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Oxidative Stress and Mitochondrial Injury in Chronic Multisymptom Conditions: From Gulf War Illness to Autism Spectrum Disorder

Background: Overlapping chronic multisymptom illnesses (CMI) include Chronic Fatigue Syndrome (CFS), fibromyalgia, irritable bowel syndrome, multiple chemical sensitivity, and Gulf War illness (GWI), and subsets of autism spectrum disorder (ASD). GWI entails a more circumscribed set of experiences that may provide insights of relevance to overlapping


OSMD -Oxidative Stress and Mitochondrial Dysfunction Q10 -Coenzyme Q10
RNS -Reactive Nitrogen Species ROS -Reactive Oxygen Species SBP -Systolic Blood Pressure for vulnerability assessment, mitigation of progression, treatment, and future prevention -with implications germane to additive and excessive environmental oxidative stressor exposures in the civilian setting.

Introduction
Chronic multisymptom illnesses (CMI), including chronic fatigue syndrome, fibromyalgia, irritable bowel syndrome, multiple chemical sensitivity and Gulf War illness (GWI), show strong overlap [1][2][3][4] . Autism spectrum disorder (ASD), despite little cooccurrence with GWI (due to military self-selection and selection), encompasses multisymptom subsets bearing muscle, gastrointestinal, sleep and other symptoms germane to CMI. These are suggested to reflect a condition arising from similar mechanisms in a different developmental milieu. GWI entails a circumscribed set of experiences that may provide insights of relevance to these overlapping conditions.
One fourth to 1/3 of US and UK personnel deployed to the Persian Gulf in the 1990-1 conflict exhibit GWI, established by excluding the fraction of nondeployed controls meeting the symptom portion of eligibility [5][6][7][8][9] . The foundation for GWI has been felt to elude physiological explanation 10,11 . GWI differs in exposure relations and symptom profiles from other post-war syndromes (e.g. post-traumatic stress disorder). This conflict had many exposures that were new (anthrax vaccine, depleted uranium, permethrin impregnated uniforms), unique or comparatively unique (pyridostigmine bromide nerve agent pretreatment pills, oil fires, flea collar use by some, botulinum toxoid vaccine, nerve agent exposure resulting from munitions depot demolitions), and excessive (organophosphate and carbamate pesticide use).
Oxidative stress (OS) and mitochondrial dysfunction (MD) (together OSMD) are closely intertwined, and each promotes the other. We evaluate characteristics of OSMD and GWI, to show that OSMD may underlie some, much, or most the excess of multi-symptom illness (and neurodegenerative disease) reported in Gulf War veterans (GWV) 12, 13 -and civilians with CMI.
within the category and/or at least moderately severe, with onset since 1990 5 . Kansas criteria are more specific (fewer non-GWV meet symptom criteria).
Symptom multiplicity and heterogeneity further typify GWI. Many additional symptoms, though less frequent, also occur at markedly elevated rates 5,10,25,26 . Other CMI also commonly bear multiple symptoms, with high overlap 2,4 .
Such symptom multiplicity 21, 27 and heterogeneity 28-37 38 also characterize MD, so much that "A mitochondrial disease should be considered in the event of dysfunction of more than 2 organ systems or processes with high energy requirements" 27 . The remaining Kansas GWI criteria --gastrointestinal dysfunction 16,36,37 , pain 29, 31, 39 , skin 40, 41 , sleep 42-45 , and breathing symptoms are common in MD 43, 46 , with many further symptoms elevated in both settings.
Symptom heterogeity in MD rests on a) random somatic segregation of mitochondrial (mt) DNA mutations 47, 48 and mitochondrial heteroplasmy 49-51 : different organs bear different prior mtDNA mutation loads leading to different vulnerability; b) variable progression of mitochondrial defects: different mutations may arise in different tissues, with some more severe and/or conducive to OS that fosters more mtDNA mutations 19,52 ; and c) clinical threshold effects 21, 53 : symptoms arise when mtDNA mutations or resulting cell death surpass a threshold. The fraction of mutated mtDNA in an organ, the mutation severity, the energetic demands of the organ and the cell loss determine clinical consequences 21, 54 . Symptom variability is an inherent feature of MD (Even persons with familial MD may vary vastly in which symptoms are expressed -and in their timecourse of expression 55 ).-and an empiric feature of GWI and other CMI 10 . (See Table   1a&b, Supplement Table 2

Symptom latency
It is often presumed that symptoms, to relate to an exposure, must arise during an exposure, and that the exposure must show acute toxicity. (Cancer and neurodegenerative disease, familiar disease conditions rather than symptoms, represent recognized exceptions.) GWI does not behave in this fashion.
GWI is characterized by variable latency to symptoms following Gulf exposures -with many new symptoms arising well after participation, and 40% of new symptoms reportedly arising more than a year after Gulf service 11 . Symptoms in MD are also characterized by variable latency to onset. MD produces (commonly) OS. OS trigger further mtDNA mutations and more MD. The severity of new mutations, and degree of heteroplasmy, determine the severity of OS production -and speed of progression. As mtDNA mutations and OS accrue, cells lose function or die, from energy depletion or OS-precipitated necrosis or apoptosis 56 -achieving phenotypic thresholds 21, 53 . (See below for autoimmune predisposition.) Even in a kindred with heritable mtDNA defects that involved neurological problems, "the age of onset of major neurological disturbance varied from 3-70 years" 55 . The principles are similar whether initial mtDNA damage is heritable or acquired; however acquired mtDNA mutations may be typified by multiple different mutations each in a low fraction 19,49 , which may particularly dispose to classical or "nonspecific" symptoms of MD, compatible with CMI. OS may predispose to autoantibodies and vulnerability to infection (below). Delayed symptoms may further arise from OS-promoted autoantibodies and colonization/infection with pathogens (below); and as new OS exposures appear, to which existing OSMD provide heightened vulnerability (due to adverse OS:antioxidant defense balance). OS may promote impaired gene expression related to detoxification, in part via alterations in DNA methylation.Add excitotoxicity?

Exposure Associations
A range of "unrelated" exposures are linked to GWI. Acetylcholinesterase inhibitor (AChEi) exposures (organophosphates, as nerve agents and pesticides; and carbamates, as pesticides and pyridostigmine bromide nerve agent pretreatment pills) show especially strong and consistent links to health problems in GWV 57 . Moreover, AChEis show a dose-response relationship to GWI (number of pyridostigmine bromide pills 57 ); and proximity to the Khamisiyah munitions depot demolition (sarin nerve agent plume) is linked to extent of brain atrophy and neuropsychological dysfunction in GWV 58, 59 . Additional findings, extending to genetic evidence (such as paraoxonase variants 60 . These support a causal association of AChEi to GWI 57 , so mechanisms of toxicity by AChEis are of special interest. (GWV/GWI is also linked to reduced paraoxonase activity levels 60, 61 ; however low activity may be effect and/or cause, as paraoxonase is HDL-associated, and OS promotes reductions in HDL.) CMI including chronic fatiguing illness and autism have also been linked to organophosphates 62-64 , gene variants in paraoxonase 62, 65 ; and other elements of organophosphate detoxification 66 , as well as low paraoxonase activity 67 .
The exposures linked to GWI appear "unrelated" in chemical structure and classical mechanism of action. However they share in common induction of toxicity via OSMD. Thus, AChEi toxicity and lethality are normally viewed in cholinergic terms. However in fact they are mediated by OSMD (contributing to apoptosis) 77,78 : the salience of OSMD in their toxicity is underscored by the relation of their lethality to impaired glutathione mechanisms; and protection from OP lethality via preexposure or immediate postexposure to relevant antioxidants in experimental animal studies [79][80][81] . Vaccines, in contrast, are not known to inhibit AChE. However these, and other exposures linked to GWI, each exerts toxicity via OSMD (Table 1a). Further, the number of such exposures (crossing different classes) also predicted GWI 11 -and predicts greater OSMD [82][83][84][85] . These considerations begin to provide a framework, coupled with individual variabilities, for genesis of some cases of CMI outside the Gulf War setting.

Proposed Mechanism
OS via reactive oxygen species (ROS) and also reactive nitrogen species, (RNS), (for simplicity of exposition we designate the joint processes as "OS") damage proteins, lipids, RNA and DNA -particularly in mitochondria 86,87 , impairing mitochondrial energy production.
Mitochondria are a leading target of ROS 88,89 due to proximity to ROS production (much of which occurs in mitochondria 88,90,91 ), such that mtDNA mutate at 10-1000x the rate of nuclear DNA 92,93 . Since all mtDNA genes are germane to oxidative phosphorylation [94][95][96] , mtDNA damage commonly hampers mitochondrial respiratory chain function, which in turn further impairs cell energy production and often further increases ROS release 86,87 104,105 , which may be magnified in settings of low mt EN production 106,107 .) It is reiterated that major Gulf exposures are known to produce toxicity via OSMD producing expectation of cell dysfunction and cell death. (Note that organophosphates further produce mitochondrial and energetic compromise through toxicity to microtubules 108 , interfering with mitochondrial biogenesis 109 and transport 110 . Mitochondria are dynamic rather than static organelles 111,112 .)

Downstream Effects -OS-induced Mechanisms
OS also depress vitamin D (vitD), vitD receptor expression and mitochondrial vitD hydroxylase activities 113,114 . Low vitD and altered receptor function are linked to risk of autoimmune disease [115][116][117][118][119] . Autoimmune markers are elevated in GWI 120,121 , as well as in other CMI 74, 75, 122 ). Vaccines have been linked to illness in GWV 6, 68-71 and in some cases chronic fatigue. (They are also a politically and scientifically contentious proposed contributor to ASD.) Reactogenic vaccines are a source of OS 82♦ Excitotoxicity is another potential downstream mechanism. Oxidative stress enhances excitotoxin effects, such as DCD (delayed calcium deregulation) which "precedes and predicts" cell death 144 . So, too, does mitochondrial calcium accumulation 144 . Moreover, excitotoxins in . Additionally, vaccine adjuvants (based on aluminum -which is an oxidative stressor, as are components of vaccine preservatives and adjuvants) are expressly incorporated for the purpose of enhancing immune/antibody reactions -in principle to the intended administered antigen, but they may also adjuvant native protein and nonprotein substances. Adjuvants associated with vaccines remain resident in the body and may continue to exert adjuvant effects, promoting "autoimmune syndromes induced by adjuvants" ("ASIA") 122, [125][126][127][128] . Low vitamin D activity (see above) is also linked to increased infection vulnerability [129][130][131][132][133][134] . These factors, coupled with EN deficits and OS-reduced NK activity 120, 135 , may account for increased autoantibodies, and increased evidence of a range of infectious agents (and antibodies to them), in GWI and associated exposures 120 136-139 -and other CMI 74, 75, 140 including ASD [141][142][143] . These contribute further to symptom heterogeneity and latency. ♦ Squalene has been politically contentious in GWI. One is not impelled to suppose that squalene-adjuvanted variants of anthrax vaccine were used, in order for squalene antibodies to arise: squalene occurs naturally in the body and may also be present in small amounts in vaccines as a contaminant123.

Objective findings
Routine laboratory tests are not classically abnormal in GWV (or CMI) or in OSMD.

Table 1a&b depict those objective findings that have been reproducibly documented in GWV
(demonstrated in at least two studies). In each case the objective finding has a demonstrated relation to OSMD (generally OS, which is more commonly tested). These include depressed paraoxonase (PON1) 60, 61, 151 , increased gamma glutamyl transferase (GGT) 152,153 , reduced natural killer cell activity 120,154 , blunted heart rate variability, 155,156 increased autoantibodies 120, a documented consequence of OSMD.

Associated Health Conditions
In addition to symptoms, several conditions have been found to be elevated in GWV.
These include hearing loss, hypertension, and amyotrophic lateral sclerosis (Table 1a&b). These conditions are also known to bear particularly strong relations to OSMD.
These findings are compatible with a common mechanism involving OSMD, targeting different tissues to varying degrees. Motor neurons are one possible (though relatively rare) target tissue, engendering ALS when affected. However other distributions of effect result in multisymptom conditions (GWI-CFS-spectrum conditions), metabolic syndrome features 159 , and a range of other conditions, which accompany one another at elevated rates [2][3][4]160 .

Triangulating Evidence from CMI
Patients with other CMI commonly have multiple "unexplained" symptoms spanning many domains. These conditions have substantial overlap with one another --and with GWI 2-4, 6, 26, 160-164 (see Table 1a&b) consistent with the hypothesis put forth here that common OSMD mechanisms target multiple domains, with factors like heteroplasmy (among others) producing differential vulnerability of potential target tissues.
Reported odds ratios for CFS range from ~4 to ~40 in GWV vs nondeployed controls (  157 (the relation to oxidative stress is discussed above). Moreover, OS levels correlate with symptoms in CFS 167 . Evidence also favors a relation of CFS to MD: functional status in CFS correlates with carnitine levels 168,169 ; and a subset of CFS cases show elevated lactate with exertion, and delayed ATP recovery after exercise, on magnetic resonance spectroscopy 170 , with OS believed to underlie the energetic effects 171 . Furthermore, an "ATP profile test" of mitochondrial function successfully (and completely) discriminated CFS cases, defined by the CDC criteria which require multisymptom illness (most similar to GWI) 172 . Additionally, CFS patients have been reported to differ from controls in genetics related to mitochondrial function 173 , energetics 173 and apoptosis 174 . Fibromyalgia and irritable bowel syndrome 26 -which are increased (~2-5 fold) in GWV -also bear evidence of a link to OSMD 39, [175][176][177] (Table   1a&b). So does ASD 67,103,148,149,[178][179][180][181][182] . MCS has been linked to mutations in genes for glutathione-S-transferase (GST), which protects from oxidative stress by conjugating glutathione, detoxifying "a large range of compounds generated by reactive oxygen species induced damage to intracellular molecules". 147 It might be conjectured that apparent instances of exposure-triggered MCS may entail exposure-triggered increased endogenous OS production (through mechanisms detailed above); and perhaps also exposure-triggered modifications in gene expression of key detoxifying enzymes.
MCS, "sensitivity" to chemicals -and also medication intolerance 183 -are significantly more common in GWV 5,6,25,26,160,184,185 and in overlap conditions [2][3][4]186 : Both chemical ( Table 3) and drug adverse effects are commonly mediated through OSMD [187][188][189][190] . (MCS, like GWI and ASD cited elsewhere, shows altered genetic profiles of PON 60,191 .) OSMD provides an account of why medication and vaccine adverse effects at the time of the Gulf were associated with increased risk of developing GWI 6,68,192,193 : These adverse effects signal less favorable OSMD status at the time of exposure and or greater oxidative stressor exposure, promoting OS dominance over antioxidant defences, which may both predict and help mediate the development of multisymptom GWI in the setting of new OS exposure.
Other conditions have been linked to OSMD but have not (yet) been evaluated in GWI.
An elevation in a number of these conditions in GWI represents a prediction of this theory. Some markers and objective conditions have been linked to GWI and OSMD, and at least one CMI; but have not been evaluated in other CMI. A prediction of this theory is that many, when examined in studies with sufficient power, will be seen in other CMI.

Discussion
An explanation focused on OSMD accounts for GWI, and other CMI. Put forth is a proposition by which exposures to oxidative stressors, in part via cumulative MD, in part via autoimmune effects in vulnerable individuals, in part via apoptosis/cell loss leading to coagulation activation, may increase risk of a range of chronic health problems in GWVincluding the multisymptom spectrum termed GWI -and other CMI. Such an account accords with known exposure relations of otherwise unlike character; explains symptoms with otherwise unexplained organ tropism, with otherwise unexplained protean character and with otherwise unexplained variable timecourse to onset. It fits with the otherwise unexplained range of objective markers linked to these conditions that cross classical boundaries. It explains observed associations to other health conditions of varying character; and accounts for increases in multisymptom "overlap" conditions (and for overlap of these syndromes with one another). A role for OSMD might be predicted on "first principles" (known pathophysiological effects of Gulf Exposures; and known clinical sequelae of these effects) 13 . However there is now direct evidence of a relation of OS and MD to each of the conditions to which GWI relates, providing further triangulating support for a role for OS and MD extending to GWI. CMI has not traditionally been thought to include autism spectrum disorder (ASD); but multisymptom cases of ASD may reflect manifestations of similar processes operating at a different developmental timepoint. ASD not uncommonly comprises multiple symptoms across a similar spectrum, 181,[194][195][196][197] with purported links to similar exposures, and observed relations to OSMD 106,149,180,182,[198][199][200][201][202][203][204][205][206][207] . (All ASD need not cohere with these principles.) Accrued evidence now more vigorously supports a paradigm by which OS and MD conduce to one another, disposing to GWI or other CMI. These mechanisms may operate in some, many or possibly most CMI. The Gulf War setting has its distinctive constellation of OS exposures. However the pathophysiological principles articulated, beyond their potential relevance to GWI, yield a new lens with which to review a range of important, interrelated health conditions -including but not confined to "overlap" CMI conditions often considered to be unexplained -and to understand their relationship to one another -in the military setting, and outside of it.  Reactogenic vaccines also consistently associated Anthrax vaccine associated 6,69 Vaccine adverse effects associated 6,193 Multiple vaccinations associated 6 254 (May be partly adaptive 255,256 ) Exposures: AChEi are particularly potent in inducing OS and MD 77 -and particularly strong consistent predictors of GWI. AChEi exposures, moreover, were also commonly recurrent when they occurred; and in addition, they cause MD by means beyond OS (such as microtubule toxicity 257,258 ). The central role of OS in mediating AChEi toxicity is underscored by findings that pretreatment (or immediate posttreatment) with antioxidants protects against AChEi-induced lethality (and enhances recovery) in animals [79][80][81] . Anthrax vaccinations and multiple vaccinations are the next most strongly and consistently linked to GWI, in epidemiologic evidence 259 . These are tied, through aluminum-based adjuvants 218, 219, 222-224, 226, 260, 261 and mercury (and other) preservatives 225 , to OS and MD ( Table 1, Supplement Table 1) -as well as to inhibition of glutathione production, reducing antioxidant defense against other exposures 219,222,225 . Each additional exposure class presumptively inculpated in GWI is known to promote OS 82-85 226, 262-264 .

Markers:
GGT is an enzymatic antioxidant 265,266 : elevations serve as an early marker of OS 267 including AChEi exposure 265,268 . PON1 is an antioxidant enzyme (also specifically involved in organophosphate detoxification 269 ) whose activity is depressed in settings of elevated OS 237 . PON1 was depressed in GWV generally (relative to military controls) -and particularly so in those with GWI or more symptoms 60, 61, 151 . Natural killer activity is reduced with OS and increased with antioxidants 135,239,240 . Blunted heart rate variability has been linked to OSMD 242,243 . Activation of the coagulation system relates to OS 248,249,251,270 . Both OS 98,99,252 and MD 271, 272 each foster apoptosis; which exposes phosphatidylserine at the cell surface, activating coagulation pathways 253 . Activation of the coagulation system has been repeatedly observed in Gulf War veterans. 157,158 OS also depress vitamin D (vitD), vitD receptor expression and mitochondrial vitD hydroxylase activities 113,114 . Low vitD and altered receptor function are linked to risk of autoimmune disease [115][116][117][118][119] . Significant elevations in self-reported hearing loss after 1990 or 1991 in GWV vs control groups have been reported 5, 6, 10, 26 . (However obviously, even with military controls, there are uncertainties regarding noise exposure comparability. Additionally, formal testing has not yet been undertaken.) Hearing loss deemed "agerelated" and "noise-related" is powerfully linked to OSMD [303][304][305][306] . Accelerated hearing loss is common in MD 28, 34, 314-322 , cited as among the most common symptoms of mitochondriopathy, together with fatigue and muscle symptoms 30 . And chemical exposures have been linked to both hair cell damage and noise-related hearing loss 323,324 . • GWV demonstrate increased incident hypertension in a range of studies (Table 1a&b) 6,26,153,282 . Hypertension, too, is a condition with powerful relationship to OSMD 284-287, 325, 326 . Indeed an evaluation of mitochondrial pedigrees estimated the fraction of patients with hypertension potentially due to mtDNA mutation involvement at 55% (95% CI 45-65%) 285 . Analogous to the Gulf War situation, increased blood pressure has been previously associated with environmental OS exposures. For instance, both arsenic and lead are reported to mediate their toxicity via OS [327][328][329] ; and exposure to each arsenic (e.g. in the water supply) 330,331 and lead 327,328 have been linked to increased rates of hypertension. Hypertension and hearing loss are both common "age-related" conditions. In contrast, amyotrophic lateral sclerosis (ALS) is an uncommon but serious age-related condition. ALS has been reported in several studies to have increased incidence in GWV (Table 1a&b). This condition has been conceptualized as resulting from "oxidative damage to mitochondrial DNA leading to the accumulation of mitochondrial DNA mutations" 332 -in this case targeting the spinal cord -compatible with the mechanism I propose for GWI more generally -and other GWV associated conditions. Extensive evidence links ALS to OSMD 297,299,300,[333][334][335][336][337][338][339][340][341][342][343] . Moreover, low concentrations and mutations of paraoxonase, central to organophosphate (AChEi) detoxification, have been linked to ALS 344-347 -and to GWI 60, 61, 151, 348 (as well as to GWI-like multisymptom illness following organophophate exposure outside the Gulf setting 62, 349, 350 ), further • (Noise "sensitivity" has been noted as a some-time feature of multiple chemical sensitivity, and is also noted in ASD. Since both conditions have been linked to impaired antioxidant defenses147. propelling the case for OSMD in GWI. By the mechanisms elucidated here (and previously elaborated by us in a different setting of exposure-induced ALS 351 ), although spinal cord motor neurons are the primary conditiondefining target, mitochondrial dysfunction in sporadic ALS should not be confined to spinal cord motor neurons but should (statistically) be evident in other tissues, particularly energetically demanding (and thus mitochondrially vulnerable) brain and muscle. Indeed, recent studies show that mitochondrial pathology in ALS extends to skeletal muscle [352][353][354][355][356][357] and symptoms extend to cognitive function in about half of cases 358,359 . Mounting evidence supports a connection of OSMD 290-293, 360, 361 to metabolic syndrome (each has been conceptualized as a unifying mechanism 293, 361 ), of which hypertension is one component. Consistent with this, studies have also reported increased incident weight gain in GWV vs controls 7,26,153 . Assessment for other elements of metabolic syndrome in GWV has not yet been undertaken, but increased metabolic syndrome represents a prediction of this model.

Preliminary Evidence or Comment
Other markers of oxidative stress and mitochondrial dysfunction will be elevated Yes 54 True for chronic fatigue syndrome 167,171,172 , a related condition that is elevated in GWV 5,6,26 True for ASD Genetic risk markers related to mitochondrial function, antioxidant defense, energetics, and apoptosis will be identified Yes, by definition Gene associations related to mitochondrial function, energetics and apoptosis have been reported for chronic fatigue syndrome 66,173,174,276 a related condition that is elevated in GWV 5,6,26 . Deletions in genes for glutathione-Stransferase enzymes (leading to loss of protection against oxidative stress) are strongly and significantly linked to multiple chemical sensitivity 147 Gene variants in paraoxonase have been observed in both GWI and ASD**, and glutathione-related variants among others in ASD 148,198, 362 GWV will have increased rates of adverse effects with many medications and interventions because many adverse effects are mediated via oxidative stress and mitochondrial problems [187][188][189][190] See Comment. Examples of drugs with adverse effects mediated by oxidative stress include acetaminophen, aminoglycosides, fluoroquinolones, amiodarone, nonsteroidal anti-inflammatory agents, chemotherapeutics, 83,188,190,[363][364][365][366][367][368][369][370][371][372][373][374][375][376][377][378] Increased drug adverse effects have been observed in irritable bowel syndrome 379 -a condition elevated in GWV 26 and linked to oxidative stress 279 . Regression reported by some parents following vaccinations in cases of ASD may be a consequence of impaired detoxification. (Such vaccination may boost the oxidative burden, however, and potentiate the process.) New oxidative stressor exposures -beyond medications and medical interventions, though those merit separate mention -will have disproportionate adverse impact in exposed and particularly symptomatic GWV and CMI Prooxidant-antioxidant balance will be adversely affected, disadvantaging ability to defend against new oxidative stressors.
Endothelial dysfunction will arise at elevated rates Endothelial dysfunction is strongly linked to oxidative stress 380 Hepatic steatosis will develop at elevated rates, as will ectopic fat deposition in other locations Hepatic steatosis relates strongly to oxidative stress 381,382 .

Low HDL and high triglycerides will emerge
These conditions (and all elements of metabolic syndrome) are linked to oxidative stress 290,383 and mitochondrial dysfunction 292 Free fatty acids will be elevated Elevated free fatty acids are linked to oxidative stress 384 Metabolic syndrome as a whole will arise at elevated rates Metabolic syndrome is linked to oxidative stress 290, 291 and mitochondrial dysfunction 292 As above, weight gain and hypertension are already reported at elevated rates. Diabetes prevalence shows variable trends likely due to selection of diabetics out of deployment to high risk areas. Rates of diabetes will rise to first match then exceed rates in nondeployed (those with diabetes were disproportionately nondeployed) Diabetes, like metabolic syndrome, is strongly linked to oxidative stress (as effect but possibly also cause) 385 and mitochondrial dysfunction 287,386 This prediction is made despite mixed direction of trends in diabetes rates in published studies 5,26 . It is predicted that a clear increase will emerge. Rates of cardiovascular disease and particularly peripheral arterial disease will emerge at an elevated rate as GWV age These conditions, and especially peripheral arterial disease, are associated with oxidative stress [387][388][389] and mitochondrial dysfunction [390][391][392] Parkinson's disease will emerge at an elevated rate as GWV age Parkinson's disease is linked to oxidative stress and mitochondrial dysfunction 393,394 Like ALS (and Gulf War illness), Parkinson's disease bears an association to polymorphisms in paraoxonase; and exposure to pesticides [395][396][397][398][399] Elevated "depression" diagnoses will be found to disproportionately focus on somatic symptoms Somatic symptoms in depression have been found to serve as markers for mitochondrial dysfunction. 400 .
"Depression" has been reported to be elevated in GWV 26 . GWV have many somatic symptoms that will contribute to elevated scores in depression scales. "Age-related" hearing loss and tinnitus will be demonstrated to occur at elevated rates 302,306,314,323,324 GWV report physician-diagnosed tinnitus at elevated rates 26 Other diagnoses linked to oxidative stress will occur at elevated rates Some reports suggest increased cancer of some types 282 and cancer death in Gulf War veterans 401,402 Exposed GWV who do not meet criteria for GWI will nonetheless show statistical abnormalities in markers of oxidative stress -and sequelae of oxidative stress (perhaps intermediate between unexposed and those with GWI) Asymptomatic persons with mt dysfunction at low heteroplasmy rates nonetheless show increased oxidative stress, proportional to the heteroplasmy level 54 .
GWI -gulf war illness; GWV -gulf war veterans; ALS -Amyotrophic lateral sclerosis; * Those with GWI have many somatic symptoms that will contribute to elevated scores in depression scales.

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