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Objective To assess the efficacy of saline nasal irrigation (S‐NI) and xylitol nasal irrigation (X‐NI) for chronic rhinosinusitis in participants with Gulf War illness (GWI). Methods This 26 week, 3‐arm (1:1:1) randomized controlled trial examined veterans meeting criteria for GWI with moderate‐to‐severe chronic rhinosinusitis and fatigue symptoms. All participants received standard of care for chronic rhinosinusitis (CRS); additionally, S‐NI or X‐NI participants added twice‐daily NI using 2% saline or 5% xylitol solutions. Outcomes included disease‐specific quality of life (primary; sino‐nasal outcome test [SNOT‐20]; 0‐100 points), overall quality of life (Short‐Form 36), and fatigue (Multidimensional Fatigue Index). Outcome assessors were blind to allocation group. Intention‐to‐treat analysis used repeated measures modeling; statistical significance was evaluated at the two‐sided α level of .05. Results Randomization (N = 40) produced three similar groups regarding sex (male, 80%), age (53.8 ± 7.8 years), duration (19.8 ± 7.7 years), and illness severity (48.5 ± 12.7 SNOT‐20 points). Age‐ and gender‐adjusted between‐group comparison showed that X‐NI participants, compared with control, reported improved SNOT‐20 scores at 8 weeks (13.5 points, 95% confidence interval [CI] −27.9 to 0.9) and at 26 weeks (15.4 points, 95% CI −30.1 to −0.6). S‐NI participants improved by 13.4 points (95% CI −28.8, 2.1) at 26 weeks compared with control. The improvement in both NI groups approached minimal clinical important difference compared to control for the SNOT‐20 in the general population. Secondary outcomes were not different between groups. Satisfaction in both irrigation groups was high. Conclusions This randomized controlled trial suggests that NI with saline or xylitol improves chronic sinus symptoms among participants with GWI with improvement scores similar to those in the general population. Level of Evidence 1b, individual randomized controlled trial.

About 25–35% of United States veterans who fought in the 1990–1991 Gulf War report several moderate or severe chronic systemic symptoms, defined as Gulf War illness (GWI). Thirty years later, there is little consensus on the causes or biological underpinnings of GWI. The Gulf War Era Cohort and Biorepository (GWECB) was designed to investigate genetic and environmental associations with GWI and consists of 1343 veterans. We investigate candidate gene–toxicant interactions that may be associated with GWI based on prior associations found in human and animal model studies, focusing on SNPs in or near ACHE, BCHE, and PON1 genes to replicate results from prior studies. SOD1 was also considered as a candidate gene. CDC Severe GWI, the primary outcome, was observed in 26% of the 810 deployed veterans included in this study. The interaction between the candidate SNP rs662 and pyridostigmine bromide (PB) pills was found to be associated with CDC Severe GWI. Interactions between PB pill exposure and rs3917545, rs3917550, and rs2299255, all in high linkage disequilibrium in PON1, were also associated with respiratory symptoms. These SNPs could point toward biological pathways through which GWI may develop, which could lead to biomarkers to detect GWI or to better treatment options for veterans with GWI.

Gulf War illness (GWI) encompasses a constellation of persistent debilitating symptoms associated with significant changes in central nervous system (CNS) and immune functioning. Currently, there is no validated biomarker for GWI risk susceptibility. Given the impact of immune responses linked to GWI symptomology, genetic variability that causes persistent inflammatory/immune alterations may be key. This Boston University-based Gulf War Illness Consortium (GWIC) study investigated the impact of single nucleotide polymorphisms (SNPs) in variants of immune and pain genetic markers IL1B, IL2, IL6, IL6R, IL10, TNF, TGF, TLR2, TLR4, MD2, MYD88, BDNF, CRP, ICE, COMT and OPRM1 on GWI occurrence in a Caucasian subset of Gulf War (GW) veterans with (cases, n = 170) and without (controls, n = 34) GWI. Logistic regression modeling created a prediction model of GWI risk that associated genetic variability in TGF (rs1800469, p = 0.009), IL6R (rs8192284, p = 0.004) and TLR4 (rs4986791, p = 0.013) with GWI occurrence. This prediction model was specific and sensitive, with a receiver operator characteristic area under the curve of 71.4%. This is the first report of immune genetic variability being predictive of GWI and warrants validation in larger independent cohorts. Future reports will present interactions of these genetic risk factors with other characteristics of GW service.

Aims: To introduce a resource supporting research on Gulf War illness (GWI) and related disorders, the Gulf War Veterans’ Illnesses Biorepository (GWVIB). Methods: Gulf War era veterans (GWVs) are recruited nationally and enrolled via telephone and email/postal mail. Enrolled veterans receive annual telephone and mail follow-up to collect health data until their passing. A postmortem neuropathological examination is performed, and fixed and frozen brain and spinal cord samples are banked to support research. Investigators studying GWI and related disorders may request tissue and data from the GWVIB. Results: As of September 2021, 127 GWVs from 39 states were enrolled; 60 met the criteria for GWI, and 14 met the criteria for chronic multisymptom illness (CMI). Enrollees have been followed up to six years. Postmortem tissue recoveries were performed on 14 GWVs. The most commonly found neuropathologies included amyotrophic lateral sclerosis, chronic traumatic encephalopathy, and Lewy body disease. Tissue was of good quality with an average RNA integrity number of 5.8 (SD = 1.0) and ≥4.8 in all of the cases. Discussion: The availability of health data and high-quality CNS tissue from this well-characterized GWV cohort will support research on GWI and related disorders affecting GWVs. Enrollment is ongoing.

By its nature, Gulf war illness (GWI) is multisymptomatic and affects several organ systems in the body. Along with other symptoms, veterans who suffer from GWI commonly report chronic gastrointestinal issues such as constipation, pain, indigestion, etc. However, until recently, most attention has been focused on neurological disturbances such as cognitive impairments, chronic fatigue, and chronic pain among affected veterans. With such high prevalence of gastrointestinal problems among Gulf war (GW) veterans, it is surprising that there is little research to investigate the mechanisms behind these issues. This review summarizes all the available works on the mechanisms behind gastrointestinal problems in GWI that have been published to date in various databases. Generally, these studies, which were done in rodent models, in vitro and human cohorts propose that an altered microbiome, a reactive enteric nervous system or a leaky gut among other possible mechanisms are the major drivers of gastrointestinal problems reported in GWI. This review aims to draw attention to the gastrointestinal tract as an important player in GWI disease pathology and a potential therapeutic target.

Background Malondialdehyde (MDA) is a candidate general marker of oxidative stress (OS). We sought to assess the relation of MDA to Gulf War illness (GWI) and to a variety of exposures. Methods This is an observational study involving subjects from Southern California recruited from October 2011 to May 2014. MDA was assessed in 81 participants (41 GWI-cases, 40 controls). General and Gulf-specific exposures were elicited. MDA case–control comparison was restricted to 40 matched pairs. The potential association between MDA and exposures was assessed using regression analyses. Gulf-specific exposures were incorporated into a case-specific model. Results Plasma MDA was significantly lower in GWI-cases than controls. Composite pesticide and fuel-solvent exposures negatively predicted MDA in the total sample, as well as in the analyses that included either GWI-cases or controls only. Self-reported exposure to organophosphate (OP) nerve gas was a strong predictor for lower MDA level in veterans with GWI. Conclusion Past pesticide exposures predicted lower MDA in both veterans with GWI and in healthy controls.

The Boston University-based Gulf War Illness Consortium (GWIC) is a multidisciplinary initiative developed to provide detailed understanding of brain and immune alterations that underlie Gulf War illness (GWI), the persistent multisymptom disorder associated with military service in the 1990–1991 Gulf War. The core GWIC case-control clinical study conducted in-depth brain and immune evaluation of 269 Gulf War veterans (223 GWI cases, 46 controls) at three U.S. sites that included clinical assessments, brain imaging, neuropsychological testing, and analyses of a broad range of immune and immunogenetic parameters. GWI cases were similar to controls on most demographic, military, and deployment characteristics although on average were two years younger, with a higher proportion of enlisted personnel vs. officers. Results of physical evaluation and routine clinical lab tests were largely normal, with few differences between GWI cases and healthy controls. However, veterans with GWI scored significantly worse than controls on standardized assessments of general health, pain, fatigue, and sleep quality and had higher rates of diagnosed conditions that included hypertension, respiratory and sinus conditions, gastrointestinal conditions, and current or lifetime depression and post-traumatic stress disorder. Among multiple deployment experiences/exposures reported by veterans, multivariable logistic regression identified just two significant GWI risk factors: extended use of skin pesticides in theater (adjusted OR = 3.25, p = 0.005) and experiencing mild traumatic brain injury during deployment (OR = 7.39, p = 0.009). Gulf War experiences associated with intense stress or trauma (e.g., participation in ground combat) were not associated with GWI. Data and samples from the GWIC project are now stored in a repository for use by GWI researchers. Future reports will present detailed findings on brain structure and function, immune function, and association of neuroimmune measures with characteristics of GWI and Gulf War service.

Aims Veterans from the 1990–91 Gulf War were exposed to acetylcholinesterase inhibitors (AChEIs), and, following service, an estimated one-third began suffering from a medically unexplained, multi-symptom illness termed Gulf War Illness (GWI). Previous research has developed validated rodent models that include exposure to exogenous corticosterone (CORT) and AChEIs to simulate high stress and chemical exposures encountered in theater. This combination of exposures in mice resulted in a marked increase in neuroinflammation, which is a common symptom of veterans suffering from GWI. To further elucidate the mechanisms associated with these mouse models of GWI, an investigation into intracellular responses in the cortex were performed to characterize the early cellular signaling changes associated with this exposure-initiated neuroinflammation. Main methods Adult male C57BL/6J mice were exposed to CORT in the drinking water (200 μg/mL) for 7 days followed by a single intraperitoneal injection of diisopropyl fluorophosphate (DFP; 4.0 mg/kg) or chlorpyrifos oxon (CPO; 8.0 mg/kg), on day 8 and euthanized 0.5, 2, and 24 h post-injection. Eleven post-translationally modified protein targets were measured using a multiplexed ELISA. Key findings Phosphoprotein responses were found to be exposure specific following AChEI insult, with and without CORT. Specifically, CORT + CPO exposure was found to sequentially activate several phosphoproteins involved in mitogen activated protein kinase signaling (p-MEK1/2, p-ERK1/2, and p-JNK). DFP alone similarly increased proteins in this pathway (p-RPS6, and p-JNK), but the addition of CORT ameliorated these affects. Significance The results of this study provide insight into differentially activated pathways depending on AChEI in these GWI models., phosphoprotein signaling; diisopropyl fluorophosphate; chlorpyrifos oxon; corticosterone; Gulf War Illness; mitogen activated protein kinase

IntroductionVeterans of the 1991 Gulf War were potentially exposed to a mixture of stress, chemicals and radiation that may have contributed to the persistent symptoms of Gulf War Illness (GWI). The genotoxic effects of some of these exposures are mediated by the DNA nucleotide excision repair (NER) pathway. We hypothesized that individuals with relatively low DNA repair capacity would suffer greater damage from cumulative genotoxic exposures, some of which would persist, causing ongoing problems.Materials and MethodsBlood samples were obtained from symptomatic Gulf War veterans and age-matched controls. The unscheduled DNA synthesis assay, a functional measurement of NER capacity, was performed on cultured lymphocytes, and lymphocyte mRNA was extracted and analyzed by sequencing.ResultsDespite our hypothesis that GWI would be associated with DNA repair deficiency, NER capacity in lymphocytes from affected GWI veterans actually exhibited a significantly elevated level of DNA repair (p = 0.016). Both total gene expression and NER gene expression successfully differentiated individuals with GWI from unaffected controls. The observed functional increase in DNA repair capacity was accompanied by an overexpression of genes in the NER pathway, as determined by RNA sequencing analysis.ConclusionWe suggest that the observed elevations in DNA repair capacity and NER gene expression are indicative of a “hormetic,” i.e., induced or adaptive protective response to battlefield exposures. Normally such effects are short-term, but in these individuals this response has resulted in a long-term metabolic shift that may also be responsible for the persistent symptoms of GWI.

Gulf War illness (GWI) is a chronic and multisymptom disorder affecting military veterans deployed to the 1991 Persian Gulf War. It is characterized by a range of acute and chronic symptoms, including but not limited to, fatigue, sleep disturbances, psychological problems, cognitive deficits, widespread pain, and respiratory and gastrointestinal difficulties. The prevalence of many of these chronic symptoms affecting Gulf War veterans occur at markedly elevated rates compared to nondeployed contemporary veterans. To date, no effective treatments for GWI have been identified. The overarching goal of this umbrella review was to critically evaluate the evidence for the potential of Tai Chi mind-body exercise to benefit and alleviate GWI symptomology. Based on the most prevalent GWI chronic symptoms and case definitions established by the Centers for Disease Control and Prevention and the Kansas Gulf War Veterans Health Initiative Program, we reviewed and summarized the evidence from 7 published systematic reviews and meta-analyses. Our findings suggest that Tai Chi may have the potential for distinct therapeutic benefits on the major prevalent symptoms of GWI. Future clinical trials are warranted to examine the feasibility, efficacy, durability and potential mechanisms of Tai Chi for improving health outcomes and relieving symptomology in GWI.

Gulf War Illness (GWI) is a chronic multi-symptom disorder experienced by as many as a third of the veterans of the 1991 Gulf War; the constellation of “sickness behavior” symptoms observed in ill veterans is suggestive of a neuroimmune involvement. Various chemical exposures and conditions in theater have been implicated in the etiology of the illness. Previously, we found that GW-related organophosphates (OPs), such as the sarin surrogate, DFP, and chlorpyrifos, cause neuroinflammation. The combination of these exposures with exogenous corticosterone (CORT), mimicking high physiological stress, exacerbates the observed neuroinflammation. The potential relationship between the effects of OPs and CORT on the brain versus inflammation in the periphery has not been explored. Here, using our established GWI mouse model, we investigated the effects of CORT and DFP exposure, with or without a chronic application of pyridostigmine bromide (PB) and N,N-diethyl-meta-toluamide (DEET), on cytokines in the liver and serum. While CORT primed DFP-induced neuroinflammation, this effect was largely absent in the periphery. Moreover, the changes found in the peripheral tissues do not correlate with the previously reported neuroinflammation. These results not only support GWI as a neuroimmune disorder, but also highlight the separation between central and peripheral effects of these exposures.

Background: Approximately 697,000 members of the U.S. Armed Forces were deployed to the Persian Gulf in support of the 1990–1991 Persian Gulf War (GW). Subsequently, many deployed and some non-deployed veterans developed a chronic multi-symptom illness, now named Gulf War Illness (GWI). This manuscript outlines the methods and rationale for studying the genomics of GWI within the Million Veteran Program (MVP), a VA-based national research program that has linked medical records, surveys, and genomic data, enabling genome-wide association studies (GWASs). Methods: MVP participants who served in the military during the GW era were contacted by mail and invited to participate in the GWI study. A structured health questionnaire, based on a previously tested instrument, was also included in the mailing. Data on deployment locations and exposures, symptoms associated with GWI, clinical diagnoses, personal habits, and health care utilization were collected. Self-reported data will be augmented with chart reviews and structured international classification of disease codes, to classify participants by GWI case status. We will develop a phenotyping algorithm, based on two commonly used case definitions, to determine GWI status, and then conduct a nested case-control GWAS. Genetic variants associated with GWI will be investigated, and gene–gene and gene–environment interactions studied. The genetic overlap of GWI with, and causative mechanisms linking this illness to, other health conditions and the effects of genomic regulatory mechanisms on GWI risk will also be explored. Conclusions: The proposed initial GWAS described in this report will investigate the genomic underpinnings of GWI with a large sample size and state-of-the-art genomic analyses and phenotyping. The data generated will provide a rich and expansive foundation on which to build additional analyses.

Impaired bioenergetics have been reported in veterans with Gulf War illness (VGWIs), including prolonged post-exercise recovery of phosphocreatine (PCr-R) assessed with 31Phosphorus magnetic resonance spectroscopy. The citric acid cycle (CAC) is considered the most important metabolic pathway for supplying energy, with relationships among CAC markers reported to shift in some but not all impaired bioenergetic settings. We sought to assess relations of CAC markers to one another and to PCr-R. Participants were 33 VGWIs and 33 healthy controls 1:1 matched on age–sex–ethnicity. We assessed seven CAC intermediates, and evaluated PCr-R in a subset of matched case–control pairs (N = 14). CAC markers did not significantly differ between cases and controls. Relationships of alpha-ketoglutarate to malate, isocitrate, and succinate were strongly significant in cases with materially weaker relationships in controls, suggesting possible shifts in these markers in concert in VGWIs. PCr-R correlated strongly with five of seven CAC markers in controls (succinate, malate, fumarate, citrate, isocitrate, range r = −0.74 to −0.88), but bore no relationship in VGWIs. In summary, PCr-R related significantly to CAC markers in healthy controls, but not VGWIs. In contrast, relations of CAC markers to one another appeared to shift (often strengthen) in VGWIs.

Published: 9 August 2021 GulfWar Illness (GWI) is a persistent chronic neuroinflammatory illness exacerbated by external stressors and characterized by fatigue, musculoskeletal pain, cognitive, and neurological problems linked to underlying immunological dysfunction for which there is no known treatment. As the immune system and the brain communicate through several signaling pathways, including the hypothalamic–pituitary–adrenal (HPA) axis, it underlies many of the behavioral and physiological responses to stressors via blood-borne mediators, such as cytokines, chemokines, and hormones. Signaling by these molecules is mediated by the semipermeable blood–brain barrier (BBB) made up of a monocellular layer forming an integral part of the neuroimmune axis. BBB permeability can be altered and even diminished by both external factors (e.g., chemical agents) and internal conditions (e.g., acute or chronic stress, or cross-signaling from the hypothalamic–pituitary–gonadal (HPG) axis). Such a complex network of regulatory interactions that possess feed-forward and feedback connections can have multiple response dynamics that may include several stable homeostatic states beyond normal health. Here we compare immune and hormone measures in the blood of human clinical samples and mouse models of Gulf War Illness (GWI) subtyped by exposure to traumatic stress for subtyping this complex illness. We do this via constructing a detailed logic model of HPA–HPG–Immune regulatory behavior that also considers signaling pathways across the BBB to neuronal–glial interactions within the brain. We apply conditional interactions to model the effects of changes in BBB permeability. Several stable states are identified in the system beyond typical health. Following alignment of the human and mouse blood profiles in the context of the model, mouse brain sample measures were used to infer the neuroinflammatory state in human GWI and perform treatment simulations using a genetic algorithm to optimize the Monte Carlo simulations of the putative treatment strategies aimed at returning the ill system back to health. We identify several ideal multi-intervention strategies and potential drug candidates that may be used to treat chronic neuroinflammation in GWI. This research was funded by the U.S. Department of Defense—Congressionally Directed Medical Research Programs—GulfWar Illness Research Program, grant numbers W81XWH-16-1-0632 (Craddock PI), and W81XWH-16-1-0552 (Craddock PI), W81XWH-13-2-0085 (Morris PI). Intramural funds from the Centers for Disease Control—National Institute for Occupational Safety and Health (O’Callaghan PI). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Veterans from the 1991 Gulf War (GW) have suffered from Gulf War illness (GWI) for nearly 30 years. This illness encompasses multiple body systems, including the central nervous system (CNS). Diagnosis and treatment of GWI is difficult because there has not been an objective diagnostic biomarker. Recently, we reported on a newly developed blood biomarker that discriminates GWI from GW healthy controls, and symptomatic controls with irritable bowel syndrome (IBS) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The present study was designed to compare levels of these biomarkers between men and women with GWI, as well as sex-specific effects in comparison to healthy GW veterans and symptomatic controls (IBS, ME/CFS). The results showed that men and women with GWI differ in 2 of 10 plasma autoantibodies, with men showing significantly elevated levels. Men and women with GWI showed significantly different levels of autoantibodies in 8 of 10 biomarkers to neuronal and glial proteins in plasma relative to controls. In summary, the present study addressed the utility of the use of plasma autoantibodies for CNS proteins to distinguish among both men and women veterans with GWI and other healthy and symptomatic control groups.

A growing number of vaccines are administered at the same time or in close succession, increasing the complexity of assessing vaccine safety. Individual vaccines are assumed to have no other effect than protection against the targeted pathogen, but vaccines also have nonspecific and interactive effects, the outcomes of which can be beneficial or harmful. To date, no controlled trials and very few observational studies have determined the impact of vaccination schedules on overall health. The balance of the risks and benefits from mass vaccination therefore remains uncertain. Recent studies worryingly suggest links between multiple vaccinations and increased risks of diverse multisystem health problems, including allergies, infections, and neuropsychiatric or neurodevelopmental disorders. Here, we propose that, in susceptible persons, multiple vaccinations activate the retinoid cascade and trigger apoptotic hepatitis, leading to cholestatic liver dysfunction, in which stored vitamin A compounds (retinyl esters and retinoic acid) enter the circulation in toxic concentrations; this induces endogenous forms of hypervitaminosis A, with the severity of adverse outcomes being directly proportional to the concentration of circulating retinoids. In very low concentrations, vitamin A and its major metabolite retinoic acid contribute to immune function and to the process of immunization, whereas excess vitamin A increases the risk of adverse events, including common “side-effects” as well as chronic adverse outcomes. The increasing rates of allergy, ear infections, and neurodevelopmental disorders (NDDs) in countries with high rates of vaccination could be related to mass vaccination and to its impact on liver function and vitamin A metabolism, collectively representing endogenous manifestations of hypervitaminosis A. Further studies of health outcomes in vaccinated and unvaccinated groups are urgently needed, to increase understanding of the pathophysiology and treatment of vaccine injury, to identify the risk factors and screen for vaccine injury, to inform public health policy on potential hazards related to vaccination schedules, and to optimize the safety and benefits of vaccines.

Gulf War illness (GWI) refers to the multitude of chronic health symptoms, spanning from fatigue, musculoskeletal pain, and neurological complaints to respiratory, gastrointestinal, and dermatologic symptoms experienced by about 250,000 GW veterans who served in the 1991 Gulf War (GW). Longitudinal studies showed that the severity of these symptoms often remain unchanged even years after the GW, and these veterans with GWI continue to have poorer general health and increased chronic medical conditions than their non-deployed counterparts. For better management and treatment of this condition, there is an urgent need for developing objective biomarkers that can help with simple and accurate diagnosis of GWI. In this study, we applied multiple neuroimaging techniques, including T1-weighted magnetic resonance imaging (T1W-MRI), diffusion tensor imaging (DTI), and novel neurite density imaging (NDI) to perform both a group-level statistical comparison and a single-subject level machine learning (ML) analysis to identify diagnostic imaging features of GWI. Our results supported NDI as the most sensitive in defining GWI characteristics. In particular, our classifier trained with white matter NDI features achieved an accuracy of 90% and F-score of 0.941 for classifying GWI cases from controls after the cross-validation. These results are consistent with our previous study which suggests that NDI measures are sensitive to the microstructural and macrostructural changes in the brain of veterans with GWI, which can be valuable for designing better diagnosis method and treatment efficacy studies.

Objective This analysis examined the relationship between Gulf War (GW) exposures and health symptoms reported in three time periods over 20 years in Ft. Devens Cohort veterans. Methods Repeated logistic regression models examined the association of exposures and health symptoms over time. Models included baseline age, active duty status, post-traumatic stress disorder status, sex, and time since deployment as covariates. Results Exposure to tent heaters was associated with increased odds of crying easily and muscle twitching. Exposure to pyridostigmine bromide (PB) pills was associated with increased odds of depression and fatigue. Exposure to the Khamisiyah sarin plume was associated with increased odds of trouble concentrating and crying easily. Conclusion This longitudinal analysis demonstrated an association between neurotoxicant exposures and increased odds of cognitive/mood, fatigue, and neurological symptoms. In addition, most symptoms increased over time since deployment regardless of exposure.

Most people have no problems when administered vaccines, however, as with all drugs, reported adverse effects (rAEs) do occur. There is a need to better understand the potential predictors of reported vaccine AEs (rVaxAEs), including modifiable (environmental) predictors. Gulf War Veterans (GWV) who have Gulf War illness (GWI) report increased experiences of drug and chemical rAEs, extending to rVaxAEs. GWV provide an opportunity to examine the relationship between their reported exposures and rAEs. Forty one GWV with GWI and 40 healthy controls reported exposure and rAEs to exposure, including for 14 vaccines. Individual and summed vaccine exposures, rVaxAEs, and reported Vaccine AE Propensity (summed rVaxAEs/summed vaccines exposures) were compared in cases vs. controls. Exposure&ndash, outcome assessments focused on GWV, using a multivariable regression with robust standard error. More designated vaccines were reported in cases than in controls: 9.0 (2.3) vs. 3.8 (2.3), p &lt, 0.0001. The fraction of vaccines received that led to rAEs was ten-fold higher in cases: 0.24 (0.21), vs. 0.023 (0.081), p &lt, 0.0001. Multivariable assessment confirmed that radiation and pesticides remained significant statistical predictors of reported Vaccine AE Propensity. Exposure tied to excess rVaxAEs in GWV may contribute to, or underlie, the reported link between rVaxAEs in GWV and later ill health.

For the past 30 years, there has been a lack of objective tools for diagnosing Gulf War Illness (GWI), which is largely characterized by central nervous system (CNS) symptoms emerging from 1991 Gulf War (GW) veterans. In a recent preliminary study, we reported the presence of autoantibodies against CNS proteins in the blood of veterans with GWI, suggesting a potential objective biomarker for the disorder. Now, we report the results of a larger, confirmatory study of these objective biomarkers in 171 veterans with GWI compared to 60 healthy GW veteran controls and 85 symptomatic civilian controls (n = 50 myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and n = 35 irritable bowel syndrome (IBS)). Specifically, we compared plasma markers of CNS autoantibodies for diagnostic characteristics of the four groups (GWI, GW controls, ME/CFS, IBS). For veterans with GWI, the results showed statistically increased levels of nine of the ten autoantibodies against neuronal “tubulin, neurofilament protein (NFP), Microtubule Associated Protein-2 (MAP-2), Microtubule Associated Protein-Tau (Tau), alpha synuclein (α-syn), calcium calmodulin kinase II (CaMKII)” and glial proteins “Glial Fibrillary Acidic Protein (GFAP), Myelin Associated Glycoprotein (MAG), Myelin Basic Protein (MBP), S100B” compared to healthy GW controls as well as civilians with ME/CFS and IBS. Next, we summed all of the means of the CNS autoantibodies for each group into a new index score called the Neurodegeneration Index (NDI). The NDI was calculated for each tested group and showed veterans with GWI had statistically significantly higher NDI values than all three control groups. The present study confirmed the utility of the use of plasma autoantibodies for CNS proteins to distinguish among veterans with GWI and other healthy and symptomatic control groups.

Gulf War Illness (GWI) is a multisymptom disorder including widespread chronic pain, fatigue and gastrointestinal problems. The objective of this study was to examine the low glutamate diet as a treatment for GWI. Forty veterans with GWI were recruited from across the US. Outcomes included symptom score, myalgic score, tender point count, dolorimetry and the Chalder Fatigue Scale. Subjects were randomized to the low glutamate diet or a wait-listed control group, with symptom score being compared after one month. Subjects then went onto a double-blind, placebo-controlled crossover challenge with monosodium glutamate (MSG)/placebo to test for return of symptoms. Symptom score was compared between diet intervention and wait-listed controls with an independent t-test and effect size was calculated with Cohen&rsquo, s d. Change scores were analyzed with Wilcoxon Signed Rank tests. Crossover challenge results were analyzed with General Linear Models and cluster analysis. The diet intervention group reported significantly less symptoms (p = 0.0009) than wait-listed controls, with a very large effect size, d = 1.16. Significant improvements in average dolorimetry (p = 0.0006), symptom score, tender point number, myalgic score and the Chalder Fatigue Scale (all p &lt, 0.0001) were observed after the 1-month diet. Challenge with MSG/placebo resulted in significant variability in individual response. These results suggest that the low glutamate diet can effectively reduce overall symptoms, pain and fatigue in GWI, but differential results upon challenge suggest that other aspects of the diet, or underlying differences within the population, may be driving these changes. Future research is needed to identify potential nutrient effects, biomarkers, and underlying metabolic differences between responders and non-responders.

Gulf War Illness is a chronic multisystem disorder affecting approximately a third of the Veterans of the Gulf War, manifesting with physical and mental health symptoms such as cognitive impairment, neurological abnormalities, and dysregulation of mood. Among the leading theories into the etiology of this multisystem disorder is environmental exposure to the various neurotoxins encountered in the Gulf Theatre, including organophosphates, nerve agents, pyridostigmine bromide, smoke from oil well fires, and depleted uranium. The relationship of toxin exposure and the pathogenesis of Gulf War Illness converges on the innate immune system: a nonspecific form of immunity ubiquitous in nature that acts to respond to both exogenous and endogenous insults. Activation of the innate immune system results in inflammation mediated by the release of cytokines. Cytokine mediated neuroinflammation has been demonstrated in a number of psychiatric conditions and may help explain the larger than expected population of Gulf War Veterans afflicted with a mood disorder. Several of the environmental toxins encountered by soldiers during the first Gulf War have been shown to cause upregulation of inflammatory mediators after chronic exposure, even at low levels. This act of inflammatory priming, by which repeated exposure to chronic subthreshold insults elicits robust responses, even after an extended period of latency, is integral in the connection of Gulf War Illness and comorbid mood disorders. Further developing the understanding of the relationship between environmental toxin exposure, innate immune activation, and pathogenesis of disease in the Gulf War Veterans population, may yield novel therapeutic targets, and a greater understanding of disease pathology and subsequently prevention.

Gulf War illness (GWI) is a chronic disease of unknown etiology affecting over 200,000 veterans with symptoms including neurocognitive problems. We previously demonstrated GWI serum toxicity on neural cell cultures manifested by compromised neural network function, decreased cell spreading, and enhanced cell apoptosis. These patients lacked six human leukocyte antigen (HLA) class II alleles, resulting in an inability to form antibodies. Therefore, we hypothesized that GWI patients have vaccine-derived, persistent pathogens, which contribute to the development of the disease. Here, we examined whether individual vaccines were toxic in cultured N2A cells. Moreover, we used antibodies against each of the 20 vaccines administered to Gulf War (GW) veterans, to examine the effects of these antibodies on cell spreading and apoptosis in N2A cells. Antibodies against cholera toxin, hepatitis B, hemagglutinin H1N1, H3N2, and B from influenza A and B strains, measles, and Salmonella Typhi polysaccharide Vi had a remarkable protective effect on both cell spreading and apoptosis, whereas none of the other antibodies administered to GW veterans had an effect. The in vitro observed adverse effects of GWI serum may be due in part to vaccine-derived pathogens, antibodies against which had a protective effect in N2A cell cultures.

Approximately 30 percent of U.S. veterans deployed during the Gulf War (1990&ndash, 1991) have been diagnosed with Gulf War Illness (GWI), a chronic multi-symptom disorder without widely available specific treatments. We investigated whether the consumption of Concord grape juice (CGJ), rich in anti-inflammatory flavonoids, would be tolerated and safe in individuals with GWI and explored improvement in cognitive function and fatigue. Thirty-six veterans with GWI enrolled in a 24-week randomized, double-blind, Phase I/IIA clinical trial to explore safety, tolerability, and feasibility of 16 ounces daily of commercially available CGJ compared to placebo. Participants completed neurocognitive tests and self-reported surveys at baseline, 12 and 24 weeks. Thirty-one participants (86%) completed the study, no dropouts were related to side effects. Thirty participants (83%) documented &ge, 80% adherence. There were no statistically significant unadjusted differences between CGJ and placebo groups in change in efficacy measures from baseline to endpoint. We employed general linear regression models controlling for baseline differences between groups which indicated statistically significant improvement in the Halstead Category Test&ndash, Russell Revised Version (RCAT) at endpoint in the CGJ group compared to placebo (8.4 points, p = 0.04). Other measures of cognitive functioning did not indicate significant improvements in the adjusted analyses (p-values: 0.09&ndash, 0.32), nor did the fatigue variable (p = 0.67). CGJ was safe and well-tolerated by veterans with GWI. Our data suggest high tolerability and potential benefit from CGJ in veterans with GWI and can be used to inform future studies of efficacy.

Background Gulf War Illness (GWI) is a poorly understood condition characterized by a constellation of mood, cognitive, and physical symptoms. A growing body of evidence demonstrates autonomic nervous system (ANS) dysfunction. Few published treatment studies exist for GWI. Method We recently completed a randomized controlled trial comparing a 10-week group yoga intervention to 10-week group cognitive behavioral therapy (CBT) for veterans with GWI. Here, we present exploratory data on ANS biomarkers of treatment response from a small pilot exploratory neurophysiological add-on study (n = 13) within that larger study. Results Findings suggest that veterans with GWI receiving either yoga or CBT for pain improved following treatment and that changes in biological ANS—especially for the yoga group—moved in the direction of healthy profiles: lower heart rate, higher square root of the mean squared differences between successive R-R intervals (RMSSD), greater parasympathetic activation/dominance (increased high-frequency heart rate variability [HF-HRV], decreased low-frequency/high-frequency [LF/HF] ratio), reduced right amygdala volume, and stronger amygdala-default mode/amygdala-salience network connectivity, both immediately posttreatment and at 6-month follow-up. Biological mechanisms of CBT appeared to underlie improvements in more psychologically loaded symptoms such as self-reported fatigue and energy. Higher tonic arousal and/or more sympathetic dominance (higher skin conductance, lower RMSSD, lower HF-HRV, higher LF/HF ratio) pretreatment predicted greater treatment-related improvements in self-reported ANS for both the yoga and CBT group. Conclusion These exploratory pilot data provide preliminary support for the suggestion that treatment (yoga, CBT) is associated with improvements in both biological and self-reported ANS dysfunctions in GWI. The major limitation for these findings is the small sample size. Larger and more controlled studies are needed to replicate these findings and directly compare biomarkers of yoga versus CBT.

Potentially linked to the basic physiology of stress response, Gulf War Illness (GWI) is a debilitating condition presenting with complex immune, endocrine and neurological symptoms. Here we interrogate the immune response to physiological stress by measuring 16 blood-borne immune markers at 8 time points before, during and after maximum exercise challenge in n = 12 GWI veterans and n = 11 healthy veteran controls deployed to the same theater. Immune markers were combined into functional sets and the dynamics of their joint expression described as classical rate equations. These empirical networks were further informed structurally by projection onto prior knowledge networks mined from the literature. Of the 49 literature-informed immune signaling interactions, 21 were found active in the combined exercise response data. However, only 4 signals were common to both subject groups while 7 were uniquely active in GWI and 10 uniquely active in healthy veterans. Feedforward mediation of IL-23 and IL-17 by IL-6 and IL-10 emerged as distinguishing control elements that were characteristically active in GWI versus healthy subjects. Simulated restructuring of the regulatory circuitry in GWI as a result of applying an IL-6 receptor antagonist in combination with either a Th1 (IL-2, IFNγ, and TNFα) or IL-23 receptor antagonist predicted a partial rescue of immune response elements previously associated with illness severity. Overall, results suggest that pharmacologically altering the topology of the immune response circuitry identified as active in GWI can inform on strategies that while not curative, may nonetheless deliver a reduction in symptom burden. A lasting and more complete remission in GWI may therefore require manipulation of a broader physiology, namely one that includes endocrine oversight of immune function.

Military service and deployment affect women differently than men, underscoring the need for studies of the health of women veterans and their receipt of health care services. Despite the large numbers of women who served during the 1990–1991 Gulf War, few studies have evaluated Gulf War illness (GWI) and other medical conditions specifically as they affect women veterans of the 1991 Gulf War. The objectives of the Gulf War Women’s Health Cohort study are: (1) to establish the Gulf War women’s cohort (GWWC), a large sample of women veterans who served in the 1990–1991 Gulf War and a comparison group of women who served in other locations during that period; and (2) to provide current, comprehensive data on the health status of women who served during the 1990–1991 Gulf War, and identify any specific conditions that affect Gulf War women veterans at excess rates. The study will utilize both existing datasets and newly collected data to examine the prevalence and patterns of Gulf War Illness symptoms, diagnosed medical conditions, reproductive health, birth outcomes and other health issues among women who served during the Gulf War. The Gulf War Women’s Health Cohort study will address the need for information about the comprehensive health of women veterans who were deployed to the Gulf War, and other wars during the Gulf War era.

Enduring brain dysfunction is amid the highly manifested symptoms in veterans with Gulf War Illness (GWI). Animal studies have established that lasting brain dysfunction in GWI is concomitant with augmented oxidative stress, inflammation, and declined neurogenesis in the brain, and systemic inflammation. We hypothesize that drugs capable of restoring redox homeostasis in GWI will improve cognitive and mood function with modulation of neuroinflammation and neurogenesis. We examined the efficacy of monosodium luminol-GVT (MSL), a drug that promotes redox homeostasis, for improving cognitive and mood function in GWI rats. Young rats were exposed to GWI-related chemicals and moderate restraint stress for four weeks. Four months later, GWI rats received different doses of MSL or vehicle for eight weeks. Behavioral analyses in the last three weeks of treatment revealed that GWI rats receiving higher doses of MSL displayed better cognitive and mood function associated with reinstatement of redox homeostasis. Such restoration was evident from the normalized expression of multiple genes encoding proteins involved in combating oxidative stress in the brain and the return of several oxidative stress markers to control levels in the brain and the circulating blood. Sustained redox homeostasis by MSL also resulted in antiinflammatory and pro-neurogenic effects, which were apparent from reduced densities of hypertrophied astrocytes and activated microglia, and increased neurogenesis with augmented neural stem cell proliferation. Moreover, MSL treatment normalized the concentration of multiple proinflammatory markers in the circulating blood. Thus, MSL treatment reinstated redox homeostasis in an animal model of GWI, which resulted in alleviation of both brain and systemic inflammation, improved neurogenesis, and better cognitive and mood function., Highlights • Brain dysfunction in an animal model of Gulf War Illness is linked with persistently elevated oxidative stress. • Monosodium Luminol treatment reinstated redox homeostasis in a model of Gulf War Illness. • Reinstatement of redox balance improved cognitive and mood function. • Restoration of redox balance modulated reactive astrocytes and activated microglia in the brain. • Return of redox homeostasis enhanced neurogenesis and suppressed systemic inflammation.

Gulf War Illness affects 25–32% of veterans from the 1990–91 Persian Gulf War. Post-exertional malaise with cognitive dysfunction, pain and fatigue following physical and/or mental effort is a defining feature of Gulf War Illness. We modelled post-exertional malaise by assessing changes in functional magnetic resonance imaging at 3T during an N-Back working memory task performed prior to a submaximal bicycle stress test and after an identical stress test 24 h later. Serial trends in postural changes in heart rate between supine and standing defined three subgroups of veterans with Gulf War Illness: Postural Orthostatic Tachycardia Syndrome (GWI-POTS, 15%, n = 11), Stress Test Associated Reversible Tachycardia (GWI-START, 31%, n = 23) and Stress Test Originated Phantom Perception (GWI-STOPP, no postural tachycardia, 54%, n = 46). Before exercise, there were no differences in blood oxygenation level-dependent activity during the N-Back task between control (n = 31), GWI-START, GWI-STOPP and GWI-POTS subgroups. Exercise had no effects on blood oxygenation level-dependent activation in controls. GWI-START had post-exertional deactivation of cerebellar dentate nucleus and vermis regions associated with working memory. GWI-STOPP had significant activation of the anterior supplementary motor area that may be a component of the anterior salience network. There was a trend for deactivation of the vermis in GWI-POTS after exercise. These patterns of cognitive dysfunction were apparent in Gulf War Illness only after the exercise stressor. Mechanisms linking the autonomic dysfunction of Stress Test Associated Reversible Tachycardia and Postural Orthostatic Tachycardia Syndrome to cerebellar activation, and Stress Test Originated Phantom Perception to cortical sensorimotor alterations, remain unclear but may open new opportunities for understanding, diagnosing and treating Gulf War Illness., Gulf War Illness (GWI) symptoms worsen after exercise. The GWI population is composed of two subgroups based on heartrate (GWI-START and GWI-STOPP). No brain activation differences between subgroups exist before exercise. After exercise, the GWI-START subgroup decreases in cerebellar activation while the GWI-STOPP subgroup increases in supplementary motor area activation., Graphical Abstract Graphical Abstract

Background Gulf War illness (GWI) is an archetypal, medically unexplained, chronic condition characterised by persistent sickness behaviour and neuroimmune and neuroinflammatory components. An estimated 25–32% of the over 900,000 veterans of the 1991 Gulf War fulfil the requirements of a GWI diagnosis. It has been hypothesised that the high physical and psychological stress of combat may have increased vulnerability to irreversible acetylcholinesterase (AChE) inhibitors leading to a priming of the neuroimmune system. A number of studies have linked high levels of psychophysiological stress and toxicant exposures to epigenetic modifications that regulate gene expression. Recent research in a mouse model of GWI has shown that pre-exposure with the stress hormone corticosterone (CORT) causes an increase in expression of specific chemokines and cytokines in response to diisopropyl fluorophosphate (DFP), a sarin surrogate and irreversible AChE inhibitor. Methods C57BL/6J mice were exposed to CORT for 4 days, and exposed to DFP on day 5, before sacrifice 6 h later. The transcriptome was examined using RNA-seq, and the epigenome was examined using reduced representation bisulfite sequencing and H3K27ac ChIP-seq. Results We show transcriptional, histone modification (H3K27ac) and DNA methylation changes in genes related to the immune and neuronal system, potentially relevant to neuroinflammatory and cognitive symptoms of GWI. Further evidence suggests altered proportions of myelinating oligodendrocytes in the frontal cortex, perhaps connected to white matter deficits seen in GWI sufferers. Conclusions Our findings may reflect the early changes which occurred in GWI veterans, and we observe alterations in several pathways altered in GWI sufferers. These close links to changes seen in veterans with GWI indicates that this model reflects the environmental exposures related to GWI and may provide a model for biomarker development and testing future treatments. Electronic supplementary material The online version of this article (10.1186/s12974-018-1113-9) contains supplementary material, which is available to authorized users.

Aims Gulf War Illness (GWI), a chronic debilitating disorder characterized by fatigue, joint pain, cognitive, gastrointestinal, respiratory, and skin problems, is currently diagnosed by self-reported symptoms. The Boston Biorepository, Recruitment, and Integrative Network (BBRAIN) is the collaborative effort of expert Gulf War Illness (GWI) researchers who are creating objective diagnostic and pathobiological markers and recommend common data elements for GWI research. Main methods BBRAIN is recruiting 300 GWI cases and 200 GW veteran controls for the prospective study. Key data and biological samples from prior GWI studies are being merged and combined into retrospective datasets. They will be made available for data mining by the BBRAIN network and the GWI research community. Prospective questionnaire data include general health and chronic symptoms, demographics, measures of pain, fatigue, medical conditions, deployment and exposure histories. Available repository biospecimens include blood, plasma, serum, saliva, stool, urine, human induced pluripotent stem cells and cerebrospinal fluid. Key findings To date, multiple datasets have been merged and combined from 15 participating study sites. These data and samples have been collated and an online request form for repository requests as well as recommended common data elements have been created. Data and biospecimen sample requests are reviewed by the BBRAIN steering committee members for approval as they are received. Significance The BBRAIN repository network serves as a much needed resource for GWI researchers to utilize for identification and validation of objective diagnostic and pathobiological markers of the illness.

Gulf War Illness (GWI) is a chronic multi-symptomatic illness that is associated with fatigue, pain, cognitive deficits, and gastrointestinal disturbances and presents a significant challenge to treat in clinics. Our previous studies show a role of an altered Gut–Brain axis pathology in disease development and symptom persistence in GWI. The present study utilizes a mouse model of GWI to study the role of a labdane diterpenoid andrographolide (AG) to attenuate the Gut–Brain axis-linked pathology. Results showed that AG treatment in mice (100 mg/kg) via oral gavage restored bacteriome alterations, significantly increased probiotic bacteria Akkermansia, Lachnospiraceae, and Bifidobacterium, the genera that are known to aid in preserving gut and immune health. AG also corrected an altered virome with significant decreases in virome families Siphoviridae and Myoviridae known to be associated with gastrointestinal pathology. AG treatment significantly restored tight junction proteins that correlated well with decreased intestinal proinflammatory mediators IL-1β and IL-6 release. AG treatment could restore Claudin-5 levels, crucial for maintaining the BBB integrity. Notably, AG could decrease microglial activation and increase neurotrophic factor BDNF, the key to neurogenesis. Mechanistically, microglial conditioned medium generated from IL-6 stimulation with or without AG in a concentration similar to circulating levels found in the GWI mouse model and co-incubated with neuronal cells in vitro, decreased Tau phosphorylation and neuronal apoptosis. In conclusion, we show that AG treatment mitigated the Gut–Brain-Axis associated pathology in GWI and may be considered as a potential therapeutic avenue for the much-needed bench to bedside strategies in GWI.

Background Gulf War Illness (GWI) is a multisystem disorder that has affected a substantial number of veterans who served in the 1990–91 Gulf War. The brain is prominently affected, as manifested by the presence of neurological, cognitive and mood symptoms. We reported previously on the protective role of six Human Leukocyte Antigen (HLA) alleles in GWI (Georgopoulos et al., 2016) and their association with regional brain function (James et al., 2016). More recently, we reported on the presence of subcortical brain atrophy in GWI (Christova et al., 2017) and discussed its possible relation to immune mechanisms. Here we focused on one of the six HLA GWI-protective HLA alleles, DRB1*13:02, which has been found to have a protective role in a broad range of autoimmune diseases (Furukawa et al., 2017), and tested its effects on brain volumes. Methods Seventy-six Gulf War veterans (55 with GWI and 21 healthy controls) underwent a structural Magnetic Resonance Imaging (sMRI) scan to measure the volumes of 9 subcortical brain regions to assess differences between participants with (N = 11) and without (N = 65) HLA class II allele DRB1*13:02. Findings We found that DRB1*13:02 spared subcortical brain atrophy in Gulf War veterans; overall subcortical volume was 6.6% higher in carriers of DRB1*13:02 (P = 0.007). The strongest effect was observed in the volume of cerebellar gray matter which was 9.6% higher (P = 0.007) in carriers of DRB1*13:02 than in non-carriers. By contrast, DRB1*13:01 had no effect. Interpretation These findings document the protective effect of DRB1*13:02 on brain atrophy in Gulf War veterans and are in keeping with recent results documenting sharing of brain mechanisms between GWI and other immune-related diseases (Georgopoulos et al., 2017). We hypothesize that the protective role of DRB1*13:02 is due to its successful elimination of external antigens to which Gulf War veterans were exposed, antigens that otherwise would persist causing low-grade inflammation and possibly leading to autoimmunity. Funding source U.S. Department of Defense (W81XWH-15-1-0520), Department of Veterans Affairs, American Legion Brain Sciences Chair, and University of Minnesota., Highlights • Subcortical brain atrophy is spared in Gulf War veterans with DRB1*13:02 allele and unaffected by the DRB1*13:01 allele. • The strongest protective effect of the DRB1*13:02 allele was observed for cerebellar gray matter volume. • No significant effects were observed at the DRB1*13 gene level, highlighting the importance of 4-digit HLA protein level. Gulf War Illness (GWI) is a chronic, debilitating disorder that prominently involves the brain and is characterized, in particular, by subcortical brain atrophy. Protective effects of specific Human Leukocyte Antigen (HLA) Class II alleles on GWI have been observed, suggesting immune system involvement in GWI. Here we evaluated protective effects of DRB1*13:02 on subcortical brain volume in Gulf War veterans. The results demonstrate a protective effect of DRB1*13:02 on brain atrophy, with a marked effect on cerebellar gray matter volume. Given the goal of HLA Class II alleles is to eliminate pathogens by producing antibodies against them, the present study provides compelling insights into the likely role of persistent, pathogenic antigens resulting from the absence of DRB1*13:02 in those with GWI.

Objective Gulf War Illness is a chronic multisymptom disorder severely impacting the health and well-being of many Veterans of the 1990–1991 Gulf War. Symptoms that define the disease include pain, fatigue, mood and memory impairments, gastrointestinal problems, lung disorders, and skin rashes. In our previous biomarker study, we discovered Gulf War Illness-associated proinflammatory blood biomarkers. Therefore, we hypothesized that chronic inflammation causes the symptoms that define this disorder. Testing the chronic inflammation hypothesis is the objective of this study. Results The biomarker fingerprint of Gulf War Illness is the end-product of a cascade of proinflammatory cytokine signals. In particular, the observed increase in C-reactive protein predicts a corresponding increase in interleukin 6, the cytokine that stimulates hepatocytes to produce C-reactive protein. Therefore, in this study we measured potential upstream cytokine signals in plasma samples from Gulf War Veterans. As predicted, a positive correlation between interleukin 6 and C-reactive protein was observed.

Gulf War Illness (GWI) is a chronic multi-symptom disorder, characterized by symptoms such as fatigue, pain, cognitive and memory impairment, respiratory, skin and gastrointestinal problems, that is experienced by approximately one-third of 1991 Gulf War veterans. Over the nearly three decades since the end of the war, investigators have worked to elucidate the initiating factors and underlying causes of GWI. A significant portion of this research has indicated a strong correlation between GWI and exposure to a number of different acetycholinesterase inhibitors (AChEIs) in theater, such as sarin and cyclosarin nerve agents, chlorpyrifos and dichlorvos pesticides, and the anti-nerve agent prophylactic pyridostigmine bromide. Through studying these exposures and their relationship to the symptoms presented by ill veterans, it has become increasingly apparent that GWI is the likely result of an underlying neuroimmune disorder. While evidence indicates that AChEIs are a key exposure in the development of GWI, particularly organophosphate AChEIs, the mechanism(s) by which these chemicals instigate illness appears to be related to "off-target", non-cholinergic effects. In this review, we will discuss the role of AChEI exposure in the development and persistence of GWI; in particular, how these chemicals, combined with other exposures, have led to a chronic neuroimmune disorder. This article is part of the special issue entitled 'Acetylcholinesterase Inhibitors: From Bench to Bedside to Battlefield'.

Gulf War Illness (GWI), affecting 30% of veterans from the 1991 Gulf War (GW), is a multi-symptom illness with features similar to those of patients with autoimmune diseases. The objective of the current work is to determine if exposure to GW-related pesticides, such as permethrin (PER), activates peripheral and central nervous system (CNS) adaptive immune responses. In the current study, we focused on a PER metabolite, 3-phenoxybenzoic acid (3-PBA), as this is a common metabolite previously shown to form adducts with endogenous proteins. We observed the presence of 3-PBA and 3-PBA modified lysine of protein peptides in the brain, blood and liver of pyridostigmine bromide (PB) and PER (PB + PER) exposed mice at acute and chronic post-exposure timepoints. We tested whether 3-PBA-haptenated albumin (3-PBA-albumin) can activate immune cells since it is known that chemically haptenated proteins can stimulate immune responses. We detected autoantibodies against 3-PBA-albumin in plasma from PB + PER exposed mice and veterans with GWI at chronic post-exposure timepoints. We also observed that in vitro treatment of blood with 3-PBA-albumin resulted in the activation of B- and T-helper lymphocytes and that these immune cells were also increased in blood of PB + PER exposed mice and veterans with GWI. These immune changes corresponded with elevated levels of infiltrating monocytes in the brain and blood of PB + PER exposed mice which coincided with alterations in the markers of blood-brain barrier disruption, brain macrophages and neuroinflammation. These studies suggest that pesticide exposure associated with GWI may have resulted in the activation of the peripheral and CNS adaptive immune responses, possibly contributing to an autoimmune-type phenotype in veterans with GWI.

Approximately 30% of the 700,000 US veterans of the 1990&ndash, 1991 Persian Gulf War developed multiple persistent symptoms called Gulf War illness. While the etiology is uncertain, several toxic exposures including pesticides and chemical warfare agents have shown associations. There is no effective medical treatment. An intervention to enhance detoxification developed by Hubbard has improved quality of life and/or reduced body burdens in other cohorts. We evaluated its feasibility and efficacy in ill Gulf War (GW) veterans in a randomized, waitlist-controlled, pilot study at a community-based rehabilitation facility in the United States. Eligible participants (n = 32) were randomly assigned to the intervention (n = 22) or a four-week waitlist control (n = 10). The daily 4&ndash, 6 week intervention consisted of exercise, sauna-induced sweating, crystalline nicotinic acid and other supplements. Primary outcomes included recruitment, retention and safety, and efficacy was measured via Veteran&rsquo, s Short Form-36 (SF-36) quality of life, McGill pain, multidimensional fatigue inventory questionnaires and neuropsychological batteries. Scoring of outcomes was blinded. All 32 completed the trial and 21 completed 3-month follow-up. Mean SF-36 physical component summary score after the intervention was 6.9 (95% CI, &minus, 0.3, 14.2) points higher compared to waitlist control and 11 of 16 quality of life, pain and fatigue measures improved, with no serious adverse events. Most improvements were retained after 3 months. The Hubbard regimen was feasible, safe and might offer relief for symptoms of GW illness.

Gulf War Illness (GWI) is a chronic multi-symptom disorder affecting the central nervous system (CNS), immune and gastrointestinal (GI) systems of Gulf War veterans (GWV). We assessed the relationships between GWI, GI symptoms, gut microbiome and inflammatory markers in GWV from the Boston Gulf War Illness Consortium (GWIC). Three groups of GWIC veterans were recruited in this pilot study, GWV without GWI and no gastrointestinal symptoms (controls), GWV with GWI and no gastrointestinal symptoms (GWI-GI), GWV with GWI who reported gastrointestinal symptoms (GW+GI). Here we report on a subset of the first thirteen stool samples analyzed. Results showed significantly different gut microbiome patterns among the three groups and within the GWI +/&minus, GI groups. Specifically, GW controls had a greater abundance of firmicutes and the GWI+GI group had a greater abundance of the phyla bacteroidetes, actinobacteria, euryarchaeota, and proteobacteria as well as higher abundances of the families Bacteroidaceae, Erysipelotrichaceae, and Bifidobacteriaceae. The GWI+GI group also showed greater plasma levels of the inflammatory cytokine TNF-RI and they endorsed significantly more chemical weapons exposure during the war and reported significantly greater chronic pain, fatigue and sleep difficulties than the other groups. Studies with larger samples sizes are needed to confirm these initial findings.

Objectives: This study aims to assess (1) the difference in the prevalence of headaches, pain, and other associated symptoms between Gulf War I (1990–1991) and Post-Gulf War I (1992–2015) veterans who served as active military personnel in the Persian Gulf and (2) how the durations of deployment may affect the prevalence of those symptoms. Methods: With institutional human subject committee approval, veterans who were accepted to the Gulf War Registry at the VA San Diego Healthcare System between July 2013 and June 2015 ( N = 367) were included in this retrospective chart review study and grouped according to the Gulf War period they served under or how long they were deployed to the Persian Gulf. Chi-square was used for categorical data analyses and analysis of variance was conducted for continuous outcomes. All analyses were two-tailed, where applicable, with α = 0.05 and Bonferroni for pairwise group comparisons. Results: Veterans who served during Post-Gulf War I or both Gulf War I and Post-Gulf War I exhibited more pain and neurological symptoms than Gulf War I veterans ( p = 0.005, p = 0.003). In addition, veterans who served ⩾12 months reported more overall pain symptoms and analgesic use than those who served less time ( p Conclusion: The findings suggest that the length of deployment and Persian Gulf deployment period may play a role in acquiring headaches, pain, and other associated symptoms with increased analgesic consumption.

Gulf War Illness (GWI) is a chronic debilitating disease of unknown etiology that affects the brain and has afflicted many veterans of the 1990-91 Gulf War (GW). We showed recently1 that blood serum from patients suffering from GWI exerts detrimental effects on neural cultures, including reduced growth, increased apoptosis, and disruption of neural network function. Remarkably, these adverse effects were prevented by the concomitant addition to the culture of serum from healthy Gulf War (GW) era veterans. We interpreted those findings1 in the context of our hypothesis that GWI is, at least partly, due to circulating pathogenic persistent antigens2, probably coming from vaccines administered to GW veterans who lacked crucial Human Leukocyte Antigen (HLA) class 2 alleles3 and, therefore, could not make antibodies against those antigens; by contrast, healthy GW veterans who received the same vaccines and possessed HLA protection3 made antibodies that neutralized the various antigens. Thus, we hypothesized that the beneficial effect of the healthy serum on preventing the adverse GWI serum effects was due to the presence of antibodies against the persistent antigens. Here we tested this hypothesis by assessing the effect of pooled human immunoglobulin G (IgG) on ameliorating the GWI adverse effects on neural growth and apoptosis in neuroblastoma N2A cultures. We tested this effect in 14 GWI patients and found that IgG exerted a potent ameliorating effect by inhibiting the reduction in growth and increased apoptosis of GWI serum. These results lend support to our persistent antigen hypothesis1,2 and suggest an immunotherapy approach for treating GWI. This approach is further strengthened by our finding that the severity of GWI neurocognitive/mood (NCM) symptoms was positively correlated with the degree of apoptosis caused by GWI serum on the neural culture, thus validating the relevance of the apoptotic effect to NCM symptomatology. Finally, we used this relation to predict NCM scores based on the reduced apoptosis effected by IgG addition and found a predicted reduction in NCM symptom severity by ~60%. Altogether, these findings point to the possible beneficial use of IgG in treating GWI.

Prevalence of nine chronic medical conditions in the population-based Ft. Devens Cohort (FDC) of GW veterans were compared with the population-based 2013&ndash, 2014 National Health and Nutrition Examination Survey (NHANES) cohort. Excess prevalence was calculated as the difference in prevalence estimates from the Ft. Devens and NHANES cohorts, and confidence intervals and p-values are based on the standard errors for the two prevalence estimates. FDC males were at increased risk for reporting seven chronic medical conditions compared with NHANES males. FDC females were at decreased risk for high blood pressure and increased risk for diabetes when compared with NHANES females. FDC veterans reporting war-related chemical weapons exposure showed higher risk of high blood pressure, diabetes, arthritis and chronic bronchitis while those reporting taking anti-nerve gas pills had increased risk of heart attack and diabetes. GW veterans are at higher risk of chronic conditions than the general population and these risks are associated with self-reported toxicant exposures.

An estimated 25%–32% of veterans of the 1991 Gulf War continue to experience multiple unexplained health problems known as Gulf War Illness (GWI). GWI encompasses chronic pain, musculoskeletal weakness, headache, fatigue, cognitive deficits, alterations in mood, and numerous multi-system complaints. Most potential exposures implicated in GWI were not well documented but included varying levels of several neurotoxicants as well as the anticholinergic drug pyridostigmine bromide (PB), which was routinely taken as prophylaxis against the nerve agent soman. While some veterans also took chloroquine as an antimalarial agent, the literature suggests an association between receipt of multiple vaccinations prior to or during the conflict (perhaps combined with other exposures), and GWI. In-theater exposures may account for any single individual veteran’s ill health but many veterans of the same era who were not deployed overseas also suffer the same or similar symptoms. The features of GWI also overlap with those of fibromyalgia, chronic fatigue syndrome and multiple chemical sensitivity, in all of which liver dysfunction has been documented, suggesting a unifying hypothesis. It is proposed that multiple vaccinations, with concurrent or subsequent exposure to PB or additional chemical insults of a liver-damaging nature, plausibly explain the pathogenesis and the observed chronicity of GWI. The suggested mechanism for GWI is thus a chemically-induced impaired liver function, with the spillage of stored vitamin A compounds (“retinoids”) into the circulation in toxic concentrations, resulting in an endogenous chronic form of hypervitaminosis A. Implications of the hypothesis are briefly reviewed.

Gulf war illness (GWI), is a chronic multi-symptom illness that has impacted approximately one-third of the veterans who served in the 1990 to 1991 Gulf War. GWI symptoms include cognitive impairments (eg, memory and concentration problems), headaches, migraines, fatigue, gastrointestinal and respiratory issues, as well as emotional deficits. The exposure to neurological chemicals such as the anti-nerve gas drug, pyridostigmine bromide (PB), and the insecticide permethrin (PER), may contribute to the etiologically related factors of GWI. Various studies utilizing mouse models of GWI have reported the interplay of these chemical agents in increasing neuroinflammation and cognitive dysfunction. Astrocytes are involved in the secretion of neuroinflammatory cytokines and chemokines in pathological conditions and have been implicated in GWI symptomology. We hypothesized that exposure to PB and PER causes lasting changes to hippocampal astrocytes, concurrent with chronic cognitive deficits that can be reversed by cervical vagus nerve stimulation (VNS). GWI was induced in CD1 mice by injecting the mixture of PER (200 mg/kg) and PB (2 mg/kg), i.p. for 10 consecutive days. VNS stimulators were implanted at 33 weeks after GWI induction. The results show age-related cognitive alterations at approximately 9 months after exposure to PB and PER. The results also showed an increased number of GFAP-labeled astrocytes in the hippocampus and dentate gyrus that was ameliorated by VNS.

Gulf War illness (GWI) research has generated an abundance of interesting but diverse data. While increased molecular mechanisms have been identified, the high levels of heterogeneity for initial trigger factors, cellular defects, and symptoms continuously challenge the efforts of clinical implications of the research, including the search for biomarkers and the common mechanism of GWI. In this analysis, I consider GWI as an adaptive illness condition where system stresses and genome instability-mediated cellular evolution play an important role. By further defining GWI as an environmental illness caused by extremely high levels of specific Gulf War (GW) stresses, the challenges for GWI research are briefly reviewed, with comparisons to other common and complex diseases such as cancer. Based on the new discovery that many GWI patients display elevated genome instability coupled with increased cellular stress, a general model of GWI is proposed to unify GW-specific stress, cellular damage, and genome-heterogeneity-mediated cellular adaptation and evolution, as well as diverse-related symptoms. Finally, some new strategies are suggested based on the general model of GWI.

Gulf War illness is associated with a combination of exposure to war-related chemical agents and traumatic stress. Currently, there are no effective treatments, and the pathophysiology remains elusive. Neurological problems are among the most commonly reported symptoms. In this study, we investigated the glutamatergic system in the hippocampi of mice exposed to war-related chemical agents and stress. Mice developed Gulf War illness-like symptoms, including mood deficits, cognitive impairments, and fatigue. They exhibited the following pathological changes in hippocampi: elevated extracellular glutamate levels, impaired glutamatergic synapses, astrocyte atrophy, loss of interneurons, and decreased neurogenesis. LDN/OSU-215111 is a small-molecule that can strengthen the structure and function of both the astrocytic processes and the glutamatergic synapses that together form the tripartite synapses. We found that LDN/OSU-215111 effectively prevented the development of mood and cognitive deficits in mice when treatment was implemented immediately following the exposure. Moreover, when symptoms were already present, LDN/OSU-215111 still significantly ameliorated these deficits; impressively, benefits were sustained one month after treatment cessation, indicating disease modification. LDN/OSU-215111 effectively normalized hippocampal pathological changes. Overall, this study provides strong evidence that restoration of tripartite glutamatergic synapses by LDN/OSU-215111 is a potential therapy for Gulf War illness., Highlights • Exposure to Gulf War-related agents and stress causes long-term hippocampal glutamatergic synapses impairment. • LDN/OSU-215111, a small-molecule that enhances tripartite synapses, normalizes hippocampal deficits in a mouse model of GWI. • LDN/OSU-215111 effectively ameliorates mood deficits, cognitive impairments, and fatigue in a mouse model of GWI.

Indications of proximal tubule effects have been observed in recent surveillance study of Gulf War veterans exposed to depleted uranium (DU). This gives some support for the suspicion that DU may represent one of the causes for the so-called Persian Gulf syndrome. Proposed effects may be especially harmful if the toxicity hits the mitochondrial DNA since the mitochondria lack the nucleotide excision repair mechanism, which is needed for repairing bulky adducts that have been associated with DU. It is a plausible working hypothesis that a significant part of the symptoms from various organs, which have been observed among veterans from Gulf War 1 and that have been grouped under the name of the Persian Gulf syndrome, may be explained as a consequence of mitochondrial DNA damage in various cell types and organs. Interpretation of observations, on military personnel and civilians after Gulf War 1, is associated with difficulties because of the abundance of potential confounding factors. The symptoms observed on veterans from Gulf War 1 may be attributed to a multiplicity of substances functioning directly or indirectly as mitochondrial mutagens. A concise analysis of the cascade of toxic effects initiated by DU exposure in the human body is the subject of this article.

Protective antigen (PA) 63 (PA63) is a protein derived from the PA83 component contained in the anthrax vaccine. The anthrax vaccine (“Biothrax”) was administered together with other vaccines to Gulf War veterans, about 35% of whom later developed a multisymptom disease (Gulf War Illness [GWI]), with prominent neurological/cognitive/mood symptoms, among others. The disease has been traditionally attributed to exposures to toxic chemicals during the war but other factors could be involved, including vaccines received. Of these, the anthrax vaccine is the most toxic. Here, we assessed directly the PA63 toxin’s harmful effects on cultured neuroblastoma 2A (N2A) cells with respect to cell spreading, process formation, apoptosis, and integrity of cell membrane, cytoskeleton, and mitochondria. We found that, when added in N2A cultures, PA63 toxin led to decreased cell spreading and cell aggregation, leading to apoptosis. The mechanisms of PA63-induced cell damage included compromised cell membrane permeability indicated by enhanced access of propidium iodide in cells. In addition, signaling pathways leading to organization of N2A cytoskeleton were negatively affected, as both actin and microtubular networks were compromised. Finally, the mitochondrial membrane potential was impaired in specific assays. Altogether, these alterations led to apoptosis as a collective toxic effect of PA63 which was substantially reduced by the concomitant addition of specific antibodies against PA63.

The Gulf War Illness Consortium (GWIC) was designed to identify objective biomarkers of Gulf War Illness (GWI) in 1991 Gulf War veterans. The symptoms of GWI include fatigue, pain, cognitive problems, gastrointestinal, respiratory, and skin problems. Neurotoxicant exposures during deployment, such as pesticides, sarin, and pyridostigmine bromide pills have been identified as contributors to GWI. We have also found an association between mild traumatic brain injury (mTBI) and increased rates of GWI. However, the combined impact of these physical and chemical exposures has not yet been explored in GWI. The objective of this study was to examine both self-reported mTBI and exposure to chemical/biological weapons (CBW) as a multiple or two hit model for increased risk of GWI and other chronic health conditions. The study population included 125 Gulf War (GW) veterans from the Boston GWIC. Exposure to CBW was reported in 47.2% of the study population, and 35.2% reported sustaining a mTBI during the war. Results confirmed that those with both exposures (mTBI and CBW) had higher rates of comorbid chronic health conditions while rates of GWI were equivalent for mTBI and CBW or mTBI alone. The timing of exposure to mTBI was found to be strikingly different between those with GWI and those without it. Correspondingly, 42.3% of GWI cases reported experiencing a mTBI during military service while none of the controls did (p = 0.0002). Rates of mTBI before and after the war did not differ between the cases and controls. In addition, 54% of cases compared to 14.3% of controls (p = &lt, 0.001) reported being exposed to CBW during military service. The current study examined the relation of the separate and combined effects of exposure to mTBI and CBW in 1991 GW veterans. The findings from this study suggest that both exposure to mTBI and CBW are associated with the development of GWI and multiple chronic health conditions and that combined exposure appears to lead to higher risk of chronic health effects.

Gulf War Illness (GWI) is a chronic multisymptom illness characterized by fatigue, musculoskeletal pain, and gastrointestinal and cognitive dysfunction believed to stem from chemical exposures during the 1990&ndash, 1991 Persian Gulf War. There are currently no treatments, however, previous studies have predicted a putative multi-intervention treatment composed of inhibiting Th1 immune cytokines followed by inhibition of the glucocorticoid receptor (GCR) to treat GWI. These predictions suggest the use of specific monoclonal antibodies or suramin to target interleukin-2 and tumor necrosis factor &alpha, followed by mifepristone to inhibit the GCR. In addition to this putative treatment strategy, there exist a variety of medications that target GWI symptomatology. As pharmaceuticals are promiscuous molecules, binding to multiple sites beyond their intended targets, leading to off-target interactions, it is key to ensure that none of these medications interfere with the proposed treatment avenue. Here, we used the drug docking programs AutoDock 4.2, AutoDock Vina, and Schr&ouml, dinger&rsquo, s Glide to assess the potential off-target immune and hormone interactions of 43 FDA-approved drugs commonly used to treat GWI symptoms in order to determine their putative polypharmacology and minimize adverse drug effects in a combined pharmaceutical treatment. Several of these FDA-approved drugs were predicted to be novel binders of immune and hormonal targets, suggesting caution for their use in the proposed GWI treatment strategy symptoms.

Background Communication between patients and providers about persistent “medically unexplained” physical symptoms (MUS) is characterized by discordance. While the difficulties are well documented, few studies have examined effective communication. We sought to determine what veterans with Gulf War Illness (GWI) perceive as the most helpful communication from their providers. Veterans with GWI, a type of MUS, have historically had complex relationships with medical providers. Determining effective communication for patients with particularly complex relationships may help identify the most critical communication elements for all patients with MUS. Methods Two hundred and-ten veterans with GWI were asked, in a written questionnaire, what was the most useful thing a medical provider had told them about their GWI. Responses were coded into three categories with 10 codes. Results The most prevalent helpful communication reported by patients was when the provider offered acknowledgement and validation (N = 70). Specific recommendations for managing GWI or its symptoms (N = 48) were also commonly reported to be helpful. In contrast, about a third of the responses indicated that nothing about the communication was helpful (N = 63). There were not differences in severity of symptoms, disability or healthcare utilization between patients who found acknowledgement and validation, specific recommendations or nothing helpful. Conclusions Previous research has documented the discord between patients and providers regarding MUS. This study suggests that most patients are able to identify something helpful a provider has said, particularly acknowledgement and validation and specific treatment recommendations. The findings also highlight missed communication opportunities with a third of patients not finding anything helpful.