits[3]. In contrast with the hypothesis that maladaptive stress responses, either due to a stress crash[26] or allostatic overload[308], are causing the immunological abnormalities seen in ME/CFS, the 4I hypothesis is based upon the premise that the immunological aberrations and oxidative/nitrosative stress can induce and sustain the endocrine abnormalities and defective stress responses through various pathways. The 4I hypotheses is consistent with the alternate homeostatic state-hypothesis of Craddock et al[309], although, the 4I incorporates an opposing cause-and-effect-relationship between the immunological and endocrine abnormalities in ME/CFS.



While the abnormalities incorporated in the 4I model have been observed in ME/CFS patients or major patient subgroups repetitively, the cause-and-effect relationships between these abnormalities have often been established in general, non-ME/CFS-specific circumstances. However, the causal relations underpinning the 4I hypothesis, although speculative, collectively offer a plausible explanation for various abnormalities frequently observed in ME/CFS and characteristic symptoms.

    Due to the heterogeneity of the CFS[2] patient group, the duration of the illness of the patients investigated, and the essential role of exertion-induced abnormalities, none of the abnormalities will be present in all CFS patients at all times and it is unlikely that here will ever be one abnormality present in all CFS[2] patients. In order to establish which abnormalities and causal relationships are applicable to specific patients, it is also essential to make a distinction between patients with post-exertional malaise, cognitive deficits and other characteristic symptoms of ME[1], and CFS[2] patients without these typical symptoms and to investigate well-defined biological and symptomatic ME and CFS patient subgroups in more detail.

    The 4I hypothesis can be tested by investigating the abnormalities in biological and clinical subgroups defined by biomarkers and objective measures of the clinical status[3], by applying correlational analyses on the abnormalities present in patient subgroups, and by testing interventions aimed at reversing specific aberrations in patients, e.g. infections, immunological aberrations and oxidative/nitrosative stress.



Immunologic abnormalities frequently observed in ME/CFS, inflammation (I1), (Th2-biased) immune activation (I2), immunosuppression (I3) and immune dysfunction (I4) seem to play a crucial role in the etiology and pathophysiology of ME/CFS. These immunological aberrations, combined with three potential immunological stimuli, can explain various other abnormalities observed in ME/CFS and underpin the 4I explanatory model for ME/CFS, which accounts for several characteristic symptoms.

    Future research should confirm various abnormalities and explore the aberrations in more detail in specific clinical and biological subgroups. Correlational analysis of co-existing abnormalities in patient subgroups and the outcomes of interventions aimed at specific abnormalities could be used to accept, refine or reject the cause-and-effect relationships incorporated in the 4I explanatory model for ME/CFS.



The Author has no conflicts of interest to declare.



1.   Carruthers BM, van de Sande MI, de Meirleir KL, Klimas NG, Broderick G, Mitchell T, et al. Myalgic encephalomyelitis: international consensus criteria. J Intern Med. 2011 Oct; 270(4): 327-338. PMID: 21777306. doi: 10.1111/j.1365-2796.2011.02428.x.

2.   Fukuda K, Straus SE, Hickie I, Sharpe M, Dobbins JG, Komaroff AL. The chronic fatigue syndrome: a comprehensive approach to its definition and study. Ann Intern Med. 1994 Dec 15; 121(12): 953-959. PMID: 7978722. doi: 10.7326/0003-4819-121-12-199412150-00009.

3.   Twisk FNM. The status of and future research into Myalgic Encephalomyelitis and chronic fatigue syndrome: the need of accurate diagnosis, objective assessment, and acknowledging biological and clinical subgroups. Front Physiol. 2014 Mar 27; 5: 109. PMID: 24734022. doi: 10.3389/fphys.2014.00109.

4.   Brenu EW, Johnston S, Hardcastle SL, Huth TK, Fuller K, Ramos SB, et al. Immune abnormalities in patients meeting new diagnostic criteria for chronic fatigue syndrome/Myalgic Encephalomyelitis. J Mol Biomark Diagn. 2013 Nov 14; 4(3): 152. doi: 10.4172/2155-9929.1000152.

5.   Maes M, Twisk FNM, Johnson C. Myalgic encephalomyelitis (ME), chronic fatigue syndrome (CFS), and chronic fatigue (CF) are distinguished accurately: results of supervised learning techniques applied on clinical and inflammatory data. Psychiatry Res. 2012 Dec 30; 200(2-3): 754-760. PMID: 22521895. doi: 10.1016/j.psychres.2012.03.031.

6.   Van der Meer JWM, Lloyd AR. A controversial consensus. J Intern Med. 2012 Jan; 271(1): 29-31. PMID: 21988219. doi: 10.1111/j.1365-2796.2011.02468.x.

7.   Broderick G. Response to 'A controversial consensus'; by the International Consensus Panel. J Intern Med. 2012 Feb; 271(2): 213-217. PMID: 22211276. doi: 10.1111/j.1365-2796.2011.02499.x.

8.   Twisk FNM, Arnoldus RJW. Comment and reply on: ME is a distinct diagnostic entity, not part of a chronic fatigue spectrum. Expert Opin Med Diagn. 2013 Jul; 7(4): 413-415. PMID: 23634762. doi: 10.1517/17530059.2013.795147.

9.   Jason LA, Sunnquist M, Brown A, Evans M, Vernon SD, Furst JD, et al. Examining case definition criteria for chronic fatigue syndrome and myalgic encephalomyelitis. Fatigue. 2014; 2(1): 40-56. PMID: 24511456. doi: 10.1080/21641846.2013.862993.

10.  Meeus M, van Eupen I, van Baarle E, De Boeck V, Luyckx A, Kos D, et al. Symptom fluctuations and daily physical activity in patients with chronic fatigue syndrome: a case-control study. Arch Phys Med Rehabil. 2011 Nov; 92(11): 1820-1826. PMID: 22032215. doi: 10.1016/j.apmr.2011.06.023.

11.  Miwa K, Fujita M. Cardiac function fluctuates during exacerbation and remission in young adults with chronic fatigue syndrome and "small heart". J Cardiol. 2009; 54(1): 29-35. PMID: 19632517. doi: 10.1016/j.jjcc.2009.02.008.

12.  Komaroff AL, Fagioli LR, Geiger AM, Doolittle TH, Lee J, Kornish RJ, et al. An examination of the working case definition of chronic fatigue syndrome. Am J Med. 1996 Jan; 100(1): 56-64. PMID: 8579088. doi: 10.1016/S0002-9343(96)90012-1.

13.  Meeus M, Ickmans K, Struyf F, Kos D, Lambrecht L, Willekens B, et al. What is in a name? Comparing diagnostic criteria for chronic fatigue syndrome with or without fibromyalgia. Clin Rheumatol. 2014 Oct 14. PMID: 25308475. doi: 10.1007/s10067-014-2793-x.

14.  Neu D, Mairesse O, Montana X, Gilson M, Corazza F, Lefevre N, et al. Dimensions of pure chronic fatigue: psychophysical, cognitive and biological correlates in the chronic fatigue syndrome. Eur J Appl Physiol. 2014 Sep; 114(9): 1841-1851. PMID: 24878689. doi: 10.1007/s00421-014-2910-1.

15.  Light AR, Bateman L, Jo D, Hughen RW, Vanhaitsma TA, White AT, et al. Gene expression alterations at baseline and following moderate exercise in patients with chronic fatigue syndrome, and fibromyalgia syndrome. J Intern Med. 2012 Jan 26; 271(1): 64-81. PMID: 21615807. doi: 10.1111/j.1365-2796.2011.02405.x.

16.  Winger A, Kvarstein G, Wyller VB, Sulheim D, Fagermoen E, Småstuen MC, et al. Pain and pressure pain thresholds in adolescents with chronic fatigue syndrome and healthy controls: a cross-sectional study. BMJ Open. 2014 Oct 6; 4(9): e005920. PMID: 25287104. doi: 10.1136/bmjopen-2014-005920.

17.  Streeten DH, Thomas D, Bell DS. The roles of orthostatic hypotension, orthostatic tachycardia, and subnormal erythrocyte volume in the pathogenesis of the chronic fatigue syndrome. Am J Med Sci. 2000 Jul; 320(1): 1-8. doi: 10.1097/00000441-200007000-00001.

18.  Hoad A, Spickett G, Elliott J, Newton J. Postural orthostatic tachycardia syndrome is an under-recognized condition in chronic fatigue syndrome. QJM. 2008 Dec; 101(12): 961-965. PMID: 18805903. doi: 10.1093/qjmed/hcn123.

19.  Attree EA, Arroll MA, Dancey CP, Griffith C, Bansal AS. Psychosocial factors involved in memory and cognitive failures in people with myalgic encephalomyelitis/chronic fatigue syndrome. Psychol Res Behav Manag. 2014 Feb 25; 7: 67-76. PMID: 24596470. doi: 10.2147/PRBM.S50645. eCollection 2014.

20.  McInnis OA, Matheson K, Anisman H. Living with the unexplained: coping, distress, and depression among women with chronic fatigue syndrome and/or fibromyalgia compared to an autoimmune disorder. Anxiety Stress Coping. 2014 Mar 3; 27(6): 601-618. PMID: 24479644. doi: 10.1080/10615806.2014.888060.

21.  Rayhan RU, Ravindran MK, Baraniuk JN. Migraine in gulf war illness and chronic fatigue syndrome: prevalence, potential mechanisms, and evaluation. Front Physiol. 2013 Jul 24; 4: 181. PMID: 23898301. doi: 10.3389/fphys.2013.00181. eCollection 2013.

22.  Petrov D, Marchalik D, Sosin M, Bal A. Factors affecting duration of chronic fatigue syndrome in pediatric patients. Indian J Pediatr. 2012 Jan; 79(1): 52-55. PMID: 21617905. doi: 10.1007/s12098-011-0463-4.

23.  Söderlund A, SAM, Malterud K. "I could not lift my arm holding the fork." Living with chronic fatigue syndrome. Scand J Prim Health Care. 2000 Sep; 18(3): 165-169. PMID: 11097102. doi: 10.1080/028134300453377.

24.  Ocon AJ, Messer Z, Medow M, Stewart J. Increasing orthostatic stress impairs neurocognitive functioning in chronic fatigue syndrome with postural tachycardia syndrome. 2012 Mar 1; 122(5): 227-238. PMID: 21919887. doi: 10.1042/CS20110241.

25.  Jackson ML, Bruck D. Sleep abnormalities in chronic fatigue syndrome/myalgic encephalomyelitis: a review. J Clin Sleep Med. 2012 Dec 15; 8(6): 719-728. PMID: 23243408. doi: 10.5664/jcsm.2276.

26.  Van Houdenhove B, Van Den Eede F, Luyten P. Does hypothalamic-pituitary-adrenal axis hypofunction in chronic fatigue syndrome reflect a 'crash' in the stress system? Med Hypotheses. 2009 Jun; 72(6): 701-705. PMID: 19237251. doi: 10.1016/j.mehy.2008.11.044.

27.  Lutgendorf SK, Antoni MH, Ironson G, Fletcher MA, Penedo F, Baum A, et al. Physical symptoms of chronic fatigue syndrome are exacerbated by the stress of Hurricane Andrew. Psychosom Med. 1995 Jul-Aug; 57(4): 310-323. PMID: 7480560. doi: 10.1097/00006842-199507000-00002.

28.  Krilov LR, Fisher M, Friedman SB, Reitman D, Mandel FS. Course and outcome of chronic fatigue in children and adolescents. Pediatrics. 1998 Aug; 102(2 Pt 1): 360-366. PMID: 9685439. doi: 10.1542/peds.102.2.360.

29.  Maes M, Leunis JC, Geffard M, Berk M. Evidence for the existence of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) with and without abdominal discomfort (irritable bowel) syndrome. Neuro Endocrinol Lett. 2014 Nov; 35(6): 445-553. PMID: 25433843.

30.  VanNess JM, Stevens SR, Bateman L, Stiles TL, Snell CR. Postexertional malaise in women with chronic fatigue syndrome. J Womens Health (Larchmt). 2010 Feb; 19(2): 239-244. PMID: 20095909. doi: 10.1089/jwh.2009.1507.

31.  White AT, Light AR, Hughen RW, Vanhaitsma TA, Light KC. 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. Psychosom Med. 2012 Jan; 74(1): 46-54. PMID: 22210239. doi: 10.1097/PSY.0b013e31824152ed.

32.  Wilson A, Hickie I, Hadzi-Pavlovic D, Wakefield D, Parker G, Straus SE, et al. What is chronic fatigue syndrome? Heterogeneity within an international multicentre study. Aust N Z J Psychiatry. 2001 Aug; 35(4): 520-527. PMID: 11531735. doi: 10.1046/j.1440-1614.2001.00888.x.

33.  Maes M, Twisk FNM. Chronic fatigue syndrome: Harvey and Wessely's (bio)psychosocial model versus a bio(psychosocial) model based on inflammatory and oxidative and nitrosative stress pathways. BMC Med. 2010 Jun 15; 8(3): 35. PMID: 20550693. doi: 10.1186/1741-7015-8-35.

34.  Aspler AL, Bolshin C, Vernon SD, Broderick G. Evidence of inflammatory immune signaling in chronic fatigue syndrome: a pilot study of gene expression in peripheral blood. Behav Brain Funct. 2008 Sep 26; 4: 44. PMID: 18822143. doi: 10.1186/1744-9081-4-44.

35.  Kaushik N, Fear D, Richards SC, McDermott CR, Nuwaysir EF, Kellam P, et al. Gene expression in peripheral blood mononuclear cells from patients with chronic fatigue syndrome. J Clin Pathol. 2005 Aug; 58(8): 826-832. PMID: 16049284. doi: 10.1136/jcp.2005.025718.

36.  Gow JW, Hagan S, Herzyk P, Cannon C, Behan PO, Chaudhuri A. A gene signature for post-infectious chronic fatigue syndrome. BMC Med Genomics. 2009 Jun 25; 2: 38. PMID: 19555476. doi: 10.1186/1755-8794-2-38.

37.  Ciregia F, Giusti L, Da Valle Y, Donadio E, Consensi A, Giacomelli C, et al. A multidisciplinary approach to study a couple of monozygotic twins discordant for the chronic fatigue syndrome: a focus on potential salivary biomarkers. J Transl Med. 2013 Oct 2; 11: 243. PMID: 24088505. doi: 10.1186/1479-5876-11-243.

38.  Klimas NG, Salvato FR, Morgan R, Fletcher MA. Immunologic abnormalities in chronic fatigue syndrome. J Clin Microbiol. 1990 Jun; 28(6): 1403-1410. PMID: 2166084.

39.  Fletcher MA, Zeng XR, Barnes Z, Levis S, Klimas NG. Plasma cytokines in women with chronic fatigue syndrome. J Transl Med. 2009 Nov 12; 7: 96. PMID: 19909538. doi: 10.1186/1479-5876-7-96.

40.  Meeus M, Mistiaen W, Lambrecht L, Nijs J. Immunological similarities between cancer and chronic fatigue syndrome: the common link to fatigue? Anticancer Res. 2009 Nov; 29(11): 4717-4726. PMID: 20032425.

41.  Brenu EW, van Driel ML, Staines DR, Ashton KJ, Ramos SB, Keane J, et al. Immunological abnormalities as potential biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis. J Transl Med. 2011 May 28; 9: 81. PMID: 21619669. doi: 10.1186/1479-5876-9-81.

42.  Lloyd AR, Wakefield D, Hickie I. Immunity and the pathophysiology of chronic fatigue syndrome. Ciba Found Symp. 1993; 173: 176-187. PMID: 8491097. doi: 10.1002/9780470514382.ch11.

43.  Broderick G, Fuite J, Kreitz A, Vernon SD, Klimas N, Fletcher MA. A formal analysis of cytokine networks in chronic fatigue syndrome. Brain Behav Immun. 2010 Oct; 24(7): 1209-1217. PMID: 20447453. doi: 10.1016/j.bbi.2010.04.012.

44.  Kerr JR, Petty R, Burke B, Gough J, Fear D, Sinclair LI, et al. Gene expression subtypes in patients with chronic fatigue syndrome/myalgic encephalomyelitis. J Infect Dis. 2008 Apr 15; 197(8): 1171-1184. PMID: 18462164. doi: 10.1086/533453.

45. Komaroff AL, Cho TA. Role of infection and neurologic dysfunction in chronic fatigue syndrome. Semin Neurol. 2011 Jul; 31(3): 325-337. PMID: 21964849. doi: 10.1055/s-0031-1287654.

46.  Nicolson GL, Gan R, Haier J. Multiple co-infections (Mycoplasma, Chlamydia, human herpes virus-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms. APMIS. 2003 May; 111(5): 557-566. PMID: 12887507. doi: 10.1034/j.1600-0463.2003.1110504.x.

47.  Hilgers A, Frank J. Chronic fatigue syndrome: evaluation of a 30-criteria score and correlation with immune activation. J Chronic Fatigue Syndr. 1996; 2(4): 35-47. doi: 10.1300/J092v02n04_04.

48.  Chia J, Chia A, Voeller M, Lee T, Chang R. Acute enterovirus infection followed by myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and viral persistence. J Clin Pathol. 2010 Feb; 63(2): 165-168. PMID: 19828908. doi: 10.1136/jcp.2009.070466.

49.  Sheedy JR, Wettenhall RE, Scanlon D, Gooley PR, Lewis DP, McGregor N, et al. Increased d-lactic acid intestinal bacteria in patients with chronic fatigue syndrome. In Vivo. 2009; 23(4): 621-628. PMID: 19567398.

50.  Maes M, Mihaylova I, Leunis JC. 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. 2007 Apr; 99(1-3): 237-240. PMID: 17007934. doi: 10.1016/j.jad.2006.08.021.

51.  Frmont M, Coomans D, Massart S, de Meirleir K. High-throughput 16S rRNA gene sequencing reveals alterations of intestinal microbiota in myalgic encephalomyelitis/chronic fatigue syndrome patients. Anaerobe. 2013 Aug; 22: 50-56. PMID: 23791918. doi: 10.1016/j.anaerobe.2013.06.002.

52.  De Meirleir KL, Khaiboullina SF, Frmont M, Hulstaert J, Rizvanov AA, Palots A, et al. Plasmacytoid dendritic cells in the duodenum of individuals diagnosed with myalgic encephalomyelitis are uniquely immunoreactive to antibodies to human endogenous retroviral proteins. In Vivo. 2013 Mar-Apr; 27(2): 177-187. PMID: 23422476.

53.  Maes M, Twisk FNM, Kubera M, Ringel K, Leunis JC, Geffard M. Increased IgA responses to the LPS of commensal bacteria is associated with inflammation and activation of cell-mediated immunity in chronic fatigue syndrome. J Affect Disord. 2012 Feb 1; 136(3): 909-917. PMID: 21967891. doi:10.1016/j.jad.2011.09.010.

54.  Groeger D, O'Mahony L, Murphy EF, Bourke JF, Dinan TG, Kiely B, et al. Bifidobacterium infantis 35624 modulates host inflammatory processes beyond the gut. Gut Microbes. 2013 Jul-Aug; 4(4): 325-339. PMID: 23842110. doi: 10.4161/gmic.25487.

55.  Scully P, McKernan DP, Keohane J, Groeger D, Shanahan F, Dinan TGQEM. Plasma cytokine profiles in females with irritable bowel syndrome and extra-intestinal co-morbidity. Am J Gastroenterol. 2010 Oct; 105(10): 2235-2243. PMID: 20407431. doi: 10.1038/ajg.2010.159.

56.  Kennedy G, Khan F, Hill A, Underwood C, Belch JF. Biochemical and vascular aspects of pediatric chronic fatigue syndrome. Arch Pediatr Adolesc Med. 2010 Sep; 164(9): 817-823. PMID: 20819963. doi: 10.1001/archpediatrics.2010.157.

57.  Meeus M, Nijs J, Hermans L, Goubert D, Calders P. The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia patients: peripheral and central mechanisms as therapeutic targets? Expert Opin Ther Targets. 2013 Sep; 17(9): 1081-1089. PMID: 23834645. doi: 10.1517/14728222.2013.818657.

58.  Tomic S, Brkic S, Maric D, Mikic AN. Lipid and protein oxidation in female patients with chronic fatigue syndrome. Arch Med Sci. 2012 Nov 9; 8(5): 886-891. PMID: 23185200. doi: 10.5114/aoms.2012.31620.

59.  Zhang C, Baumer A, Mackay IR, Linnane AW, Nagley P. Unusual pattern of mitochondrial DNA deletions in skeletal muscle of an adult human with chronic fatigue syndrome. Hum Mol Genet. 1995; 4(4): 751-754. PMID: 7633428. doi: 10.1093/hmg/4.4.751.

60.  Booth NE, Myhill S, McLaren-Howard J. Mitochondrial dysfunction and the pathophysiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Int J Clin Exp Med. 2012; 5(3): 208-220. PMID: 22837795.

61.  Vernon SD, Whistler T, Cameron B, Hickie IB, Reeves WC, Lloyd A. Preliminary evidence of mitochondrial dysfunction associated with post-infective fatigue after acute infection with Epstein Barr virus. BMC Infect Dis. 2006 Jan 31; 6: 15. PMID: 16448567. doi: 10.1186/1471-2334-6-15.

62.  Pietrangelo T, Mancinelli R, Toniolo L, Toniolo L, Vecchiet J, Fan G, et al. Transcription profile analysis of vastus lateralis muscle from patients with chronic fatigue syndrome. Int J Immunopathol Pharmacol. 2009 Jul-Sep; 22(3): 795-807. PMID: 19822097.

63.  Behan WM, More IA, Behan PO. Mitochondrial abnormalities in the postviral fatigue syndrome. Acta Neuropathol. 1991; 83(1): 61-65. PMID: 1792865. doi: 10.1007/BF00294431.

64.  Streeten DH, Bell DS. Circulating blood volume in chronic fatigue syndrome. J Chronic Fatigue Syndr. 1998; 4(1): 3-11. doi: 10.1300/J092v04n01_02.

65.  Hurwitz BE, Coryell VT, Parker M, Martin P, Laperriere A, Klimas NG, et al. Chronic fatigue syndrome: illness severity, sedentary lifestyle, blood volume and evidence of diminished cardiac function. Clin Sci (Lond). 2009 Oct 19; 118(2): 125-135. PMID: 19469714. doi: 10.1042/CS20090055.

66.  Hollingsworth KG, Hodgson T, Macgowan GA, Blamire AM, Newton JL. Impaired cardiac function in chronic fatigue syndrome measured using magnetic resonance cardiac tagging. J Intern Med. 2012 Mar; 271(3): 264-270. PMID: 21793948. doi: 10.1111/j.1365-2796.2011.02429.x.

67. Biswal B, Kunwar P, Natelson BH. Cerebral blood flow is reduced in chronic fatigue syndrome as assessed by arterial spin labeling. J Neurol Sci. 2011 Feb 15; 301(1-2): 9-11. PMID: 21167506. doi: 10.1016/j.jns.2010.11.018.

68.  Shungu DC, Weiduschat N, Murrough JW, Mao X, Pillemer S, Dyke JP, et al. Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed. 2012 Sep; 25(9): 1073-1087. PMID: 22281935. doi: 10.1002/nbm.2772.

69.  McCully KK, Natelson BH. Impaired oxygen delivery to muscle in chronic fatigue syndrome. Clin Sci (Lond). 1999; 97(5): 603-608. PMID: 10545311. doi: 10.1042/CS19980372.

70.  Ocon AJ. Caught in the thickness of brain fog: exploring the cognitive symptoms of chronic fatigue syndrome. Front Physiol. 2013; 4: 63. PMID: 23576989. doi: 10.3389/fphys.2013.00063.

71.  Patrick Neary J, Roberts AD, Leavins N, Harrison MF, Croll JC, Sexsmith JR. Prefrontal cortex oxygenation during incremental exercise in chronic fatigue syndrome. Clin Physiol Funct Imaging. 2008 Nov; 28(6): 364-372. PMID: 18671793. doi: 10.1111/j.1475-097X.2008.00822.x.

72.  Wyller VB, Due R, Saul JP, Amlie JP, Thaulow E. Usefulness of an abnormal cardiovascular response during low-grade head-up tilt-test for discriminating adolescents with chronic fatigue from healthy controls. Am J Cardiol. 2007 Apr 1; 99(7): 997-1001. PMID: 17398200. doi: 10.1016/j.amjcard.2006.10.067.

73.  LaManca JJ, Peckerman A, Walker J, Kesil W, Cook S, Taylor A, et al. Cardiovascular response during head-up tilt in chronic fatigue syndrome. Clin Physiol. 1999 Mar; 19(1): 111-120. PMID: 10200892. doi: 10.1046/j.1365-2281.1999.00154.x.

74.  Peckerman A, LaManca JJ, Dahl KA, Chemitiganti R, Qureishi B, Natelson BH. Abnormal impedance cardiography predicts symptom severity in chronic fatigue syndrome. Am J Med Sci. 2003 Aug; 326(2): 55-60. PMID: 12920435. doi: 10.1097/00000441-200308000-00001.

75.  Farquhar WB, Hunt BE, Taylor JA, Darling SE, Freeman R. Blood volume and its relation to peak O(2) consumption and physical activity in patients with chronic fatigue. Am J Physiol Heart Circ Physiol. 2002 Jan; 282(1): H66-H71. PMID: 11748048.

76.  Jones DE, Hollingsworth KG, Jakovljevic DG, Fattakhova G, Pairman J, Blamire AM, et al. Loss of capacity to recover from acidosis on repeat exercise in chronic fatigue syndrome: a case-control study. Eur J Clin Invest. 2012 Feb; 42(2): 186-194. PMID: 21749371. doi: 10.1111/j.1365-2362.2011.02567.x.

77.  Vermeulen RCW, Kurk RM, Visser FC, Sluiter W, Scholte HR. Patients with chronic fatigue syndrome performed worse than controls in a controlled repeated exercise study despite a normal oxidative phosphorylation capacity. J Transl Med. 2010 Oct 11; 8: 93. PMID: 20937116. doi: 10.1186/1479-5876-8-93.

78.  Weinstein AA, Drinkard BM, Diao G, Furst G, Dale JK, Straus SE, et al. Exploratory analysis of the relationships between aerobic capacity and self-reported fatigue in patients with rheumatoid arthritis, polymyositis, and chronic fatigue syndrome. PM R. 2009 Jul; 1(7): 620-628. PMID: 19627955. doi: 10.1016/j.pmrj.2009.04.007.

79.  Chen R, Liang FX, Moriya J, Yamakawa J, Sumino H, Kanda T, et al. Chronic fatigue syndrome and the central nervous system. J Int Med Res. 2008 Sep-Oct; 36(5): 867-874. PMID: 18831878. doi: 10.1177/147323000803600501.

80.  Lange G, Steffener J, Cook DB, Bly BM, Christodoulou C, Liu WC, et al. Objective evidence of cognitive complaints in chronic fatigue syndrome: a BOLD fMRI study of verbal working memory. Neuroimage. 2005 Jun; 26(2): 513-524. PMID: 15907308. doi: 10.1016/j.neuroimage.2005.02.011.

81.  Natelson BH. Brain dysfunction as one cause of CFS symptoms including difficulty with attention and concentration. Front Physiol. 2013 May 20; 4: 109. PMID: 23730290. doi: 10.3389/fphys.2013.00109.

82.  Puri BK, Jakeman PM, Agour M, Gunatilake KD, Fernando KA, Gurusinghe AI, et al. Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): a voxel-based morphometry 3 T MRI study. Br J Radiol. 2012 Jul; 85(1015): e270-e273. PMID: 22128128. doi: 10.1259/bjr/93889091.

83.  Papadopoulos AS, Cleare AJ. Hypothalamic-pituitary-adrenal axis dysfunction in chronic fatigue syndrome. Nat Rev Endocrinol. 2011 Sep 27; 8(1): 22-32. PMID: 21946893. doi: 10.1038/nrendo.2011.153.

84.  Tak LM, Cleare AJ, Ormel J, Manoharan A, Kok IC, Wessely S, et al. Meta-analysis and meta-regression of hypothalamic-pituitary-adrenal axis activity in functional somatic disorders. Biol Psychol. 2011 May; 87(2): 183-194. PMID: 21315796. doi: 10.1016/j.biopsycho.2011.02.002.

85.  Demitrack MA, Dale JK, Straus SE, Laue L, Listwak SJ, Kruesi MJ, et al. Evidence for impaired activation of the hypothalamic-pituitary-adrenal axis in patients with chronic fatigue syndrome. J Clin Endocrinol Metab. 1991 Dec; 73(6): 1224-1234. PMID: 1659582. doi: 10.1210/jcem-73-6-1224.

86.  Torres-Harding S, Sorenson M, Jason LA, Maher KA, Fletcher MA, Reynolds N, et al. The associations between basal salivary cortisol and illness symptomatology in chronic fatigue syndrome. J Appl Biobehav Res. 2008 Jan 1; 13: 157-180. PMID: 19701493. doi: 10.1111/j.1751-9861.2008.00033.x.

87.  Whistler T, Jones JF, Unger ER, Vernon SD. Exercise responsive genes measured in peripheral blood of women with chronic fatigue syndrome and matched control subjects. BMC Physiol. 2005 Mar 24; 5(1): 5. PMID: 15790422. doi: 10.1186/1472-6793-5-5.

88.  Broderick G, Craddock RC, Whistler T, Taylor R, Klimas N, Unger ER. Identifying illness parameters in fatiguing syndromes using classical projection methods. Pharmacogenomics. 2006 Apr; 7(3): 407-419. PMID: 16610951. doi: 10.2217/14622416.7.3.407.

89.  Watson WS, McCreath GT, Chaudhuri A, Behan PO. Possible cell membrane transport defect in chronic fatigue syndrome? J Chronic Fatigue Syndr. 1997; 3(3): 1-13. doi: 10.1300/J092v03n03_01.

90.  Cameron B, Galbraith S, Zhang Y, Davenport T, Vollmer-Conna U, Wakefield D, et al. Gene expression correlates of postinfective fatigue syndrome after infectious mononucleosis. J Infect Dis. 2007 Jul 1; 196(1): 56-66. PMID: 17538884. doi: 10.1086/518614.

91.  Snell CR, Stevens SR, Davenport TE, VanNess JM. Discriminative validity of metabolic and workload measurements to identify individuals with chronic fatigue syndrome. Phys Ther. 2013 Nov; 93(11): 1484-1492. PMID: 23813081. doi: 10.2522/ptj.20110368.

92.  Thambirajah AA, Sleigh K, Stiver HG, Chow AW. Differential heat shock protein responses to strenuous standardized exercise in chronic fatigue syndrome patients and matched healthy controls. Clin Invest Med. 2008 Dec 1; 31(6): E319-E327. PMID: 19032901.

93.  Jammes Y, Steinberg JG, Delliaux S, Brgeon F. Chronic fatigue syndrome combines increased exercise-induced oxidative stress and reduced cytokine and Hsp responses. J Intern Med. 2009 Aug; 266(2): 196-206. PMID: 19457057. doi: 10.1111/j.1365-2796.2009.02079.x.

94.  De Becker P, McGregor N, de Meirleir K. Possible triggers and mode of onset of chronic fatigue syndrome. J Chronic Fatigue Syndr. 2002; 10(2): 3-18. doi: 10.1300/J092v10n02.

95.  Evengård B, Jonzon E, Sandberg A, Theorell T, Lindh G. Differences between patients with chronic fatigue syndrome and with chronic fatigue at an infectious disease clinic in Stockholm, Sweden. Psychiatry Clin Neurosci. 2003 Aug; 57(4): 361-368. PMID: 12839515. doi: 10.1046/j.1440-1819.2003.01132.x.

96.  Mawle AC, Nisenbaum R, Dobbins JG, Gary HEJ, Stewart JA, Reyes M, et al. Immune responses associated with chronic fatigue syndrome: a case-control study. J Infect Dis. 1997 Jan; 175(1): 136-141. PMID: 8985207. doi: 10.1093/infdis/175.1.136.

97.  Porter N, Lerch A, Jason LA, Sorenson M, Fletcher MA, Herrington J. A comparison of immune functionality in viral versus non-viral CFS subtypes. J Behav Neurosci Res. 2010; 8(2): 1-8. PMID: 24634898.

98.  DeLuca J, Johnson SK, Ellis SP, Natelson BH. Sudden vs gradual onset of chronic fatigue syndrome differentiates individuals on cognitive and psychiatric measures. J Psychiatr Res. 1997 Jan-Feb; 31(1): 83-90. PMID: 9201650. doi: 10.1016/S0022-3956(96)00052-0.

99.  Claypoole KH, Noonan C, Mahurin RK, Goldberg J, Erickson T, Buchwald D. A twin study of cognitive function in chronic fatigue syndrome: the effects of sudden illness onset. Neuropsychology. 2007 Jul; 21(4): 507-513. PMID: 17605583. doi: 10.1037/0894-4105.21.4.507.

100. Katz BZ, Shiraishi Y, Mears CJ, Binns HJ, Taylor R. Chronic fatigue syndrome after infectious mononucleosis in adolescents. Pediatrics. 2009 Jul; 124(1): 189-193. PMID: 19564299. doi: 10.1542/peds.2008-1879.

101. Kerr JR, Bracewell J, Laing I, Mattey DL, Bernstein RM, Bruce IN, et al. Chronic fatigue syndrome and arthralgia following parvovirus B19 infection. J Rheumatol. 2002 Mar; 29(3): 595-602. PMID: 11911112.

102. Hickie I, Davenport T, Wakefield D, Vollmer-Conna U, Cameron B, Vernon SD, et al. Post-infective and chronic fatigue syndromes precipitated by viral and non-viral pathogens: prospective cohort study. BMJ. 2006 Sep 16; 333(7568): 575. PMID: 16950834. doi: 10.1136/bmj.38933.585764.AE.

103. Jason LA, Katz BZ, Shiraishi Y, Mears CJ, Im Y, Taylor RA. Predictors of post-infectious chronic fatigue syndrome in adolescents. Health Psychol Behav Med. 2014 Jan 1; 2(1): 41-51. PMID: 24660116. doi: 10.1080/21642850.2013.869176.

104. Watt T, Oberfoell S, Balise R, Lunn MR, Kar AK, Merrihew L, et al. Response to valganciclovir in chronic fatigue syndrome patients with human herpesvirus 6 and Epstein-Barr virus IgG antibody titers. J Med Virol. 2012 Dec; 84(12): 1967-1974. PMID: 23080504. doi: 10.1002/jmv.23411.

105. Lerner AM, Ariza ME, Williams M, Jason L, Beqaj S, Fitzgerald JT, et al. Antibody to Epstein-Barr virus deoxyuridine triphosphate nucleotidohydrolase and deoxyribonucleotide polymerase in a chronic fatigue syndrome subset. PLoS One. 2012; 7(11): e47891. PMID: 23155374. doi: 10.1371/journal.pone.0047891.

106. Sairenji T, Yamanishi K, Tachibana Y, Bertoni G, Kurata T. Antibody responses to Epstein-Barr virus, human herpesvirus 6 and human herpesvirus 7 in patients with chronic fatigue syndrome. Intervirology. 1995; 38(5): 269-273. PMID: 8724857. doi: 10.1159/000150450.

107. Beqaj SH, Lerner AM, Fitzgerald JT. Immunoassay with cytomegalovirus early antigens from gene products p52 and CM2 (UL44 and UL57) detects active infection in patients with chronic fatigue syndrome. J Clin Pathol. 2008 May; 61(5): 623-626. PMID: 18037660. doi:10.1136/jcp.2007.050633.

108. Levine S. Prevalence in the cerebrospinal fluid of the following infectious agents in a cohort of 12 CFS subjects: Human Herpes Virus-6 and 8; Chlamydia species; Mycoplasma species; EBV; CMV; and Coxsackievirus. J Chronic Fatigue Syndr. 2001; 9(1): 41. doi: 10.1300/J092v09n01_05.

109. Ablashi DV, Eastman HB, Owen CB, Roman MM, Friedman J, Zabriskie JB, et al. Frequent HHV-6 reactivation in multiple sclerosis (MS) and chronic fatigue syndrome (CFS) patients. J Clin Virol. 2000 May; 16(3): 179-191. PMID: 10738137. doi: 10.1016/S1386-6532(99)00079-7.

110. Patnaik M, Komaroff AL, Conley E, Ojo-Amaize EA, Peter JB. Prevalence of IgM antibodies to human herpesvirus 6 early antigen (p41/38) in patients with chronic fatigue syndrome. J Infect Dis. 1995 Nov; 172(5): 1364-1367. PMID: 7594679. doi: 10.1093/infdis/172.5.1364.

111. Chapenko S, Krumina A, Logina I, Rasa S, Chistjakovs M, Sultanova A, et al. Association of active human herpesvirus-6, -7 and parvovirus B19 infection with clinical outcomes in patients with myalgic encephalomyelitis/chronic fatigue syndrome. Adv Virol. 2012; 2012: 205085. PMID: 22927850. doi: 10.1155/2012/205085.

112. Berneman ZN, Ablashi DV, Li G, Eger-Fletcher M, Reitz MSJ, Hung CL, et al. Human herpesvirus 7 is a T-lymphotropic virus and is related to, but significantly different from, human herpesvirus 6 and human cytomegalovirus. Proc Natl Acad Sci U S A. 1992 Nov 1; 89(21): 10552-10556. PMID: 1332051. doi: 10.1073/pnas.89.21.10552.

113. Yousef GE, Bell EJ, Mann GF, Murugesan V, Smith DG, McCartney RA, et al. Chronic enterovirus infection in patients with postviral fatigue syndrome. Lancet. 1988 Jan 23; 1(8578): 146-150. PMID: 2892990. doi: 10.1016/S0140-6736(88)92722-5.

114. Bowles NE, Bayston TA, Zhang HY, Doyle D, Lane RJ, Cunningham L, et al. Persistence of enterovirus RNA in muscle biopsy samples suggests that some cases of chronic fatigue syndrome result from a previous, inflammatory viral myopathy. J Med. 1993; 24(2-3): 145-160. PMID: 8409778.

115. Chia JK, Chia AY. Chronic fatigue syndrome is associated with chronic enterovirus infection of the stomach. J Clin Pathol. 2008; 61: 43-48. PMID: 17872383. doi: 10.1136/jcp.2007.050054.

116. Jacobson SK, Daly JS, Thorne GM, McIntosh K. Chronic parvovirus B19 infection resulting in chronic fatigue syndrome: case history and review. Clin Infect Dis. 1997 Jun; 24(6): 1048-1051. PMID: 9195056. doi: 10.1086/513627.

117. Kerr JR, Gough J, Richards SC, Main J, Enlander D, McCreary M, et al. Antibody to parvovirus B19 nonstructural protein is associated with chronic arthralgia in patients with chronic fatigue syndrome/myalgic encephalomyelitis. J Gen Virol. 2010 Apr; 91(Pt 4): 893-897. PMID: 20007355. doi: 10.1099/vir.0.017590-0.

118. Frmont M, Metzger K, Rady H, Hulstaert J, de Meirleir K. Detection of herpesviruses and parvovirus B19 in gastric and intestinal mucosa of chronic fatigue syndrome patients. In Vivo. 2009 Mar-Apr; 23(2): 209-213. PMID: 19414405.

119. Zhang L, Xu MM, Zeng L, Liu S, Liu X, Wang X, et al. Evidence for Borna disease virus infection in neuropsychiatric patients in three western China provinces. Eur J Clin Microbiol Infect Dis. 2014 Apr; 33(4): 621-627. PMID: 24170181. doi: 10.1007/s10096-013-1996-4.

120. Kitani T, Kuratsune H, Fuke I, Nakamura Y, Nakaya T, Asahi S, et al. Possible correlation between Borna disease virus infection and Japanese patients with chronic fatigue syndrome. Microbiol Immunol. 1996; 40(6): 459-462. PMID: 8839433. doi: 10.1111/j.1348-0421.1996.tb01094.x.

121. Nakaya T, Takahashi H, Nakamura Y, Asahi S, Tobiume M, Kuratsune H, et al. Demonstration of Borna disease virus RNA in peripheral blood mononuclear cells derived from Japanese patients with chronic fatigue syndrome. FEBS Lett. 1996 Jan 8; 378(2): 145-149. PMID: 8549821. doi: 10.1016/0014-5793(95)01439-X.

122. Kato K, Arashima Y, Asai S, Furuya Y, Yoshida Y, Murakami M, et al. Detection of Coxiella burnetii specific DNA in blood samples from Japanese patients with chronic nonspecific symptoms by nested polymerase chain reaction. FEMS Immunol Med Microbiol. 1998 Jun; 21(2): 139-144. PMID: 9685003. doi: 10.1111/j.1574-695X.1998.tb01159.x.

123. Harris RJ, Storm PA, Lloyd A, Arens M, Marmion BP. Long-term persistence of Coxiella burnetii in the host after primary Q fever. Epidemiol Infect. 2000 Jun; 124(3): 543-549. PMID: 10982079. doi: 10.1017/S0950268899003763.

124. Marmion BP, Sukocheva O, Storm PA, Lockhart M, Turra M, Kok T, et al. Q fever: persistence of antigenic non-viable cell residues of Coxiella burnetii in the host - implications for post Q fever infection fatigue syndrome and other chronic sequelae. QJM. 2009 Oct; 102(10): 673-684. PMID: 19556396. doi: 10.1093/qjmed/hcp077.

125. Treib J, Grauer MT, Haass A, Langenbach J, Holzer G, Woessner R. Chronic fatigue syndrome in patients with Lyme borreliosis. Eur Neurol. 2000; 43(2): 107-109. PMID: 10686469. doi: 10.1159/000008144.

126. Nicolson GL, Nicolson NL, Haier J. Chronic fatigue syndrome patients subsequently diagnosed with Lyme disease Borrelia burgdorferi: evidence for Mycoplasma species coinfections. J Chronic Fatigue Syndr. 2008; 14(4): 5-17. doi: 10.1080/10573320802091809.

127. Vojdani A, Choppa PC, Tagle C, Andrin R, Samimi B, Lapp CW. Detection of mycoplasma genus and mycoplasma fermentans by PCR in patients with chronic fatigue syndrome. FEMS Immunol Med Microbiol. 1998 Dec; 22(4): 355-365. PMID: 9879928. doi: 10.1111/j.1574-695X.1998.tb01226.x.

128. Nasralla M, Haier J, Nicolson GL. Multiple mycoplasmal infections detected in blood of patients with chronic fatigue syndrome and/or fibromyalgia syndrome. Eur J Clin Microbiol Infect Dis. 1999 Dec; 18(12): 859-865. PMID: 10691196. doi: 10.1007/s100960050420.

129. Nijs J, Nicolson GL, de Becker P, Coomans D, de Meirleir K. 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. 2002 Nov 15; 34(3): 209-214. PMID: 12423773. doi: 10.1111/j.1574-695X.2002.tb00626.x.

130. Lakhan SE, Kirchgessner A. Gut inflammation in chronic fatigue syndrome. Nutr Metab (Lond). 2010 Oct 12; 7: 79. PMID: 20939923. doi: 10.1186/1743-7075-7-79.

131. Borody TJ, Nowak A, Torres M, Campbell J, Finlayson S, Leis S, et al. Bacteriotherapy in chronic fatigue syndrome: a retrospective review. Am J Gastroenterol. 2012; 107(Suppl 1): S591CS592. PMID: 23074713. doi:10.1038/ajg.2012.275.

132. Klimas NG, Koneru AO. Chronic fatigue syndrome: inflammation, immune function, and neuroendocrine interactions. Curr Rheumatol Rep. 2007 Dec; 9(6): 482-487. PMID: 18177602. doi: 10.1007/s11926-007-0078-y.

133. Maes M, Mihaylova I, Bosmans E. Not in the mind of neurasthenic lazybones but in the cell nucleus: patients with chronic fatigue syndrome have increased production of nuclear factor kappa beta. Neuro Endocrinol Lett. 2007; 28(4): 456-462. PMID: 17693979.

134. Torres-Harding S, Sorenson M, Jason LA, Maher K, Fletcher MA. Evidence for T-helper 2 shift and association with illness parameters in chronic fatigue syndrome (CFS). Bull IACFS ME. 2008 Fall;16(3):19-33. PMID: 21234277.

135. Skowera A, Cleare A, Blair D, Bevis L, Wessely SC, Peakman M. High levels of type 2 cytokine-producing cells in chronic fatigue syndrome. Clin Exp Immunol. 2004 Feb; 135(2): 294-302. PMID: 14738459. doi: 10.1111/j.1365-2249.2004.02354.x.

136. Khaiboullina SF, De Meirleir KL, Rawat S, Berk GS, Gaynor-Berk RS, Mijatovic T, et al. Cytokine expression provides clues to the pathophysiology of Gulf War illness and myalgic encephalomyelitis. Cytokine. 2014 Dec 13; 72(1): 1-8. PMID: 25514671. doi: 10.1016/j.cyto.2014.11.019.

137. Brenu EW, Huth TK, Hardcastle SL, Fuller K, Kaur M, Johnston S, et al. The role of adaptive and innate immune cells in chronic fatigue syndrome/Myalgic Encephalomyelitis. Int Immunol. 2014 Apr; 26(4): 233-242. PMID: 24343819. doi: 10.1093/intimm/dxt068.

138. Brenu EW, van Driel ML, Staines DR, Ashton KJ, Hardcastle SL, Keane J, et al. Longitudinal investigation of natural killer cells and cytokines in chronic fatigue syndrome/Myalgic Encephalomyelitis. J Transl Med. 2012 May 9; 10: 88. PMID: 22571715. doi: 10.1186/1479-5876-10-88.

139. Lorusso L, Mikhaylova SV, Capelli E, Ferrari D, Ngonga GK, Ricevuti G. Immunological aspects of chronic fatigue syndrome. Autoimmun Rev. 2009; 8(4): 287-291. PMID: 18801465. doi: 10.1016/j.autrev.2008.08.003.

140. Patarca R. Cytokines and chronic fatigue syndrome. Ann N Y Acad Sci. 2001 Mar; 933: 185-200. PMID: 12000020. doi: 10.1111/j.1749-6632.2001.tb05824.x.

141. Read R, Spickett G, Harvey J, Edwards AJ, Larson HE. IgG1 subclass deficiency in patients with chronic fatigue syndrome. Lancet. 1988 Jan 30; 1(8579): 241-242. PMID: 2893063. doi: 10.1016/S0140-6736(88)91091-4.

142. Lloyd AR, Wakefield D, Boughton CR, Dwyer JM. Immunological abnormalities in the chronic fatigue syndrome. Med J Aust. 1989 Aug 7; 151(3): 122-124. PMID: 2787888.

143. Visser JT, de Kloet ER, Nagelkerken L. Altered glucocorticoid regulation of the immune response in the chronic fatigue syndrome. Ann N Y Acad Sci. 2000; 917: 868-875. PMID: 11268418. doi: 10.1111/j.1749-6632.2000.tb05453.x.

144. Visser J, Lentjes E, Haspels I, Graffelman W, Blauw B, de Kloet R, et al. Increased sensitivity to glucocorticoids in peripheral blood mononuclear cells of chronic fatigue syndrome patients, without evidence for altered density or affinity of glucocorticoid receptors. J Investig Med. 2001 Mar; 49(2): 195-204. PMID: 11288761. doi: 10.2310/6650.2001.34047.

145. Suhadolnik RJ, Lombardi V, Peterson DL, Welsch S, Cheney PR, Furr EG, et al. Biochemical dysregulation of the 2-5A synthetase/RNase L antiviral defense pathway in chronic fatigue syndrome. J Chronic Fatigue Syndr. 1999; 5(3): 223-242. doi: 10.1300/J092v05n03_19.

146. Nijs J, de Meirleir K. Impairments of the 2-5A synthetase / RNase L pathway in chronic fatigue syndrome. In Vivo. 2005; 19(6): 1013-1021. PMID: 16277015.

147. Fulle S, Mecocci P, Fan G, Vecchiet I, Vecchini A, Racciotti D, et al. Specific oxidative alterations in vastus lateralis muscle of patients with the diagnosis of chronic fatigue syndrome. Free Radic Biol Med. 2000; 29(12): 1252-1259. PMID: 11118815. doi: 10.1016/S0891-5849(00)00419-6.

148. Maes M, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. Increased plasma peroxides as a marker of oxidative stress in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Med Sci Monit. 2011 Apr; 17(4): SC11-SC15. PMID: 21455120. doi: 10.12659/MSM.881699.

149. Maes M, Mihaylova I, Kubera M, Uytterhoeven M, Vrydags N, Bosmans E. Increased 8-hydroxy-deoxyguanosine, a marker of oxidative damage to DNA, in major depression and myalgic encephalomyelitis/chronic fatigue syndrome. Neuro Endocrinol Lett. 2009; 30(6): 715-722. PMID: 20035260.

150. Jammes Y, Steinberg JG, Delliaux S. 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. J Intern Med. 2012 Jul; 272(1): 74-84. PMID: 22112145. doi: 10.1111/j.1365-2796.2011.02488.x.

151. Heap LC, Peters TJ, Wessely S. Vitamin B status in patients with chronic fatigue syndrome. J R Soc Med. 1999 Apr; 92(4): 183-185. PMID: 10450194.

152. Berkovitz S, Ambler G, Jenkins M, Thurgood S. Serum 25-hydroxy vitamin D levels in chronic fatigue syndrome: a retrospective survey. Int J Vitam Nutr Res. 2009 Jul; 79(4): 250-254. PMID: 20209476. doi: 10.1024/0300-9831.79.4.250.

153. Richards RS, Roberts TK, Dunstan RH, McGregor NR, Butt HL. Free radicals in chronic fatigue syndrome: cause or effect? Redox Rep. 2000; 5(2-3): 146-147. PMID: 10939298. doi: 10.1179/135100000101535519.

154. Maes M, Mihaylova I, De Ruyter M. Lower serum zinc in Chronic Fatigue Syndrome (CFS): relationships to immune dysfunctions and relevance for the oxidative stress status in CFS. J Affect Disord. 2006 Feb; 90(2-3): 141-147. PMID: 16338007. doi: 10.1016/j.jad.2005.11.002.

155. Vecchiet L, Montanari G, Pizzigallo E, Iezzi S, de Bigontina P, Dragani L, et al. Sensory characterization of somatic parietal tissues in humans with chronic fatigue syndrome. Neurosci Lett. 1996 Apr 19; 208(2): 117-120. PMID: 8859904. doi: 10.1016/0304-3940(96)12559-3.

156. Armstrong CW, McGregor NR, Butt HL, Gooley PR. Metabolism in chronic fatigue syndrome. Adv Clin Chem. 2014; 66: 121-172. PMID: 25344988. doi: 10.1016/B978-0-12-801401-1.00005-0.

157. Tirelli U, Chierichetti F, Tavio M, Simonelli C, Bianchin G, Zanco P, et al. Brain positron emission tomography (PET) in chronic fatigue syndrome: preliminary data. Am J Med. 1998 Sep 28; 105(3A): 54S-58S. PMID: 9790483. doi: 10.1016/S0002-9343(98)00179-X.

158. Vermeulen RC, Vermeulen-van Eck IW. Decreased oxygen extraction during cardiopulmonary exercise test in patients with chronic fatigue syndrome. J Transl Med. 2014 Jan 23; 12(1): 20. PMID: 24456560. doi: 10.1186/1479-5876-12-20.

159. Miwa K, Fujita M. Small heart syndrome in patients with chronic fatigue syndrome. Clin Cardiol. 2008 Jul; 31(7): 328-333. PMID: 18636530. doi: 10.1002/clc.20227.

160. Miwa K, Fujita M. Cardiovascular dysfunction with low cardiac output due to a small heart in patients with chronic fatigue syndrome. Intern Med. 2009; 48(21): 1849-1854. PMID: 19881233. doi: 10.2169/internalmedicine.48.2347.

161. De Becker P, Roeykens J, Reynders M, McGregor N, de Meirleir K. Exercise capacity in chronic fatigue syndrome. Arch Intern Med. 2000 Nov 27; 160(21): 3270-3277. PMID: 11088089. doi: 10.1001/archinte.160.21.3270.

162. Hollingsworth KG, Jones DE, Taylor R, Blamire AM, Newton JL. Impaired cardiovascular response to standing in chronic fatigue syndrome. Eur J Clin Invest. 2010 Jul; 40(7): 608-615. PMID: 20497461. doi: 10.1111/j.1365-2362.2010.02310.x.

163. Stewart JM, Gewitz MH, Weldon A, Arlievsky N, Li K, Munoz J. Orthostatic intolerance in adolescent chronic fatigue syndrome. Pediatrics. 1999 Jan; 103(1): 116-121. PMID: 9917448. doi: 10.1542/peds.103.1.116.

164. Stewart JM, Medow MS, Messer ZR, Baugham IL, Terilli C, Ocon AJ. Postural neurocognitive and neuronal activated cerebral blood flow deficits in young chronic fatigue syndrome patients with postural tachycardia syndrome. Am J Physiol Heart Circ Physiol. 2012 Mar 1; 302(5): H1185-H1194. PMID: 22180650. doi: 10.1152/ajpheart.00994.2011.

165. Lewis I, Pairman J, Spickett G, L NJ. Clinical characteristics of a novel subgroup of chronic fatigue syndrome patients with postural orthostatic tachycardia syndrome. J Intern Med. 2013 May; 273(5): 501-510. PMID: 23206180. doi: 10.1111/joim.12022.

166. Frith J, Zalewski P, Klawe JJ, Pairman J, Bitner A, Tafil-Klawe M, et al. Impaired blood pressure variability in chronic fatigue syndrome - a potential biomarker. QJM. 2012 Sep; 105(9): 831-818. PMID: 22670061. doi: 10.1093/qjmed/hcs085.

167. Okada T, Tanaka M, Kuratsune H, Watanabe Y, Sadato N. Mechanisms underlying fatigue: a voxel-based morphometric study of chronic fatigue syndrome. BMC Neurol. 2004 Oct 4; 4(1): 14. PMID: 15461817. doi: 10.1186/1471-2377-4-14.

168. Barnden LR, Crouch B, Kwiatek R, Burnet R, Mernone A, Chryssidis S, et al. A brain MRI study of chronic fatigue syndrome: evidence of brainstem dysfunction and altered homeostasis. NMR Biomed. 2011 Dec; 24(10): 1302-1312. PMID: 21560176. doi: 10.1002/nbm.1692.

169. Ichise M, Salit IE, Abbey SE, Chung DG, Gray B, Kirsh JC, et al. Assessment of regional cerebral perfusion by 99Tcm-HMPAO SPECT in chronic fatigue syndrome. Nucl Med Commun. 1992 Oct; 13(10): 767-772. PMID: 1491843. doi: 10.1097/00006231-199210000-00011.

170. Costa DC, Tannock C, Brostoff J. Brainstem perfusion is impaired in chronic fatigue syndrome. QJM. 1995 Nov; 88(11): 767-773. PMID: 8542261.

171. Siessmeier T, Nix WA, Hardt J, Schreckenberger M, Egle UT, Bartenstein P. Observer independent analysis of cerebral glucose metabolism in patients with chronic fatigue syndrome. J Neurol Neurosurg Psychiatry. 2003 Jul; 74(7): 922-928. PMID: 12810781. doi: 10.1136/jnnp.74.7.922.

172. Schwartz RB, Komaroff AL, Garada BM, Gleit M, Doolittle TH, Bates DW, et al. SPECT imaging of the brain: comparison of findings in patients with chronic fatigue syndrome, AIDS dementia complex, and major unipolar depression. AJR Am J Roentgenol. 1994; 162(4): 943-951. PMID: 8141022.

173. Schwartz RB, Garada BM, Komaroff AL, Tice HM, Gleit M, Jolesz FA, et al. Detection of intracranial abnormalities in patients with chronic fatigue syndrome: comparison of MR imaging and SPECT. AJR Am J Roentgenol. 1994 Apr; 162(4): 935-941. PMID: 8141020. doi: 10.2214/ajr.162.4.8141020.

174. Nakatomi Y, Mizuno K, Ishii A, Wada Y, Tanaka M, Tazawa S, et al. Neuroinflammation in patients with chronic fatigue syndrome/Myalgic Encephalomyelitis: an 11C-(R)-PK11195 PET study. J Nucl Med. 2014 Mar 24; 55(6): 945-950. PMID: 24665088. doi: 10.2967/jnumed.113.131045.

175. Natelson BH, Weaver SA, Tseng CL, Ottenweller JE. Spinal fluid abnormalities in patients with chronic fatigue syndrome. Clin Diagn Lab Immunol. 2005 Jan; 12(1): 52-55. PMID: 15642984. doi: 10.1128/CDLI.12.1.52-55.2005.

176. Lloyd A, Hickie I, Brockman A, Dwyer J, Wakefield D. Cytokine levels in serum and cerebrospinal fluid in patients with chronic fatigue syndrome and control subjects. J Infect Dis. 1991 Nov; 164(5): 1023-1024. PMID: 1940455. doi: 10.1093/infdis/164.5.1023.

177. Tomas C, Newton J, Watson S. A review of hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. ISRN Neurosci. 2013; 2013: 784520: PMID: 24959566. doi: 10.1155/2013/784520.

178. Powell DJ, Liossi C, Moss-Morris R, Schlotz W. Unstimulated cortisol secretory activity in everyday life and its relationship with fatigue and chronic fatigue syndrome: a systematic review and subset meta-analysis. Psychoneuroendocrinology. 2013 Nov; 38(11): 2405-2422. PMID: 23916911. doi: 10.1016/j.psyneuen.2013.07.004.

179. Nater UM, Youngblood LS, Jones JF, Unger ER, Miller AH, Reeves WC, et al. Alterations in diurnal salivary cortisol rhythm in a population-based sample of cases with chronic fatigue syndrome. 2008 Apr; 70(3): 298-305. PMID: 18378875. doi: 10.1097/PSY.0b013e3181651025.

180. Scott LV, Medbak S, Dinan TG. The low dose ACTH test in chronic fatigue syndrome and in health. Clin Endocrinol (Oxf). 1998 Jun; 48(6): 733-737. PMID: 9713562. doi: 10.1046/j.1365-2265.1998.00418.x.

181. Gaab J, Hster D, Peisen R, Engert V, Heitz V, Schad T, et al. Hypothalamic-pituitary-adrenal axis reactivity in chronic fatigue syndrome and health under psychological, physiological, and pharmacological stimulation. Psychosom Med. 2002 Nov-Dec; 64(6): 951-962. PMID: 12461200. doi: 10.1097/01.PSY.0000038937.67401.61.

182. Strahler J, Fischer S, Nater UM, Ehlert U, Gaab J. Norepinephrine and epinephrine responses to physiological and pharmacological stimulation in chronic fatigue syndrome. Biol Psychol. 2013 Jun 13; 94(1): 160-166. PMID: 23770415. doi: 10.1016/j.biopsycho.2013.06.002.

183. Jerjes WK, Taylor NF, Wood PJ, Cleare AJ. Enhanced feedback sensitivity to prednisolone in chronic fatigue syndrome. Psychoneuroendocrinology. 2007 Feb; 32(2): 192-198. PMID: 17276605. doi: 10.1016/j.psyneuen.2006.12.005.

184. Van den Eede F, Moorkens G, van Houdenhove B, Cosyns P, Claes SJ. Hypothalamic-pituitary-adrenal axis function in chronic fatigue syndrome. Neuropsychobiology. 2007; 55(2): 112-120. PMID: 17596739. doi: 10.1159/000104468.

185. Keller BA, Pryor JL, Giloteaux L. Inability of myalgic encephalomyelitis/chronic fatigue syndrome patients to reproduce VO2peak indicates functional impairment. J Transl Med. 2014 Apr 23; 12: 104. PMID: 24755065. doi: 10.1186/1479-5876-12-104.

186. VanNess JM, Snell CR, Stevens SR, Stiles TL. Metabolic and neurocognitive responses to an exercise challenge in chronic fatigue syndrome (CFS). Med Sci Sports Exerc. 2007 May; 39(5 Suppl): S445. doi: 10.1249/01.mss.0000274760.28522.df.

187. Surez A, Guillamo E, Roig T, Blzquez A, Alegre J, Bermdez J, et al. Nitric oxide metabolite production during exercise in chronic fatigue syndrome: a case-control study. J Womens Health (Larchmt). 2010 Jun; 19(6): 1073-1077. PMID: 20469961. doi: 10.1089/jwh.2008.1255.

188. White AT, Light AR, Hughen RW, Bateman L, Martins TB, Hill HR, et al. Severity of symptom flare after moderate exercise is linked to cytokine activity in chronic fatigue syndrome. Psychophysiology. 2010 Jul; 47(4): 615-624. PMID: 20230500. doi: 10.1111/j.1469-8986.2010.00978.x.

189. Nijs J, Nees A, Paul L, De Kooning M, Ickmans K, Meeus M, et al. Altered immune response to exercise in patients with chronic fatigue syndrome/myalgic encephalomyelitis: a systematic literature review. Exerc Immunol Rev. 2014; 20: 94-116. PMID: 24974723.

190. Sukocheva OA, Marmion BP, Storm PA, Lockhart M, Turra M, S G. Long-term persistence after acute Q fever of non-infective Coxiella burnetii cell components, including antigens. QJM. 2010 Nov; 103(11): 847-863. PMID: 20639288. doi: 10.1093/qjmed/hcq113.

191. Loebel M, Strohschein K, Giannini C, Koelsch U, Bauer S, Doebis C, et al. Deficient EBV-specific B- and T-cell response in patients with chronic fatigue syndrome. PLoS ONE. 2014 Jan 15; 9(1): e85387. PMID: 24454857. doi: 10.1371/journal.pone.0085387.

192. Kondo K, Yamanishi K. HHV-6A, 6B, and 7: molecular basis of latency and reactivation. In Arvin A, Campadelli-Fiume G, Mocarski E, Moore PS, Roizman B, Whitley R, et al., editors. Human Herpesviruses: Biology, therapy, and immunoprophylaxis. Cambridge: Cambridge University Press; 2007. p. 843-849. PMID: 21348064. doi: 10.1017/CBO9780511545313.048.

193. Buchwald D, Cheney PR, Peterson DL, Henry B, Wormsley SB, Geiger A, et al. A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection. Ann Intern Med. 1992 Jan 15; 116(2): 103-113. PMID: 1309285. doi: 10.7326/0003-4819-116-2-103.

194. Cameron B, Flamand L, Juwana H, Middeldorp J, Naing Z, Rawlinson W, et al. Serological and virological investigation of the role of the herpesviruses EBV, CMV and HHV-6 in post-infective fatigue syndrome. J Med Virol. 2010 Oct; 82(10): 1684-1688. PMID: 20827765. doi: 10.1002/jmv.21873.

195. Brander C, Walker BD. Modulation of host immune responses by clinically relevant human DNA and RNA viruses. Curr Opin Microbiol. 2000 Aug; 3(4): 379-386. PMID: 10972498. doi: 10.1016/S1369-5274(00)00108-9.

196. Hornef MW, Wick MJ, Rhen M, Normark S. Bacterial strategies for overcoming host innate and adaptive immune responses. Nat Immunol. 2002 Nov; 3(11): 1033-1040. PMID: 12407412. doi: 10.1038/ni1102-1033.

197. Banks WA. The blood-brain barrier: connecting the gut and the brain. Regul Pept. 2008 Aug 7; 149(1-3): 11-14. PMID: 18486244. doi: 10.1016/j.regpep.2007.08.027.

198. Maes M, Mihaylova I, Kubera M, Leunis JC, Twisk FNM, Geffard M. IgM-mediated autoimmune responses directed against anchorage epitopes are greater in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) than in major depression. Metab Brain Dis. 2012 Dec; 27(4): 415-423. PMID: 22614823. doi: 10.1007/s11011-012-9316-8.

199. Maes M, Mihaylova I, Kubera M, Leunis JC. An IgM-mediated immune response directed against nitro-bovine serum albumin (nitro-BSA) in chronic fatigue syndrome (CFS) and major depression: evidence that nitrosative stress is another factor underpinning the comorbidity between major depression and CF. Neuro Endocrinol Lett. 2008 Jun; 29(3): 313-319. PMID: 18580855.

200. Klein R, Berg PA. High incidence of antibodies to 5-hydroxytryptamine, gangliosides and phospholipids in patients with chronic fatigue and fibromyalgia syndrome and their relatives: evidence for a clinical entity of both disorders. Eur J Med Res. 1995 Oct 16; 1(1): 21-26. PMID: 9392689.

201. Maes M, Ringel K, Kubera M, Anderson G, Morris G, Galecki P, et al. In myalgic encephalomyelitis/chronic fatigue syndrome, increased autoimmune activity against 5-HT is associated with immuno-inflammatory pathways and bacterial translocation. J Affect Disord. 2013 Sep 5; 150(2): 223-230. PMID: 23664637. doi: 10.1016/j.jad.2013.03.029.

202. Hokama Y, Campora CE, Hara C, Kuribayashi T, Le Huynh D, Yabusaki K. Anticardiolipin antibodies in the sera of patients with diagnosed chronic fatigue syndrome. J Clin Lab Anal. 2009; 23(4): 210-212. PMID: 19623655. doi: 10.1002/jcla.20325.

203. Hokama Y, Empey-Campora C, Hara C, Higa N, Siu N, Lau R, et al. Acute phase phospholipids related to the cardiolipin of mitochondria in the sera of patients with chronic fatigue syndrome (CFS), chronic Ciguatera fish poisoning (CCFP), and other diseases attributed to chemicals, Gulf War, and marine toxins. J Clin Lab Anal. 2008; 22(2): 99-105. PMID: 18348309. doi: 10.1002/jcla.20217.

204. Tanaka S, Kuratsune H, Hidaka Y, Hakariya Y, Tatsumi KI, Takano T, et al. Autoantibodies against muscarinic cholinergic receptor in chronic fatigue syndrome. Int J Mol Med. 2003 Aug; 12(2): 225-230. PMID: 12851722. doi: 10.3892/ijmm.12.2.225.

205. Vernon SD, Reeves WC. Evaluation of autoantibodies to common and neuronal cell antigens in chronic fatigue syndrome. J Autoimmune Dis. 2005 May 25; 2: 5. PMID: 15916704. doi: 10.1186/1740-2557-2-5.

206. Liu SF, Malik AB. NF-kappa B activation as a pathological mechanism of septic shock and inflammation. Am J Physiol Lung Cell Mol Physiol. 2006 Apr; 290(4): L622-L645. PMID: 16531564. doi: 10.1152/ajplung.00477.2005.

207. Conner EM, Grisham MB. Inflammation, free radicals, and antioxidants. Nutrition. 1996 Apr; 12(4): 274-277. PMID: 8862535. doi: 10.1016/S0899-9007(96)00000-8.

208. Christman JW, Blackwell TS, Juurlink BH. Redox regulation of nuclear factor kappa B: therapeutic potential for attenuating inflammatory responses. Brain Pathol. 2000; 10(1): 153-162. PMID: 10668905. doi: 10.1111/j.1750-3639.2000.tb00252.x.

209. Gloire G, Legrand-Poels S, Piette J. NF-kappaB activation by reactive oxygen species: fifteen years later. Biochem Pharmacol. 2006 Nov 30; 72(11): 1493-1505. PMID: 16723122. doi: 10.1016/j.bcp.2006.04.011.

210. Guzik TJ, Korbut R, Adamek-Guzik T. Nitric oxide and superoxide in inflammation and immune regulation. J Physiol Pharmacol. 2003 Dec; 54(4): 469-487. PMID: 14726604.

211. Bogdan C, Röllinghoff M, Diefenbach A. Reactive oxygen and reactive nitrogen intermediates in innate and specific immunity. Curr Opin Immunol. 2000 Feb; 12(1): 64-76. PMID: 10679404. doi: 10.1016/S0952-7915(99)00052-7.

212. Zheng MZ, Pan HD, Pan JX, Guo JX. Monocyte-induced NK cell inactivation: role of reactive oxygen and nitrogen metabolites. Immunopharmacol Immunotoxicol. 2011 Mar; 33(1): 150-156. PMID: 20515294. doi: 10.3109/08923973.2010.489051.

213. Zeng Y, Huang Q, Zheng M, Guo J, Pan J. Effects of reactive nitrogen scavengers on NK-cell-mediated killing of K562 cells. J Biomed Biotechnol. 2012 Feb 5; 2012: 101737. PMID: 22505802. doi: 10.1155/2012/101737.

214. Kono K, Salazar-Onfray F, Petersson M, Hansson J, Masucci G, Wasserman K, et al. Hydrogen peroxide secreted by tumor-derived macrophages down-modulates signal-transducing zeta molecules and inhibits tumor-specific T cell-and natural killer cell-mediated cytotoxicity. Eur J Immunol. 1996 Jun; 26(6): 1308-1313. PMID: 8647210. doi: 10.1002/eji.1830260620.

215. Ferlito M, Irani K, Faraday N, Lowenstein CJ. Nitric oxide inhibits exocytosis of cytolytic granules from lymphokine-activated killer cells. Proc Natl Acad Sci U S A. 2006 Aug 1; 103(31): 11689-11694. PMID: 16857739. doi: 10.1073/pnas.0600275103.

216. Hibbs JBJ, Taintor RR, Vavrin Z, Rachlin EM. Nitric oxide: a cytotoxic activated macrophage effector molecule. Biochem Biophys Res Commun. 1988 Nov 30; 157(1): 87-94. PMID: 3196352. doi: 10.1016/S0006-291X(88)80015-9.

217. Wink DA, Hines HB, Cheng RY, Switzer CH, Flores-Santana W, Vitek MP, et al. Nitric oxide and redox mechanisms in the immune response. J Leukoc Biol. 2011 Jun; 89(6): 873-891. PMID: 21233414. doi: 10.1189/jlb.1010550.

218. Niedbala W, Cai B, Liew FY. Role of nitric oxide in the regulation of T cell functions. Ann Rheum Dis. 2006 Nov; 65 Suppl 3: iii37-iii40. PMID: 17038470. doi: 10.1136/ard.2006.058446.

219. Van der Veen RC. Nitric oxide and T helper cell immunity. Int Immunopharmacol. 2000 Aug 1; 1(8): 1491-1500. PMID: 11515814. doi: 10.1016/S1567-5769(01)00093-5.

220. Pall ML. Common etiology of posttraumatic stress disorder, fibromyalgia, chronic fatigue syndrome and multiple chemical sensitivity via elevated nitric oxide/peroxynitrite. Med Hypotheses. 2001 Aug; 57(2): 139-145. PMID: 11461161. doi: 10.1054/mehy.2001.1325.

221. Bailey M, Engler H, Hunzeker J, Sheridan JF. The hypothalamic-pituitary-adrenal axis and viral infection. Viral Immunol. 2003; 16(2): 141-157. PMID: 12828866. doi: 10.1089/088282403322017884.

222. Parker AJ, Wessely S, Cleare AJ. The neuroendocrinology of chronic fatigue syndrome and fibromyalgia. Psychol Med. 2001 Nov; 31(8): 1331-1345. PMID: 11722149. doi: 10.1017/S0033291701004664.

223. Cleare AJ. The HPA axis and the genesis of chronic fatigue syndrome. Trends Endocrinol Metab. 2004 Mar; 15(2): 55-59. PMID: 15036250. doi: 10.1016/j.tem.2003.12.002.

224. Gaab J, Engert V, Heitz V, Schad T, Schrmeyer TH, Ehlert U. Associations between neuroendocrine responses to the insulin tolerance test and patient characteristics in chronic fatigue syndrome. J Psychosom Res. 2004 Apr; 56(4): 419-424. PMID: 15094026. doi: 10.1016/S0022-3999(03)00625-1.

225. Jäättelä M, Ilvesmäki V, Voutilainen R, Stenman UH, Saksela E. Tumor necrosis factor as a potent inhibitor of adrenocorticotropin-induced cortisol production and steroidogenic P450 enzyme gene expression in cultured human fetal adrenal cells. Endocrinology. 1991 Jan; 128(1): 623-629. PMID: 1702707. doi: 10.1210/endo-128-1-623.

226. Straub RH, Pongratz G, Cutolo M, Wijbrandts CA, Baeten D, Fleck M, et al. Increased cortisol relative to adrenocorticotropic hormone predicts improvement during anti-tumor necrosis factor therapy in rheumatoid arthritis. Arthritis Rheum. 2008 Apr; 58(4): 976-984. PMID: 18383357. doi: 10.1002/art.23385.

227. Zimmerman PA, J A Betz JA, Poth M. Nitric oxide: a potential modulator of adrenal hormone secretion. Pediatr Res. 1993 May; 33(S5): S21-S21. doi: 10.1203/00006450-199305001-00108.

228. Sweep CG, van der Meer MJ, Hermus AR, Smals AG, van der Meer JWM, Pesman GJ, et al. Chronic stimulation of the pituitary-adrenal axis in rats by interleukin-1 beta infusion: in vivo and in vitro studies. Endocrinology. 1992 Mar; 130(3): 1153-1164. PMID: 1311230. doi: 10.1210/en.130.3.1153.

229. Valls A, Mart O, Harbuz MS, Armario A. A single lipopolysaccharide administration is sufficient to induce a long-term desensitization of the hypothalamic-pituitary-adrenal axis. Neuroscience. 2002; 112(2): 383-389. PMID: 12044455. doi: 10.1016/S0306-4522(02)00047-7.

230. Beishuizen A, Thijs LG. Endotoxin and the hypothalamo-pituitary-adrenal (HPA) axis. J Endotoxin Res. 2003; 9(1): 3-24. PMID: 12691614. doi: 10.1179/096805103125001298.

231. Koldzic-Zivanovic N, Tu H, Juelich TL, Rady PL, Tyring SK, Hudnall SD, et al. Regulation of adrenal glucocorticoid synthesis by interleukin-10: a preponderance of IL-10 receptor in the adrenal zona fasciculata. Brain Behav Immun. 2006 Sep; 20(5): 460-468. PMID: 16256304. doi: 10.1016/j.bbi.2005.09.003.

232. McCubrey JA, Lahair MM, Franklin RA. Reactive oxygen species-induced activation of the MAP kinase signaling pathways. Antioxid Redox Signal. 2006 Sep-Oct; 8(9-10): 1775-1789. PMID: 16987031. doi: 10.1089/ars.2006.8.1775.

233. Abidi P, Zhang H, Zaidi SM, Shen WJ, Leers-Sucheta S, Cortez Y, et al. Oxidative stress-induced inhibition of adrenal steroidogenesis requires participation of p38 mitogen-activated protein kinase signaling pathway. J Endocrinol. 2008 Jul; 198(1): 193-207. PMID: 18417530. doi: 10.1677/JOE-07-0570.

234. Cymeryng CB, Lotito SP, Colonna C, Finkielstein C, Pomeraniec Y, Grin N, et al. Expression of nitric oxide synthases in rat adrenal zona fasciculata cells. Endocrinology. 2002 Apr; 143(4): 1235-1242. PMID: 11897679. doi: 10.1210/en.143.4.1235.

235. Drewett JG, Adams-Hays RL, Ho BY, Hegge DJ. Nitric oxide potently inhibits the rate-limiting enzymatic step in steroidogenesis. Mol Cell Endocrinol. 2002 Aug 30; 194(1-2): 39-50. PMID: 12242026. doi: 10.1016/S0303-7207(02)00214-9.

236. Radi R, Cassina A, Hodara R. Nitric oxide and peroxynitrite interactions with mitochondria. Biol Chem. 2002 Mar-Apr; 383(3-4): 401-409. PMID: 12033431. doi: 10.1515/BC.2002.044.

237. Richter C, Gogvadze V, Laffranchi R, Schlapbach R, Schweizer M, Suter M, et al. Oxidants in mitochondria: from physiology to diseases. Biochim Biophys Acta. 1995 May 24; 1271(1): 67-74. PMID: 7599228. doi: 10.1016/0925-4439(95)00012-S.

238. Brown GC. Nitric oxide and mitochondria. Front Biosci. 2007 Jan 1; 12: 1024-1033. PMID: 17127357. doi: 10.2741/2122.

239. Loscalzo J, Welch G. Nitric oxide and its role in the cardiovascular system. Prog Cardiovasc Dis. 1995 Sep-Oct; 38(3): 87-104. PMID: 7647603. doi: 10.1016/S0033-0620(05)80001-5.

240. Waldman SA, Murad F. Biochemical mechanisms underlying vascular smooth muscle relaxation: the guanylate cyclase-cyclic GMP system. J Cardiovasc Pharmacol. 1988; 12 Suppl 5: S115-S118. PMID: 2469867. doi: 10.1097/00005344-198800125-00020.

241. Förstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J. 2012 Apr; 33(7): 829-837. PMID: 21890489. doi: 10.1093/eurheartj/ehr304.

242. Nijs J, de Meirleir K, Meeus M, McGregor NR, Englebienne P. Chronic fatigue syndrome: intracellular immune deregulations as a possible etiology for abnormal exercise response. Med Hypotheses. 2004 May; 62(5): 759-765. PMID: 15082102. doi: 10.1016/j.mehy.2003.11.030.

243. Halliwill JR, Buck TM, Lacewell AN, Romero SA. Postexercise hypotension and sustained postexercise vasodilatation: what happens after we exercise? Exp Physiol. 2013 Jan; 98(1): 7-18. PMID: 22872658. doi: 10.1113/expphysiol.2011.058065.

244. Panas D, Khadour FH, Szab C, Schulz R. Proinflammatory cytokines depress cardiac efficiency by a nitric oxide-dependent mechanism. Am J Physiol. 1998 Sep; 275(3 Pt 2): H1016-H1023. PMID: 9724308.

245. Chowdhary S, Vaile JC, Fletcher J, Ross HF, Coote JH, Townend JN. Nitric oxide and cardiac autonomic control in humans. Hypertension. 2000 Aug; 36(2): 264-269. PMID: 10948088. doi: 10.1161/01.HYP.36.2.264.

246. Biesmans S, Meert TF, Bouwknecht JA, Acton PD, Davoodi N, De Haes P, et al. Systemic immune activation leads to neuroinflammation and sickness behavior in mice. Mediators Inflamm. 2013; 2013: 271359. PMID: 23935246. doi: 10.1155/2013/271359.

247. Capuron L, Miller AH. Immune system to brain signaling: neuropsychopharmacological implications. Pharmacol Ther. 2011 May; 130(2): 226-238. PMID: 21334376. doi: 10.1016/j.pharmthera.2011.01.014.

248. Raison CL, Miller AH. Do cytokines really sing the blues? Cerebrum. 2013 Jul-Aug; 2013: 10. eCollection 2013. PMID: 24116267.

249. Vollmer-Conna U, Lloyd A, Hickie I, Wakefield D. Chronic fatigue syndrome: an immunological perspective. Aust N Z J Psychiatry. 1998 Aug; 32(4): 523-527. PMID: 9711366. doi: 10.3109/00048679809068326.

250. Staines DR, Brenu EW, Marshall-Gradisnik S. Postulated vasoactive neuropeptide immunopathology affecting the blood-brain/blood-spinal barrier in certain neuropsychiatric fatigue-related conditions: A role for phosphodiesterase inhibitors in treatment? Neuropsychiatr Dis Treat. 2009; 5: 81-89. PMID: 19557103. doi: 10.2147/NDT.S4176.

251. Loggia ML, Chonde DB, Akeju O, Arabasz G, Catana C, Edwards RR, et al. Evidence for brain glial activation in chronic pain patients. Brain. 2015 Jan 12; pi: awu377. PMID: 25582579. doi: 10.1093/brain/awu377.

252. Lin Q, Palecek J, Paleckov V, Peng YB, Wu J, Cui M, et al. Nitric oxide mediates the central sensitization of primate spinothalamic tract neurons. J Neurophysiol. 1999 Mar; 81(3): 1075-1085. PMID: 10085334.

253. Watanabe C, Okuda K, Sakurada C, Ando R, Sakurada T, Sakurada S. Evidence that nitric oxide-glutamate cascade modulates spinal antinociceptive effect of morphine: a behavioural and microdialysis study in rats. Brain Res. 2003 Nov 14; 990(1-2): 77-86. PMID: 14568332. doi: 10.1016/S0006-8993(03)03440-1.

254. Kim HY, Wang J, Lu Y, Chung JM, Chung K. Superoxide signaling in pain is independent of nitric oxide signaling. Neuroreport. 2009 Oct 28; 20(16): 1424-1428. PMID: 19794317. doi: 10.1097/WNR.0b013e328330f68b.

255. Schwartz ES, Lee I, Chung K, Chung JM. Oxidative stress in the spinal cord is an important contributor in capsaicin-induced mechanical secondary hyperalgesia in mice. Pain. 2008 Sep 15; 138(3): 514-524. PMID: 18375065. doi: 10.1016/j.pain.2008.01.029.

256. Tanaka H, Matsushima R, Tamai H, Kajimoto Y. Impaired postural cerebral hemodynamics in young patients with chronic fatigue with and without orthostatic intolerance. J Pediatr. 2002 Apr; 140(4): 412-417. PMID: 12006954. doi: 10.1067/mpd.2002.122725.

257. Walsh NP, Gleeson M, Shephard RJ, Gleeson M, Woods JA, Bishop NC, et al. Position statement. Part one: Immune function and exercise. Exerc Immunol Rev. 2011; 17: 6-63.PMID: 21446352.

258. Walsh NP, Gleeson M, Pyne DB, Nieman DC, Dhabhar FS, Shephard RJ, et al. Position statement. Part two: Maintaining immune health. Exerc Immunol Rev. 2011; 17: 64-103. PMID: 21446353.

259. Ostrowski K, Rohde T, Asp S, Schjerling P, Pedersen BK. Pro- and anti-inflammatory cytokine balance in strenuous exercise in humans. J Physiol. 1999 Feb 15; 515(Pt 1): 287-291. PMID: 9925898. doi: 10.1111/j.1469-7793.1999.287ad.x.

260. Pedersen BK, Steensberg A, Fischer C, Keller C, Ostrowski K, Schjerling P. Exercise and cytokines with particular focus on muscle-derived IL-6. Exerc Immunol Rev. 2001; 7: 18-31. PMID: 11579746.

261. Cooper DM, Radom-Aizik S, Schwindt C, Zaldivar FJ. Dangerous exercise: lessons learned from dysregulated inflammatory responses to physical activity. J Appl Physiol. 2007 Aug; 103(2): 700-709. PMID: 17495117. doi: 10.1152/japplphysiol.00225.2007.

262. White PD, Nye KE, Pinching AJ, Yap TM, Power N, Vleck V, et al. Immunological changes after both exercise and activity in chronic fatigue syndrome: a pilot study. J Chronic Fatigue Syndr. 2004; 12(2): 51-66. doi: 10.1300/J092v12n02_06.

263. Elenkov IJ, Chrousos GP. Stress hormones, Th1/Th2 patterns, pro/anti-inflammatory cytokines and susceptibility to disease. Trends Endocrinol Metab. 1999 Nov; 10(9): 359-368. PMID: 10511695. doi: 10.1016/S1043-2760(99)00188-5.

264. Black PH, Garbutt LD. Stress, inflammation and cardiovascular disease. J Psychosom Res. 2002 Jan; 52(1): 1-23. PMID: 11801260. doi: 10.1016/S0022-3999(01)00302-6.

265. Pedersen BK, Toft AD. Effects of exercise on lymphocytes and cytokines. Br J Sports Med. 2000 Aug; 34(4): 246-251. PMID: 10953894. doi: 10.1136/bjsm.34.4.246.

266. Shephard RJ, Shek PN. Effects of exercise and training on natural killer cell counts and cytolytic activity: a meta-analysis. Sports Med. 1999 Sep; 28(3): 177-195. PMID: 10541441. doi: 10.2165/00007256-199928030-00003.

267. Suzuki K, Nakaji S, Kurakake S, Totsuka M, Sato K, Kuriyama T, et al. Exhaustive exercise and type-1/type-2 cytokine balance with special focus on interleukin-12 p40/p70. Exerc Immunol Rev. 2003; 9: 48-57. PMID: 14686094.

268. Steensberg A, Toft AD, Bruunsgaard H, Sandmand M, Halkjaer-Kristensen J, Pedersen BK. Strenuous exercise decreases the percentage of type 1 T cells in the circulation. J Appl Physiol (1985). 2001 Oct; 91(4): 1708-1712. PMID: 11568154.

269. Elenkov IJ, Papanicolaou DA, Wilder RL, Chrousos GP. Modulatory effects of glucocorticoids and catecholamines on human interleukin-12 and interleukin-10 production: clinical implications. Proc Assoc Am Physicians. 1996 Sep; 108(5): 374-381. PMID: 8902882.

270. Pals KL, Chang RT, Ryan AJ, Gisolfi CV. Effect of running intensity on intestinal permeability. J Appl Physiol. 1997 Feb; 82(2): 571-576. PMID: 9049739.

271. Yano H, Kato Y, Matsuda T. Acute exercise induces gastrointestinal leakage of allergen in lysozyme-sensitized mice. Eur J Appl Physiol. 2002 Aug; 87(4-5): 358-364. PMID: 12172874. doi: 10.1007/s00421-002-0653-x.

272. Lambert GP. Stress-induced gastrointestinal barrier dysfunction and its inflammatory effects. J Anim Sci. 2009 Apr; 87(14 Suppl): E101-E108. PMID: 18791134. doi: 10.2527/jas.2008-1339.

273. Söderholm JD, Perdue MH. Stress and gastrointestinal tract. II. Stress and intestinal barrier function. Am J Physiol Gastrointest Liver Physiol. 2001 Jan; 280(1): G7-G13. PMID: 11123192.

274. Cuevas MJ, Almar M, Garca-Glez JC, Garca-Lpez D, De Paz JA, Alvear-Ordenes I, et al. Changes in oxidative stress markers and NF-kappaB activation induced by sprint exercise. Free Radic Res. 2005 Apr; 39(4): 431-439. PMID: 16028368. doi: 10.1080/10715760500072149.

275. Powers SK, Jackson MJ. Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production. Physiol Rev. 2008 Oct; 88(4): 1243-1276. PMID: 18923182. doi: 10.1152/physrev.00031.2007.

276. Suhr F, Gehlert S, Grau M, Bloch W. Skeletal muscle function during exercise - Fine-tuning of diverse subsystems by nitric oxide. Int. J. Mol. Sci. 2013 Mar 28; 14(4): 7109-7139. PMID: 23538841. doi: 10.3390/ijms14047109.

277. Madrigal JL, Moro MA, Lizasoain I, Lorenzo P, Castrillo A, Bosc L, et al. Inducible nitric oxide synthase expression in brain cortex after acute restraint stress is regulated by nuclear factor kappaB-mediated mechanisms. J Neurochem. 2001 Jan; 76(2): 532-538. PMID: 11208916. doi: 10.1046/j.1471-4159.2001.00108.x.

278. Khovryakov AV, Podrezova EP, Kruglyakov PP, Shikhanov NP, Balykova MN, Semibratova NV, et al. Involvement of the NO synthase system in stress-mediated brain reactions. Neurosci Behav Physiol. 2010 Mar; 40(3): 333-337. PMID: 20151330. doi: 10.1007/s11055-010-9260-1.

279. Twisk FNM, Maes M. A review on cognitive behavorial therapy (CBT) and graded exercise therapy (GET) in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS): CBT/GET is not only ineffective and not evidence-based, but also potentially harmful for many patients. Neuro Endocrinol Lett. 2009 Aug 26; 30(3): 284-299. PMID: 19855350.

280. Fitts RH, McDonald KS, Schluter JM. The determinants of skeletal muscle force and power: their adaptability with changes in activity pattern. J Biomech. 1991; 24 Suppl 1: 111-122. doi: 10.1016/0021-9290(91)90382-W.

281. McCartney N, Heigenhauser GJ, Sargeant AJ, Jones NL. A constant-velocity cycle ergometer for the study of dynamic muscle function. J Appl Physiol Respir Environ Exerc Physiol. 1983 Jul; 55(1 Pt 1): 212-217. PMID: 6885572.

282. Haller RG, Lewis SF. Pathophysiology of exercise performance in muscle disease. Med Sci Sports Exerc. 1984 Oct; 16(5): 456-459. PMID: 6595492. doi: 10.1249/00005768-198410000-00006.

283. Cook DB, O'Connor PJ, Eubanks SA, Smith JC, Lee M. Naturally occurring muscle pain during exercise: assessment and experimental evidence. Med Sci Sports Exerc. 1997 Aug; 29(8): 999-1012. PMID: 9268956. doi: 10.1097/00005768-199708000-00004.

284. Dantzer R, Capuron L, Irwin MR, Miller AH, Ollat H, Perry VH, et al. Identification and treatment of symptoms associated with inflammation in medically ill patients. Psychoneuroendocrinology. 2008 Jan; 33(1): 18-29. PMID: 18061362. doi: 10.1016/j.psyneuen.2007.10.008.

285. Niederberger E, Geisslinger G. The IKK-NF-kappaB pathway: a source for novel molecular drug targets in pain therapy? FASEB J. 2008 Oct; 22(10): 3432-3442. PMID: 18559989. doi: 10.1096/fj.08-109355.

286. Lee KM, Kang BS, Lee HL, Son SJ, Hwang SH, Kim DS, et al. Spinal NF-kB activation induces COX-2 upregulation and contributes to inflammatory pain hypersensitivity. Eur J Neurosci. 2004 Jun; 19(12): 3375-3381. PMID: 15217394. doi: 10.1111/j.0953-816X.2004.03441.x.

287. Cury Y, Picolo G, Gutierrez VP, Ferreira SH. Pain and analgesia: the dual effect of nitric oxide in the nociceptive system. Nitric Oxide. 2011 Oct 30; 25(3): 243-254. PMID: 21723953. doi: 10.1016/j.niox.2011.06.004.

288. Gao X, Kim HK, Chung JM, Chung K. Reactive oxygen species (ROS) are involved in enhancement of NMDA-receptor phosphorylation in animal models of pain. Pain. 2007 Oct; 131(3): 262-271. PMID: 17317010. doi: 10.1016/j.pain.2007.01.011.

289. Ji RR, Berta T, Nedergaard, M. Glia and pain: is chronic pain a gliopathy? Pain. 2013 Dec; 154 Suppl 1: S10-S28. PMID: 23792284. doi: 10.1016/j.pain.2013.06.022.

290. Lepori M, Sartori C, Trueb L, Owlya R, Nicod P, Scherrer U. Haemodynamic and sympathetic effects of inhibition of nitric oxide synthase by systemic infusion of N(G)-monomethyl-L-arginine into humans are dose dependent. J Hypertens. 1998 Apr; 16(4): 519-523. PMID: 9797197. doi: 10.1097/00004872-199816040-00013.

291. Dantzer R. Cytokine, sickness behavior, and depression. Immunol Allergy Clin North Am. 2009 May; 29(2): 247-264. PMID: 19389580. doi: 10.1016/j.iac.2009.02.002.

292. Loftis JM, Huckans M, Morasco BJ. Neuroimmune mechanisms of cytokine-induced depression: current theories and novel treatment strategies. Neurobiol Dis. 2010 Mar; 37(3): 519-533. PMID: 19944762. doi: 10.1016/j.nbd.2009.11.015.

293. Smith RS. The cytokine theory of headache. Med Hypotheses. 1992 Oct; 39(2): 168-174. PMID: 1461182. doi: 10.1016/0306-9877(92)90181-B.

294. Cheng MH, Wen SL, Zhou HJ, Lian-Fang B, Li JF, Xie LJ. Evaluation of headache and regional cerebral flood flow in patients with migraine. Clin Nucl Med. 2013 Nov; 38(11): 874-877. PMID: 24089063. doi: 10.1097/RLU.0b013e3182a75927.

295. Watanabe H, Kuwabara T, Ohkubo M, Tsuji S, Yuasa T. Elevation of cerebral lactate detected by localized 1H-magnetic resonance spectroscopy in migraine during the interictal period. Neurology. 1996 Oct; 47(4): 1093-1095. PMID: 8857754. doi: 10.1212/WNL.47.4.1093.

296. Samad TA, Moore KA, Sapirstein A, Billet S, Allchorne A, Poole S, et al. Interleukin-1beta-mediated induction of COX-2 in the CNS contributes to inflammatory pain hypersensitivity. Nature. 2001 Mar 22; 410(6827): 471-475. PMID: 11260714. doi: 10.1038/35068566.

297. Wu J, Fang L, Lin Q, Willis WD. Nitric oxide synthase in spinal cord central sensitization following intradermal injection of capsaicin. Pain. 2001 Oct; 94(1): 47-58. PMID: 11576744. doi: 10.1016/S0304-3959(01)00340-2.

298. Liu J, Zhu YS, Khan MA, Brunk E, Martin-Cook K, Weiner MF, et al. Global brain hypoperfusion and oxygenation in amnestic mild cognitive impairment. Alzheimers Dement. 2014 Mar; 10(2): 162-170. PMID: 23871763. doi: 10.1016/j.jalz.2013.04.507.

299. De La Garza R2. Endotoxin- or pro-inflammatory cytokine-induced sickness behavior as an animal model of depression: focus on anhedonia. Neurosci Biobehav Rev. 2005; 29(4-5): 761-770. PMID: 15878621. doi: 10.1016/j.neubiorev.2005.03.016.

300. Kelley KW, Bluth RM, Dantzer R, Zhou JH, Shen WH, Johnson RW, et al. Cytokine-induced sickness behavior. Brain Behav Immun. 2003 Feb; 17 Suppl 1: S112-S118. PMID: 12615196. doi: 10.1016/S0889-1591(02)00077-6.

301. Opp MR, Imeri L. Sleep as a behavioral model of neuro-immune interactions. Acta Neurobiol Exp (Wars). 1999; 59(1): 45-53. PMID: 10230076.

302. Shulman RJ, Eakin MN, Czyzewski DI, Jarrett M, Ou CN. Increased gastrointestinal permeability and gut inflammation in children with functional abdominal pain and irritable bowel syndrome. J Pediatr. 2008 Nov; 153(5): 646-650. PMID: 18538790. doi: 10.1016/j.jpeds.2008.04.062.

303. Bures J, Cyrany J, Kohoutova D, Förstl M, Rejchrt S, Kvetina J, et al. Small intestinal bacterial overgrowth syndrome. World J Gastroenterol. 2010 Jun 28; 16(24): 2978-2990. PMID: 20572300. doi: 10.3748/wjg.v16.i24.2978.

304. Ramsay AM. Myalgic encephalomyelitis and postviral fatigue states: the saga of Royal Free disease. 2nd ed. London: Gower Publishing Corporation; 1988.

305. Pall ML, Satterlee JD. Elevated nitric oxide/peroxynitrite mecha­nism for the common etiology of multiple chemical sensitivity, chronic fatigue syndrome, and posttraumatic stress disorder. Ann N Y Acad Sci. 2001 Mar; 933: 323-329. PMID: 12000033. doi: 10.1111/j.1749-6632.2001.tb05836.x.

306. Meeus M, Nijs J, Hermans L, Goubert D, Calders P. The role of mitochondrial dysfunctions due to oxidative and nitrosative stress in the chronic pain or chronic fatigue syndromes and fibromyalgia patients: peripheral and central mechanisms as therapeutic targets? Expert Opin Ther Targets. 2013 Sep; 17(9): p. 1081-1089. PMID: 23834645. doi: 10.1517/14728222.2013.818657.

307. Morris G, Maes M. A neuro-immune model of Myalgic Encepha­lomyelitis/chronic fatigue syndrome. Metab Brain Dis. 2013 Dec; 28(4): 523-540. PMID: 22718491. doi: 10.1007/s11011-012-9324-8.

308. Arroll MA. Allostatic overload in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Med Hypotheses. 2013 Sep; 81(3): 506-508. PMID: 23850395. doi: 10.1016/j.mehy.2013.06.023.

309. Craddock TJ, Fritsch P, Rice MAJ, Del Rosario RM, Miller DB, Fletcher MA, et al. A role for homeostatic drive in the perpetuation of complex chronic illness: gulf war illness and chronic fatigue syndrome. PLoS One. 2014 Jan 8; 9(1): e84839. PMID: 24416298. doi: 10.1371/journal.pone.0084839.


Peer reviewer: Thorsten Rudroff, Department of Health and Exercise Science, Colorado State University, USA.



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