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Aims: In light of the evidence supporting a significant role of the gut microbiome in Gulf War Illness (GWI) pathology, we sought to examine its contribution to GWI susceptibility in a mouse model. We also aimed to identify bacterial taxa and microbially-derived metabolites associated with disease susceptibility., Main Methods: Male mice receiving pyridostigmine bromide (PB) orally, and controls were evaluated for symptoms of GWI at 8 weeks post-treatment. The Kansas criteria were adapted to assess behaviors associated with the following domains: gastrointestinal alterations, pain, mood, cognitive function, skin and respiratory disturbances. PB-treated subjects were classified into susceptible (GWI-S) or resilient (GWI-R). The status of the gut microbiome was assessed via analyses of the 16S rRNA gene and microbial-derived metabolites were evaluated with metabolomics tools., Key Findings: Our results indicate that application of the Kansas criteria to behavioral outcomes in PB-treated mice resulted in a GWI susceptibility rate of ~35 %, similar to the one reported in humans. The composition and structure of the gut microbiome was different in GWI-S subjects compared to both control and GWI-R mice at 8 weeks but differences in microbial community structure were observed prior to PB treatment between GWI-R and GWI-S mice. GWI-S subjects exhibited a pattern of differentially abundant bacterial taxa and microbial metabolites., Significance: To our knowledge, this is the first preclinical report in which a stratification by susceptibility to GWI and its association with the gut microbiome is described. In light of the research conundrum that vulnerability to GWI represents, the use of tools that could provide further insight into this complex factor should be considered., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Mariana Angoa-Perez reports financial support was provided by US Department of Defense. Mariana Angoa-Perez reports financial support was provided by US Department of Veterans Affairs. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Gulf War Illness (GWI) is a chronic disorder characterized by a heterogeneous set of symptoms that include pain, fatigue, anxiety, and cognitive impairment. These are thought to stem from damage caused by exposure under unpredictable stress to toxic Gulf War (GW) chemicals, which include pesticides, nerve agents, and prophylactic drugs. We hypothesized that GWI pathogenesis might be rooted in long-lasting disruption of the endocannabinoid (ECB) system, a signaling complex that serves important protective functions in the brain. Using a mouse model of GWI, we found that tissue levels of the ECB messenger, anandamide, were significantly reduced in the brain of diseased mice, compared to healthy controls. In addition, transcription of the Faah gene, which encodes for fatty acid amide hydrolase (FAAH), the enzyme that deactivates anandamide, was significant elevated in prefrontal cortex of GWI mice and brain microglia. Behavioral deficits exhibited by these animals, including heightened anxiety-like and depression-like behaviors, and defective extinction of fearful memories, were corrected by administration of the FAAH inhibitor, URB597, which normalized brain anandamide levels. Furthermore, GWI mice displayed unexpected changes in the microglial transcriptome, implying persistent dampening of homeostatic surveillance genes and abnormal expression of pro-inflammatory genes upon immune stimulation. Together, these results suggest that exposure to GW chemicals produce a deficit in brain ECB signaling which is associated with persistent alterations in microglial function. Pharmacological normalization of anandamide-mediated ECB signaling may offer an effective therapeutic strategy for ameliorating GWI symptomology., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Organophosphates (OPs) are found in hundreds of important products used worldwide; however, they have been associated with adverse long-term health consequences ranging from neurodevelopmental deficits to age-related neurological diseases. OP exposure has also been implicated in Gulf War Illness; a cluster of medically unexplained chronic symptoms estimated to affect 25-32% of veterans of the Persian Gulf war in 1991. The development of multiple types of chronic illnesses in these veterans at an early age compared to the general population has led to the suggestion that they are experiencing signs of premature or accelerated aging. The process of cellular senescence and the development of the senescence-associated secretory phenotype (SASP) is believed to lead to chronic inflammation, chronic illnesses, as well as accelerated biological aging, and a role of environmental exposures in these processes has been suggested, but not extensively studied to date. In the studies described here, we evaluated the persistent effects of a single (acute) exposure of a representative nerve agent OP, diisopropylfluorophosphate (DFP) 4.0 mg/kg on cognitive function, noncognitive behaviors, cellular senescence markers and proinflammatory cytokines in the mouse brain. The results indicated modest, but persistent DFP-related impairments in spatial learning and working memory, but not contextual or cued fear conditioning. DFP exposure was also not associated with negative effects on weight or impairments of the various noncognitive (e.g., motor function or exploratory activity) behavioral assessments. Both histology and quantitative PCR experiments indicated that DFP was associated with persistent alterations in several senescence markers and proinflammatory cytokines in brain regions that are relevant to the performance of the memory-related tasks (e.g., hippocampus, prefrontal cortex). The results thus suggest that single acute exposures to OPs like DFP can lead to persistent impairments in specific domains of cognition that may be related to alterations in cellular senescence and inflammaging in the brain., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Terry, Beck, Zona, Itokazu, Tripathi, Madeshiya and Pillai.)

Background: Veterans of the 1990-1991 Gulf War have experienced excess health problems, most prominently the multisymptom condition Gulf War illness (GWI). The Department of Veterans Affairs (VA) Cooperative Studies Program #2006 "Genomics of Gulf War Illness in Veterans" project was established to address important questions concerning pathobiological and genetic aspects of GWI. The current study evaluated patterns of chronic ill health/GWI in the VA Million Veteran Program (MVP) Gulf War veteran cohort in relation to wartime exposures and key features of deployment, 27-30 years after Gulf War service., Methods: MVP participants who served in the 1990-1991 Gulf War completed the MVP Gulf War Era Survey in 2018-2020. Survey responses provided detailed information on veterans' health, Gulf War exposures, and deployment time periods and locations. Analyses determined associations of three defined GWI/ill health outcomes with Gulf War deployment characteristics and exposures., Results: The final cohort included 14,103 veterans; demographic and military characteristics of the sample were similar to the full population of U.S. 1990-1991 Gulf War veterans. Overall, a substantial number of veterans experienced chronic ill health, as indicated by three defined outcomes: 49% reported their health as fair or poor, 31% met Centers for Disease Control and Prevention criteria for severe GWI, and 20% had been diagnosed with GWI by a healthcare provider. Health outcomes varied consistently with veterans' demographic and military characteristics, and with exposures during deployment. All outcomes were most prevalent among youngest veterans (< 50 years), Army and Marine Corps veterans, enlisted personnel (vs. officers), veterans located in Iraq and/or Kuwait for at least 7 days, and veterans who remained in theater from January/February 1991 through the summer of 1991. In multivariable models, GWI/ill health was most strongly associated with three exposures: chemical/biological warfare agents, taking pyridostigmine bromide pills, and use of skin pesticides., Conclusions: Results from this large cohort indicate that GWI/chronic ill health continues to affect a large proportion of Gulf War veterans in patterns associated with 1990-1991 Gulf War deployment and exposures. Findings establish a foundation for comprehensive evaluation of genetic factors and deployment exposures in relation to GWI risk and pathobiology., (© 2024. The Author(s).)

Gulf War Illness (GWI) has been consistently linked to exposure to pyridostigmine (PB), N,N-Diethyl-meta-toluamide (DEET), permethrin (PER), and traces of sarin. In this study, diisopropylfluorophosphate (DFP, sarin surrogate) and the GWI-related chemicals were found to reduce the number of functionally active neurons in rat hippocampal slices. These findings confirm a link between GWI neurotoxicants and N-Methyl-D-Aspartate (NMDA)-mediated excitotoxicity, which was successfully reversed by Edelfosine (a phospholipase Cβ (PLCβ3) inhibitor) and Flupirtine (a Kv7 channel agonist). To test whether 4R-cembranoid (4R), a nicotinic α7 acetylcholinesterase receptor (α7AChR) modulator known for its neuroprotective properties, can restore hippocampal neurons from glutamate-induced neurotoxicity, we exposed rat hippocampal slices with DFP for 10 min followed by 60 min treatment with 4R. We investigated the 4R mechanisms of neuroprotection after preincubation with LY294002, PD98059, and KN-62. The inhibition of the phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MEK1/2), and calcium/calmodulin-dependent protein kinase (CaMKII) abrogated the protective effect of 4R against DFP-induced neurotoxicity. In separate experiments, after incubation with DFP, followed by 4R for 1 h, cellular extracts were prepared for Western blotting of phospho-Akt, phospho-GSK3β, phosphorylated extracellular signal-regulated kinase (ERK)1/2, CaMKII and cAMP response element-binding protein (CREB). Our results show that DFP induces neuronal dysfunction by dephosphorylation, while 4R restores the phosphorylation of Akt, GSK3, ERK1/2, CREB, and CaMKII. Moreover, our proteomics analysis supported the notion that 4R activates additional signaling pathways related to enhancing neuronal signaling, synaptic plasticity, and apoptotic inhibition to promote cell survival against DFP, offering biomarkers for developing treatment against GWI., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Nadezhda Sabeva reports financial support, article publishing charges, equipment, drugs, supplies, travel, and writing assistance were provided by the National Institutes of Health. Pedro A. Ferchmin has a patent issued to Universidad Central del Caribe. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Ltd.)

Gulf War Illness (GWI) is a disorder experienced by many veterans of the 1991 Gulf War, with symptoms including fatigue, chronic pain, respiratory and memory problems. Exposure to toxic chemicals during the war, such as oil well fire smoke, pesticides, physiological stress, and nerve agents, is thought to have triggered abnormal neuroinflammatory responses that contribute to GWI. Previous studies have examined the acute effects of combined physiological stress and chemical exposures using GWI rodent models and presented findings related to neuroinflammation and changes in diffusion magnetic resonance imaging (MRI) measures, suggesting a neuroimmune basis for GWI. In the current study, using ex vivo MRI, cytokine mRNA expression, and immunohistological analyses of brain tissues, we examined the brain structure and immune function of a chronic rat model of GWI. Our data showed that a combination of long-term corticosterone treatment (to mimic high physiological stress) and diisopropyl fluorophosphate exposure (to mimic sarin exposure) primed the response to subsequent systemic immune challenge with lipopolysaccharide resulting in elevations of multiple cytokine mRNAs, an increased activated glial population, and disrupted brain microstructure in the cingulate cortex and hippocampus compared to control groups. Our findings support the critical role of neuroinflammation, dysregulated glial activation, and their relationship to disrupted brain microstructural integrity in the pathophysiology of GWI and highlight the unique consequences of long-term combined exposures on brain biochemistry and structural connectivity., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Bang-Bon Koo reports financial support was provided by US Office of 10.13039/100000090Congressionally Directed Medical Research Programs. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Exposure to environmental hazards exacerbates the risks inherent in military service, but many veterans do not experience the health consequences until many years later. The 2022 Sergeant First Class Heath Robinson Honoring Our Promise to Address Comprehensive Toxics (PACT) Act tasked the U.S. Department of Veterans Affairs with streamlining benefits and health care eligibility for certain veterans who have been exposed to military hazards. However, questions and concerns remain about the equitability, scientific robustness, and timeliness of the associated decisionmaking processes. There are opportunities to use structures from existing programs-specifically, the World Trade Center Health Program-as a template to improve engagement with veterans and their families, caregivers, providers, and advocates to ensure that their experiences and needs are heard, understood, and an integral part of the PACT Act's implementation., (Copyright © 2024 RAND Corporation.)

Gulf War Illness (GWI) affects nearly 30% of veterans from the 1990-1991 Gulf War (GW) and is a multi-symptom illness with many neurological effects attributed to in-theater wartime chemical overexposures. Brain-focused studies have revealed persistent structural and functional alterations in veterans with GWI, including reduced volumes, connectivity, and signaling that correlate with poor cognitive and motor performance. GWI symptomology components have been recapitulated in rodent models as behavioral, neurochemical, and neuroinflammatory aberrations. However, preclinical structural imaging studies remain limited. This study aimed to characterize the progression of brain structural alterations over the course of 12 months in two established preclinical models of GWI. In the PB/PM model, male C57BL/6 J mice (8-9 weeks) received daily exposure to the nerve agent prophylactic pyridostigmine bromide (PB) and the pyrethroid insecticide permethrin (PM) for 10 days. In the PB/DEET/CORT/DFP model, mice received daily exposure to PB and the insect repellent DEET (days 1-14) and corticosterone (CORT; days 7-14). On day 15, mice received a single injection of the sarin surrogate diisopropylfluorophosphate (DFP). Using a Varian 7 T Bore MRI System, structural (sagittal T2-weighted) scans were performed at 6-, 9-, and 12-months post GWI exposures. Regions of interest, including total brain, ventricles, cortex, hippocampus, cerebellum, and brainstem were delineated in the open source Aedes Toolbox in MATLAB, followed by brain volumetric and cortical thickness analyses in ImageJ. Limited behavioral testing 1 month after the last MRI was also performed. The results of this study compare similarities and distinctions between these exposure paradigms and aid in the understanding of GWI pathogenesis. Major similarities among the models include relative ventricular enlargement and reductions in hippocampal volumes with age. Key differences in the PB/DEET/CORT/DFP model included reduced brainstem volumes and an early and persistent loss of total brain volume, while the PB/PM model produced reductions in cortical thickness with age. Behaviorally, at 13 months, motor function was largely preserved in both models. However, the GWI mice in the PB/DEET/CORT/DFP model exhibited an elevation in anxiety-like behavior., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Carpenter, Hughes and Filipov.)

Gulf War Illness (GWI) is a debilitating condition marked by chronic fatigue, cognitive problems, pain, and gastrointestinal (GI) complaints in veterans who were deployed to the 1990-1991 Gulf War. Fatigue, GI complaints, and other chronic symptoms continue to persist more than 30 years post-deployment. Several potential mechanisms for the persistent illness have been identified and our prior pilot study linked an altered gut microbiome with the disorder. This study further validates and builds on our prior preliminary findings of host gut microbiome dysbiosis in veterans with GWI. Using stool samples and Multidimensional Fatigue Inventory (MFI) data from 89 GW veteran participants (63 GWI cases and 26 controls) from the Boston biorepository, recruitment, and integrative network (BBRAIN) for Gulf War Illness, we found that the host gut bacterial signature of veterans with GWI showed significantly different Bray-Curtis beta diversity than control veterans. Specifically, a higher Firmicutes to Bacteroidetes ratio, decrease in Akkermansia sp., Bacteroides thetaiotamicron , Bacteroides fragilis , and Lachnospiraceae genera and increase in Blautia , Streptococcus , Klebsiella , and Clostridium genera, that are associated with gut, immune, and brain health, were shown. Further, using MaAsLin and Boruta algorithms, Coprococcus and Eisenbergiella were identified as important predictors of GWI with an area under the curve ROC predictive value of 74.8%. Higher self-reported MFI scores in veterans with GWI were also significantly associated with an altered gut bacterial diversity and species abundance of Lachnospiraceae and Blautia . These results suggest potential therapeutic targets for veterans with GWI that target the gut microbiome and specific symptoms of the illness.

Introduction: Gulf War illness (GWI) is an environmentally-triggered chronic multisymptom illness typified by protean symptoms, in which mitochondrial impairment is evident. It has been likened to accelerated aging. Nuclear genetics of detoxification have been linked to GWI., Objective: To see whether mitochondrial (mt) haplogroup U - a heritable profile of mitochondrial DNA that has been tied to aging-related conditions - significantly predicts greater GWI severity; and to assess whether GWI severity is influenced by mitochondrial as well as nuclear genetics. 54 consenting Gulf War veterans gave information on GWI severity, of whom 52 had nuclear DNA assessment; and 45 had both nuclear and mitochondrial DNA assessments. Regression with robust standard errors assessed prediction of GWI severity as a function of nuclear genetics (butyrylcholinesterase variants), mitochondrial genetics (haplogroup U, previously tied to aging-related conditions); or both., Results: BChE "adverse" variants significantly predicted GWI severity (β(SE) = 23.4(11.4), p = 0.046), as did mt haplogroup U (β(SE) = 36.4(13.6), p = 0.010). In a model including both, BChE was no longer significant, but mt haplogroup U retained significance (β(SE) = 36.7(13.0), p = 0.007). This is the first study to show that mitochondrial genetics are tied to GWI severity in Gulf-deployed veterans. Other data affirm a tie to nuclear genetics, making GWI indeed a "tale of two genomes.", (© 2024. The Author(s).)

Objective : Gulf War Illness (GWI) is a debilitating multisymptom condition that affects nearly a third of 1990-91 Gulf War (GW) veterans. Symptoms include pain, fatigue, gastrointestinal issues, and cognitive decrements. Our work has shown that GWI rates and potential causes for symptoms vary between men and women veterans. Studies have documented neuropsychological and neuroimaging findings mostly in men or combined sex datasets. Data are lacking for women veterans due to lack of power and repositories of women veteran samples. Methods : We characterized GW women veterans in terms of demographics, exposures, neuropsychological and neuroimaging outcomes from the newly collated Boston, Biorepository and Integrative Network (BBRAIN) for GWI. Results : BBRAIN women veterans are highly educated with an average age of 54 years. 81% met GWI criteria, 25% met criteria for current PTSD, 78% were white, and 81% served in the Army. Exposure to combined acetylcholinesterase inhibitors (AChEi) including skin pesticides, fogs/sprays and/or pyridostigmine bromide (PB) anti-nerve gas pill exposure resulted in slower processing speed on attentional tasks and a trend for executive impairment compared with non-exposed women. Brain imaging outcomes showed lower gray matter volumes and smaller caudate in exposed women. Conclusions : Although subtle and limited findings were present in this group of women veterans, it suggests that continued follow-up of GW women veterans is warranted. Future research should continue to evaluate differences between men and women in GW veteran samples. The BBRAIN women sub-repository is recruiting and these data are available to the research community for studies of women veterans.

Background: Deployment-related neurotoxicant exposures are implicated in the etiology of Gulf War illness (GWI), the multisymptom condition associated with military service in the 1990-1991 Gulf War (GW). A Q/R polymorphism at position 192 of the paraoxonase (PON)-1 enzyme produce PON1 192 variants with different capacities for neutralizing specific chemicals, including certain acetylcholinesterase inhibitors., Methods: We evaluated PON1 192 status and GW exposures in 295 GWI cases and 103 GW veteran controls. Multivariable logistic regression determined independent associations of GWI with GW exposures overall and in PON1 192 subgroups. Exact logistic regression explored effects of exposure combinations in PON1 192 subgroups., Results: Hearing chemical alarms (proxy for possible nerve agent exposure) was associated with GWI only among RR status veterans (OR = 8.60, p = 0.014). Deployment-related skin pesticide use was associated with GWI only among QQ (OR = 3.30, p = 0.010) and QR (OR = 4.22, p < 0.001) status veterans. Exploratory assessments indicated that chemical alarms were associated with GWI in the subgroup of RR status veterans who took pyridostigmine bromide (PB) (exact OR = 19.02, p = 0.009) but not RR veterans who did not take PB (exact OR = 0.97, p = 1.00). Similarly, skin pesticide use was associated with GWI among QQ status veterans who took PB (exact OR = 6.34, p = 0.001) but not QQ veterans who did not take PB (exact OR = 0.59, p = 0.782)., Conclusion: Study results suggest a complex pattern of PON1 192 exposures and exposure-exposure interactions in the development of GWI.

Gulf War Illness (GWI) is a chronic multi-symptom neurological disorder affecting veterans of the Gulf War that is commonly comorbid with depression. A secondary data analysis was conducted to examine serum homocysteine and inflammatory cytokines (IFN-γ, IL-6, IL-1β, TNF-α) as potential biomarkers of depression improvement among veterans with GWI after a one-month dietary intervention aimed at reducing excitotoxicity and increasing micronutrients. Analyses, including multiple linear and logistic regression, were conducted in R studio. Dietary adherence was estimated using a specialized excitotoxin food frequency questionnaire (FFQ), and depression was measured using the Center for Epidemiologic Studies Depression (CES-D) scale. After one month on the diet, 52% of participants reported a significant decrease in depression ( p < 0.01). Greater dietary adherence (FFQ) was associated with increased likelihood of depression improvement; OR (95% CI) = 1.06 (1.01, 1.11), ( p = 0.02). Reduced homocysteine was associated with depression improvement after adjusting for FFQ change (β = 2.58, p = 0.04), and serum folate and vitamin B12 were not mediators of this association. Reduction in IFN-γ was marginally associated with likelihood of depression improvement (OR (95% CI) = 1.11 (0.00, 1.42), ( p = 0.06)), after adjustment for potential confounders. Findings suggest that homocysteine, and possibly IFN-γ, may serve as biomarkers for depression improvement in GWI. Larger trials are needed to replicate this work.

Gulf War Illness (GWI) is characterized by a wide range of symptoms that manifests largely as gastrointestinal symptoms. Among these gastrointestinal symptoms, motility disorders are highly prevalent, presenting as chronic constipation, stomach pain, indigestion, diarrhea, and other conditions that severely impact the quality of life of GWI veterans. However, despite a high prevalence of gastrointestinal impairments among these veterans, most research attention has focused on neurological disturbances. This perspective provides a comprehensive overview of current in vivo research advancements elucidating the underlying mechanisms contributing to gastrointestinal disorders in GWI. Generally, these in vivo and in vitro models propose that neuroinflammation alters gut motility and drives the gastrointestinal symptoms reported in GWI. Additionally, this perspective highlights the potential and challenges of in vitro bioengineering models, which could be a crucial contributor to understanding and treating the pathology of gastrointestinal related-GWI., (© 2024. The Author(s).)

Objectives: To examine whether severe Gulf War illness (SGWI) case status was associated with longitudinal multimorbidity patterns. Methods: Participants were users of the Veteran Health Administration Health Care System drawn from the Gulf War Era Cohort and Biorepository ( n = 840). Longitudinal measures of multimorbidity were constructed using (1) electronic health records (Charlson Comorbidity Index; Elixhauser; and Veterans Affairs Frailty Index) from 10/1/1999 to 6/30/2023 and (2) self-reported medical conditions (Deficit Accumulation Index) since the war until the survey date. Accelerated failure time models examined SGWI case status as a predictor of time until threshold level of multimorbidity was reached, adjusted for age and sociodemographic and military characteristics. Results: Models, adjusted for covariates, revealed that (1) relative to the SWGI- group, the SGWI+ group was associated with an accelerated time for reaching each threshold and (2) the relationship between SGWI and each threshold was not moderated by age. Discussion: Findings suggest that veterans with SGWI experienced accelerated aging., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Operations Desert Shield and Storm occurred over 30 years ago, yet many of those who were deployed continue to experience chronic and debilitating symptoms, now recognized as Gulf War Illness (GWI). While efforts have been made to explore clinical treatments for GWI, misperceptions and skepticism about its complex nature and a lack of consensus on its etiology impede progress in this area. A critical necessity remains to better understand the experiences, needs, and concerns of veterans with GWI. In this qualitative research study, 40 Gulf War veterans were interviewed about their perceptions regarding symptoms of physical health, cognitive functioning, quality of life, and the quality of care received. In addition, they depicted their experiences through an artistic elicitation collage. Through a grounded theory method, key findings indicated that there are remaining hurdles, such as challenging symptoms, persisting unknowns about the illness, and variations in treatment quality. Veterans have mostly managed and coped with GWI, but they voice the need for acknowledgment and support. The main implication from this study is the significance of both clinical and institutional validation and recognition of the GWI experience as well as the need for specific support systems., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Time for post-exercise phosphocreatine-recovery (PCr-R), deemed a robust index of mitochondrial function in vivo, was previously reported to be elevated (signifying impaired ATP production) in veterans with Gulf War illness (GWI). Here we sought to replicate the finding and assess the impact of contravening previous eligibility requirements. The replication sample comprised white males. Cases reported ≥ moderate muscle-weakness to match the organ assessed to an organ affected; controls lacked recent headache or multiple symptoms. The expansion sample added cases without muscle-weakness, controls with recent headache, females, nonwhites. PCr-R, following pedal-depression-exercise, was compared in veterans with GWI versus controls (sample N = 38). In the replication sample, PCr-R results closely matched the prior report: PCr-R veterans with GWI mean(SD) = 47.7(16.5); control mean(SD) = 30.3(9.2), p = 0.017. (Prior-study PCr-R veterans with GWI mean(SD) = 46.1(17.9), control mean(SD) = 29.0(8.7), p = 0.023. Combined replication + prior samples: p = 0.001.) No case-control difference was observed in the expansion sample. In cases, PCr-R related to muscle-weakness: PCr-R = 29.9(7.1), 38.2(8.9), 47.8(15.2) for muscle-weakness rated none/low, intermediate, and high respectively (p for trend = 0.02), validating desirability of matching tissue assessed to tissue affected. In controls, headache/multiple symptoms, sex, and ethnicity each mattered (affecting PCr-R significantly). This study affirms mitochondrial/bioenergetic impairment in veterans with GWI. The importance of careful case/control selection is underscored., (© 2024. The Author(s).)

Neuroinflammatory and neurodegenerative disorders including Alzheimer's disease (AD), Parkinson's disease (PD), traumatic brain injury (TBI) and Amyotrophic lateral sclerosis (ALS) are chronic major health disorders. The exact mechanism of the neuroimmune dysfunctions of these disease pathogeneses is currently not clearly understood. These disorders show dysregulated neuroimmune and inflammatory responses, including activation of neurons, glial cells, and neurovascular unit damage associated with excessive release of proinflammatory cytokines, chemokines, neurotoxic mediators, and infiltration of peripheral immune cells into the brain, as well as entry of inflammatory mediators through damaged neurovascular endothelial cells, blood-brain barrier and tight junction proteins. Activation of glial cells and immune cells leads to the release of many inflammatory and neurotoxic molecules that cause neuroinflammation and neurodegeneration. Gulf War Illness (GWI) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are chronic disorders that are also associated with neuroimmune dysfunctions. Currently, there are no effective disease-modifying therapeutic options available for these diseases. Human induced pluripotent stem cell (iPSC)-derived neurons, astrocytes, microglia, endothelial cells and pericytes are currently used for many disease models for drug discovery. This review highlights certain recent trends in neuroinflammatory responses and iPSC-derived brain cell applications in neuroinflammatory disorders.

Background: Healthcare systems, like the US Department of Veterans Affairs (VA), need policies and procedures for delivering care to special populations including those with environmental exposure concerns. Despite being common and pervasive, especially among Veterans, environmental exposures are largely overlooked by healthcare providers. To successfully implement care for Veterans with military environmental exposure concerns, an understanding of contextual factors impeding care on the provider (e.g., knowledge and beliefs) and organizational (e.g., leadership's priorities) level is needed. Our goal was to conduct an operational needs assessment of providers to examine provider educational needs regarding Veterans' military environmental exposure concerns., Methods: In 2020, we surveyed 2,775 VA medical and behavioral health providers. Our cross-sectional assessment was informed by the Consolidated Framework for Implementation Research (CFIR) and assessed barriers and facilitators to the uptake and application of knowledge regarding interdisciplinary care for environmental exposure concerns. The web-based survey was emailed to providers across the United States representing a variety of disciplines and practice settings to reflect the interdisciplinary approach to care for environmental exposures. We used bivariate statistics to investigate the intervention setting, inner setting, and individual characteristics of providers regarding care for environmental exposure concerns., Results: Approximately one-third of VA medical and behavioral health clinicians report low to no knowledge of environmental exposure concerns. We find 88% of medical and 91% of behavioral health providers report they are ready to learn more about environmental exposures. Half of medical and behavioral health providers report they have access to information on environmental exposures and less than half report care for environmental exposures is a priority where they practice., Conclusions: Our findings suggest interdisciplinary providers' knowledge of and discussion with Veterans about environmental exposures may be influenced by contextual factors at the organizational level. Considering individual-level factors and organizational culture is important to consider when supporting care for environmental exposures. Since this needs assessment, VA established targeted programs to improve care related to military environmental exposures in response to legislation; future exploration of these same variables or contextual factors is warranted., (© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Gulf War Illness (GWI) is a multi-symptom disorder that manifests with fatigue, sleep disturbances, mood-cognition pathologies, and musculoskeletal symptoms. GWI affects at least 25% of the military personnel that served in Operations Desert Shield and Desert Storm from 1990 to 1991. We modeled Gulf War toxicant exposure in C57BL/6J mice by combined exposure to pyridostigmine bromide (an anti-sarin drug), chlorpyrifos (an organophosphate insecticide), and DEET (an insect repellent) for 10 days followed by oral treatment with Withania somnifera root extract for 21 days beginning at 12 weeks post-exposure. W. somnifera , commonly referred to as ashwagandha, has been used in traditional Ayurvedic medicine for centuries to improve memory and reduce inflammation, and its roots contain bioactive molecules which share functional groups with modern pain, cancer, and anti-inflammatory drugs. Previously, we observed that GWI mice displayed chronic reductions in dendritic arbor and loss of spines in granule cells of the dentate gyrus of the hippocampus at 14 weeks post-exposure. Here, we examined the effects of treatment with W. somnifera root extract on chronic dendrite and spine morphology in dentate granule cells of the mouse hippocampus following Gulf War toxicant exposure. GWI mice showed approximately 25% decreases in dendritic length ( p < 0.0001) and overall dendritic spine density with significant reductions in thin and mushroom spines. GWI mice treated with the Ayurvedic W. somnifera extract exhibited dendritic lengths and spine densities near normal levels. These findings demonstrate the efficacy of the Ayurvedic treatment for neuroprotection following these toxic exposures. We hope that the extract and the neuronal processes influenced will open new avenues of research regarding treatment of Gulf War Illness and neurodegenerative disorders., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Shaikh, Murray, Ravindranath and Citron.)

Gulf War Illness (GWI) is a chronic multi-symptom disorder affecting approximately 30 % of Veterans deployed to the Persian Gulf from 1990 to 91. GWI encompasses a wide spectrum of symptoms which frequently include neurological problems such as learning and memory impairments, mood disorders, and an increased incidence of neurodegenerative disorders. Combined exposure to both reversible and irreversible acetylcholinesterase (AChE) inhibitors has been identified as a likely risk factor for GWI. It is possible that the exposures affected connectivity in the brain, and it was also unknown whether this could benefit from treatment. We assessed chronic changes in dendritic architecture in granule cells of the dentate gyrus following exposure to pyridostigmine bromide (PB, 0.7 mg/kg), chlorpyrifos (CPF, 12.5 mg/kg), and N,N-diethyl-m-toluamide (DEET, 7.5 mg/kg) in male C57Bl/6J mice. We also evaluated the therapeutic effects of dietary administration for eight weeks of 1 % tert-butylhydroquinone (tBHQ), a Nrf2 activator, on long-term neuronal morphology. We found that Gulf War toxicant exposure resulted in reduced dendritic length and branching as well as overall spine density in dentate granule cells at 14 weeks post-exposure and that these effects were ameliorated by treatment with tBHQ. These findings indicate that Gulf War toxicant exposure results in chronic changes to dentate granule cell morphology and that modulation of neuroprotective transcription factors such as Nrf2 may improve long-term neuronal health in the hippocampus., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier B.V.)

To address gaps in understanding the pathophysiology of Gulf War Illness (GWI), the VA Million Veteran Program (MVP) developed and implemented a survey to MVP enrollees who served in the U.S. military during the 1990-1991 Persian Gulf War (GW). Eligible Veterans were invited via mail to complete a survey assessing health conditions as well as GW-specific deployment characteristics and exposures. We evaluated the representativeness of this GW-era cohort relative to the broader population by comparing demographic, military, and health characteristics between respondents and non-respondents, as well as with all GW-era Veterans who have used Veterans Health Administration (VHA) services and the full population of U.S. GW-deployed Veterans. A total of 109,976 MVP GW-era Veterans were invited to participate and 45,270 (41%) returned a completed survey. Respondents were 84% male, 72% White, 8% Hispanic, with a mean age of 61.6 years ( SD = 8.5). Respondents were more likely to be older, White, married, better educated, slightly healthier, and have higher socioeconomic status than non-respondents, but reported similar medical conditions and comparable health status. Although generally similar to all GW-era Veterans using VHA services and the full population of U.S. GW Veterans, respondents included higher proportions of women and military officers, and were slightly older. In conclusion, sample characteristics of the MVP GW-era cohort can be considered generally representative of the broader GW-era Veteran population. The sample represents the largest research cohort of GW-era Veterans established to date and provides a uniquely valuable resource for conducting in-depth studies to evaluate health conditions affecting 1990-1991 GW-era Veterans.

Background: One-third of veterans returning from the 1990-1991 Gulf War reported a myriad of symptoms including cognitive dysfunction, skin rashes, musculoskeletal discomfort, and fatigue. This symptom cluster is now referred to as Gulf War Illness (GWI). As the underlying mechanisms of GWI have yet to be fully elucidated, diagnosis and treatment are based on symptomatic presentation. One confounding factor tied to the illness is the high presence of post-traumatic stress disorder (PTSD). Previous research efforts have demonstrated that both GWI and PTSD are associated with immunological dysfunction. As such, this research endeavor aimed to provide insight into the complex relationship between GWI symptoms, cytokine presence, and immune cell populations to pinpoint the impact of PTSD on these measures in GWI., Methods: Symptom measures were gathered through the Multidimensional fatigue inventory (MFI) and 36-item short form health survey (SF-36) scales and biological measures were obtained through cytokine & cytometry analysis. Subgrouping was conducted using Davidson Trauma Scale scores and the Structured Clinical Interview for Diagnostic and statistical manual of mental disorders (DSM)-5, into GWI with high probability of PTSD symptoms (GWI H ) and GWI with low probability of PTSD symptoms (GWI L ). Data was analyzed using Analysis of variance (ANOVA) statistical analysis along with correlation graph analysis. We mapped correlations between immune cells and cytokine signaling measures, hormones and GWI symptom measures to identify patterns in regulation between the GWI H , GWI L , and healthy control groups., Results: GWI with comorbid PTSD symptoms resulted in poorer health outcomes compared with both Healthy control (HC) and the GWI L subgroup. Significant differences were found in basophil levels of GWI compared with HC at peak exercise regardless of PTSD symptom comorbidity (ANOVA F = 4.7, P = 0.01,) indicating its potential usage as a biomarker for general GWI from control. While the unique identification of GWI with PTSD symptoms was less clear, the GWI L subgroup was found to be delineated from both GWI H and HC on measures of IL-15 across an exercise challenge (ANOVA F > 3.75, P < 0.03). Additional differences in natural killer (NK) cell numbers and function highlight IL-15 as a potential biomarker of GWI in the absence of PTSD symptoms., Conclusion: We conclude that disentangling GWI and PTSD by defining trauma-based subgroups may aid in the identification of unique GWI biosignatures that can help to improve diagnosis and target treatment of GWI more effectively., (© 2024. The Author(s).)

Post-traumatic stress disorder (PTSD) develops after trauma exposure and involves symptoms of avoidance, intrusive re-experiencing, mood and cognitive dysfunction, and hypervigilance. PTSD is often comorbid with Gulf War Illness (GWI), a neurological condition involving widespread pain, cognitive dysfunction, digestive problems, and other symptoms, in Gulf War veterans. PTSD tends to be more severe when comorbid with GWI. Low cortisol and elevated homocysteine levels have been found in PTSD, making them potential PTSD biomarkers. The low-glutamate diet, which aims to reduce excitotoxicity by eliminating the consumption of free glutamate and aspartate, has been shown to significantly reduce GWI and PTSD symptoms. This study examined whether changes in serum cortisol and homocysteine are associated with reduced PTSD severity in veterans with GWI after one month on the low-glutamate diet, and whether reducing the consumption of dietary excitotoxins was associated changes in PTSD and serum biomarkers. Data were analyzed for 33 veterans. No serum biomarkers significantly changed post-diet; however, cortisol increased as dietary excitotoxin consumption decreased, which held in a multivariable linear regression after adjustment for sex. Reduced dietary excitotoxin consumption was also associated with reduced hyperarousal symptoms, which held in a multivariable linear regression after adjustment for sex. Cortisol increase was associated with reduced avoidance symptoms after adjustment for change in BMI, and was marginally associated with overall PTSD reduction. Change in homocysteine was not significantly related to dietary adherence nor change in PTSD. Results suggest that reducing the consumption of dietary excitotoxins may normalize cortisol levels, which has been associated with alleviating PTSD.

The work of the Gulf War Illness (GWI) Consortium and that of basic and clinical researchers across the USA have resulted in a better understanding in recent years of the pathological basis of GWI, as well as of the mechanisms underlying the disorder. Among the most concerning symptoms suffered by veterans with GWI are cognitive decrements including those related to memory functioning. These decrements are not severe enough to meet dementia criteria, but there is significant concern that the mild cognitive impairment of these veterans will progress to dementia as they become older. Recent studies on GWI using human brain organoids as well as a rat model suggest that one potential cause of the cognitive problems may be elevated levels of tau in the brain, and this is supported by high levels of tau autoantibodies in the blood of veterans with GWI. There is urgency in finding treatments and preventive strategies for these veterans before they progress to dementia, with added value in doing so because their current status may represent an early phase of tauopathy common to many neurodegenerative diseases., (© 2023 Wiley Periodicals LLC.)

Gulf War (GW) veterans show gastrointestinal disturbances and gut dysbiosis. Prolonged antibiotic treatments commonly employed in veterans, especially the use of fluoroquinolones and aminoglycosides, have also been associated with dysbiosis. This study investigates the effect of prolonged antibiotic exposure on risks of adverse renal pathology and its association with gut bacterial species abundance in underlying GWI and aims to uncover the molecular mechanisms leading to possible renal dysfunction with aging. Using a GWI mouse model, administration of a prolonged antibiotic regimen involving neomycin and enrofloxacin treatment for 5 months showed an exacerbated renal inflammation with increased NF-κB activation and pro-inflammatory cytokines levels. Involvement of the high mobility group 1 (HMGB1)-mediated receptor for advanced glycation end products (RAGE) activation triggered an inflammatory phenotype and increased transforming growth factor-β (TGF-β) production. Mechanistically, TGF-β- induced microRNA-21 upregulation in the renal tissue leads to decreased phosphatase and tensin homolog (PTEN) expression. The above event led to the activation of protein kinase-B (AKT) signaling, resulting in increased fibronectin production and fibrosis-like pathology. Importantly, the increased miR-21 was associated with low levels of Lachnospiraceae in the host gut which is also a key to heightened HMGB1-mediated inflammation. Overall, though correlative, the study highlights the complex interplay between GWI, host gut dysbiosis, prolonged antibiotics usage, and renal pathology via miR-21/PTEN/AKT signaling.

Background: During deployment, veterans of the 1991 Gulf War (GW) were exposed to multiple war-related toxicants. Roughly a third of these veterans continue to exhibit neurotoxicant induced symptoms of Gulf War Illness (GWI), a multi-faceted condition that includes fatigue, pain and cognitive decrements. When studied empirically, both deployed veterans with exposures and those who meet the criteria for GWI are more likely to show deficits in the area of neuropsychological functioning. Although studies have shown cognitive impairments in small sample sizes, it is necessary to revisit these findings with larger samples and newer cohorts to see if other areas of deficit emerge with more power to detect such differences. A group of researchers and clinicians with expertise in the area of GWI have identified common data elements (CDE) for use in research samples to compare data sets. At the same time, a subgroup of researchers created a new repository to share these cognitive data and biospecimens within the GWI research community., Methods: The present study aimed to compare cognitive measures of attention, executive functioning, and verbal memory in a large sample of GWI cases and healthy GW veteran controls using neuropsychological tests recommended in the CDEs. We additionally subdivided samples based on the specific neurotoxicant exposures related to cognitive deficits and compared exposed versus non-exposed veterans regardless of case criteria status. The total sample utilized cognitive testing outcomes from the newly collated Boston, Biorepository, Recruitment, and Integrative Network (BBRAIN) for GWI., Results: Participants included 411 GW veterans, 312 GWI (cases) and 99 healthy veterans (controls). Veterans with GWI showed significantly poorer attention, executive functioning, learning, and short-and-long term verbal memory than those without GWI. Further, GW veterans with exposures to acetylcholinesterase inhibiting pesticides and nerve gas agents, had worse performance on executive function tasks. Veterans with exposure to oil well fires had worse performance on verbal memory and those with pyridostigmine bromide anti-nerve gas pill exposures had better verbal memory and worse performance on an attention task compared to unexposed veterans., Conclusions: This study replicates prior results regarding the utility of the currently recommended CDEs in determining impairments in cognitive functioning in veterans with GWI in a new widely-available repository cohort and provides further evidence of cognitive decrements in GW veterans related to war-related neurotoxicant exposures., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Background: Approximately 30% of the 700 000 Gulf War veterans report a chronic symptom-based illness of varying severity referred to as Gulf War illness (GWI). Toxic deployment-related exposures have been implicated in the cause of GWI, some of which contribute to metabolic dysregulation and lipid abnormalities. As this cohort ages, the relationship between GWI and atherosclerotic cardiovascular disease (ASCVD) is a growing concern. We evaluated associations between GWI and ASCVD, diabetes, hyperlipidemia, and hypertension in veterans of the Gulf War (1990-1991)., Methods and Results: Analysis of survey data collected in 2014 to 2016 from a national sample of deployed Gulf War veterans (n=942) and Veterans Health Administration electronic health record data (n=669). Multivariable logistic regression models tested for associations of GWI with self-reported ASCVD, diabetes, hyperlipidemia, and hypertension, controlling for confounding factors. Separate models tested for GWI associations with ASCVD and risk factors documented in the electronic health record. GWI was associated with self-reported hypertension (adjusted odds ratio [aOR], 1.67 [95% CI, 1.18-2.36]), hyperlipidemia (aOR, 1.46 [95% CI, 1.03-2.05]), and ASCVD (aOR, 2.65 [95% CI, 1.56-4.51]). In the subset of veterans with electronic health record data, GWI was associated with documented diabetes (aOR, 2.34 [95% CI, 1.43-3.82]) and hypertension (aOR, 2.84 [95% CI, 1.92-4.20]). Hyperlipidemia and hypertension served as partial mediators of the association between GWI and self-reported ASCVD., Conclusions: Gulf War veterans with GWI had higher odds of hyperlipidemia, hypertension, diabetes, and ASCVD compared with Gulf War veterans without GWI. Further examination of the mechanisms underlying this association, including a possible shared exposure-related mechanism, is necessary.

Background: Clinical Practice Guidelines for Gulf War Illness (GWI) recommend integrative health approaches such as yoga for relief from symptoms, yet little is known about the long-term efficacy of yoga in reducing symptoms of GWI. Here, we evaluated the long-term efficacy of yoga and cognitive-behavioral therapy (CBT) chronic pain treatment in a randomized controlled trial (RCT) of 75 Veterans (57 men, 42-71 ± 7.1 years of age) with Gulf War Illness (GWI)., Methods: Participants received either 10 weeks of yoga or 10 weeks of CBT for chronic pain. The primary outcome measures were pain severity, and pain interference (Brief Pain Inventory-Short Form). The secondary outcome measures were fatigue, as indicated by a measure of functional exercise capacity (6-Minute Walk Test), depression, autonomic symptom severity, and quality of life. Piecewise linear mixed models were used to examine study hypotheses., Results: Compared to the CBT group, yoga was associated with greater reductions in pain severity during the 6-month follow-up period (group × time interaction: b = 0.036, se = 0.014, p = .011). Although we did not find between-group differences in the other primary or secondary outcome measures during follow-up (p's > 0.05), exploratory analyses revealed within-group improvements in pain interference, total pain (an experimental outcome variable which combines pain severity and interference), and fatigue in the yoga group (p's < 0.05) but not in the CBT group., Conclusions: This is the first study to report long-term follow-up results of yoga as a treatment for GWI. Our results suggest that yoga may offer long-term efficacy in reducing pain, which is a core symptom of GWI., Trial Registration: Secondary analyses of ClinicalTrials.gov NCT02378025., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: Gulf War Illness (GWI) is a chronic, multisymptom (e.g., fatigue, muscle/joint pain, memory and concentration difficulties) condition estimated to affect 25-32% of Gulf War (GW) veterans. Longitudinal studies suggest that few veterans with GWI have recovered over time and that deployed GW veterans may be at increased risks for age-related conditions., Methods: We performed a retrospective cohort study to examine the current health status of 703 GW veterans who participated in research studies at the San Francisco VA Health Care System (SFVAHCS) between 2002 and 2018. We used the Veterans Affairs Frailty Index (VA-FI) as a proxy measure of current health and compared the VA-FIs of GW veterans to a group of randomly selected age- and sex-matched, non-GW veterans. We also examined GW veterans' VA-FIs as a function of different GWI case definitions and in relationship to deployment-related experiences and exposures., Results: Compared to matched, non-GW veterans, GW veterans had lower VA-FIs (0.10 ± 0.10 vs. 0.12 ± 0.11, p < 0.01). However, the subset of GW veterans who met criteria for severe Chronic Multisymptom Illness (CMI) at the time of the SFVAHCS studies had the highest VA-FI (0.13 ± 0.10, p < 0.001). GW veterans who had Kansas GWI exclusionary conditions had higher VA-FI (0.12 ± 0.12, p < 0.05) than veterans who were Kansas GWI cases (0.08 ± 0.08) and controls (i.e., veterans with little or no symptoms, 0.04 ± 0.06) at the time of the SFVAHCS research studies. The VA-FI was positively correlated with several GW deployment-related exposures, including the frequency of wearing flea collars., Discussion: Although GW veterans, as a group, were less frail than non-GW veterans, the subset of GW veterans who met criteria for severe CDC CMI and/or who had Kansas GWI exclusionary conditions at the time of the SFVAHCS research studies were frailest at index date. This suggests that many ongoing studies of GWI that use the Kansas GWI criteria may not be capturing the group of GW veterans who are most at risk for adverse chronic health outcomes., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Chao.)

Aims: Gulf War Illness (GWI) is a multi-system condition of complex etiology and pathophysiology without specific treatment. There is an overlap between the symptoms of GWI and endocrinopathies. This study aimed to identify hormonal alterations in 1990-91 Gulf War (GW) veterans and the relationship between GWI and hormonal dysregulation., Main Methods: Data from 81 GW veterans (54 with GWI and 27 controls without GWI) was analyzed in a cross-sectional, case-control observational study. Participants completed multiple questionnaires, neuropsychiatric assessments, and a comprehensive set of hormone assays including a glucagon stimulation test (GST) for adult growth hormone deficiency (AGHD) and a high-dose adrenocorticotropic hormone (ACTH) stimulation test for adrenal insufficiency., Key Findings: The GWI group had lower quality of life and greater severity of all symptoms compared to controls. Pain intensity and pain-related interference with general activity were also higher in the GWI group. AGHD was observed in 18 of 51 veterans with GWI (35.3 %) and 2 of 26 veterans without GWI (7.7 %) (p = 0.012 for interaction). Veterans with GWI also exhibited reduced insulin-like growth factor 1 (IGF-1) levels and IGF-1 Z-scores compared to controls. One participant with GWI met the criteria for adrenal insufficiency. No significant changes were observed in other hormonal axes., Significance: The frequency of AGHD was significantly higher in veterans with GWI compared to controls. Recombinant human growth hormone replacement therapy (GHRT) may become a breakthrough therapeutic option for this subgroup. A large clinical trial is needed to evaluate the efficacy of GHRT in patients with GWI and AGHD., Competing Interests: Declaration of competing interest I declare that the authors have no competing interests related to this study or manuscript that might be perceived to influence the results and discussion reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Environmental exposures may influence sleep; however, the contributions of environmental chemical pollutants to sleep health have not been systematically investigated. We conducted a systematic review to identify, evaluate, summarize, and synthesize the existing evidence between chemical pollutants (air pollution, exposures related to the Gulf War and other conflicts, endocrine disruptors, metals, pesticides, solvents) and dimensions of sleep health (architecture, duration, quality, timing) and disorders (sleeping pill use, insomnia, sleep-disordered breathing)). Of the 204 included studies, results were mixed; however, the synthesized evidence suggested associations between particulate matter, exposures related to the Gulf War, dioxin and dioxin-like compounds, and pesticide exposure with worse sleep quality; exposures related to the Gulf War, aluminum, and mercury with insomnia and impaired sleep maintenance; and associations between tobacco smoke exposure with insomnia and sleep-disordered breathing, particularly in pediatric populations. Possible mechanisms relate to cholinergic signaling, neurotransmission, and inflammation. Chemical pollutants are likely key determinants of sleep health and disorders. Future studies should aim to evaluate environmental exposures on sleep across the lifespan, with a particular focus on developmental windows and biological mechanisms, as well as in historically marginalized or excluded populations., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Introduction: Exposure to nerve agents, pyridostigmine bromide (PB), pesticides, and oil-well fires during the 1991 Gulf War (GW) are major contributors to the etiology of Gulf War Illness (GWI). Since the apolipoprotein E (APOE) ε4 allele is associated with the risk of cognitive decline with age, particularly in the presence of environmental exposures, and cognitive impairment is one of the most common symptoms experienced by veterans with GWI, we examined whether the ε4 allele was associated with GWI., Methods: Using a case-control design, we obtained data on APOE genotypes, demographics, and self-reported GW exposures and symptoms that were deposited in the Boston Biorepository and Integrative Network (BBRAIN) for veterans diagnosed with GWI (n = 220) and healthy GW control veterans (n = 131). Diagnosis of GWI was performed using the Kansas and/or Center for Disease Control (CDC) criteria., Results: Age- and sex-adjusted analyses showed a significantly higher odds ratio for meeting the GWI case criteria in the presence of the ε4 allele (Odds ratio [OR] = 1.84, 95% confidence interval [CI = 1.07-3.15], p ≤ 0.05) and with two copies of the ε4 allele (OR = 1.99, 95% CI [1.23-3.21], p ≤ 0.01). Combined exposure to pesticides and PB pills (OR = 4.10 [2.12-7.91], p ≤ 0.05) as well as chemical alarms and PB pills (OR = 3.30 [1.56-6.97] p ≤ 0.05) during the war were also associated with a higher odds ratio for meeting GWI case criteria. There was also an interaction between the ε4 allele and exposure to oil well fires (OR = 2.46, 95% CI [1.07-5.62], p ≤ 0.05) among those who met the GWI case criteria., Conclusion: These findings suggest that the presence of the ε4 allele was associated with meeting the GWI case criteria. Gulf War veterans who reported exposure to oil well fires and have an ε4 allele were more likely to meet GWI case criteria. Long-term surveillance of veterans with GWI, particularly those with oil well fire exposure, is required to better assess the future risk of cognitive decline among this vulnerable population., (© 2023. The Author(s).)

Competing Interests: Disclosure of interests: The author has no potential conflicts of interest to report.

Background: Many Gulf War (GW) Veterans report chronic symptoms including pain, fatigue, and cognitive impairment, commonly defined as Gulf War Illness (GWI). Complementary and integrative health (CIH) therapies may potentially improve multiple symptoms of GWI., Objective: To examine the effectiveness of combining 2 commonly available CIH therapies, mindfulness meditation and auricular acupuncture, in improving health-related functioning and multiple symptom domains of GWI (e.g., pain, fatigue)., Methods: This study was a randomized controlled trial in which Veterans with GWI were randomly assigned to either the intervention group (n = 75), wherein they received 2 distinct CIH therapies - mindfulness meditation and auricular acupuncture, or the active control group, wherein they received a GW Health Education (GWHE) program (n = 74), each lasting 8 weeks. Self-report health measures were assessed at baseline, endpoint, and 3 month follow-up., Results: In the intention-to-treat analyses, there were significant between-group differences for mental-health related functioning, fatigue, depression symptoms, and Kansas total severity scores for symptoms in which the CIH group had improved scores for these outcomes at endpoint compared to the GWHE group (all P ≤ .05). The CIH group also had significant reductions in pain interference at endpoint and follow-up compared to baseline (estimated marginal mean difference: -2.52 and -2.22, respectively; all P = .01), whereas no significant changes were observed in the GWHE group. For pain characteristics, the GWHE group had a worsening of pain at endpoint compared to baseline (estimated marginal mean difference: +2.83; P = .01), while no change was observed in the CIH group., Conclusion: Findings suggest a possible beneficial effect of combining 2 CIH therapies, mindfulness meditation and auricular acupuncture, in reducing overall symptom severity and individual symptom domains of fatigue, musculoskeletal, and mood/cognition in Veterans with GWI., Trial Registration: Clinical Trials identifier NCT02180243., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The opinions presented in this article are those of the authors and do not reflect the views of any institution/agency of the U.S. government, the Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., or Georgetown University., (© The Author(s) 2023.)

Gulf War Illness (GWI) results from chemical exposure during the Gulf War, with notable impacts on gastrointestinal motility. Due to the limited demographic impacted by this ailment, an in-depth investigation of the GWI has yielded little regarding the underlying pathophysiological mechanisms. Here, the hypothesis that exposure to pyridostigmine bromide (PB) results in severe enteric neuro-inflammation, that cascades to disruptions in colonic motility, is tested. The analyses are performed on male C57BL/6 mice that are treated with physiologically similar doses of PB given to GW veterans. When colonic motility is assessed, GWI colons have significantly reduced forces in response to acetylcholine or electrical field stimulation. GWI is also accompanied by high levels of pro-inflammatory cytokines and chemokines, associated with increased numbers of CD40 + pro-inflammatory macrophages within the myenteric plexus. Enteric neurons responsible for mediating colonic motility reside within the myenteric plexus, and PB exposure reduced their numbers. Significant smooth muscle hypertrophy is also observed due to increased inflammation. Together, the results show that PB exposure caused functional and anatomical dysfunction, promoting impaired motility within the colon. Achieving a greater understanding of the mechanisms of GWI will allow more refinement in therapeutic options that improve veterans' quality of life., (© 2023 Wiley-VCH GmbH.)

This article describes the pathophysiology and potential treatments for Gulf War Illness (GWI), which is a chronic neuropsychiatric illness linked to a combination of chemical exposures experienced by service personnel during the first Gulf War in 1991. However, there is currently no effective treatment for veterans with GWI. The article focuses on the current status and efficacy of existing therapeutic interventions in preclinical models of GWI, as well as potential perspectives of promising therapies. GWI stems from changes in brain and peripheral systems in veterans, leading to neurocognitive deficits, as well as physiological and psychological effects resulting from multifaceted changes such as neuroinflammation, oxidative stress, and neuronal damage. Aging not only renders veterans more susceptible to GWI symptoms, but also attenuates their immune capabilities and response to therapies. A variety of experimental models are being used to investigate the pathophysiology and develop therapies that have the ability to alleviate devastating symptoms. Over two dozen therapeutic interventions targeting neuroinflammation, mitochondrial dysfunction, neuronal injury, and neurogenesis are being tested, including agents such as curcumin, curcumin nanoparticles, monosodium luminol, melatonin, resveratrol, fluoxetine, rolipram, oleoylethanolamide, ketamine, levetiracetam, nicotinamide riboside, minocycline, pyridazine derivatives, and neurosteroids. Preclinical outcomes show that some agents have promise, including curcumin, resveratrol, and ketamine, which are being tested in clinical trials in GWI veterans. Neuroprotectants and other compounds such as monosodium luminol, melatonin, levetiracetam, oleoylethanolamide, and nicotinamide riboside appear promising for future clinical trials. Neurosteroids have been shown to have neuroprotective and disease-modifying properties, which makes them a promising medicine for GWI. Therefore, accelerated clinical studies are urgently needed to evaluate and launch an effective therapy for veterans displaying GWI., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Gulf War Illness (GWI) has been reported in 25%-35% of veterans returned from the Gulf war. Symptoms of GWI are varied and include both neurological and gastrointestinal symptoms as well as chronic fatigue. Development of GWI has been associated with chemical exposure particularly with exposure to pyridostigmine bromide (PB) and permethrin. Recent studies have found that the pathology of GWI is connected to changes in the gut microbiota, that is the gut dysbiosis. In studies using animal models, the exposure to PB and permethrin resulted in similar changes in the gut microbiome as these found in GW veterans with GWI. Studies using animal models have also shown that phytochemicals like curcumin are beneficial in reducing the symptoms and that the extracellular vesicles (EV) released from gut bacteria and from the intestinal epithelium can both promote diseases and suppress diseases through the intercellular communication mechanisms. The intestinal epithelium cells produce EVs and these EVs of intestinal epithelium origin are found to suppress inflammatory bowel disease severity, suggesting the benefits of utilizing EV in treatments. On the contrary, EV from the plasma of septic mice enhanced the level of proinflammatory cytokines in vitro and neutrophils and macrophages in vivo, suggesting differences in the EV depending on the types of cells they were originated and/or influences of environmental changes. These studies suggest that targeting the EV that specifically have positive influences may become a new therapeutic strategy in the treatment of veterans with GWI., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

To examine associations between the pyridostigmine bromide (PB) pill and/or pesticide exposure during the 1990-1991 Gulf War (GW) and eye findings years after deployment. A cross-sectional study of South Florida veterans who were deployed on active duty during the GW Era (GWE). Information on GW exposures and ocular surface symptoms were collected via standardized questionnaires and an ocular surface examination was performed. Participants underwent spectral domain-ocular coherence tomography (SD-OCT) imaging that included retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and macular maps. We examined for differences in eye findings between individuals exposed versus not exposed to PB pills or pesticides during service. A total of 40.7% (n = 44) of individuals reported exposure to PB pills and 41.7% (n = 45) to pesticides; additionally, 24 reported exposure to both in the GW arena. Demographics were comparable across groups. Individuals exposed to PB pills reported higher dry eye (DE) symptoms scores (the 5-Item Dry Eye Questionnaire, DEQ-5: 9.3 ± 5.3 vs. 7.3 ± 4.7, p = 0.04) and more intense ocular pain (average over the last week: 2.4 ± 2.6 vs. 1.5 ± 1.8, p = 0.03; Neuropathic Pain Symptom Inventory modified for the Eye (NPSI-E): 18.2 ± 20.0 vs. 10.8 ± 13.8, p = 0.03) compared to their non-exposed counterparts. DE signs were comparable between the groups. Individuals exposed to PB pills also had thicker OCT measurements, with the largest difference in the outer temporal segment of the macula (268.5 ± 22.2 μm vs. 260.6 ± 14.5 μm, p = 0.03) compared to non-exposed individuals. These differences remained significant when examined in multivariable models that included demographics and deployment history. Individuals exposed to pesticides had higher neuropathic ocular pain scores (NPSI-E: 17.1 ± 21.1 vs. 11.6 ± 12.9, p = 0.049), but this difference did not remain significant in a multivariable model. Individuals exposed to PB pills during the GWE reported more severe ocular surface symptoms and had thicker OCT measures years after deployment compared to their non-exposed counterparts.

Gulf War illness (GWI) is a chronic multifaceted condition with debilitating pain and fatigue, as well as sleep, behavioral, and cognitive impairments in war veterans. Currently, there is no effective treatment or cure for GWI; therefore, there is a critical need to develop experimental models to help better understand its mechanisms and interventions related to GWI-associated neuropsychiatric disorders. Chemical neurotoxicity appears to be one cause of GWI, and its symptoms manifest as disruptions in neuronal function. However, the mechanisms underlying such incapacitating neurologic and psychiatric symptoms are poorly understood. The etiology of GWI is complex, and many factors including chemical exposure, psychological trauma, and environmental stressors have been associated with its development. Attempts have been made to create GWI-like symptomatic models, including through chronic induction in mice and rats. Here, we present a brief protocol of GWI in rats and mice, which exhibit robust neuropsychiatric signs and neuropathologic changes reminiscent of GWI. This article provides a guide to working protocols, application of therapeutic drugs, outcomes, troubleshooting, and data analysis. Our broad profiling of GWI-like symptoms in rodents reveals features of progressive morphologic and long-lasting neuropsychiatric features. Together, the GWI model in rodents shows striking consistency in recapitulating major hallmark features of GWI in veterans. These models help identify mechanisms and interventions for GWI. © 2023 Wiley Periodicals LLC. Basic Protocol 1: Experimental induction of Gulf War illness in rats Support Protocol 1: Monitoring of Gulf War illness signs and neuroimaging analysis in rats Basic Protocol 2: Experimental induction of Gulf War illness in mice Support Protocol 2: Monitoring of Gulf War illness signs and neuropathology analysis in mice., (© 2023 Wiley Periodicals LLC.)

Background: Many of the 700,000 American military personnel deployed to the Persian Gulf region in 1990 and 1991 have since reported health symptoms of unknown etiology. This cluster of symptoms has been labeled Gulf War Illness and include chronic musculoskeletal pain, fatigue, headaches, memory and attention difficulties, gastrointestinal complaints, skin abnormalities, breathing problems, and mood and sleep problems [1,2]. There have been few high-quality intervention trials and no strong evidence to support available treatments [3]. Tai Chi is an ancient Chinese martial art with benefits that include enhancing physical and mental health and improving quality of life for those with chronic conditions., Proposed Methods: In this randomized controlled trial, GW Veterans are randomly assigned to either Tai Chi or a Wellness control condition, with both remotely delivered intervention groups meeting twice a week for 12 weeks. The primary aim is to examine if Tai Chi is associated with greater improvements in GWI symptoms in Veterans with GWI compared to a Wellness intervention. Participants will receive assessments at baseline, 12 weeks (post-intervention), and follow-up assessments 3- and 9-months post-intervention. The primary outcome measure is the Brief Pain Inventory that examines pain intensity and pain interference., Conclusion: This trial will produce valuable results that can have a meaningful impact on healthcare practices for GWI. If proven as a helpful treatment for individuals with GWI, it would support the implementation of remotely delivered Tai Chi classes that Veterans can access from their own homes., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Gulf War Illness (GWI), a chronic multisymptom illness with a complex and uncertain etiology and pathophysiology, is highly prevalent among veterans deployed to the 1990-1991 GW. We examined how GWI phenotypes varied by demographic and military characteristics among GW-era veterans. Data were from the VA's Cooperative Studies Program 2006/Million Veteran Program (MVP) 029 cohort, Genomics of GWI. From June 2018 to March 2019, 109,976 MVP enrollees (out of a total of over 676,000) were contacted to participate in the 1990-1991 GW-era Survey. Of 109,976 eligible participants, 45,169 (41.1%) responded to the 2018-2019 survey, 35,902 respondents met study inclusion criteria, 13,107 deployed to the GW theater. GWI phenotypes were derived from Kansas (KS) and Centers for Disease Control and Prevention (CDC) GWI definitions: (a) KS Symptoms (KS Sym+), (b) KS GWI (met symptom criteria and without exclusionary health conditions) [KS GWI: Sym+/Dx-], (c) CDC GWI and (d) CDC GWI Severe. The prevalence of each phenotype was 67.1% KS Sym+, 21.5% KS Sym+/Dx-, 81.1% CDC GWI, and 18.6% CDC GWI severe. These findings affirm the persistent presence of GWI among GW veterans providing a foundation for further exploration of biological and environmental underpinnings of this condition.

In a companion paper we examined whether combinations of K v 7 channel openers (Retigabine and Diclofenac; RET, DIC) could be effective modifiers of deep tissue nociceptor activity; and whether such combinations could then be optimized for use as safe analgesics for pain-like signs that developed in a rat model of GWI (Gulf War Illness) pain. In the present report, we examined the combinations of Retigabine/Meclofenamate (RET/MEC) and Meclofenamate/Diclofenac (MEC/DIC). Voltage clamp experiments were performed on deep tissue nociceptors isolated from rat DRG (dorsal root ganglion). In voltage clamp studies, a stepped voltage protocol was applied (-55 to -40 mV; V h =-60 mV; 1500 msec) and K v 7 evoked currents were subsequently isolated by Linopirdine subtraction. MEC greatly enhanced voltage dependent conductance and produced exceptional maximum sustained currents of 6.01 ± 0.26 pA/pF (EC 50 : 62.2 ± 8.99 μM). Combinations of RET/MEC, and MEC/DIC substantially amplified resting currents at low concentrations. MEC/DIC also greatly improved voltage dependent conductance. In current clamp experiments, a cholinergic challenge test (Oxotremorine-M, 10 μM; OXO), associated with our GWI rat model, produced powerful action potential (AP) bursts (85 APs). Optimized combinations of RET/MEC (5 and 0.5 μM) and MEC/DIC (0.5 and 2.5 μM) significantly reduced AP discharges to 3 and 7 Aps, respectively. Treatment of pain-like ambulatory behavior in our rat model with a RET/MEC combination (5 and 0.5 mg/kg) successfully rescued ambulation deficits, but could not be fully separated from the effect of RET alone. Further development of this approach is recommended., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Chemical overexposures and war-related stress during the 1990-1991 Gulf War (GW) are implicated in the persisting pathological symptoms that many GW veterans continue to endure. These symptoms culminate into a disease known as Gulf War Illness (GWI) and affect about a third of the GW veteran population. Currently, comprehensive effective GWI treatment options are unavailable. Here, an established GWI mouse model was utilized to explore the (1) long-term behavioral and neuroinflammatory effects of deployment-related GWI chemicals exposure and (2) ability of the immunotherapeutic lacto-N-fucopentaose III (LNFPIII) to improve deficits when given months after the end of exposure. Male C57BL6/J mice (8-9 weeks old) were administered pyridostigmine bromide (PB) and DEET for 14 days along with corticosterone (CORT; latter 7 days) to emulate wartime stress. On day 15, a single injection of the nerve agent surrogate diisopropylfluorophosphate (DFP) was given. LNFPIII treatment began 7 months post GWI chemicals exposure and continued until study completion. A battery of behavioral tests for assessment of cognition/memory, mood, and motor function in rodents was performed beginning 8 months after exposure termination and was then followed by immunohistochemcal evaluation of neuroinflammation and neurogenesis. Within tests of motor function, prior GWI chemical exposure led to hyperactivity, impaired sensorimotor function, and altered gait. LNFPIII attenuated these motor-related deficits and improved overall grip strength. GWI mice also exhibited more anxiety-like behavior that was reduced by LNFPIII; this was test-specific. Short-term, but not long-term memory, was impaired by prior GWI exposure; LNFPIII improved this measure. In the brains of GWI mice, but not in mice treated with LNFPIII, glial activation was increased. Overall, it appears that months after exposure to GWI chemicals, behavioral deficits and neuroinflammation are present. Many of these deficits were attenuated by LNFPIII when treatment began long after GWI chemical exposure termination, highlighting its therapeutic potential for veterans with GWI., (© 2022 The Authors.)

Gulf War Illness (GWI) is a chronic illness that affects upward of 32% of deployed Veterans to the 1991 Gulf War (GW). The symptoms are medically unexplained, ranging across cognitive deficits, fatigue, gastrointestinal problems, and musculoskeletal pain. Research indicates that chemical warfare agents play a key role in the onset and progression of GWI. The Khamisiyah ammunition storage that housed chemical warfare agents such as sarin, an acetylcholinesterase (AChE) inhibitor, was demolished during the GW, releasing toxicants into the atmosphere affecting deployed troops. Exposure to other chemical agents such as pyridostigmine bromide, N,N-diethyl-m-toluamide, permethrin and chlorpyrifos, were also prevalent during the war. These additional chemical agents have also been shown to inhibit AChE. AChE inhibition induces an acetylcholine build-up, disrupting signals between nerves and muscles, which in high doses leads to asphyxiation. Little is known about low dose exposure. As bioactive compounds tend to interact with multiple proteins with various physiological effect, we aimed to identify other potential shared targets to understand the extent in which these chemicals could lead to GWI. We followed a reverse screening approach where each chemical is computationally docked to a library of protein targets. The programs PharmMapper and TargetNet were used for this purpose, and further analyses were conducted to mark significant changes in participants with GWI. Previously published work on DNA methylation status in GWI was reanalyzed focusing specifically on the predicted shared targets indicating significant changes in DNA methylation of the associated genes. Our findings thus suggest that exposure to GWI-related agents may converge on similar targets with roles in inflammation, neurotransmitter and lipid metabolism, and detoxification which may have impacts on neurodegenerative-like disease and oxidative stress in Veterans with GWI., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Objectives: Gulf War Illness (GWI) is a chronic, multi-symptom disorder with underlying central nervous system dysfunction and cognitive impairments. The objective of this study was to test the low glutamate diet as a novel treatment for cognitive dysfunction among those with GWI, and to explore if baseline resting-state electroencephalography (EEG) could predict cognitive outcomes. Methods: Cognitive functioning was assessed at baseline, after one-month on the diet, and across a two-week double-blind, placebo-controlled crossover challenge with monosodium glutamate (MSG) relative to placebo. Results: Significant improvements were seen after one-month on the diet in overall cognitive functioning, and in all other domains tested (FDR p  < 0.05), except for memory. Challenge with MSG resulted in significant inter-individual response variability ( p  < 0.0001). Participants were clustered according to baseline resting-state EEG using k-means clustering to explore the inter-individual response variability. Three distinct EEG clusters were observed, and each corresponded with differential cognitive effects during challenge with MSG: cluster 1 had cognitive benefit (24% of participants), cluster 2 had cognitive detriment (42% of participants), and cluster 3 had mild/mixed effects (33% of participants). Discussion: These findings suggest that the low glutamate diet may be a beneficial treatment for cognitive impairment in GWI. Future research is needed to understand the extent to which resting-state EEG can predict response to the low glutamate diet and to explore the mechanisms behind the varied response to acute glutamate challenge.

Complementary and integrative health (CIH) approaches have gained empirical support and are increasingly being utilized among veterans to treat a myriad of conditions. A cluster of medically unexplained chronic symptoms including fatigue, headaches, joint pain, indigestion, insomnia, dizziness, respiratory disorders, and memory problems, often referred to as Gulf War Illness (GWI) prominently affect US Gulf War era (GWE) veterans, yet little is known about CIH use within this population. Using data collected as part of a larger study (n = 1153), we examined the influence of demographic characteristics, military experiences, and symptom severity on CIH utilization, and utilization differences between GWE veterans with and without GWI. Over half of the sample (58.5%) used at least one CIH modality in the past six months. Women veterans, white veterans, and veterans with higher levels of education were more likely to use CIH. GWE veterans with a GWI diagnosis and higher GWI symptom severity were more likely to use at least one CIH treatment in the past six months. Over three quarters (82.7%) of veterans who endorsed using CIH to treat GWI symptoms reported that it was helpful for their symptoms. Almost three quarters (71.5%) of veterans indicated that they would use at least one CIH approach if it was available at VA. Results provide a deeper understanding of the likelihood and characteristics of veterans utilizing CIH to treat health and GWI symptoms and may inform expansion of CIH modalities for GWE veterans, particularly those with GWI., Competing Interests: Declaration of competing interest A grant from the Health Services Research and Development Service of the Department of Veterans AffairsOffice of Research and Development #1I01HX001682 to Drs. Kimbrel and Pugh supported this research. Dr. Kelton is supported by a VA Office of Academic Affiliations Advanced Fellowship in a Geriatric Research Education Clinical Center. Dr. Young is supported by U.S. Department of Veterans Affairs, Office of Research and Development, Clinical Science Research and Development, Career Development Award (CDA-1) IK1 CX002187. Dr. Blakey was supported by a VA Office of Academic Affiliations Advance Fellowship in Mental Illness Research and Treatment. Dr. Beckham was funded by a Senior Research Career Scientist award from VA Clinical Sciences Research and Development (IK6BX00377). Dr. Pugh was funded by a Research Career Scientist Award from VAHealth Services Research and Development (IK6HX002608)., (Published by Elsevier Ltd.)

Chemical and pharmaceutical exposures have been associated with the development of Gulf War Illness (GWI), but how these factors interact with the pathophysiology of traumatic brain injury (TBI) remains an area of study that has received little attention thus far. We studied the effects of pyridostigmine bromide (an anti-nerve agent) and permethrin (a pesticide) exposure in a mouse model of repetitive mild TBI (r-mTBI), with 5 impacts over a 9-day period, followed by Gulf War (GW) toxicant exposure for 10 days beginning 30 days after the last head injury. We then assessed the chronic behavioral and pathological sequelae 5 months after GW agent exposure. We observed that r-mTBI and GWI cumulatively affect the spatial memory of mice in the Barnes maze and result in a shift of search strategies employed by r-mTBI/GW exposed mice. GW exposure also produced anxiety-like behavior in sham animals, but r-mTBI produced disinhibition in both the vehicle and GW treated mice. Pathologically, GW exposure worsened r-mTBI dependent axonal degeneration and neuroinflammation, increased oligodendrocyte cell counts, and increased r-mTBI dependent phosphorylated tau, which was found to colocalize with oligodendrocytes in the corpus callosum. These results suggest that GW exposures may worsen TBI-related deficits. Veterans with a history of both GW chemical exposures as well as TBI may be at higher risk for worse symptoms and outcomes. Subsequent exposure to various toxic substances can influence the chronic nature of mTBI and should be considered as an etiological factor influencing mTBI recovery., (© 2022. The Author(s).)

Gulf War illness (GWI) is a chronic illness with no known validated biomarkers that affects the lives of hundreds of thousands of people. As a result, there is an urgent need for the development of an untargeted and unbiased method to distinguish GWI patients from non-GWI patients. We report on the application of laser-induced breakdown spectroscopy (LIBS) to distinguish blood plasma samples from a group of subjects with GWI and from subjects with chronic low back pain as controls. We initially obtained LIBS data from blood plasma samples of four GWI patients and four non-GWI patients. We used an analytical method based on taking the difference between a mean LIBS spectrum obtained with those of GWI patients from the mean LIBS spectrum of those of the control group, to generate a "difference" spectrum for our classification model. This model was cross-validated using different numbers of differential LIBS emission peaks. A subset of 17 of the 82 atomic and ionic transitions that provided 70% of correct diagnosis was selected test in a blinded fashion using 10 additional samples and was found to yield 90% classification accuracy, 100% sensitivity, and 83.3% specificity. Of the 17 atomic and ionic transitions, eight could be assigned unambiguously to species of Na, K, and Fe.