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Understanding the complex pathology of Gulf War Illness (GW), with its multisymptomatic condition, and identifying an efficient treatment has been a longstanding challenge for researchers. Researchers have made significant efforts in conducting mechanistic studies using different combinations of representative Gulf War (GW) chemicals in various experimental animal models in an attempt to create a translatable GWI pre-clinical model. However, there remain confounding factors like paucity of information regarding the actual amount of exposure among the GW Veterans, route, and duration of exposure impede the process.Our lab has been pioneering GWI research for the past decade. From the very first report about the association of altered gut microbiome in GWI pathology, we have attempted to approach the condition considering the translatable impact of the results on present-day Veterans. In the first study, the impact of metabolic disorders in underlying GWI conditions has been studied. GW Veterans living in a sedentary lifestyle now have an increased risk of xii developing conditions like obesity. The results showed that administration of a Western diet in a mouse model pre-exposed to GW chemicals decreased the abundance of beneficial gut bacteria. A decrease in bacterial diversity is strongly associated with gastrointestinal, hepatic, and systemic inflammation along with increased neurodegeneration. This study further provides cues of pleiotropic marker IL-6 being responsible for GWI pathology via the microbiome-gut-brain axis. In the second study, the alteration of gut resistome profile due to GW chemical exposure is long-lasting and closely associated with bacterial dysbiosis. In this study, a similar trend in resistome profile has been observed in an experimental murine model and GW Veterans. It was also observed that the altered antibiotic resistance genes were associated with gastrointestinal and systemic inflammation and decreased synaptic plasticity in the brain

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.

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

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

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

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.

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

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

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

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

AimsTo examine whether cognitive behavioral therapy for insomnia (CBT-I), delivered by telephone, improves sleep and non-sleep symptoms of Gulf War Illness (GWI).Main methodsEighty-five Gulf War veterans (21 women, mean age: 54 years, range 46-72 years) who met the Kansas GWI case definition, the Centers for Disease Control and Prevention (CDC) case definition for Chronic Multisymptom Illness (CMI), and research diagnostic criteria for insomnia disorder were randomly assigned to CBT-I or monitor-only wait list control. Eight weekly sessions of individual CBT-I were administered via telephone by Ph.D. level psychologists to study participants. Outcome measures included pre-, mid-, and post-treatment assessments of GWI and insomnia symptoms, subjective sleep quality, and continuous sleep monitoring with diary. Outcomes were re-assessed 6-months post-treatment in participants randomized to CBT-I.Key findingsCompared to wait list, CBT-I produced significant improvements in overall GWI symptom severity, individual measures of fatigue, cognitive dysfunction, depression and anxiety, insomnia severity, subjective sleep quality, and sleep diary outcome measures. The beneficial effects of CBT-I on overall GWI symptom severity and most individual GWI symptom measures were maintained 6-months after treatment.SignificanceGWI symptoms have historically been difficult to treat. Because CBT-I, which is associated with low stigma and is increasingly readily available to veterans, improved both sleep and non-sleep symptoms of GWI, these results suggest that a comprehensive approach to the treatment of GWI should include behavioral sleep interventions.

Published: 9 August 2021, GulfWar Illness (GWI) is a persistent chronic neuroinflammatory illness exacerbated by external stressors and characterized by fatigue, musculoskeletal pain, cognitive, and neurological problems linked to underlying immunological dysfunction for which there is no known treatment. As the immune system and the brain communicate through several signaling pathways, including the hypothalamic–pituitary–adrenal (HPA) axis, it underlies many of the behavioral and physiological responses to stressors via blood-borne mediators, such as cytokines, chemokines, and hormones. Signaling by these molecules is mediated by the semipermeable blood–brain barrier (BBB) made up of a monocellular layer forming an integral part of the neuroimmune axis. BBB permeability can be altered and even diminished by both external factors (e.g., chemical agents) and internal conditions (e.g., acute or chronic stress, or cross-signaling from the hypothalamic–pituitary–gonadal (HPG) axis). Such a complex network of regulatory interactions that possess feed-forward and feedback connections can have multiple response dynamics that may include several stable homeostatic states beyond normal health. Here we compare immune and hormone measures in the blood of human clinical samples and mouse models of Gulf War Illness (GWI) subtyped by exposure to traumatic stress for subtyping this complex illness. We do this via constructing a detailed logic model of HPA–HPG–Immune regulatory behavior that also considers signaling pathways across the BBB to neuronal–glial interactions within the brain. We apply conditional interactions to model the effects of changes in BBB permeability. Several stable states are identified in the system beyond typical health. Following alignment of the human and mouse blood profiles in the context of the model, mouse brain sample measures were used to infer the neuroinflammatory state in human GWI and perform treatment simulations using a genetic algorithm to optimize the Monte Carlo si

Approximately one-third of Persian Gulf War veterans are afflicted by Gulf War Illness (GWI), a chronic multisymptom condition that fundamentally presents with cognitive deficits (i.e., learning and memory impairments) and neuroimmune dysfunction (i.e., inflammation). Factors associated with GWI include overexposures to neurotoxic pesticides and nerve agent prophylactics such as permethrin (PM) and pyridostigmine bromide (PB), respectively. GWI-related neurological impairments associated with PB-PM overexposures have been recapitulated in animal models; however, there is a paucity of studies assessing PB-PM-related aberrations in hippocampal synaptic plasticity and transmission that may underlie behavioral impairments. Importantly, FDA-approved neuroactive treatments are currently unavailable for GWI. In the present study, we assessed the efficacy of an immunomodulatory therapeutic, lacto-N-fucopentaose-III (LNFPIII), on ameliorating acute effects of in vivo PB-PM exposure on synaptic plasticity and transmission as well as trophic factor/cytokine expression along the hippocampal dorsoventral axis. PB-PM exposure resulted in hippocampal synaptic transmission deficits 48 h post-exposure, a response that was ameliorated by LNFPIII coadministration, particularly in the dorsal hippocampus (dH). LNFPIII coadministration also enhanced synaptic transmission in the dH and the ventral hippocampus (vH). Notably, LNFPIII coadministration elevated long-term potentiation in the dH. Further, PB-PM exposure and LNFPIII coadministration uniquely altered key inflammatory cytokine and trophic factor production in the dH and the vH. Collectively, these findings demonstrate that PB-PM exposure impaired hippocampal synaptic responses 48 h post-exposure, impairments that differentially manifested along the dorsoventral axis. Importantly, LNFPIII ameliorated GWI-related electrophysiological deficits, a beneficial effect indicating the potential efficacy of LNFPIII for treating GWI.

Residual effects of the 1990-1991 Gulf War (GW) still plague veterans 30 years later as Gulf War Illness (GWI). Thought to stem mostly from deployment-related chemical overexposures, GWI is a disease with multiple neurological symptoms with likely immunological underpinnings. Currently, GWI remains untreatable, and the long-term neurological disease manifestation is not characterized fully. The present study sought to expand and evaluate the long-term implications of prior GW chemicals exposure on neurological function 6-8 months post GWI-like symptomatology induction. Additionally, the beneficial effects of delayed treatment with the glycan immunotherapeutic lacto-Nfucopentaose III (LNFPIII) were evaluated. Male C57BL/6J mice underwent a 10-day combinational exposure (i.p.) to GW chemicals, the nerve agent prophylactic pyridostigmine bromide (PB) and the insecticide permethrin (PM; 0.7 and 200 mg/kg, respectively). Beginning 4 months after PB/PM exposure, a subset of the mice were treated twice a week until study completion with LNFPIII. Evaluation of cognition/memory, motor function, and mood was performed beginning 1 month after LNFPIII treatment initiation. Prior exposure to PB/PM produced multiple locomotor, neuromuscular, and sensorimotor deficits across several motor tests. Subtle anxiety-like behavior was also present in PB/PM mice in mood tests. Further, PB/PM-exposed mice learned at a slower rate, mostly during early phases of the learning and memory tests employed. LNFPIII treatment restored or improved many of these behaviors, particularly in motor and cognition/memory domains. Electrophysiology data collected from hippocampal slices 8 months post PB/PM exposure revealed modest aberrations in basal synaptic transmission and long-term potentiation in the dorsal or ventral hippocampus that were improved by LNFPIII treatment. Immunohistochemical analysis of tyrosine hydroxylase (TH), a dopaminergic marker, did not detect major PB/PM effects along the nigros

AimsTo examine whether cognitive behavioral therapy for insomnia (CBT-I), delivered by telephone, improves sleep and non-sleep symptoms of Gulf War Illness (GWI).Main methodsEighty-five Gulf War veterans (21 women, mean age: 54 years, range 46-72 years) who met the Kansas GWI case definition, the Centers for Disease Control and Prevention (CDC) case definition for Chronic Multisymptom Illness (CMI), and research diagnostic criteria for insomnia disorder were randomly assigned to CBT-I or monitor-only wait list control. Eight weekly sessions of individual CBT-I were administered via telephone by Ph.D. level psychologists to study participants. Outcome measures included pre-, mid-, and post-treatment assessments of GWI and insomnia symptoms, subjective sleep quality, and continuous sleep monitoring with diary. Outcomes were re-assessed 6-months post-treatment in participants randomized to CBT-I.Key findingsCompared to wait list, CBT-I produced significant improvements in overall GWI symptom severity, individual measures of fatigue, cognitive dysfunction, depression and anxiety, insomnia severity, subjective sleep quality, and sleep diary outcome measures. The beneficial effects of CBT-I on overall GWI symptom severity and most individual GWI symptom measures were maintained 6-months after treatment.SignificanceGWI symptoms have historically been difficult to treat. Because CBT-I, which is associated with low stigma and is increasingly readily available to veterans, improved both sleep and non-sleep symptoms of GWI, these results suggest that a comprehensive approach to the treatment of GWI should include behavioral sleep interventions.

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

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

Aims: The present study investigated if treatment with the immunotherapeutic, lacto-N-fucopentaose-III (LNFPIII), resulted in amelioration of acute and persisting deficits in synaptic plasticity and transmission as well as trophic factor expression along the hippocampal dorsoventral axis in a mouse model of Gulf War Illness (GWI). Main methods: Mice received either coadministered or delayed LNFPIII treatment throughout or following, respectively, exposure to a 15-day GWI induction paradigm. Subsets of animals were subsequently sacrificed 48 h, seven months, or 11 months post GWI-related (GWIR) exposure for hippocampal qPCR or in vitro electrophysiology experiments. Key findings: Progressively worsened impairments in hippocampal synaptic plasticity, as well as a biphasic effect on hippocampal synaptic transmission, were detected in GWIR-exposed animals. Dorsoventral-specific impairments in hippocampal synaptic responses became more pronounced over time, particularly in the dorsal hippocampus. Notably, delayed LNFPIII treatment ameliorated GWI-related aberrations in hippocampal synaptic plasticity and transmission seven and 11 months post-exposure, an effect that was consistent with enhanced hippocampal trophic factor expression and absence of increased interleukin 6 (IL-6) in animals treated with LNFPIII. Significance: Approximately a third of Gulf War Veterans have GWI; however, GWI therapeutics are presently limited to targeted and symptomatic treatments. As increasing evidence underscores the substantial role of persisting neuroimmune dysfunction in GWI, efficacious neuroactive immunotherapeutics hold substantial promise in yielding GWI remission. The findings in the present report indicate that LNFPIII may be an efficacious candidate for ameliorating persisting neurological abnormalities presented in GWI.

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

The microbiota’s influence on host (patho) physiology has gained interest in the context of Gulf War Illness (GWI), a chronic disorder featuring dysregulation of the gut–brain–immune axis. This study examined short- and long-term effects of GWI-related chemicals on gut health and fecal microbiota and the potential benefits of Lacto-N-fucopentaose-III (LNFPIII) treatment in a GWI model. Male C57BL/6J mice were administered pyridostigmine bromide (PB; 0.7 mg/kg) and permethrin (PM; 200 mg/kg) for 10 days with concurrent LNFPIII treatment (35 μg/mouse) in a short-term study (12 days total) and delayed LNFPIII treatment (2×/week) beginning 4 months after 10 days of PB/PM exposure in a long-term study (9 months total). Fecal 16S rRNA sequencing was performed on all samples post-LNFPIII treatment to assess microbiota effects of GWI chemicals and acute/delayed LNFPIII administration. Although PB/PM did not affect species composition on a global scale, it affected specific taxa in both short- and long-term settings. PB/PM elicited more prominent long-term effects, notably, on the abundances of bacteria belonging to Lachnospiraceae and Ruminococcaceae families and the genus Allobaculum. LNFPIII improved a marker of gut health (i.e., decreased lipocalin-2) independent of GWI and, importantly, increased butyrate producers (e.g., Butyricoccus, Ruminococcous) in PB/PM-treated mice, indicating a positive selection pressure for these bacteria. Multiple operational taxonomic units correlated with aberrant behavior and lipocalin-2 in PB/PM samples; LNFPIII was modulatory. Overall, significant and lasting GWI effects occurred on specific microbiota and LNFPIII treatment was beneficial.

Gulf War Illness (GWI) manifests a multitude of symptoms, including neurological and immunological, and approximately a third of the 1990-1991 Gulf War (GW) veterans suffer from it. This study sought to characterize the acute neurochemical (monoamine) and neuroinflammatory profiles of two established GWI animal models and examine the potential modulatory effects of the novel immunotherapeutic Lacto-N-fucopentaose III (LNFPIII). In Model 1, male C57BL/6J mice were treated for 10 days with pyridostigmine bromide (PB) and permethrin (PM). In Model 2, a separate cohort of mice were treated for 14 days with PB and N,N-Diethylmethylbenzamide (DEET), plus corticosterone (CORT) via drinking water on days 8-14 and diisopropylfluorophosphate (DFP) on day 15. LNFPIII was administered concurrently with GWI chemicals treatments. Brain and spleen monoamines and hippocampal inflammatory marker expression were examined by, respectively, HPLC-ECD and qPCR, 6 h post treatment cessation. Serotonergic (5-HT) and dopaminergic (DA) dyshomeostasis caused by GWI chemicals was apparent in multiple brain regions, primarily in the nucleus accumbens (5-HT) and hippocampus (5-FIT, DA) for both models. Splenic levels of 5-HT (both models) and norepinephrine (Model 2) were also disrupted by GWI chemicals. LNFPIII treatment prevented many of the GWI chemicals induced monoamine alterations. Hippocampal inflammatory cytokines were increased in both models, but the magnitude and spread of inflammation was greater in Model 2; LNFPIII was anti-inflammatory, more so in the apparently milder Model 1. Overall, in both models, GWI chemicals led to monoamine disbalance and neuroinflammation. LNFPIII co-treatment prevented many of these disruptions in both models, which is indicative of its promise as a potential GWI therapeutic.

The microbiota’s influence on host (patho) physiology has gained interest in the context of Gulf War Illness (GWI), a chronic disorder featuring dysregulation of the gut–brain–immune axis. This study examined short- and long-term effects of GWI-related chemicals on gut health and fecal microbiota and the potential benefits of Lacto-N-fucopentaose-III (LNFPIII) treatment in a GWI model. Male C57BL/6J mice were administered pyridostigmine bromide (PB; 0.7 mg/kg) and permethrin (PM; 200 mg/kg) for 10 days with concurrent LNFPIII treatment (35 μg/mouse) in a short-term study (12 days total) and delayed LNFPIII treatment (2×/week) beginning 4 months after 10 days of PB/PM exposure in a long-term study (9 months total). Fecal 16S rRNA sequencing was performed on all samples post-LNFPIII treatment to assess microbiota effects of GWI chemicals and acute/delayed LNFPIII administration. Although PB/PM did not affect species composition on a global scale, it affected specific taxa in both short- and long-term settings. PB/PM elicited more prominent long-term effects, notably, on the abundances of bacteria belonging to Lachnospiraceae and Ruminococcaceae families and the genus Allobaculum. LNFPIII improved a marker of gut health (i.e., decreased lipocalin-2) independent of GWI and, importantly, increased butyrate producers (e.g., Butyricoccus, Ruminococcous) in PB/PM-treated mice, indicating a positive selection pressure for these bacteria. Multiple operational taxonomic units correlated with aberrant behavior and lipocalin-2 in PB/PM samples; LNFPIII was modulatory. Overall, significant and lasting GWI effects occurred on specific microbiota and LNFPIII treatment was beneficial.

The microbiota’s influence on host (patho) physiology has gained interest in the context of Gulf War Illness (GWI), a chronic disorder featuring dysregulation of the gut–brain–immune axis. This study examined short- and long-term effects of GWI-related chemicals on gut health and fecal microbiota and the potential benefits of Lacto-N-fucopentaose-III (LNFPIII) treatment in a GWI model. Male C57BL/6J mice were administered pyridostigmine bromide (PB; 0.7 mg/kg) and permethrin (PM; 200 mg/kg) for 10 days with concurrent LNFPIII treatment (35 μg/mouse) in a short-term study (12 days total) and delayed LNFPIII treatment (2×/week) beginning 4 months after 10 days of PB/PM exposure in a long-term study (9 months total). Fecal 16S rRNA sequencing was performed on all samples post-LNFPIII treatment to assess microbiota effects of GWI chemicals and acute/delayed LNFPIII administration. Although PB/PM did not affect species composition on a global scale, it affected specific taxa in both short- and long-term settings. PB/PM elicited more prominent long-term effects, notably, on the abundances of bacteria belonging to Lachnospiraceae and Ruminococcaceae families and the genus Allobaculum. LNFPIII improved a marker of gut health (i.e., decreased lipocalin-2) independent of GWI and, importantly, increased butyrate producers (e.g., Butyricoccus, Ruminococcous) in PB/PM-treated mice, indicating a positive selection pressure for these bacteria. Multiple operational taxonomic units correlated with aberrant behavior and lipocalin-2 in PB/PM samples; LNFPIII was modulatory. Overall, significant and lasting GWI effects occurred on specific microbiota and LNFPIII treatment was beneficial.

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

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

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

Cognitive slowing is a prevalent symptom observed in Gulf War Illness (GWI). The present study assessed the extent to which functional connectivity between dorsolateral prefrontal cortex (DLPFC) and other task-relevant brain regions was predictive of GWI-related cognitive slowing. GWI patients (n = 54) and healthy veteran controls (n = 29) were assessed on performance of a processing speed task (the Digit Symbol Substitution Task; DSST) while undergoing functional magnetic resonance imaging (fMRI). GWI patients were slower on the DSST relative to controls. Bilateral DLPFC connectivity with task-relevant nodes was altered in GWI patients compared to healthy controls during DSST performance. Moreover, hyperconnectivity in these networks predicted GWI-related increases in reaction time on the DSST, whereas hypoconnectivity did not. These results suggest that GWI-related cognitive slowing reflects reduced efficiency in cortical networks.

Veterans of Operation Desert Storm/Desert Shield - the 1991 Gulf War (GW) - are a unique population who returned from theater with multiple health complaints and disorders. Studies in the U.S. and elsewhere have consistently concluded that approximately 25-32% of this population suffers from a disorder characterized by symptoms that vary somewhat among individuals and include fatigue, headaches, cognitive dysfunction, musculoskeletal pain, and respiratory, gastrointestinal and dermatologic complaints. Gulf War illness (GWI) is the term used to describe this disorder. In addition, brain cancer occurs at increased rates in subgroups of GW veterans, as do neuropsychological and brain imaging abnormalities. Chemical exposures have become the focus of etiologic GWI research because nervous system symptoms are prominent and many neurotoxicants were present in theater, including organophosphates (OPs), carbamates, and other pesticides; sarin/cyclosarin nerve agents, and pyridostigmine bromide (PB) medications used as prophylaxis against chemical warfare attacks. Psychiatric etiologies have been ruled out. This paper reviews the recent literature on the health of 1991 GW veterans, focusing particularly on the central nervous system and on effects of toxicant exposures. In addition, it emphasizes research published since 2008, following on an exhaustive review that was published in that year that summarizes the prior literature (RACGWI, 2008). We conclude that exposure to pesticides and/or to PB are causally associated with GWI and the neurological dysfunction in GW veterans. Exposure to sarin and cyclosarin and to oil well fire emissions are also associated with neurologically based health effects, though their contribution to development of the disorder known as GWI is less clear. Gene-environment interactions are likely to have contributed to development of GWI in deployed veterans. The health consequences of chemical exposures in the GW and other conflicts have been call

Veterans of Operation Desert Storm/Desert Shield - the 1991 Gulf War (GW) - are a unique population who returned from theater with multiple health complaints and disorders. Studies in the U.S. and elsewhere have consistently concluded that approximately 25-32% of this population suffers from a disorder characterized by symptoms that vary somewhat among individuals and include fatigue, headaches, cognitive dysfunction, musculoskeletal pain, and respiratory, gastrointestinal and dermatologic complaints. Gulf War illness (GWI) is the term used to describe this disorder. In addition, brain cancer occurs at increased rates in subgroups of GW veterans, as do neuropsychological and brain imaging abnormalities. Chemical exposures have become the focus of etiologic GWI research because nervous system symptoms are prominent and many neurotoxicants were present in theater, including organophosphates (OPs), carbamates, and other pesticides; sarin/cyclosarin nerve agents, and pyridostigmine bromide (PB) medications used as prophylaxis against chemical warfare attacks. Psychiatric etiologies have been ruled out. This paper reviews the recent literature on the health of 1991 GW veterans, focusing particularly on the central nervous system and on effects of toxicant exposures. In addition, it emphasizes research published since 2008, following on an exhaustive review that was published in that year that summarizes the prior literature (RACGWI, 2008). We conclude that exposure to pesticides and/or to PB are causally associated with GWI and the neurological dysfunction in GW veterans. Exposure to sarin and cyclosarin and to oil well fire emissions are also associated with neurologically based health effects, though their contribution to development of the disorder known as GWI is less clear. Gene-environment interactions are likely to have contributed to development of GWI in deployed veterans. The health consequences of chemical exposures in the GW and other conflicts have been call

Cognitive slowing is a prevalent symptom observed in Gulf War Illness (GWI). The present study assessed the extent to which functional connectivity between dorsolateral prefrontal cortex (DLPFC) and other task-relevant brain regions was predictive of GWI-related cognitive slowing. GWI patients (n = 54) and healthy veteran controls (n = 29) were assessed on performance of a processing speed task (the Digit Symbol Substitution Task; DSST) while undergoing functional magnetic resonance imaging (fMRI). GWI patients were slower on the DSST relative to controls. Bilateral DLPFC connectivity with task-relevant nodes was altered in GWI patients compared to healthy controls during DSST performance. Moreover, hyperconnectivity in these networks predicted GWI-related increases in reaction time on the DSST, whereas hypoconnectivity did not. These results suggest that GWI-related cognitive slowing reflects reduced efficiency in cortical networks.

Cognitive slowing is a prevalent symptom observed in Gulf War Illness (GWI). The present study assessed the extent to which functional connectivity between dorsolateral prefrontal cortex (DLPFC) and other task-relevant brain regions was predictive of GWI-related cognitive slowing. GWI patients (n = 54) and healthy veteran controls (n = 29) were assessed on performance of a processing speed task (the Digit Symbol Substitution Task; DSST) while undergoing functional magnetic resonance imaging (fMRI). GWI patients were slower on the DSST relative to controls. Bilateral DLPFC connectivity with task-relevant nodes was altered in GWI patients compared to healthy controls during DSST performance. Moreover, hyperconnectivity in these networks predicted GWI-related increases in reaction time on the DSST, whereas hypoconnectivity did not. These results suggest that GWI-related cognitive slowing reflects reduced efficiency in cortical networks.

Veterans of Operation Desert Storm/Desert Shield - the 1991 Gulf War (GW) - are a unique population who returned from theater with multiple health complaints and disorders. Studies in the U.S. and elsewhere have consistently concluded that approximately 25-32% of this population suffers from a disorder characterized by symptoms that vary somewhat among individuals and include fatigue, headaches, cognitive dysfunction, musculoskeletal pain, and respiratory, gastrointestinal and dermatologic complaints. Gulf War illness (GWI) is the term used to describe this disorder. In addition, brain cancer occurs at increased rates in subgroups of GW veterans, as do neuropsychological and brain imaging abnormalities. Chemical exposures have become the focus of etiologic GWI research because nervous system symptoms are prominent and many neurotoxicants were present in theater, including organophosphates (OPs), carbamates, and other pesticides; sarin/cyclosarin nerve agents, and pyridostigmine bromide (PB) medications used as prophylaxis against chemical warfare attacks. Psychiatric etiologies have been ruled out. This paper reviews the recent literature on the health of 1991 GW veterans, focusing particularly on the central nervous system and on effects of toxicant exposures. In addition, it emphasizes research published since 2008, following on an exhaustive review that was published in that year that summarizes the prior literature (RACGWI, 2008). We conclude that exposure to pesticides and/or to PB are causally associated with GWI and the neurological dysfunction in GW veterans. Exposure to sarin and cyclosarin and to oil well fire emissions are also associated with neurologically based health effects, though their contribution to development of the disorder known as GWI is less clear. Gene-environment interactions are likely to have contributed to development of GWI in deployed veterans. The health consequences of chemical exposures in the GW and other conflicts have been call

Chemical exposures are thought to precipitate the chronic symptoms associated with GWI. Chief among these are nerve agents encountered during deployment, treatment with a reversible cholinesterase inhibitor, and the use of pesticides. Cholinesterase inhibition has been proposed as a basis for the symptoms of GWI, and sarin is known to result in neuroinflammation. Physiologic stress experienced in theater also has been proposed as a contributor to GWI, and our results confirm that prior exposure to corticosterone (CORT) can enhance neuroinflammation. In this work we demonstrate that the sarin surrogate diisopropylphosphorofluoridate (DFP) results in neuroinflammation in mouse brain, an effect on multiple proinflammatory cytokines that is markedly enhanced by prior exposure to CORT and suggests the pathophysiological basis of GWI. GWI is characteristic of the sickness behavior typical of an inflammatory response to infection or injury, and a protracted condition is consistent with symptoms observed in ill veterans. We also have demonstrated that episodic exposure to CORT over an 180-day post-DFP period reveals a markedly enhanced priming effect that persists indefinitely. Finally, we found that an anti-inflammatory response, suggesting the use of non-steroidal anti-inflammatory drugs in the chronic treatment of GWI., The original document contains color images.

The term small-fiber polyneuropathy (SFPN) refers to body-wide dysfunction/degeneration of small-diameter axons that transmit pain and control the body s autonomic functions. The vague, widespread symptoms of SFPN overlap with those of Gulf War Illness (GWI). We propose that there may be a SFPN component to GWI. To diagnose SFPN in Gulf War-ill veterans, we tested normal control subjects and patients with definite SFPN to compare the sensitivity and specificity of the best known tests. We also tested Gulf War veterans with and without GWI to identify how often this neurological illness is masquerading as GWI, and we applied the same tests (autonomic function test, skin biopsy, and neurological exam) to subjects diagnosed with fibromyalgia (FM). We also characterized our subjects' health with a series of validated questionnaires. By doing so, we found markers of SFPN in Gulf War veterans and FM patients in approximately the same ratio., The original document contains color images.

The overall objective of the study is to determine whether probiotic VSL#3 will improve 1) intestinal symptoms of Irritable Bowel Syndrome and 2) non-intestinal symptoms (fatigue, joint pain, insomnia, general stiffness and headache) associated with IBS. All of these symptoms are part of the Gulf War illness. We screened our first participant in September 2013. Overall we have screened 47 and enrolled 26 Gulf War Veterans so far. Our efforts are ongoing to recruit more Gulf War veterans. The first set of stool samples have been sent to Lawrence Berkeley Laboratory microbiota analysis.

The purpose of this project is to evaluate subjects with Gulf War illness (GWI) for pathogens and potential biomarkers. The scope of this work will primarily encompass transcriptional analysis of lymphocytes from individual with GWI and compare the results to the same data from healthy control volunteers. Any potential pathogens identified will be confirmed by complimentary methods. Additionally, we will also survey the production of inflammatory cytokines and chemokines from the same individuals as well as evaluate lymphocyte populations. This information will be used to produce a diagnostic signature that can be used to delineate those who suffer from GWI from those who do not. At this time, we are developing a potential diagnostic signature that can be used to distinguish GWI from healthy controls and a closely related illness, chronic fatigue syndrome (ME/CFS)., The original document contains color images.

This study will provide symptomatic veterans with acupressure treatment and determine its effectiveness in fatigue relief and pain management for GWI disease. We plan to recruit patients who report they have symptoms of GWI through the Department of Veterans Affairs (VA), and randomize them into acupressure group (to receive acupressure treatment) and control group (Reiki). The acupressure treatment will be offered twice per week for 6 weeks. Evaluations will be made before and after treatment, and clinical outcomes will be compared between groups (acupressure group vs control group) and between different stages (before treatment vs. after treatment) within the same group.

Analyses were run on serum samples provided from 22 individuals who provided blood draws over 25 consecutive days. We examined 21 secreted serum cytokines and chemokines in this analysis. There are 8 individuals with GWI, 8 healthy veterans who served in the 1991 Persian Gulf War, and 6 non-veteran men with fibromyalgia (FM). These simple analyses were run on the entire group. We hypothesized that the GWI group would demonstrate greater variability of analytes than the healthy controls. We indeed found that GWI participants showed greater fluctuations (as measured by the coefficient of variation) of Eotaxin-1 and IL-1beta than did the healthy group. Interestingly, the fibromyalgia group ALSO showed elevated variability in those exact same two analytes when contrasted against the healthy controls. There were no differences between the GWI and FM groups. Those results suggest that GWI and FM may involve a common immunological dysregulation. We also hypothesized that GWI individuals would have elevated levels of proinflammatory markers. We see what previous reports have shown. IL-1beta, in addition to having greater variability in GWI and FM, is also higher than in healthy controls. Again, we see that there are no differences between the GWI and FM groups. Based on the serum cytokines results so far, GWI and FM are indistinguishable from each other. Third, we hypothesized that proinflammatory markers would predict day-to-day changes in symptom severity. We found that IL-1beta, MMP3, MMP9, MCP1, MIP1B, IL12p40, IL18, and IL23 changes are associated with symptom changes in GWI (some are anti-correlated). The same list also predicted symptoms in fibromyalgia individuals, with the exception of MCP1 and IL23. The results of our preliminary analyses suggest that men with GWI look very similar to men with FM in terms of cytokine levels, day-to-day variability, and relationship between cytokines and symptom fluctuations. The two disorders may share the same pathophysiological, The original document contains color images.

Subjects are being recruited for the proposed study and the study is still ongoing during the project extension period approved by DoD. There is no finding to report from the study as of 30/06/2014.

The overall goal of this project is to determine the underlying mechanisms for the neurological symptoms associated with Gulf War Illness. The central hypothesis is that subthreshold exposures to organophosphates-OPs (defined as exposures not associated with acute signs of toxicity) may have adversely affected axonal transport and/or myelin integrity in affected individuals. We are studying two OPs, a representative insecticide that was used in the first gulf war, chlorpyrifos (CPF), and a representative, nerve agent, diisopropylfluorophosphate (DFP) in rats. The first two years of this proposal have been primarily dedicated to Specific Aim #1: which has been designed to evaluate OP effects on axonal transport in the living rat brain using manganese-enhanced magnetic resonance imaging (MEMRI) of the optic nerve axonal projections from the retina to the superior colliculus. The following procedures have been conducted to date (N=6): 1) baseline MRI scans; 2) daily injections of vehicle or chlorpyrifos (3.0-18.0 mg/kg) x 14 days; 2) a second MRI scan on the day following the last drug injection; 3) a third scan after a 4 week (OP-free) washout period. For each animal, a separate 6 hour and 24 hour scan was performed after Mn2+ eye injection. For this work a manuscript is currently under review for publication. In this work we also evaluated the effects of an acute (single) exposure to CPF. We have also completed the MR scanning portion for the DFP study and a preliminary analysis indicates similar results (persistent impairments of axonal transport). The experiments for specific aim #2 (devoted to the evaluation of OP-related effects on myelin with diffusion tensor imaging-(DTI) and histology are currently underway., The original document contains color images.

The complex of multiple symptoms known as Gulf War Illness (GWI) continues to affect a substantial number of veterans who served in the 1990-1991 Gulf War. Despite considerable research, the biological processes underlying veterans symptoms have not been clearly elucidated. In order to develop useful diagnostic tests and optimize the search for effective GWI treatments, it is imperative to establish a more definitive and integrated understanding of the pathophysiology of this problem. This study utilizes a case-control design to evaluate diverse biological measures in a single, well-characterized and population-based sample of 130 Gulf War veterans residing in Central Texas. Eighty veterans with GWI are compared to 50 healthy veteran controls in a protocol that includes physical and neuropsychological evaluations, neuroimaging (MRI, fMRI, DTI), adrenal function tests, and diverse immune, inflammatory, and coagulation measures. Statistical analyses will determine which objective measures significantly distinguish GWI cases from controls, and explore the extent to which biological findings are interrelated and are associated with identifiable veteran subgroups. When complete, the study is expected to clarify many of the ambiguities currently associated with GWI and improve understanding of the biological processes that underlie veterans symptoms. This will facilitate efforts to identify useful diagnostic tests and promising treatments.

We examined whether chronic exposure to combinations of two neurotoxicants (chlorpyrifos and permethrin) with pyridostigmine bromide (PB) could produce a delayed neuropathic pain condition in rats; and whether corroccur in nociceptive neurons coding for pain in skin, muscle or vasculature. Following a 60 day exposure to neurotoxicants/PB esponding molecular changes would (NTPB), we observed molecular dysfunctions in membrane Kv (Kv7) and Nav (Nav1.8, Nav1.9) proteins that persisted 8 weeks after exposure had ended. Functional changes (spontaneous activity, action potential duration) were also documented. Most of the maladaptations were present in vascular nociceptors. The physical location of vascular nociceptive neurons renders them most exposed to concentrations of circulating neurotoxicants/PB as well as to any blood borne secondary influences (endocrine, immune) these agents might induce. As a result, vascular nociceptors could be the first nervous system component damaged by neurotoxicants/PB. An imbalance between Kv7 and other Na+ channel proteins (Nav1.9) could prove to be a basis for a chronic pain condition sourced from a vulnerable subset of vascular nociceptors. A resulting neurovascular reflex dysfunction could cause widespread pain and also contribute to the development of CNS symptoms that have been identified in Gulf War veterans, The original document contains color images.

This project is based on the premise of developing a new method to identify and establish the presence of phenotypic diversity/genetic heterogeneity in Gulf War Illness patients. In our previous research, we successfully established a link between genomic instability (displayed as elevated frequencies of non clonal chromosome aberrations or NCCAs) and cancer progression. In this DOD supported grant during the current study period, we have analyzed GWI patient samples using multiple-color spectral karyotype profiling or SKY and expression profiles. Elevated NCCAs have been observed in all GWI patient samples tested so far representing a highly statistically significant finding. We have tested 15 GWI patients and 35 controls to date. We believe that our methodology represents a means to identify a clinical biomarker based on phenotypic diversity/heterogeneity in GWI patients. We are developing a theory that links stress to the increased genome instability observed. This new concept and findings will support future translational projects that will result in vastly improving diagnosis and assessment of GWI patients.

This study will provide symptomatic veterans with acupressure treatment and determine its effectiveness in fatigue relief and pain management for GWI disease. We plan to recruit patients who report they have symptoms of GWI through the Department of Veterans Affairs (VA), and randomize them into acupressure group (to receive acupressure treatment) and control group (without acupressure treatment). The acupressure treatment, twice per week for 6 weeks, will be offered by licensed acupressure practitioner, with at least 5 years of clinical experience, who have received 20 hours of training related to symptoms of GWI. Evaluations will be made before and after treatment, and clinical outcomes will be compared between groups (acupressure group vs. control group) and between different stages (before treatment vs. after treatment) within the same group.

The specific aim of this study was to perform gene expression profiling and group comparison analyses of differential gene expression in RNA-stabilized blood samples of the approximately 150 veterans meeting the Factor case definition and Gulf War-era veteran controls. From the banked blood samples collected previously and stored frozen at -80 C in PAXgene tubes from 2 population subsamples of Gulf War veteran cases and controls, we were able to obtain sufficient high quality peripheral blood mononuclear cell (PBMC) RNA from 142. Our Genomics Core Laboratory performed Next Generation Transcriptome Sequencing (RNA-Seq), using Illumina s multiplexing mRNA-Seq to generate full sequence libraries from the poly-A tailed RNA to a read depth of 30 million reads. Bioinformatics analyses for replicable differences in the expression levels among the 4 clinical groups were completed with the Dozmorov method to test for multiple comparisons-corrected group differences. In the tests for differentially expressed single target genes, no significant group differences were found, but the second stage using Ingenuity Pathway Analysis to test for common regulator genes identified 6 transcription regulators whose downstream target genes differed between syndrome group 2 and controls in the Developmental subsample and the Replication subsample. Most noteworthy was the finding of apparent instability in expression of the STAT3 regulatory oncogene, which, if confirmed, could explain increased rates of brain cancer in Gulf War veterans. Future research for a Gulf War illness diagnostic test should employ methods, such as pharmacologic stimulation and analysis of pure cell types, to reduce high background variability of gene expression in peripheral blood cells., The original document contains color images.

We examined whether chronic exposure to combinations of two neurotoxicants (chlorpyrifos and permethrin) with pyridostigmine bromide (PB) could produce a delayed neuropathic pain condition in rats; and whether corresponding molecular changes would occur in nociceptive neurons coding for pain in skin, muscle or vasculature. Following a 60 day exposure to neurotoxicants/PB (NTPB), we observed molecular dysfunctions in membrane Kv (Kv7) and Nav (Nav1.8, Nav1.9) proteins that persisted 8 weeks after exposure had ended. Functional changes (spontaneous activity, action potential duration) were also documented. Most of the maladaptations were present in vascular nociceptors. The physical location of vascular nociceptive neurons renders them most exposed to concentrations of circulating neurotoxicants/PB as well as to any blood borne secondary influences (endocrine, immune) these agents might induce. As a result, vascular nociceptors could be the first nervous system component damaged by neurotoxicants/PB. An imbalance between Kv7 and other Na+ channel proteins (Nav1.9) could prove to be a basis for a chronic pain condition sourced from a vulnerable subset of vascular nociceptors. A resulting neurovascular reflex dysfunction could cause widespread pain and also contribute to the development of CNS symptoms that have been identified in Gulf War veterans., The original document contains color images.

Shortly after return from Gulf War (GW) deployment in 1991, some GW veterans began reporting a constellation of health symptoms that did not meet criteria for well-defined medical conditions or syndromes. Symptoms included pain, cognitive deficits, skin rash, gastrointestinal difficulties and sleep problems. The initial attempts at identifying case definition used a one-time cross-sectional health symptom report, which is insufficient for determining a case definition given that symptoms often show remitting and relapsing tendencies. Current estimates suggest that 25 percent of GW veterans (nearly 170,000) have reported persisting multisymptom illness and in order to stimulate more appropriate treatment avenues for ill veterans, it is essential that a refined case definition be found taking change over time into account and examining the impact of symptoms previously reported on current health status. This will be accomplished by employing a longitudinal design with a large longitudinally followed cohort. Current health symptom survey data will therefore be compared with prior survey data. The practical application of this study is to provide a gold standard definition to be used in future treatment trials. The study goals include, devising a new case definition for GW illness, where possible assisting in the management of specific disease states, and collecting outcome data about treatment avenues employed and their efficacy. Year 2 goals have primarily been met including collecting initial data of the first 100 participants.

The purpose of this project is to evaluate subjects with Gulf War illness (GWI) for pathogens and potential biomarkers. The scope of this work will primarily encompass transcriptional analysis of lymphocytes from individual with GWI and compare the results to the same data from healthy control volunteers. Any potential pathogens identified will be confirmed by complimentary methods. Additionally, we will also survey the production of inflammatory cytokines and chemokines from the same individuals as well as evaluate lymphocyte populations. This information will be used to produce a diagnostic signature that can be used to delineate those who suffer from GWI from those who do not. At this time, we are developing a potential diagnostic signature that can be used to distinguish GWI from healthy controls and a closely related illness, chronic fatigue syndrome (ME/CFS)., The original document contains color images.

The use of pyridostigmine bromide (PB) in the Gulf War of 1991 has been associated with increased incidence and symptom severity of Gulf War Illness. The goal of our research program was to use zebrafish as a model organism to characterize the effects of PB using locomotive/behavioral phenotyping and unbiased, high-throughput techniques, specifically mRNA-seq. Fish treated with PB exhibited perturbed behavioral patterns as indicated by changes in place preference. Exposure to PB altered expression of genes related to the synapse, calcium binding and signaling, cytoskeleton, cell junctions, oxidation-reduction reactions, and regulation of transcription in both larval and adult zebrafish. We studied the impact of genetic background using three strains of zebrafish. We also investigated the effect of stress on the PB response in both larval and adult zebrafish. The study of adult zebrafish allowed for characterization of tissue-specific gene expression in the brain and skeletal muscle, both immediately following PB exposure and at 8 weeks thereafter. These findings provide new insight into the effects of PB at the molecular level, which may aid in the development of therapies for Gulf War Illness., The original document contains color images.

The complex of multiple symptoms known as Gulf War Illness (GWI) continues to affect a substantial number of veterans who served in the 1990-1991 Gulf War. Despite considerable research, the biological processes underlying veterans symptoms have not been clearly elucidated. In order to develop useful diagnostic tests and optimize the search for effective GWI treatments, it is imperative to establish a more definitive and integrated understanding of the pathophysiology of this problem. This study utilizes a case-control design to evaluate diverse biological measures in a single, well-characterized and population-based sample of 130 Gulf War veterans residing in Central Texas. Eighty veterans with GWI are compared to 50 healthy veteran controls in a protocol that includes physical and neuropsychological evaluations, neuroimaging (MRI, fMRI, DTI), adrenal function tests, and diverse immune, inflammatory, and coagulation measures. Statistical analyses will determine which objective measures significantly distinguish GWI cases from controls, and explore the extent to which biological findings are interrelated or are associated with identifiable veteran subgroups. Data collection has not yet begun, as we finalize the process of obtaining regulatory approvals. When complete, the study is expected to clarify many of the ambiguities currently associated with GWI and improve understanding of the biological processes that underlie veterans symptoms. This will facilitate efforts to identify useful diagnostic tests and promising treatments.