Ketamine Produces Antidepressant Effects by Inhibiting Histone Deacetylases and Upregulating Hippocampal Brain-Derived Neurotrophic Factor Levels in a Diisopropyl Fluorophosphate-Based Rat Model of Gulf War Illness.

Approximately one-third of Gulf War veterans suffer from Gulf War Illness (GWI), which encompasses mood disorders and depressive symptoms. Deployment-related exposure to organophosphate compounds has been associated with GWI development. Epigenetic modifications have been reported in GWI veterans. We previously showed that epigenetic histone dysregulations were associated with decreased brain-derived neurotrophic factor (BDNF) expression in a GWI rat model. GWI has no effective therapies. Ketamine (KET) has recently been approved by the Food and Drug Administration for therapy-resistant depression. Interestingly, BDNF upregulation underlies KET's antidepressant effect in GWI-related depression. Here, we investigated whether KET's effect on histone mechanisms signals BDNF upregulations in GWI. Male Sprague-Dawley rats were injected once daily with diisopropyl fluorophosphate (DFP; 0.5 mg/kg, s.c., 5 days). At 6 months following DFP exposure, KET (10 mg/kg, i.p.) was injected, and brains were dissected 24 hours later. Western blotting was used for protein expression, and epigenetic studies used chromatin immunoprecipitation methods. Dil staining was conducted for assessing dendritic spines. Our results indicated that an antidepressant dose of KET inhibited the upregulation of histone deacetylase (HDAC) enzymes in DFP rats. Furthermore, KET restored acetylated histone occupancy at the Bdnf promoter IV and induced BDNF protein expression in DFP rats. Finally, KET treatment also increased the spine density and altered the spine diversity with increased T-type and decreased S-type spines in DFP rats. Given these findings, we propose that KET's actions involve the inhibition of HDAC expression, upregulation of BDNF, and dendritic modifications that together ameliorates the pathologic synaptic plasticity and exerts an antidepressant effect in DFP rats. SIGNIFICANCE STATEMENT: This study offers evidence supporting the involvement of epigenetic histone pathways in the antidepressant effects of ketamine (KET) in a rat model of Gulf War Illness (GWI)-like depression. This effect is achieved through the modulation of histone acetylation at the Bdnf promoter, resulting in elevated brain-derived neurotrophic factor expression and subsequent dendritic remodeling in the hippocampus. These findings underscore the rationale for considering KET as a potential candidate for clinical trials aimed at managing GWI-related depression.

Olfactory and cognitive decrements in 1991 Gulf War veterans with gulf war illness/chronic multisymptom illness.

BACKGROUND: Gulf War illness (GWI)/Chronic Multisymptom Illness (CMI) is a disorder related to military service in the 1991 Gulf War (GW). Prominent symptoms of GWI/CMI include fatigue, pain, and cognitive dysfunction. Although anosmia is not a typical GWI/CMI symptom, anecdotally some GW veterans have reported losing their sense smell shortly after the war. Because olfactory deficit is a prodromal symptom of neurodegenerative diseases like Parkinson's and Alzheimer's disease, and because we previously reported suggestive evidence that deployed GW veterans may be at increased risk for Mild Cognitive Impairment (MCI) and dementia, the current study examined the relationship between olfactory and cognitive function in deployed GW veterans. METHODS: Eighty deployed GW veterans (mean age: 59.9 ±7.0; 4 female) were tested remotely with the University of Pennsylvania Smell Identification Test (UPSIT) and the Montreal Cognitive Assessment (MoCA). Veterans also completed self-report questionnaires about their health and deployment-related exposures and experiences. UPSIT and MoCA data from healthy control (HC) participants from the Parkinson's Progression Markers Initiative (PPMI) study were downloaded for comparison. RESULTS: GW veterans had a mean UPSIT score of 27.8 ± 6.3 (range 9-37) and a mean MoCA score of 25.3 ± 2.8 (range 19-30). According to age- and sex-specific normative data, 31% of GW veterans (vs. 8% PPMI HCs) had UPSIT scores below the 10th percentile. Nearly half (45%) of GW veterans (vs. 8% PPMI HCs) had MoCA scores below the cut-off for identifying MCI. Among GW veterans, but not PPMI HCs, there was a positive correlation between UPSIT and MoCA scores (Spearman's ρ = 0.39, p < 0.001). There were no significant differences in UPSIT or MoCA scores between GW veterans with and without history of COVID or between those with and without Kansas GWI exclusionary conditions. CONCLUSIONS: We found evidence of olfactory and cognitive deficits and a significant correlation between UPSIT and MoCA scores in a cohort of 80 deployed GW veterans, 99% of whom had CMI. Because impaired olfactory function has been associated with increased risk for MCI and dementia, it may be prudent to screen aging, deployed GW veterans with smell identification tests so that hypo- and anosmic veterans can be followed longitudinally and offered targeted neuroprotective therapies as they become available.

Military exposures and Gulf War illness in veterans with and without posttraumatic stress disorder.

Gulf War illness (GWI) is a chronic multisymptom disorder of unknown etiology that is believed to be caused by neurotoxicant exposure experienced during deployment to the Gulf War. Posttraumatic stress disorder (PTSD) covaries with GWI and is believed to play a role in GWI symptoms. The present study examined the association between self-reported military exposures and GWI, stratified by PTSD status, in veterans from the Gulf War Era Cohort and Biorepository who were deployed to the Persian Gulf during the war. Participants self-reported current GWI and PTSD symptoms as well as military exposures (e.g., pyridostigmine [PB] pills, pesticides/insecticides, combat, chemical attacks, and oil well fires) experienced during the Gulf War. Deployed veterans' (N = 921) GWI status was ascertained using the Centers for Disease Control and Prevention definition. Individuals who met the GWI criteria were stratified by PTSD status, yielding three groups: GWI-, GWI+/PTSD-, and GWI+/PTSD+. Multivariable logistic regression, adjusted for covariates, was used to examine associations between GWI/PTSD groups and military exposures. Apart from insect bait use, the GWI+/PTSD+ group had higher odds of reporting military exposures than the GWI+/PTSD- group, adjusted odds ratio (aOR) = 2.15, 95% CI [1.30, 3.56]-aOR = 6.91, 95% CI [3.39, 14.08]. Except for PB pills, the GWI+/PTSD- group had a higher likelihood of reporting military exposures than the GWI- group, aOR = 2.03, 95% CI [1.26, 3.26]-aOR = 4.01, 95% CI [1.57, 10.25]. These findings are consistent with roles for both PTSD and military exposures in the etiology of GWI.

Sleep Apnea Among Gulf War Veterans: An Examination of VA Utilization Rates, Treatment Initiation, and Health Outcomes.

OBJECTIVES: Obstructive sleep apnea (OSA) among veterans is frequently underdiagnosed and undertreated. The present study sought to: 1) characterize the prevalence and rate of treatment of OSA among VA users and non-users and 2) examine the associations between diagnosed or probable OSA and key physical and mental health outcomes. METHODS: Gulf-War I-era Veterans were recruited as part of a national survey assessing mental and physical health concerns, healthcare needs, and healthcare utilization. OSA diagnoses were self-reported while sleep apnea risk was assessed via the STOP-Bang. Veterans also completed questionnaires assessing overall health, pain, depression, PTSD, and psychosocial functioning. RESULTS: 1,153 veterans were included in the present analyses (Mean age = 58.81; 21.84% female). Compared to non-VA healthcare users, veterans receiving care at the VA were more likely to have been diagnosed with OSA (p < .001) and report receiving treatment for OSA (p = .005). Compared to veterans at low risk for OSA, veterans at elevated risk reported higher levels of pain (p = .001), depression (p = .02), and poorer psychosocial functioning (p < .001). CONCLUSIONS: OSA diagnoses appear to be more common among VA healthcare users. Findings suggest that OSA remains underdiagnosed and associated with important physical and mental health consequences. Additional screening for OSA, especially among non-VA clinics, is warranted.

Dry eye symptoms and signs in United States Gulf War era veterans with myalgic encephalomyelitis/chronic fatigue syndrome.

BACKGROUND: To examine ocular symptoms and signs of veterans with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) diagnosis, ME/CFS symptoms, and controls. METHODS: This was a prospective, cross-sectional study of 124 South Florida veterans in active duty during the Gulf War era. Participants were recruited at an ophthalmology clinic at the Miami Veterans Affairs Hospital and evaluated for a diagnosis of ME/CFS, or symptoms of ME/CFS (intermediate fatigue, IF) using the Canadian Consensus criteria. Ocular symptoms were assessed via standardised questionnaires and signs via comprehensive slit lamp examination. Inflammatory blood markers were analysed and compared across groups. RESULTS: Mean age was 55.1 ± 4.7 years, 88.7% identified as male, 58.1% as White, and 39.5% as Hispanic. Ocular symptoms were more severe in the ME/CFS (n = 32) and IF (n = 48) groups compared to controls (n = 44) across dry eye (DE; Ocular Surface Disease Index [OSDI]: 48.9 ± 22.3 vs. 38.8 ± 23.3 vs. 19.1 ± 17.8, p < 0.001; 5 item Dry Eye Questionnaire [DEQ-5]: 10.8 ± 3.9 vs. 10.0 ± 4.6 vs. 6.6 ± 4.2, p < 0.001) and pain-specific questionnaires (Numerical Rating Scale 1-10 [NRS] right now: 2.4 ± 2.8 vs. 2.4 ± 2.9 vs 0.9 ± 1.5; p = 0.007; Neuropathic Pain Symptom Inventory modified for the Eye [NPSI-E]: 23.0 ± 18.6 vs. 19.8 ± 19.1 vs. 6.5 ± 9.0, p < 0.001). Ocular surface parameters and blood markers of inflammation were generally similar across groups. CONCLUSION: Individuals with ME/CFS report increased ocular pain but similar DE signs, suggesting that mechanisms beyond the ocular surface contribute to symptoms.

Living With Toxic Wounds: The Voices and Visual Self-Representations of Gulf War Veterans.

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.

Dysbiosis in gastrointestinal pathophysiology: Role of the gut microbiome in Gulf War Illness.

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.

Delayed cognitive impairments in a rat model of Gulf War Illness are stimulus-dependent.

Gulf War Illness (GWI) collectively describes the multitude of central and peripheral disturbances affecting soldiers who served in the 1990-1991 Gulf War. While the mechanisms responsible for GWI remain elusive, the prophylactic use of the reversible acetylcholinesterase inhibitor, pyridostigmine bromide (PB), and war-related stress have been identified as chief factors in GWI pathology. Post-deployment stress is a common challenge faced by veterans, and aberrant cholinergic and/or immune responses to these psychological stressors may play an important role in GWI pathology, especially the cognitive impairments experienced by many GWI patients. Therefore, the current study investigated if an immobilization stress challenge would produce abnormal responses in PB-treated rats three months later. Results indicate that hippocampal cholinergic responses to an immobilization stress challenge are impaired three months after PB administration. We also assessed if an immune or stress challenge reveals deficits in PB-treated animals during hippocampal-dependent learning and memory tasks at this delayed timepoint. Novel object recognition (NOR) testing paired with either acute saline or lipopolysaccharide (LPS, 30 µg/kg, i.p.), as well as Morris water maze (MWM) testing was conducted approximately three months after PB administration and/or repeated restraint stress. Rats with a history of PB treatment exhibited 24-hour hippocampal-dependent memory deficits when challenged with LPS, but not saline, in the NOR task. Similarly, in the same cohort, PB-treated rats showed 24-hour memory deficits in the MWM task. Ultimately, these studies highlight the long-term effects of PB treatment on hippocampal function and provide insight into the progressive cognitive deficits observed in veterans with GWI.

The effect of disease misclassification on the ability to detect a gene-environment interaction: implications of the specificity of case definitions for research on Gulf War illness.

BACKGROUND: Since 1997, research on Gulf War illness (GWI) has predominantly used 3 case definitions-the original Research definition, the CDC definition, and modifications of the Kansas definition-but they have not been compared against an objective standard. METHODS: All 3 case definitions were measured in the U.S. Military Health Survey by a computer-assisted telephone interview in a random sample (n = 6,497) of the 1991 deployed U.S. military force. The interview asked whether participants had heard nerve agent alarms during the conflict. A random subsample (n = 1,698) provided DNA for genotyping the PON1 Q192R polymorphism. RESULTS: The CDC and the Modified Kansas definition without exclusions were satisfied by 41.7% and 39.0% of the deployed force, respectively, and were highly overlapping. The Research definition, a subset of the others, was satisfied by 13.6%. The majority of veterans meeting CDC and Modified Kansas endorsed fewer and milder symptoms; whereas, those meeting Research endorsed more symptoms of greater severity. The group meeting Research was more highly enriched with the PON1 192R risk allele than those meeting CDC and Modified Kansas, and Research had twice the power to detect the previously described gene-environment interaction between hearing alarms and RR homozygosity (adjusted relative excess risk due to interaction [aRERI] = 7.69; 95% CI 2.71-19.13) than CDC (aRERI = 2.92; 95% CI 0.96-6.38) or Modified Kansas without exclusions (aRERI = 3.84; 95% CI 1.30-8.52) or with exclusions (aRERI = 3.42; 95% CI 1.20-7.56). The lower power of CDC and Modified Kansas relative to Research was due to greater false-positive disease misclassification from lower diagnostic specificity. CONCLUSIONS: The original Research case definition had greater statistical power to detect a genetic predisposition to GWI. Its greater specificity favors its use in hypothesis-driven research; whereas, the greater sensitivity of the others favor their use in clinical screening for application of future diagnostic biomarkers and clinical care.

Impact of the first Gulf war on multiple sclerosis risk in Kuwait: a quasi-experimental study.

OBJECTIVE: It has been reasoned that stressful life events tend to alter immune function thereby increasing the susceptibility to autoimmune diseases including multiple sclerosis (MS). Using the database of Kuwait National MS Registry, this quasi-experimental study assessed the impact of the first Gulf War (Iraqi invasion of Kuwait in 1990) on MS risk in Kuwait. METHODS: MS incidence data from 1980 to 2019 were obtained from the Kuwait National MS Registry. Annual age-standardized incidence rates (ASIRs) (per 105 person-years) were computed using the World Standard Population as a reference. Interrupted time series analysis with the option of autoregressive order (1) was used to evaluate the impact of the first Gulf War on MS risk by treating 1990 as an intervention year. RESULTS: Estimated baseline annual ASIR (per 105 person-years) was 0.38 (95% CI: -1.02, 1.78; p = 0.587). MS ASIRs (per 105 person-years) tended to increase significantly every year prior to 1990 by 0.45 (ASIR per 105 person-years = 0.45; 95% CI: 0.15, 0.76; p = 0.005). During the first year of the first Gulf War, there seemed to be a non-significant increase (step change) in ASIRs (per 105 person-years) of MS (ASIR per 105 person-years = 0.85; 95% CI: - 5.16, 6.86; p = 0.775) followed by a non-significant increase in the annual trend in MS ASIRs per 105 person-years (relative to the preintervention trend i.e., the difference between the pre-first Gulf War versus the post-first Gulf War trends) by 0.65 (ASIR per 105 person-years = 0.65; 95% CI: - 0.22, 1.52; p = 0.138). However, a postestimation measure of the post-first Gulf War trend was statistically significant (ASIR per 105 person-years = 1.10; 95% CI: 0.40, 1.80; p = 0.003), which implies that the post-first Gulf War trend in the annual ASIRs (per 105 person-years) inclined to be the same as was the pre-first Gulf War (i.e., counterfactual of the pre-first Gulf War trend in annual ASIRs (per 105 person-years) as if no first Gulf War took place).The Durbin-Watson test statistic (d = 1.89) showed almost non-significant autocorrelations across the time series observations on ASIRs (per 105 person-years). CONCLUSIONS: This study suggests that the first Gulf War was not significantly associated with the increasing trend in MS risk at population level in Kuwait neither with any short-term change nor with secular trend. Future studies may consider confirming the role of conflict-related stress or other stressful life events in potential exacerbation of MS risk along with unraveling biologically plausible mechanistic pathways.

Cognitive decrements in 1991 Gulf War veterans: associations with Gulf War illness and neurotoxicant exposures in the Boston Biorepository, Recruitment, and Integrative Network (BBRAIN) cohorts.

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.

Cannabis use and suicide risk among Gulf War veterans.

Cannabis use has been indicated as a risk factor for suicide in veterans. This study of Gulf War veterans tested the relationship between self-report past year cannabis use and (a) past year suicidal ideation and (b) risk for suicidal behavior. Data were from a national sample (N = 1126) of Gulf War veterans. Logistic regression models indicated cannabis use was associated with past year suicidal ideation and elevated risk for suicidal behavior, independent of key covariates. In corroboration with research on other military populations, this study indicates a potentially concerning association between cannabis use and suicide risk in Gulf War veterans.

Microbiome Dysbiosis Shows Strong Association of Gut-Derived Altered Metabolomic Profile in Gulf War Chronic Multisymptom Illness Symptom Persistence Following Western Diet Feeding and Development of Obesity.

The pathophysiology of Gulf War Illness (GWI) remains elusive even after three decades. The persistence of multiple complex symptoms along with metabolic disorders such as obesity worsens the health of present Gulf War (GW) Veterans often by the interactions of the host gut microbiome and inflammatory mediators. In this study, we hypothesized that the administration of a Western diet might alter the host metabolomic profile, which is likely associated with the altered bacterial species. Using a five-month symptom persistence GWI model in mice and whole-genome sequencing, we characterized the species-level dysbiosis and global metabolomics, along with heterogenous co-occurrence network analysis, to study the bacteriome-metabolomic association. Microbial analysis at the species level showed a significant alteration of beneficial bacterial species. The beta diversity of the global metabolomic profile showed distinct clustering due to the Western diet, along with the alteration of metabolites associated with lipid, amino acid, nucleotide, vitamin, and xenobiotic metabolism pathways. Network analysis showed novel associations of gut bacterial species with metabolites and biochemical pathways that could be used as biomarkers or therapeutic targets to ameliorate symptom persistence in GW Veterans.

Strategies for cost-effective remediation of widespread oil-contaminated soils in Kuwait, an environmental legacy of the first Gulf War.

The Kuwaiti oil fire during the first Gulf War resulted in the formation of approximately 300 "oil lakes" of varying sizes that covered over 110 km2 of the desert land. This threatens the fragile desert ecosystems and human health. Following the award of over US$2 billion to the State of Kuwait by the United Nations, large-scale remediation of the oil-contaminated soils has now been on the agenda. However, how to implement the remediation program in a cost-effective way represents a major challenge. In this study, cost-effective remediation strategies were developed based on field and laboratory investigations in a typical oil lake area. Overall, most of the lighter petroleum hydrocarbons (PHCs) were lost due to evaporation. Long-chain aliphatic PHCs dominated the PHCs in the investigated oil lake area. This has implications for developing remediation strategies. Toxicity assessment results showed that the majority of soils pose a low environmental risk with a hazard index <1. Therefore, intensive treatment of these PHCs may not be necessary for these soils. Although active treatment methods are needed to remove the contaminants as soon as practical for the relatively small areas of high contamination, more cost-effective passive methods should be considered to minimize the remedial costs for the larger area of the non-hotspot areas. Given the extremely low risk in terms of groundwater contamination by the contaminated soils, it may not be necessary to remove the soils from the contaminated sites. A low-cost capping method should be sufficient to minimize human exposure to the PHC-contaminated soils.

Sex-specific differences in plasma lipid profiles are associated with Gulf War Illness.

BACKGROUND: Nearly 250,000 veterans from the 1990-1991 Gulf War have Gulf War Illness (GWI), a condition with heterogeneous pathobiology that remains difficult to diagnose. As such, availability of blood biomarkers that reflect the underlying biology of GWI would help clinicians provide appropriate care to ill veterans. In this study, we measured blood lipids to examine the influence of sex on the association between blood lipids and GWI diagnosis. METHODS: Plasma lipid extracts from GWI (n = 100) and control (n = 45) participants were subjected to reversed-phase nano-flow liquid chromatography-mass spectrometry analysis. RESULTS: An influence of sex and GWI case status on plasma neutral lipid and phospholipid species was observed. Among male participants, triglycerides, diglycerides, and phosphatidylcholines were increased while cholesterol esters were decreased in GWI cases compared to controls. In female participants, ceramides were increased in GWI cases compared to controls. Among male participants, unsaturated triglycerides, phosphatidylcholine and diglycerides were increased while unsaturated cholesterol esters were lower in GWI cases compared to controls. The ratio of arachidonic acid- to docosahexaenoic acid-containing triglyceride species was increased in female and male GWI cases as compared to their sex-matched controls. CONCLUSION: Differential modulation of neutral lipids and ratios of arachidonic acid to docosahexaenoic acid in male veterans with GWI suggest metabolic dysfunction and inflammation. Increases in ceramides among female veterans with GWI also suggest activation of inflammatory pathways. Future research should characterize how these lipids and their associated pathways relate to GWI pathology to identify biomarkers of the disorder.

Health symptom trajectories and neurotoxicant exposures in Gulf War veterans: the Ft. Devens cohort.

BACKGROUND: Thirty years ago, Gulf War (GW) veterans returned home with numerous health symptoms that have been associated with neurotoxicant exposures experienced during deployment. The health effects from these exposures have been termed toxic wounds. Most GW exposure-outcome studies utilize group analyses and thus individual fluctuations in symptoms may have been masked. This study investigates health symptom trajectories in the same veterans over 25 years. METHODS: Veterans were categorized into 5 a priori trajectory groups for each health symptom and Chronic Multisymptom Illness (CMI) clinical case status. Multinomial logistic regression models were used to investigate associations between these trajectories and neurotoxicant exposures. RESULTS: Results indicate that more than 21 Pyridostigmine Bromide (PB) pill exposure was associated with consistent reporting of fatigue, pain, and cognitive/mood symptoms as well as the development of six additional symptoms over time. Chemical weapons exposure was associated with both consistent reporting and development of neurological symptoms over time. Reported exposure to tent heater exhaust was associated with later development of gastrointestinal and pulmonary symptoms. Veterans reporting exposure to more than 21 PB pills were more than 8 times as likely to consistently meet the criteria for CMI over time. CONCLUSION: This study highlights the importance of the continued documentation of the health impacts experienced by GW veterans', their resulting chronic health symptoms, and the importance of exposure-outcome relationships in these veterans now 30 years post-deployment.

A cellular approach to understanding and treating Gulf War Illness.

Gulf War Illness (GWI), a disorder suffered by approximately 200,000 veterans of the first Gulf War, was caused by exposure to low-level organophosphate pesticides and nerve agents in combination with battlefield stress. To elucidate the mechanistic basis of the brain-related symptoms of GWI, human-induced pluripotent stem cells (hiPSCs) derived from veterans with or without GWI were differentiated into forebrain glutamatergic neurons and then exposed to a Gulf War (GW) relevant toxicant regimen consisting of a sarin analog and cortisol, a human stress hormone. Elevated levels of total and phosphorylated tau, reduced microtubule acetylation, altered mitochondrial dynamics/transport, and decreased neuronal activity were observed in neurons exposed to the toxicant regimen. Some of the data are consistent with the possibility that some veterans may have been predisposed to acquire GWI. Wistar rats exposed to a similar toxicant regimen showed a mild learning and memory deficit, as well as cell loss and tau pathology selectively in the CA3 region of the hippocampus. These cellular responses offer a mechanistic explanation for the memory loss suffered by veterans with GWI and provide a cell-based model for screening drugs and developing personalized therapies for these veterans.

A review of chemical warfare agents linked to respiratory and neurological effects experienced in Gulf War Illness.

Over 40% of veterans from the Persian Gulf War (GW) (1990-1991) suffer from Gulf War Illness (GWI). Thirty years since the GW, the exposure and mechanism contributing to GWI remain unclear. One possible exposure that has been attributed to GWI are chemical warfare agents (CWAs). While there are treatments for isolated symptoms of GWI, the number of respiratory and cognitive/neurological issues continues to rise with minimum treatment options. This issue does not only affect veterans of the GW, importantly these chronic multisymptom illnesses (CMIs) are also growing amongst veterans who have served in the Afghanistan-Iraq war. What both wars have in common are their regions and inhaled exposures. In this review, we will describe the CWA exposures, such as sarin, cyclosarin, and mustard gas in both wars and discuss the various respiratory and neurocognitive issues experienced by veterans. We will bridge the respiratory and neurological symptoms experienced to the various potential mechanisms described for each CWA provided with the most up-to-date models and hypotheses.

The impact of neurotoxicant exposures on posttraumatic stress disorder trajectories: The Ft. Devens Gulf War Veterans Cohort.

Gulf War veterans (GWVs) were exposed to neurotoxicants, including sarin nerve gas, anti-nerve agent pills, pesticides, oil well fires, and fumes from unvented tent heaters, all of which have been associated with subsequent adverse health. Posttraumatic stress disorder (PTSD) symptoms have also been associated with GW deployment; however, associations between exposures and PTSD symptoms have not been investigated. We assessed PTSD symptom trajectories and associations with neurotoxicant exposures in Ft. Devens Cohort (FDC) veterans (N = 259) who endorsed trauma exposure during deployment and completed the PTSD Checklist at three follow-ups (1992-1993, 1997-1998, 2013-2017). Results indicate that among veterans with more severe initial PTSD symptoms, symptoms remained significantly higher across follow-ups, Bs = -1.489-1.028, whereas among those with low initial PTSD symptoms, symptom severity increased significantly over time, Bs = 1.043-10.304. Additionally, neurotoxicant exposure was associated with a significant increase in PTSD symptoms, Bs = -1.870-9.003. Significant interactions between time and exposures were observed for PTSD symptom clusters, suggesting that among participants with high initial PTSD symptom, unexposed veterans experienced symptom alleviation, whereas exposed veterans' PTSD symptoms remained high. In GWVs with low initial PTSD symptoms, both unexposed and exposed veterans experienced PTSD symptom exacerbations over time; however, this occurred at a faster rate among exposed veterans. These findings suggest that in the years following deployment, GWVs who were exposed to both traumatic events and neurotoxicants may experience more severe and chronic PTSD symptoms than those without neurotoxicant exposures.

Correlates and clinical associations of military sexual assault in Gulf War era U.S. veterans: Findings from a national sample.

Military sexual assault (MSA) is a prevalent issue among military personnel that can have direct implications on postmilitary mental health. Gulf War era U.S. veterans represent the first cohort in which women veterans were integrated into most aspects of military service except for combat. The present study sought to build on prior studies by identifying characteristics associated with the occurrence of MSA and clinical correlates of MSA and examining how these differ between men and women. This study analyzed cross-sectional survey data from a national sample of treatment-seeking Gulf War era veterans. Participants (N = 1,153) reported demographic information, clinical outcomes, military background, and history of MSA. MSA was more common among female veterans (n = 100, 41.3%) than male veterans (n = 32, 3.6%). The odds of experiencing MSA were approximately 19 times higher for female veterans relative to their male peers, OR = 18.92, p < .001. Moreover, as expected, MSA was robustly associated with probable current posttraumatic stress disorder, probable current depression, and past-year suicidal ideation in female veterans, whereas combat exposure was robustly associated with these sequelae in male veterans. The present findings confirm that a large proportion of female veterans from the Gulf War era experienced MSA and highlight the deleterious correlates of MSA on veterans' mental health. Sex differences of correlates of MSA and subsequent clinical associations are highlighted.